WO2018195450A1 - Combination therapies with ehmt2 inhibitors - Google Patents

Combination therapies with ehmt2 inhibitors Download PDF

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Publication number
WO2018195450A1
WO2018195450A1 PCT/US2018/028609 US2018028609W WO2018195450A1 WO 2018195450 A1 WO2018195450 A1 WO 2018195450A1 US 2018028609 W US2018028609 W US 2018028609W WO 2018195450 A1 WO2018195450 A1 WO 2018195450A1
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WIPO (PCT)
Prior art keywords
inhibitor
halo
optionally substituted
alkyl
independently
Prior art date
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PCT/US2018/028609
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English (en)
French (fr)
Inventor
John Emmerson Campbell
Kenneth William Duncan
Maria Alejandra Raimondi
Christine KLAUS
Elayne PENEBRE
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Epizyme Inc
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Epizyme Inc
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Priority to CA3060416A priority Critical patent/CA3060416A1/en
Priority to CN202410032276.1A priority patent/CN118021814A/zh
Priority to CN201880028882.9A priority patent/CN110621316B/zh
Priority to AU2018254577A priority patent/AU2018254577B2/en
Priority to EP18788629.6A priority patent/EP3612181A4/en
Priority to US16/606,833 priority patent/US11672800B2/en
Application filed by Epizyme Inc filed Critical Epizyme Inc
Priority to JP2019556647A priority patent/JP2020517618A/ja
Publication of WO2018195450A1 publication Critical patent/WO2018195450A1/en
Anticipated expiration legal-status Critical
Priority to JP2022184887A priority patent/JP2023009301A/ja
Priority to US18/188,691 priority patent/US20230364086A1/en
Ceased legal-status Critical Current

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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Definitions

  • Methylation of protein lysine residues is an important signaling mechanism in eukaryotic cells, and the methylation state of histone lysines encodes signals that are recognized by a multitude of proteins and protein complexes in the context of epigenetic gene regulation.
  • Histone methylation is catalyzed by histone methyltransferases (HMTs), and HMTs have been implicated in various human diseases.
  • HMTs can play a role in either activating or repressing gene expression, and certain HMTs (e.g., Vietnamese histone-lysine N- methyltransferase 2 or EHMT2, also called G9a) may methylate many nonhistone proteins, such as tumor suppressor proteins (see, e.g., Liu et al., Journal of Medicinal Chemistry 56:8931-8942, 2013 and Krivega et al., Blood 126(5):665-672, 2015).
  • HMTs histone methyltransferases
  • EHMT1 and EHMT2 Two related HMTs, EHMT1 and EHMT2, are overexpressed or play a role in diseases and disorders such as sickle cell anemia (see, e.g., Renneville et al., Blood 126(16): 1930– 1939, 2015) and proliferative disorders (e.g., cancers), and other blood disorders.
  • diseases and disorders such as sickle cell anemia (see, e.g., Renneville et al., Blood 126(16): 1930– 1939, 2015) and proliferative disorders (e.g., cancers), and other blood disorders.
  • the present disclosure features a method of preventing or treating a cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an EHMT2 inhibitor. In some embodiments, the method further comprises administering one or more additional therapeutic agent in a therapeutically effective amount.
  • the EHMT2 inhibitor is a compound disclosed herein.
  • the EHMT2 inhibitor is not 2-cyclohexyl-6-methoxy-N-[1-(1-methylethyl)-4- piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine; N-(1-isopropylpiperidin-4-yl)- 6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine; 2-(4,4-difluoropiperidin-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-1- yl)propoxy)quinazolin-4-amine; or 2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidin- 4-yl
  • the disclosure also provides a method of inhibiting or decreasing growth, viability, survival, or proliferation of a cancer cell comprising (1) contacting the cell with (a) an effective amount of EHMT2 inhibitor, and (b) one or more additional therapeutic agent.
  • the effective amount of the EHMT2 inhibitor is an amount sufficient to inhibit or decrease growth, viability, survival, or proliferation of the cancer cell by at least 50%, at least 70%, or at least 90%.
  • the contacting is in vitro or ex vivo. In some embodiments, the contacting is in vivo by administering the EHMT2 inhibitor and the one or more additional therapeutic agent to a subject harboring the cancer cell.
  • the cancer is a hematological cancer, leukemia, hepatocellular carcinoma, lung cancer, brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, lymphoma, myeloma, sarcoma, breast cancer, prostate cancer, adrenal cancer, adrenal gland cancer, bladder cancer, breast cancer, cervix caner, colon cancer, eye cancer, duodenum cancer, glioma, liver cancer,
  • CNS central nervous system
  • the cancer is a hematological cancer, leukemia, hepatocellular carcinoma, lung cancer, brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, lymphoma, myeloma, sarcoma, breast cancer, prostate cancer, adrenal cancer, adrenal gland cancer, bladder cancer, breast cancer, cervix caner, colon cancer, eye cancer, duodenum cancer, glioma, liver cancer,
  • CNS central nervous system
  • medulloblastoma melanoma
  • myeloma neuroblastoma
  • SCLC small cell lung cancer
  • NSCLC non- small cell lung cancer
  • osteosarcoma placenta cancer
  • stomach cancer testicular cancer
  • thyroid cancer thyroid cancer
  • uterine cancer or vulvar caner.
  • the cancer is brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, prostate cancer, or skin cancer.
  • CNS central nervous system
  • the EHMT2 inhibitor is a compound of any one of Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'''):
  • the one or more additional therapeutic agent comprises a standard-of-care treatment modality for treating AML, a standard-of-care treatment modality for treating melanoma, an epigenetic drug, a targeted therapy, or a combination thereof.
  • the one or more additional therapeutic agent comprises an antimetabolite, a topoisomerase II inhibitor, DNA hypomethylating agent, a DNA
  • DNMT methyltransferase
  • HDAC HDAC
  • EZH2 EZH2
  • DOT1L DOT1L
  • differentiation agent a FLT3 inhibitor
  • BCL2 BCL2
  • GRag glucocorticoid receptor agonist
  • BCR corticosteroid
  • the one or more additional therapeutic agent comprises Ara-C, CHOP, Daunorubicin, Azacitidine, Decitabine, Pracinostat, Panobinostat, Tazemetostat, Pinometostat, All trans retinoic acid (ATRA), Gilteritinib, Midostaurin, Venetoclax, AG-120, AG-221, Cytarabine, Midostaurin, pembrolizumab, ipilimumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, Dexamethasone, Prednisolone, Pomalidomide, Lenalidomide,
  • Thalidomide Ixazomib, Bortezomib, Carfilzomib, Melphalan, Vincristine, Mafosfamide, Etoposide, Doxorubicin, Bendamustine, Trametinib, Idelalisib, Ibrutinib, Tamatinib, Alisertib, Enzastaurin, Ipatasertib, doxorubicin, cytarabine, vincristine, everolimus, alisertib, topotecan, etoposide, carboplatin, entinostat, panobinostat, romidepsin, palbociclib, abemaciclib, selumetinib, trametinib, MK-2206, Vorinostat, Navitoclax, Rituximab, Obatoclax, atezolizumab, ABT-199, Velcade, Dasatinib, GSK1070916, GSK69
  • the cancer is leukemia and the one or more additional therapeutic agent comprises Ara-C, Daunorubicin, Azacitidine, Decitabine, Pracinostat, Panobinostat, Tazemetostat, Pinometostat, All trans retinoic acid (ATRA), Gilteritinib, Midostaurin, Venetoclax, AG-120, AG-221, Cytarabine, Midostaurin, or a combination thereof.
  • Ara-C Daunorubicin
  • Azacitidine Decitabine
  • Pracinostat Panobinostat
  • Tazemetostat Pinometostat
  • All trans retinoic acid (ATRA) Gilteritinib, Midostaurin, Venetoclax, AG-120, AG-221, Cytarabine, Midostaurin, or a combination thereof.
  • the cancer is melanoma and the one or more additional therapeutic agent comprises pembrolizumab, ipilimumab, atezolizumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, or a combination thereof.
  • the one or more additional therapeutic agent comprises pembrolizumab, ipilimumab, atezolizumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, or a combination thereof.
  • the EHMT2 inhibitor and the one or more additional therapeutic agent are administered simultaneously.
  • the EHMT2 inhibitor and the one or more additional therapeutic agent are administered sequentially.
  • the EHMT2 inhibitor and the one or more additional therapeutic agent are administered in alternation.
  • the one or more additional therapeutic agent is administered prior to the EHMT2 inhibitor.
  • the EHMT2 inhibitor is administered prior to the one or more additional therapeutic agent.
  • the therapeutically effective amount of the EHMT2 inhibitor is an amount sufficient to sensitize the subject to a treatment by administration of the one or more additional therapeutic agent, e.g., simultaneously with, subsequent to, or prior to the administration of the EHMT2 inhibitor.
  • the therapeutically effective amount of the EHMT2 inhibitor is an amount sufficient to sensitize the subject to a subsequent treatment by administration of the one or more additional therapeutic agent.
  • the amount of the one or more additional therapeutic agent that is therapeutically effective is smaller than the amount of the same agent that is therapeutically effective in a subject not administered with the EHMT2 inhibitor.
  • the disclosure relates to a method of treating cancer by administering to a subject in need thereof an EHMT2 inhibitor in an amount sufficient to sensitize the subject to a treatment with one or more cancer treatment modalities.
  • sensitizing a subject includes inducing sensitivity to treatment with a standard of care treatment, or another agents, or a combination of agents in a subject having a cancer that is resistant or refractory to treatment with said standard of care treatment or another agents, or combination of agents.
  • sensitizing a subject includes increasing the efficacy of a standard of care treatment, or another agents, or a combination of agents.
  • sensitizing may be achieved by administering the standard of care treatment, other agents, or combination of agents in combination with an EHMT2 inhibitor.
  • sensitizing may be achieved by administering an EHMT2 inhibitor prior to the treatment with standard of care treatment, or another agents, or a combination of agents, or, sensitizing may be achieved by administering an EHMT2 inhibitor concurrently with the treatment with standard of care treatment, or another agents, or a combination of agents.
  • sensitizing a subject may include that a lower dose of a standard of care treatment, or another agents, or a combination of agents could be administered when used in combination with an EHMT2 inhibitor.
  • sensitizing may include that inhibition of proliferation of diseased cells is increased.
  • inhibition of proliferation may be increased by 5%, 10% 15%, 20%, 25%, 30%, 50%, 75%, 90% or more as compared to the standard of care treatment, or treatment with agents, or treatment with a combination of agents without administration of an EHMT2 inhibitor.
  • sensitizing may result in an improvement in the clinical response of a patient to the combination treatment, e.g., in a complete response (CR) in a patient who showed only partial response (PR), stable disease (SD), or progressive disease (PD), in response to standard of care treatment, or treatment with agents, or treatment with a combination of agents without administration of an EHMT2 inhibitor.
  • sensitizing may result in an improvement in the clinical response of a patient to the combination treatment, e.g., in a complete response (CR) or a partial response (PR) in a patient who showed only stable disease (SD), or progressive disease (PD) in response to standard of care treatment, or treatment with agents, or treatment with a combination of agents without administration of an EHMT2 inhibitor.
  • sensitizing may result in an improvement in the clinical response of a patient to the combination treatment, e.g., in a complete response (CR), partial response (PR), or stable disease (SD), in a patient who showed progressive disease (PD) in response to standard of care treatment, or treatment with agents, or treatment with a combination of agents without administration of an EHMT2 inhibitor.
  • CR complete response
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • the EHMT2 inhibitor is administered prior to the
  • the EHMT2 inhibitor is administered after the administration of a combination of the EHMT2 inhibitor and the one or more additional therapeutic agent.
  • the one or more additional therapeutic agent comprises an antimetabolite, a topoisomerase II inhibitor, a DNA hypomethylating agent, an HDAC inhibitor, an EZH2 inhibitor, a DOT1L inhibitor, a differentiation agent, an FLT3 inhibitor, or a BCL2 inhibitor.
  • the one or more additional therapeutic agent comprises cytarabine (Ara-C), daunorubicin, azacitidine, decitabine, pracinostat, panobinostat, tazemetostat, pinometostat, all-trans retinoic acid (ATRA), gilteritinib, midostaurin, venetoclax, pembrolizumab, ipilimumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, or cobimetinib.
  • ATRA all-trans retinoic acid
  • the compounds of any of Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') inhibit a kinase with an enzyme inhibition IC 50 value of about 100 nM or greater, 1 ⁇ M or greater, 10 ⁇ M or greater, 100 ⁇ M or greater, or 1000 ⁇ M or greater.
  • the compounds of any of Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') inhibit a kinase with an enzyme inhibition IC50 value of about 1 mM or greater.
  • the compounds of any of Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') inhibit a kinase with an enzyme inhibition IC 50 value of 1 ⁇ M or greater, 2 ⁇ M or greater, 5 ⁇ M or greater, or 10 ⁇ M or greater, wherein the kinase is one or more of the following: AbI, AurA, CHK1, MAP4K, IRAK4, JAK3, EphA2, FGFR3, KDR, Lck, MARK1, MNK2, PKCb2, SIK, and Src.
  • compositions comprising one or more pharmaceutically acceptable carriers and a combination comprising one or more compounds of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III''') described herein and one or more additional therapeutic agent.
  • the present disclosure provides an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') disclosed herein) for use in the prevention or treatment of a cancer, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of one or more additional therapeutic agent disclosed herein.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • the present disclosure provides one or more additional therapeutic agent disclosed herein for use in the prevention or treatment of a cancer, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III''') disclosed herein).
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein.
  • the present disclosure provides a combination of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') disclosed herein) and one or more additional therapeutic agent disclosed herein in for use in the prevention or treatment of a cancer.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • additional therapeutic agent disclosed herein in for use in the prevention or treatment of a cancer.
  • the present disclosure provides use of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') disclosed herein) in the manufacture of a medicament for the prevention or treatment of a cancer, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of one or more additional therapeutic agent disclosed herein.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • the present disclosure provides use of one or more additional therapeutic agent disclosed herein in the manufacture of a medicament for the prevention or treatment of a cancer, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III''') disclosed herein).
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein.
  • the present disclosure provides use of a combination of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') disclosed herein) and one or more additional therapeutic agent disclosed herein in the manufacture of a medicament for the prevention or treatment of a cancer.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • additional therapeutic agent disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • Another aspect of this disclosure is a method of preventing or treating an EHMT- mediated disorder.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a compound of any of Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III''), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and a therapeutically effective amount of one or more additional therapeutic agent.
  • the EHMT-mediated disorder is a disease, disorder, or condition that is mediated at least in part by the activity of EHMT1 or EHMT2 or both.
  • the EHMT-mediated disorder is a blood disease or disorder.
  • the EHMT-mediated disorder is selected from proliferative disorders (e.g. Cancers such as leukemia, hepatocellular carcinoma, prostate carcinoma, lung cancer, and melanoma), addiction (e.g., cocaine addiction), and mental retardation.
  • proliferative disorders e.g. Cancers such as leukemia, hepatocellular carcinoma, prostate carcinoma, lung cancer, and melanoma
  • addiction e.g., cocaine addiction
  • the present disclosure provides an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') disclosed herein) for use in the prevention or treatment of an EHMT-mediated disorder, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of one or more additional therapeutic agent disclosed herein.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • the present disclosure provides one or more additional therapeutic agent disclosed herein for use in the prevention or treatment of an EHMT-mediated disorder, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III''') disclosed herein).
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein.
  • the present disclosure provides a combination of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III''') disclosed herein) and one or more additional therapeutic agent disclosed herein in for use in the prevention or treatment of an EHMT-mediated disorder.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • additional therapeutic agent disclosed herein in for use in the prevention or treatment of an EHMT-mediated disorder.
  • the present disclosure provides use of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') disclosed herein) in the manufacture of a medicament for the prevention or treatment of an EHMT-mediated disorder, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of one or more additional therapeutic agent disclosed herein.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • the present disclosure provides use of one or more additional therapeutic agent disclosed herein in the manufacture of a medicament for the prevention or treatment of an EHMT-mediated disorder, wherein the prevention or treatment further comprises administering to a subject in need thereof a therapeutically effective amount of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein).
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein.
  • the present disclosure provides use of a combination of an EHMT2 inhibitor disclosed herein (e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II''), and (III'') disclosed herein) and one or more additional therapeutic agent disclosed herein in the manufacture of a medicament for the prevention or treatment of an EHMT- mediated disorder.
  • an EHMT2 inhibitor disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • additional therapeutic agent disclosed herein e.g., a compound of any of the Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'''), and (III''') disclosed herein
  • Compounds that are suitable for the methods of the disclosure include subsets of the compounds of Formulae (I), (I′), (I′′), (II′′), (III′′), (I'''), (II'') and specific examples that are described in U.S. Application Nos.62/323,602, 62/348,837, 62/402,997, 62/402,863,
  • the one or more additional therapeutic agent consists of a single additional therapeutic agent.
  • the one or more additional therapeutic agent comprises a therapeutic agent provided herein.
  • the one or more additional therapeutic agent comprises a plurality of therapeutic agents, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional therapeutic agents.
  • the one or more additional therapeutic agent comprises more than 10 additional therapeutic agents.
  • any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models. Methods described herein may be used to identify suitable candidates for treating or preventing EHMT-mediated disorders.
  • the disclosure also provides methods of identifying an inhibitor of EHMT1 or EHMT2 or both.
  • the EHMT-mediated disease or disorder comprises a disorder that is associated with gene silencing by EHMT1 or EHMT2, e.g., cancer associated with gene silencing by EHMT2.
  • the cancer is a hematological cancer or skin cancer.
  • the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • the skin cancer is melanoma.
  • the method further comprises the steps of performing an assay to detect the degree of histone methylation by EHMT1 or EHMT2 in a sample comprising blood cells from a subject in need thereof.
  • performing the assay to detect methylation of H3-K9 in the histone substrate comprises measuring incorporation of labeled methyl groups.
  • the labeled methyl groups are isotopically labeled methyl groups.
  • performing the assay to detect methylation of H3-K9 in the histone substrate comprises contacting the histone substrate with an antibody that binds specifically to dimethylated H3-K9.
  • Still another aspect of the disclosure is a method of inhibiting conversion of H3-K9 to dimethylated H3-K9.
  • the method comprises the step of contacting a mutant EHMT, the wild- type EHMT, or both, with a histone substrate comprising H3-K9 and an effective amount of an EHMT2 inhibitor disclosed herein and an effective amount of one or more additional therapeutic agent, wherein the combination of the EHMT2 inhibitor and the one or more additional therapeutic agent inhibits histone methyltransferase activity of EHMT, thereby inhibiting conversion of H3-K9 to dimethylated H3-K9.
  • the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic purposes.
  • Figure 1 is a series of tables and graphs illustrates the in vitro or in vivo studies of combining Compound 205 (an EHMT2 or G9a inhibitor) with various second agents.
  • Figure 2 is a series of schematic diagrams depicting indications which are suitable for treatment via EHMT2 inhibition via a single agent, e.g., an EHMT2 inhibitor.
  • Figure 3 is a table of indications which are suitable for treatment via EHMT2 inhibition via a single agent, e.g., an EHMT2 inhibitor.
  • Figure 4 shows examples of synergy of Compound 205 with various second therapeutic agents in AML cell lines in a pre-treatment assay.
  • Figure 5 shows examples of synergy of Compound 205 with various second therapeutic agents in AML cell lines in a co-treatment assay.
  • Figure 6 shows examples of synergy in WM-266-4 and MeWo melanoma cell lines with combination of Compound 205 and Everolimus.
  • the present disclosure provides a method of preventing or treating a cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an EHMT2 inhibitor.
  • the method may further comprise administering a therapeutically effective amount of one or more additional therapeutic agent.
  • the EHMT2 inhibitor is a compound disclosed herein.
  • the EHMT2 inhibitor is not 2-cyclohexyl-6-methoxy-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3- (1-pyrrolidinyl)propoxy]-4-quinazolinamine; N-(1-isopropylpiperidin-4-yl)-6-methoxy-2-(4- methyl-1,4-diazepan-1-yl)-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine; 2-(4,4- difluoropiperidin-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-1- yl)propoxy)quinazolin-4-amine; or 2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidin- 4-yl)
  • the one or more additional therapeutic agent comprises a standard-of-care treatment modality for treating AML, a standard-of-care treatment modality for treating melanoma, an epigenetic drug, a targeted therapy, or a combination thereof.
  • the one or more additional therapeutic agent comprises an antimetabolite, a topoisomerase II inhibitor, DNA hypomethylating agent, a DNA
  • DNMT methyltransferase
  • HDAC HDAC
  • EZH2 EZH2
  • DOT1L DOT1L
  • differentiation agent a FLT3 inhibitor
  • BCL2 BCL2
  • GRag glucocorticoid receptor agonist
  • BCR corticosteroid
  • the one or more additional therapeutic agent comprises Ara-C, CHOP, Daunorubicin, Azacitidine, Decitabine, Pracinostat, Panobinostat, Tazemetostat, Pinometostat, All trans retinoic acid (ATRA), Gilteritinib, Midostaurin, Venetoclax, AG-120, AG-221, Cytarabine, Midostaurin, pembrolizumab, ipilimumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, Dexamethasone, Prednisolone, Pomalidomide, Lenalidomide,
  • Thalidomide Ixazomib, Bortezomib, Carfilzomib, Melphalan, Vincristine, Mafosfamide, Etoposide, Doxorubicin, Bendamustine, Trametinib, Idelalisib, Ibrutinib, Tamatinib, Alisertib, Enzastaurin, Ipatasertib, doxorubicin, cytarabine, vincristine, everolimus, alisertib, topotecan, etoposide, carboplatin, entinostat, panobinostat, romidepsin, palbociclib, abemaciclib, selumetinib, trametinib, MK-2206, Vorinostat, Navitoclax, Rituximab, Obatoclax,
  • Atezolizumab ABT-199, Velcade, Dasatinib, GSK1070916, GSK690693, Sorafenib,
  • the one or more additional therapeutic agent comprises an antimetabolite, a topoisomerase II inhibitor, a DNA hypomethylating agent, an HDAC inhibitor, an EZH2 inhibitor, a DOT1L inhibitor, a differentiation agent, an FLT3 inhibitor, or a BCL2 inhibitor.
  • the one or more additional therapeutic agent comprises cytarabine (Ara-C), daunorubicin, azacitidine, decitabine, pracinostat, panobinostat, tazemetostat, pinometostat, all-trans retinoic acid (ATRA), gilteritinib, midostaurin, venetoclax, pembrolizumab, ipilimumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, or cobimetinib.
  • ATRA all-trans retinoic acid
  • the cancer is a
  • hematological cancer leukemia, hepatocellular carcinoma, lung cancer, brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, lymphoma, myeloma, sarcoma, breast cancer, prostate cancer, adrenal cancer, adrenal gland cancer, bladder cancer, breast cancer, cervix caner, colon cancer, eye cancer, duodenum cancer, glioma, liver cancer, medulloblastoma, melanoma, myeloma, neuroblastoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), osteosarcoma, placenta cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, vulvar caner,
  • oligodendroglioma ovarian clear cell adenocarcinoma, ovarian endometrioid adenocarcinoma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, carcinosarcoma, chordoma, extragonadal germ cell tumor, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, clear cell sarcoma of soft tissue, e
  • the cancer is a
  • hematological cancer leukemia, hepatocellular carcinoma, lung cancer, brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, lymphoma, myeloma, sarcoma, breast cancer, prostate cancer, adrenal cancer, adrenal gland cancer, bladder cancer, breast cancer, cervix caner, colon cancer, eye cancer, duodenum cancer, glioma, liver cancer, medulloblastoma, melanoma, myeloma, neuroblastoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), osteosarcoma, placenta cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, or vulvar caner.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • osteosarcoma placenta cancer
  • stomach cancer testicular cancer
  • testicular cancer thyroid cancer
  • uterine cancer or vulvar caner
  • the cancer is brain and/or central nervous system (CNS) cancer, head and/or neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, prostate cancer, or skin cancer.
  • CNS central nervous system
  • the cancer is leukemia and the one or more additional therapeutic agent comprises Ara-C, Daunorubicin, Azacitidine, Decitabine, Pracinostat, Panobinostat, Tazemetostat, Pinometostat, All trans retinoic acid (ATRA), Gilteritinib, Midostaurin, Venetoclax, AG-120, AG-221, Cytarabine, Midostaurin, or a combination thereof.
  • Ara-C Daunorubicin
  • Azacitidine Decitabine
  • Pracinostat Panobinostat
  • Tazemetostat Pinometostat
  • All trans retinoic acid (ATRA) Gilteritinib, Midostaurin, Venetoclax, AG-120, AG-221, Cytarabine, Midostaurin, or a combination thereof.
  • the cancer is melanoma and the one or more additional therapeutic agent comprises pembrolizumab, ipilimumab, atezolizumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, or a combination thereof.
  • the one or more additional therapeutic agent comprises pembrolizumab, ipilimumab, atezolizumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, or a combination thereof.
  • EZH2 inhibitors More examples of EZH2 inhibitors, DOT1L inhibitors, and one or more additional therapeutic agents are described in US 2012/0264734, WO 2013/155464, WO 2015/085325, WO 2016/172199, WO 2016/043874, WO 2016/201328, WO 2014/026198, and WO
  • the EHMT2 inhibitor is a compound of Formula (I) below:
  • ring A is phenyl or a 5- or 6-membered heteroaryl
  • X 1 is N, CR 2 , or NR 2 ’ as valency permits;
  • X 2 is N, CR 3 , or NR 3 ’ as valency permits;
  • X 3 is N, CR 4 , or NR 4 ’ as valency permits;
  • X 4 is N or CR 5 , or X 4 is absent such that ring A is a 5-membered heteroaryl containing at least one N atom;
  • X 5 is C or N as valency permits
  • B is absent or a ring structure selected from the group consisting of C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S;
  • T is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo; or C 1 -C 6 alkoxy when B is present; or T is H and n is 0 when B is absent; or T is C1-C6 alkyl optionally substituted with (R 7 )n when B is absent; or when B is absent, T and R 1 together with the atoms to which they are attached optionally form a 4-7 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with (R 7 ) n ;
  • R 1 is H or C1-C4 alkyl
  • each of R 2 , R 3 , and R 4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, NR a R b , C(O)NR a R b , NR a C(O)R b , C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C 1 -C 6 alkyl, wherein C 1 -C 6 alkoxyl and C1-C6 alkyl are optionally substituted with one or more of halo, OR a , or NR a R b , in which each of R a and R b independently is H or C 1 -C 6 alkyl, or R 3 is–Q 1 -T 1 , in which Q 1 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 al
  • each of R 2 ’, R 3 ’ and R 4 ’ independently is H or C 1 -C 3 alkyl
  • R 5 is selected from the group consisting of H, F, Br, cyano, C1-C6 alkoxyl, C6-C10 aryl, NR a R b , C(O)NR a R b , NR a C(O)R b , C3-C8 cycloalkyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, C 1 -C 6 alkyl optionally substituted with one or more of halo, OR a or NR a R b , and C2-C6 alkynyl optionally substituted with 4- to 12- membered heterocycloalkyl; wherein said C 3 -C 8 cycloalkyl or 4- to 12-membered
  • heterocycloalkyl are optionally substituted with one or more of halo, C(O)R a , OR a , NR a R b , 4- to 7-membered heterocycloalkyl, -C 1 -C 6 alkylene-4- to 7-membered heterocycloalkyl, or C 1 -C 4 alkyl optionally substituted with one or more of halo, OR a or NR a R b , in which each of R a and R b independently is H or C 1 -C 6 alkyl; or
  • R 5 and one of R 3 or R 4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R 5 and one of R 3 ’or R 4 ’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6- membered heteroaryl as formed is optionally substituted with one or more of halo, C 1 -C 3 alkyl, hydroxyl or C1-C3 alkoxyl;
  • R 6 is absent when X 5 is N and ring A is a 6-membered heteroaryl; or R 6 is–Q 1 -T 1 , in which Q 1 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C1-C6 alkoxyl, and T 1 is H, halo, cyano, NR 8 R 9 , C(O)NR 8 R 9 , C(O)R 9 , OR 8 , OR 9 , or R S1 , in which R S1 is C 3 -C 8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1 is optionally substituted with one or more of halo, C1-C6
  • each R 8 independently is H or C1-C6 alkyl
  • each R 9 is independently–Q 3 -T 3 , in which Q 3 is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 3 is H, halo, OR 12 , OR 13 , NR 12 R 13 , NR 12 C(O)R 13 ,
  • R S2 is C3-C8 cycloalkyl, C6- C 10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R S2 is optionally substituted with one or more– Q 4 -T 4 , wherein each Q 4 independently is a bond or C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1- C 6 alkoxy, and each T 4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl
  • R 8 and R 9 taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, which is optionally substituted with one or more of–Q 5 -T 5 , wherein each Q 5 independently is a bond or C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T 5 independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6- membered heteroaryl, OR e , C(O)R e ,
  • R 10 is selected from the group consisting of H and C 1 -C 6 alkyl
  • R 11 is–Q 6 -T 6 , in which Q 6 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C 1 - C6 alkoxyl, and T 6 is H, halo, OR g , NR g R h , NR g C(O)R h , C(O)NR g R h , C(O)R g , S(O)2R g , or R S3 , in which each of R g and R h independently is H, phenyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted with C3-C8 cycloalkyl, or R g and R h together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclo
  • R 10 and R 11 taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more of halo, C 1 -C 6 alkyl, hydroxyl, or C 1 -C 6 alkoxyl;
  • R 12 is H or C 1 -C 6 alkyl
  • R 13 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more–Q 8 -T 8 , wherein each Q 8 independently is a bond or C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T 8 independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocyclo
  • n 0, 1, 2, 3, or 4, provided that
  • the compounds of Formula (I) may have one or more of the following features when applicable.
  • the EHMT2-inhibitor is not a compound selected from the group consisting of:
  • B when T is a bond, B is substituted phenyl, and R 6 is NR 8 R 9 , in which R 9 is–Q 3 -R S2 , and R S2 is optionally substituted 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, then B is substituted with at least one substituent selected from (i)–Q 2 -OR 11 in which R 11 is–Q 6 -R S3 and Q 6 is optionally substituted C 2 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker and (ii)–Q 2 -NR 10 R 11 in which R 11 is–Q 6 -R S3 ;
  • R 6 when T is a bond and B is optionally substituted phenyl, then R 6 is not OR 9 or NR 8 R 9 in which R 9 is optionally substituted naphthyl;
  • R 6 is not NR 8 R 9 in which R 9 is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl;
  • R 6 when T is a bond and B is optionally substituted phenyl or thiazolyl, then R 6 is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NR 8 R 9 in which R 9 is optionally substituted imidazolyl or 6- to 10-membered heteroaryl; or [091] In some embodiments, when T is a C 1 -C 6 alkylene linker and B is absent or optionally substituted C6-C10 aryl or 4- to 12-membered heterocycloalkyl; or when T is a bond and B is optionally substituted C 3 -C 10 cycloalkyl or 4- to 12-membered heterocycloalkyl, then R 6 is not NR 8 C(O)R 13 ;
  • X 1 and X 3 are N
  • X 2 is CR 3
  • X 4 is CR 5
  • X 5 is C
  • R 5 is 4- to 12-membered heterocycloalkyl substituted with one or more C 1 -C 6 alkyl
  • R 6 and R 3 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C 1 -C 3 alkoxyl
  • B is absent, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or 5- to 10-membered heteroaryl, or
  • X 1 is CR 2
  • X 4 is CR 5
  • X 5 is C
  • R 5 is C 3 - C8 cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C 1 -C 6 alkyl
  • R 6 and R 2 together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C1-C3 alkoxyl
  • B is absent, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or 5- to 10-membered heteroaryl.
  • ring A is a 6-membered heteroaryl, at least one of X 1 , X 2 , X 3 and X 4 is N and X 5 is C.
  • ring A is a 6-membered heteroaryl, two of X 1 , X 2 , X 3 and X 4 are N and X 5 is C.
  • R 6 and one of R 2 or R 3 together with the ring A to which they are attached form a 6,5- fused bicyclic heteroaryl; or R 6 and one of R 2 ’ or R 3 ’ together the ring A to which they are attached form a 6,5-fused bicyclic heteroaryl.
  • At least one of R 6 , R 2 , R 3 , and R 4 is not H.
  • R 2 ’, R 3 ’, and R 4 ’ when one or more of R 2 ’, R 3 ’, and R 4 ’ are present, at least one of R 6 , R 2 ’, R 3 ’, and R 4 ’ is not H.
  • the EHMT2 inhibitor is a compound of Formula (II):
  • ring B is phenyl or pyridyl
  • X 1 and X 2 are N while X 3 is CR 4 and X 4 is CR 5 or one or both of X 1 and X 3 are N while X 2 is CR 3 and X 4 is CR 5 ;
  • n 1, 2, or 3.
  • the EHMT2 inhibitor is a compound of Formula (IIa1), (IIa2), (IIa3), (IIa4), or (IIa5):
  • the EHMT2 inhibitor is a compound of Formula (IIb1), (IIb2), (IIb3), (IIb4), or (IIb5):
  • At most one of R 3 , R 4 and R 5 is not H.
  • the EHMT2 inhibitor is a compound of Formula (IIc1), (IIc2), (IIc3), (IIc4), or (IIc5):
  • At most one of R 4 and R 5 is not H.
  • the EHMT2 inhibitor is a compound of Formula (IId1), (IId2), (IId3), (IId4), or (IId5):
  • At most one of R 2 , R 4 , and R 5 is not H.
  • ring A is a 5-membered heteroaryl.
  • the EHMT2 inhibitor is a compound of Formula (III):
  • ring B is phenyl or pyridyl
  • At least one of X 2 and X 3 is N;
  • n 1 or 2.
  • the EHMT2 inhibitor is a compound of Formula (IIIa):
  • At most one of R 4 ’ and R 2 is not H.
  • the optionally substituted 6,5- fused bicyclic heteroaryl contains 1-4 N atoms.
  • T is a bond and ring B is phenyl or pyridyl.
  • n 1 or 2.
  • the EHMT2 inhibitor is a compound of Formula (IV):
  • ring B is C3-C6 cycloalkyl
  • each of R 20 , R 21 , R 22 and R 23 independently is H, halo, C1-C3 alkyl, hydroxyl, or C1-C3 alkoxyl;
  • n 1 or 2.
  • ring B is cyclohexyl
  • R 1 is H or CH3.
  • n is 1 or 2
  • at least one of R 7 is–Q 2 -OR 11 in which R 11 is– Q 6 -R S3 and Q 6 is optionally substituted C 2 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker.
  • n is 1 or 2
  • at least one of R 7 is–Q 2 -NR 10 R 11 in which R 11 is–Q 6 -R S3 .
  • Q 6 is C 2 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with a hydroxyl and R S3 is 4- to 7-membered heterocycloalkyl optionally substituted with one or more–Q 7 -T 7 .
  • Q 6 is C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with a hydroxyl and R S3 is C 3 -C 6 cycloalkyl optionally substituted with one or more
  • each Q 7 is independently a bond or a C1-C3 alkylene, C2-C3 alkenylene, or C 2 -C 3 alkynylene linker and each T 7 is independently H, halo, C 1 -C 6 alkyl, or phenyl.
  • Q 2 is a bond or a C 1 -C 4 alkylene, C 2 -C 4 alkenylene, or C 2 -C 4 alkynylene linker.
  • At least one of R 7 is ,
  • n is 2 and the compound further comprises another R 7 selected from halo and methoxy.
  • ring B is selected from phenyl, pyridyl, and cyclohexyl, and the halo or methoxy is at the para-position to NR 1 .
  • R 6 is NR 8 R 9 .
  • R 9 is–Q 3 -T 3 , in which T 3 is OR 12 , NR 12 C(O)R 13 , C(O)R 13 , C(O)NR 12 R 13 , S(O)2NR 12 R 13 , or R S2 .
  • Q 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with a hydroxyl.
  • R S2 is C 3 -C 6 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, and R S2 is optionally substituted with one or more–Q 4 -T 4 .
  • each Q 4 is independently a bond or C1-C3 alkylene, C2-C3 alkenylene, or C 2 -C 3 alkynylene linker optionally substituted with one or more of hydroxyl and halo
  • each T 4 is independently H, halo, C1-C6 alkyl, or phenyl; or -Q 4 -T 4 is oxo.
  • R 6 or NR 8 R 9 is selected from the group consisting of:
  • B is absent and T is unsubstituted C 1 -C 6 alkyl or T is C 1 -C 6 alkyl substituted with at least one R 7 .
  • B is 4- to 12-membered heterocycloalkyl and T is unsubstituted C1-C6 alkyl.
  • the EHMT2 inhibitor is a compound of Formula (V):
  • ring B is absent or C3-C6 cycloalkyl
  • X 3 is N or CR 4 in which R 4 is H or C1-C4 alkyl
  • R 1 is H or C 1 -C 4 alkyl
  • R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C 3 -C 8 cycloalkyl and 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of 4- to 7-membered heterocycloalkyl, -C1-C6 alkylene-4- to 7-membered
  • heterocycloalkyl -C(O)C 1 -C 6 alkyl or C 1 -C 6 alkyl optionally substituted with one or more of halo or OR a ;
  • R 9 is–Q 3 -T 3 , in which Q 3 is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 3 is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more–Q 4 -T 4 , wherein each Q 4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy, and each T 4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl
  • n 0, 1 or 2.
  • the EHMT2 inhibitor is a compound of Formula (VI):
  • R 5 and R 6 are independently selected from the group consisting of C1-C6 alkyl and NR 8 R 9 , or R 6 and R 3 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl.
  • R 6 is methyl
  • the EHMT2 inhibitor is a compound of Formula (VII):
  • n 0, 1, or 2.
  • both of X 1 and X 3 are N while X 2 is CR 3 and X 4 is CR 5 .
  • the EHMT2 inhibitor is a compound of Formula (VIIIa):
  • X 1 is N or CR 2 ;
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 4 ;
  • X 4 is N or CR 5 ;
  • R 2 is selected from the group consisting of H, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkyl optionally substituted with one or more of halo, OR a , or NR a R b ;
  • each of R 3 and R 4 is H;
  • R 5 are independently selected from the group consisting of H, C3-C8 cycloalkyl, and C1- C 6 alkyl optionally substituted with one or more of halo or OR a ; or
  • R 5 and one of R 3 or R 4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R 5 and one of R 3 ’or R 4 ’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6- membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C1-C3 alkoxyl; and
  • the EHMT2 inhibitor is a compound of Formula (VIIIb): ( ),
  • X 1 is N or CR 2 ;
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 4 ;
  • X 4 is N or CR 5 ;
  • R 2 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl each of R 3 and R 4 is H;
  • R 5 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl; or R 5 and one of R 3 or R 4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R 5 and one of R 3 ’or R 4 ’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6- membered heteroaryl as formed is optionally substituted with one or more of halo, C 1 -C 3 alkyl, hydroxyl or C1-C3 alkoxyl; and
  • R 2 or R 5 are not H.
  • the EHMT2 inhibitor is a compound of Formula (VIIIc):
  • X 1 is N or CR 2 ;
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 4 ;
  • X 4 is N or CR 5 ;
  • R 2 is selected from the group consisting of H, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkyl each of R 3 and R 4 is H;
  • R 5 is selected from the group consisting of H, C3-C8 cycloalkyl, and C1-C6 alkyl; or R 5 and one of R 3 or R 4 together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R 5 and one of R 3 ’or R 4 ’ together with the atoms to which they are attached form a 5- or 6-membered heteroaryl, in which the phenyl or 5- or 6- membered heteroaryl as formed is optionally substituted with one or more of halo, C1-C3 alkyl, hydroxyl or C 1 -C 3 alkoxyl; and
  • the EHMT2 inhibitor is a compound of (IX):
  • X 6 is N or CH
  • X 7 is N or CH
  • X 3 is N or CR 4 ;
  • R 4 independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkoxyl, C6-C10 aryl, NR a R b , C(O)NR a R b , NR a C(O)R b , C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C 1 -C 6 alkyl, wherein C 1 -C 6 alkoxyl and C 1 - C6 alkyl are optionally substituted with one or more of halo, OR a , or NR a R b , in which each of R a and R b independently is H or C 1 -C 6 alkyl;
  • each R 9 is independently–Q 3 -T 3 , in which Q 3 is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 3 is H, halo, OR 12 , OR 13 , NR 12 R 13 , NR 12 C(O)R 13 ,
  • R S2 is C 3 -C 8 cycloalkyl, C 6 - C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R S2 is optionally substituted with one or more– Q 4 -T 4 , wherein each Q 4 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1- C 6 alkoxy, and each T 4 independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C
  • R 12 is H or C1-C6 alkyl
  • R 13 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more–Q 8 -T 8 , wherein each Q 8 independently is a bond or C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T 8 independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N
  • R 15 is C1-C6 alkyl, NHR 17 , C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl, wherein each of said C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl, and 5- to 10-membered heteroaryl is optionally substituted with one or more –Q 9 -T 9 , wherein each Q 9 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2- C 3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T 9 independently is selected from the group consisting of H, halo, cyano, C 1 -
  • R 16 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more–Q 10 -T 10 , wherein each Q 10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 - C6 alkoxy, and each T 10 independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 7-membered heterocyclo
  • R 17 is H or C 1 -C 6 alkyl
  • v 0, 1, or 2.
  • each T 3 independently is OR 12 or OR 13 .
  • each Q 3 independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with a hydroxyl.
  • R 15 is C1-C6 alkyl, NHR 17 , or 4- to 12-membered
  • R 16 is C1-C6 alkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more–Q 10 -T 10 .
  • each T 10 independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, and 4- to 7-membered heterocycloalkyl.
  • each Q 10 independently is a bond or C1-C3 alkylene, C2-C3 alkenylene, or C 2 -C 3 alkynylene linker optionally substituted with a hydroxyl.
  • the EHMT2 inhibitor is a compound of Formula (X):
  • X 3 is N or CR 4 , wherein R 4 is selected from the group consisting of H, halo, and cyano.
  • the EHMT2 inhibitor is a compound of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), or (Xg):
  • At least one of X 1 , X 2 , X 3 and X 4 is N.
  • X 2 and X 3 is CH, and X 1 and X 4 is N.
  • X 2 and X 3 is N
  • X 1 is CR 2
  • X 4 is CR 5 .
  • R 6 is NR 8 R 9 and R 5 is C1-6 alkyl or R 5 and R 3 together with the atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl ring.
  • the EHMT2 inhibitor is a compound of Formula (I′):
  • X 1a is O, S, CR 1a R 11a , or NR 1a’ when is a single bond, or X 1a is N when is a double bond;
  • X 2a is N or CR 2a when is a double bond, or X 2a is NR 2a’ when is a single bond;
  • X 3a is N or C; when X 3a is N, is a double bond and is a single bond, and when X 3a is C, is a single bond and is a double bond;
  • each of R 1a , R 2a and R 11a is–Q 1a -T 1a , in which each Q 1a independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and each T 1a independently is H, halo, cyano, NR 5a R 6a , C(O)NR 5a R 6a , -OC(O)NR 5a R 6a , C(O)OR 5a , - OC(O)R 5a , C(O)R 5a , -NR 5a C(O)R 6a ,
  • R S1a is C3-C12 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1a is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, -C(O)R 6a , -SO 2 R 5a , -SO 2 N(R 5a ) 2 , -NR 5a C(O)R 6a , amino, mono- or di- alkylamino, or C 1 - C6 alkoxyl; or
  • R 1a and R 11a together with the carbon atom to which they are attached form a C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; each of R 1a’ and R 2a’ , independently, is–Q 2a -T 2a , in which Q 2a is a bond or C1-C6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 2a is H
  • R 3a is H, NR aa R ba , OR aa , or R S4a , in which R S4a is C 1 -C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C3-C12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C1-C6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each of
  • R 3a is oxo and is a single bond
  • each R 4a independently is–Q 3a -T 3a , in which each Q 3a independently is a bond or C1-C6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T 3a independently is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 - C10 aryl, 5- to
  • heterocycloalkyl is optionally substituted with one or more of halo, hydroxyl, cyano, C 1 -C 6 haloalkyl, -SO2R 5a , C1-C6 alkoxyl or C1-C6 alkyl optionally substituted with one or more of NR 5a R 6a ; each of R 5a , R 6a , and R 7a , independently, is H or C1-C6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl;
  • R 8a is–Q 4a -T 4a , in which Q 4a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 4a is H, halo, or R S3a , in which R S3a is C3-C12 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R S3a is optionally substituted with one or more–Q 5a -T 5a , wherein each Q 5a independently is a bond or C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 alkynylene linker each optionally substituted with one or
  • n 1, 2, 3, or 4.
  • the compound is not
  • R 1a and R 11a are–Q 1a -T 1a , in which Q 1a is a C 1 -C 6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 1a is cyano, NR 5a R 6a , C(O)NR 5a R 6a , -OC(O)NR 5a R 6a , C(O)OR 5a , -OC(O)R 5a , C(O)R 5a , - NR 5a C(O)R 6a , -NR 5a C(O)OR 6a , OR 5a , or R S1a , in which R S1a is C3-C12 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R
  • R 1a and R 11a are–Q 1a -T 1a , in which Q 1a is a C2-C6 alkenylene or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 1a is H, halo, cyano, NR 5a R 6a , C(O)NR 5a R 6a , -OC(O)NR 5a R 6a , C(O)OR 5a , - OC(O)R 5a , C(O)R 5a , -NR 5a C(O)R 6a , -NR 5a C(O)OR 6a , OR 5a , or R S1a , in which R S1a is C 3 -C 12 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O,
  • R 1a and R 11a together with the carbon atom to which they are attached form a C 7 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C 7 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl.
  • At least one of X 2a and X 3a is N.
  • At least two of X 1a , X 2a , and X 3a comprise N.
  • At least one of is a double bond.
  • X 2a is NR 2a’ and R 3a is oxo.
  • X 2a is N and X 3a is C.
  • X 2a is CR 2a and X 3a is N.
  • X 1a is S.
  • X 1a is NR 1a’ .
  • X 1a is CR 1a R 11a .
  • R 1a and R 11a together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl.
  • n 1 or 2.
  • n is 2.
  • the compound is of Formula (IIa′), (IIb′), (IIc′), (IId′), (IIe′), (IIIa′), (IIIb′), (IIIc′), (IIId′), (IIIe′), (IIIf′), (IVa′), or (IVb′):
  • the compound is of Formula (IIf′), (IIg′), (IIh′), (IIIi′), (IIIj′), (IIIk′), or (IIIl′):
  • R 3a is H, NR aa R ba , OR aa , or R S4a , in which R S4a is C 1 -C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, C3-C12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C1-C6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each of
  • each of R 4a and R 4a’ independently is–Q 3a -T 3a , in which each Q 3a independently is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T 3a independently is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C6-C10
  • each of R 5a , R 6a , and R 7a is H or C1-C6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl;
  • R 8a is–Q 4a -T 4a , in which Q 4a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 4a is H, halo, or R S3a , in which R S3a is C3-C12 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R S3a is optionally substituted with one or more–Q 5a -T 5a , wherein each Q 5a independently is a bond or C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 -C 3 alkynylene linker each optionally substituted with one or
  • the compound is not one of those described in EP 0356234; US 5,106,862; US 6,025,379; US 9,284,272; WO2002/059088; and/or WO2015/200329.
  • R 1a is CR 1a R 11a
  • X 2a is N
  • X 3a is C
  • R 3a is NH2
  • at least one R 4a is OR 7a
  • at least one of R 1a and R 11a is–Q 1a -T 1a
  • Q 1a is a C1-C6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl
  • T 1a is cyano
  • NR 5a R 6a C(O)NR 5a R 6a , -OC(O)NR 5a R 6a , C(O)OR 5a , -OC(O)R 5a , C(O)R 5a , -NR 5a C(O)R 6a , -NR 5a C(O)OR 6a , OR 5a , or R S1a , in which R S
  • R 1a is CR 1a R 11a
  • X 2a is N
  • X 3a is C
  • R 3a is NH2
  • at least one R 4a is OR 7a
  • at least one of R 1a and R 11a is–Q 1a -T 1a , in which Q 1a is a C 2 -C 6 alkenylene or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl
  • T 1a is H, halo, cyano, NR 5a R 6a , C(O)NR 5a R 6a , -OC(O)NR 5a R 6a , C(O)OR 5a , -OC(O)R 5a , C(O)R 5a , -NR 5a C(O)R 6a , -NR 5a C(O)OR 6a
  • R 1a when n is 2, X 1a is CR 1a R 11a , X 2a is N , X 3a is C, R 3a is NH 2 , and at least one R 4a is OR 7a , then at least one of R 1a and R 11a is–Q 1a -T 1a , in which Q 1a is a bond, and T 1a is halo, cyano, NR 5a R 6a , C(O)NR 5a R 6a , -OC(O)NR 5a R 6a , C(O)OR 5a , -OC(O)R 5a , C(O)R 5a , -NR 5a C(O)R 6a , -NR 5a C(O)OR 6a , OR 5a , or R S1a , in which R S1a is C3-C12 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl (e.
  • R 1a and R 11a together with the carbon atom to which they are attached form a C 7 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7- membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, wherein the C 7 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl.
  • R 2a is–Q 1a -T 1a , in which Q 1a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 1a is H, halo, cyano, or R S1a , in which R S1a is C 3 -C 12 cycloalkyl (e.g., C3-C8 cycloalkyl), phenyl, 4- to 12-membered heterocycloalkyl (e.g., 4- to 7- membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1a is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, o
  • R 2a is C1-C6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl. In some embodiments, R 2a is unsubstituted C 1 -C 6 alkyl.
  • Q 1a is a bond or C 1 -C 6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl
  • T 1a is H, halo, cyano, or R S1a , in which R S1a is C 3 -C 12 cycloalkyl (e.g., C 3 -C 8 cycloalkyl), phenyl, 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1a is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1- C 6 alkoxyl.
  • Q 1a is a C2-C6 alkenylene or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl
  • T 1a is H, halo, cyano, or R S1a , in which R S1a is C3-C12 cycloalkyl (e.g., C3-C8 cycloalkyl), phenyl, 4- to 12- membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1a is optionally substituted with one or more of halo, C 1 -C 6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl.
  • R 1a’ is–Q 2a -T 2a , in which Q 2a is a bond or C 1 -C 6 alkylene, C 2 - C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 2a is H, halo, cyano, or R S2a , in which R S2a is C 3 -C 12 cycloalkyl (e.g., C3-C8 cycloalkyl), phenyl, 4- to 12-membered heterocycloalkyl (e.g., 4- to 7- membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S2a is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxy
  • R 2a’ is–Q 2a -T 2a , in which Q 2a is a bond or C1-C6 alkylene, C2- C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 2a is H, halo, cyano, or R S2a , in which R S2a is C3-C12 cycloalkyl (e.g., C3-C8 cycloalkyl), phenyl, 4- to 12-membered heterocycloalkyl (e.g., 4- to 7- membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S2a is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl,
  • each Q 2a independently is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo and each T 2a independently is H, halo, C 3 -C 12 cycloalkyl (e.g., C3-C8 cycloalkyl), or a 4- to 7-membered heterocycloalkyl.
  • each Q 2a independently is C 2 -C 6 alkenylene or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl.
  • R 2a’ is H or C1-C6 alkyl.
  • R 3a is H.
  • R 3a is NR aa R ba or OR aa , wherein each of R aa and R ba independently is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, hydroxyl, CN, amino, mono- or di- alkylamino, or C1-C6 alkoxyl.
  • R 3a is NR aa R ba or OR aa , wherein each of R aa and R ba independently is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, hydroxyl, amino, mono- or di- alkylamino, C1-C6 alkoxyl, C3-C12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S.
  • each of R aa and R ba independently is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, hydroxyl, amino, mono- or di- alkylamino, C1-C6 alkoxyl, C3-C12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-member
  • R 3a is NR aa R ba .
  • each of R aa and R ba independently is H or R S5a .
  • one of R aa and R ba is H and the other is R S5a .
  • R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered
  • heterocycloalkyl which is optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl).
  • R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered
  • heterocycloalkyl which is optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl.
  • R S5a is C1-C6 alkyl, and R S5a is optionally substituted with one or more of halo, hydroxyl, CN, amino, mono- or di- alkylamino, C1-C6 alkoxyl, C3-C12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl).
  • R S5a is phenyl, 5- or 6-membered heteroaryl, or 4- to 12- membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl), and R S5a is optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 - C6 alkyl, C1-C6 alkoxyl, C3-C12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12- membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl).
  • the compound is of Formulae (Va′), (Vb′), (Vc′), (Vd′), (Ve′), or (Vf′):
  • R 3a is H, NR aa R ba , OR aa , or R S4a , in which R S4a is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3 -C 12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C 1 -C 6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each
  • each of R 4a and R 4a’ independently is–Q 3a -T 3a , in which each Q 3a independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl, and each T 3a independently is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10
  • each of R 5a , R 6a , and R 7a is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; and R 8a is–Q 4a -T 4a , in which Q 4a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 4a is H, halo, or R S3a , in which R S3a is C3-C12 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R S
  • R 4a is not–OCH3.
  • R 4a’ is not OR 8a .
  • R 3a is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C1-C6 alkoxyl, C3-C12 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S; in which each of the C3-C12 cycloalkyl, phenyl, 5- or 6- membered heteroaryl, and 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) is independently optionally substituted with one or more of halo, hydroxyl,
  • R 3a is C 3 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C 3 -C 12 cycloalkyl and 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) is independently optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyl.
  • R 3a is C 3 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C 3 -C
  • R 3a is NH2.
  • R 3a is NR aa R ba , in which one of R aa and R ba is H and the other is C1-C6 alkyl optionally substituted with one or more of halo or C1-C6 alkoxyl.
  • R 3a is oxo and is a single bond.
  • R 3a is OH
  • R 3a is C1-C6 alkoxyl.
  • the compound is of Formulae (VIa′), (VIb′), (VIc′), (VId′), (VIe′), or (VIf′):
  • each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C 1 -C 6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each of R S4a , R S5a , and the heterocycloalkyl formed by R aa and R ba is independently optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, phenyl, 5- or 6- membered heteroaryl, or 4- to
  • each of R 4a and R 4a’ independently is–Q 3a -T 3a , in which each Q 3a independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl, and each T 3a independently is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10
  • each of R 5a , R 6a , and R 7a is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; and R 8a is–Q 4a -T 4a , in which Q 4a is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 4a is H, halo, or R S3a , in which R S3a is C 3 -C 12 cycloalkyl, C 6 -C 10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered hetero
  • At least one of R aa and R ba is R S5a .
  • R 4a is not–OCH3.
  • R 4a’ is not OR 8a .
  • each of R 4a and R 4a’ is independently–Q 3a -T 3a , in which each Q 3a independently is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T 3a independently is H, halo, OR 7a , OR 8a , NR 7a R 8a , C6- C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl, or 4- to 12-membered
  • R 4a is–Q 3a -T 3a , in which Q 3a is a bond or C1-C6 alkylene linker, and T 3a is H, halo, OR 7a , C 6 -C 10 aryl, or 5- to 10-membered heteroaryl.
  • R 4a’ is–Q 3a -T 3a , in which Q 3a independently is a bond or C1-C6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T 3a independently is H, OR 7a , OR 8a , NR 7a R 8a , C 3 -C 12 cycloalkyl, or 4- to 12-membered
  • At least one of R 4a and R 4a’ is C 1 -C 6 alkyl.
  • R 4a is C1-C6 alkyl.
  • At least one of R 4a and R 4a’ is CH 3. In some embodiments, R 4a is [0221] In some embodiments, at least one of R 4a and R 4a’ is halo. In some embodiments, R 4a is halo.
  • At least one of R 4a and R 4a’ is F or Cl. In some embodiments, R 4a is F or Cl. [0223] In some embodiments, at least one of R 4a and R 4a’ is C6-C10 aryl. In some
  • R 4a is C 6 -C 10 aryl. [0224] In some embodiments, at least one of R 4a and R 4a’ is . In some embodiments, R 4a is
  • At least one of R 4a and R 4a’ is 5- to 10-membered heteroaryl. In some embodiments, R 4a is 5- to 10-membered heteroaryl. [0226] In some embodiments, at least one of R 4a and R 4a’ is , , In some embodiments, R 4a is , , [0227] In some embodiments, at least one of R 4a and R 4a’ is wherein T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1- 4 heteroatoms selected from N, O, and S, and wherein the C6-C10 aryl, 5-
  • R 4a’ is , wherein T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, hydroxyl, cyano, C 1 -C 6 haloalkyl, -SO 2 R 5a , C 1 -C 6 alkoxyl or C 1 -C 6 al
  • At least one of R 4a and R 4a’ is , wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C1-C6 alkoxyl or C1-C6 alkyl.
  • R 4a’ is , wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C1-C6 alkoxyl or C1-C6 alkyl.
  • At least one of R 4a and R 4a’ is wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C1-C6 alkoxyl or C1-C6 alkyl and the other of R 4a and R 4a’ is halo, C 1 -C 6 alkyl, or OR 7a .
  • R 7a is H or C 1 -C 6 alkyl optionally substituted with one or more of hydroxyl, amino or mono- or di- alkylamino.
  • At least one of R 4a and R 4a’ is–OCH 3 , -OCH 2 CH 3 , or– OCH(CH 3 ) 2 .
  • at least one of R 4a and R 4a’ is , wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C 1 -C 6 alkoxyl or C 1 -C 6 alkyl and the other of R 4a and R 4a’ is OCH3, -OCH2CH3, or–OCH(CH3)2.
  • At least one of R 4a and R 4a’ is–OCH 3 . [0234] In some embodiments, at least one of R 4a and R 4a’ is
  • R 4a’ is , , , ,
  • R 4a and R 4a’ are OR 7a .
  • R 4a is OR 7a .
  • R 4a’ is OR 7a
  • R 4a and R 4a’ are OR 8a .
  • R 4a’ is OR 8a .
  • R 4a and R 4a’ is -CH2-T 3a , wherein T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C 6 -C 10 aryl, 5- to 10- membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1- 4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, hydroxyl, cyano, C1-C6 haloalkyl, -SO2R 5a , C1-
  • R 4a’ is -CH2-T 3a , wherein T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 - C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, hydroxyl, cyano, C 1 -C 6 haloalkyl, -SO 2 R 5a , C 1 -C 6 alk
  • At least one of R 4a and R 4a’ is -CH 2 -OR 8 .
  • R 4a’ is -CH2-OR8.
  • R 4a and R 4a’ are -CH 2 -NR 7 R 8 . In some embodiments, R 4a’ is -CH2-NR7R8.
  • R 4a and R 4a’ are halo, C 1 -C 6 alkyl, or OR 7a .
  • R 4a is halo, C1-C6 alkyl, or OR 7a .
  • At least one of R 4a and R 4a’ is C 1 -C 6 alkoxyl. In some embodiments, R 4a is C1-C6 alkoxyl.
  • At least one of R 4a and R 4a’ is–OCH 3 , -OCH 2 CH 3 , or–
  • R 4a is–OCH3, -OCH2CH3, or–OCH(CH3)2.
  • R 4a and R 4a’ are–OCH3. In some embodiments, R 4a is–OCH3.
  • R 7a is H or C1-C6 alkyl optionally substituted with one or more of hydroxyl, amino or mono- or di- alkylamino.
  • R 8a is–Q 4a -T 4a , in which Q 4a is a C1-C6 alkylene, C2-C6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 4a is C3-C12 cycloalkyl, C6-C10 aryl, or 4- to 12-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl) containing 1-4 heteroatoms selected from N, O and S which is optionally substituted with one or more–Q 5a -T 5a .
  • Q 4a is a C1-C6 alkylene, C2-C6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl
  • each 4- to 12-membered heterocycloalkyl described herein include, e.g., a 4 to 7-membered monocyclic heterocycloalkyl or 7 to 12-membered bicyclic heterocycloalkyl such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6- tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro- 2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-aza
  • R 8a is–Q 4a -R S3a , in which Q 4a is a bond or a C 1 -C 6 alkylene linker (e.g., C2-C6 alkylene linker) optionally substituted with a hydroxyl and R S3a is 4- to 12- membered heterocycloalkyl (e.g., a 4 to 7-membered monocyclic heterocycloalkyl or 7 to 12- membered bicyclic heterocycloalkyl such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H
  • Q 4a is C1-C6 alkylene linker optionally substituted with a hydroxyl and R S3a is C 3 -C 6 cycloalkyl optionally substituted with one or more–Q 5a -T 5a .
  • Q 4a is an optionally substituted C2-C6 alkenylene or C2-C6 alkynylene linker and R S3a is 4- to 12-membered heterocycloalkyl (e.g., a 4 to 7-membered monocyclic heterocycloalkyl or 7 to 12-membered bicyclic heterocycloalkyl such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro- 2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,
  • Q 4a is an optionally substituted C2-C6 alkenylene or C2-C6 alkynylene linker and R S3a is C 3 -C 6 cycloalkyl optionally substituted with one or more–Q 5a - T 5a .
  • each Q 5a independently is a bond or C 1 -C 3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy
  • each T 5a independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 - C12cycloalkyl (e.g., C3-C8 cycloalkyl), or 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.
  • each Q 5a independently is a C2-C3 alkenylene, or C2-C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 - C6 alkoxy
  • each T 5a independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl (e.g., C 3 -C 8 cycloalkyl), or 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.
  • R 4a and R 4a’ are . In some embodiments, R 4a’ is
  • R 4a’ is
  • one of R 4a and R 4a’ is halo, C 1 -C 6 alkyl, or OR 7a , and the other is wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C1-C6 alkoxyl or C 1 -C 6 alkyl.
  • R 4a is halo, C1-C6 alkyl, or OR 7a
  • R 4a’ is , wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C1-C6 alkoxyl or C1-C6 alkyl.
  • one of R 4a and R 4a’ is C1-C6 alkoxyl and the other is , wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C1-C6 alkoxyl or C 1 -C 6 alkyl.
  • R 4a is C 1 -C 6 alkoxyl
  • R 4a’ is , wherein T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C 1 -C 6 alkoxyl or C 1 -C 6 alkyl.
  • one of R 4a and R 4a’ is–OCH3, and the other is [0271] In some embodiments, R 4a is–OCH 3 , and R 4a’ is .
  • R 4a and R 4a’ are–OCH3, and the other is [0273] In some embodiments, R 4a is–OCH 3 , and R 4a’ is
  • the compound is of Formula (VIIa′), (VIIb′), (VIIc′), (VIId′), (VIIe′), or (VIIf′):
  • each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C 1 -C 6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each of R S4a , R S5a , and the heterocycloalkyl formed by R aa and R ba is independently optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, phenyl, 5- or 6- membered heteroaryl, or 4- to
  • R 4a is halo, C1-C6 alkyl, or OR 7a ;
  • T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered
  • heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C6- C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl or 4- to 12-membered
  • heterocycloalkyl is optionally substituted with one or more of halo, hydroxyl, cyano, C1-C6 haloalkyl, -SO 2 R 5a , C 1 -C 6 alkoxyl or C 1 -C 6 alkyl optionally substituted with one or more of NR 5a R 6a ;
  • each of R 5a , R 6a , and R 7a is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; and each R 8a independently is–Q 4a -T 4a , in which Q 4a is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C S3a
  • T 4a is H, halo, or R S3a , in which R is C 3 -C 12 cycloalkyl, C 6 - C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl, and R S3a is optionally substituted with one or more– Q 5a -T 5a , wherein each Q 5a independently is a bond or C 1 -C 3 alkylene, C 2 -C 3 alkenylene, or C 2 - C3 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy, and each T 5a independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, C3-C12 cycloalkyl, C6-C10 aryl, 4- to 7
  • R 4a is–OCH 3 .
  • T 3a is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C 1 -C 6 alkoxyl or C1-C6 alkyl.
  • the compound is of Formula (VIIIa′), (VIIIb′), (VIIIc′), (VIIId′), (VIIIe′), or (VIIIf′):
  • each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C1-C6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each of R S4a , R S5a , and the heterocycloalkyl formed by R aa and R ba is independently optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, phenyl, 5- or 6- membered heteroaryl, or 4- to 12-
  • R 4a is–Q 3a -T 3a , in which Q 3a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl,
  • each of R 5a , R 6a , and R 7a is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; and each R 8a independently is–Q 4a -T 4a , in which Q 4a is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 4a is H, halo, or R S3a , in which R S3a is C 3 -C 12 cycloalkyl, C 6 - C10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered
  • R 4a is halo, C 1 -C 6 alkyl, or OR 7a . In some embodiments, R 4a is C1-C6 alkoxyl. In some embodiments, R 4a is–OCH3.
  • the compound is of Formulae (IXa′), (IXb′), (IXc′), (IXd′), (IXe′), or (IXf′):
  • each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C 1 -C 6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each of R S4a , R S5a , and the heterocycloalkyl formed by R aa and R ba is independently optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, phenyl, 5- or 6- membered heteroaryl, or 4- to
  • R 4a is–Q 3a -T 3a , in which Q 3a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl,
  • each of R 5a , R 6a , and R 7a is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; and each R 8a independently is–Q 4a -T 4a , in which Q 4a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C 2 -C 6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 4a is H, halo, or R S3a , in which R S3a is C3-C12 cycloalkyl, C6- C 10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl,
  • R 4a is halo, C 1 -C 6 alkyl, or OR 7a . In some embodiments, R 4a is C1-C6 alkoxyl. In some embodiments, R 4a is–OCH3.
  • the compound is of Formula (Xa′), (Xb′), (Xc′), (Xd′), (Xe′), or (Xf′):
  • each of R aa and R ba independently is H or R S5a , or R aa and R ba together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; in which R S5a is C 1 -C 6 alkyl, phenyl, 5- or 6-membered heteroaryl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and each of R S4a , R S5a , and the heterocycloalkyl formed by R aa and R ba is independently optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 12 cycloalkyl, phenyl, 5- or 6- membered heteroaryl, or 4- to
  • R 4a is–Q 3a -T 3a , in which Q 3a is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and T 3a is H, halo, cyano, OR 7a , OR 8a , C(O)R 8a , NR 7a R 8a , C(O)NR 7a R 8a , NR 7a C(O)R 8a , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl,
  • each of R 5a , R 6a , and R 7a is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl; and each R 8a independently is–Q 4a -T 4a , in which Q 4a is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 4a is H, halo, or R S3a , in which R S3a is C3-C12 cycloalkyl, C6- C 10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, or a 5- to 10-membered heteroaryl
  • R 4a is halo, C 1 -C 6 alkyl, or OR 7a . In some embodiments, R 4a is C1-C6 alkoxyl. In some embodiments, R 4a is–OCH3.
  • the EHMT2 inhibitor is a compound of Formula (I′′), (II′′), or (III′′):
  • X 1b is N or CR 2b ;
  • X 2b is N or CR 3b ;
  • X 3b is N or CR 4b ;
  • X 4b is N or CR 5b ;
  • each of X 5b , X 6b and X 7b is independently N or CH;
  • B is C6-C10 aryl or 5- to 10-membered heteroaryl
  • R 1b is H or C 1 -C 4 alkyl
  • each of R 2b , R 3b , R 4b , and R 5b independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkoxyl, C 6 -C 10 aryl, OH, NR ab R bb , C(O)NR ab R bb , NR ab C(O)R bb , C(O)OR ab , OC(O)R ab , OC(O)NR ab R bb , NR ab C(O)OR bb , C3-C8 cycloalkyl, 4- to 7- membered
  • heterocycloalkyl 5- to 6-membered heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein the C6-C10 aryl, C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6- membered heteroaryl, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, are each optionally substituted with one or more of halo, OR ab , or NR ab R bb , in which each of R ab and R bb independently is H or C 1 -C 6 alkyl; R 6b is–Q 1b -T 1b , in which Q 1b is a bond, or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each
  • R 7b is–Q 2b -T 2b , in which Q 2b is a bond, C(O)NR eb , or NR eb C(O), R eb being H or C1-C6 alkyl and T 2b is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, and wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more–Q 3b -T 3b , wherein each Q 3b independently is a bond or C 1 -C 3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy, and each T 3b independently is selected from the group consisting of H, halo, cyano, C 1 - C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl,
  • R 8b is H or C1-C6 alkyl
  • R 9b is–Q 4b -T 4b , in which Q 4b is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1- C 6 alkoxyl, and T 4b is H, halo, OR hb , NR hb R ib , NR hb C(O)R ib , C(O)NR hb R ib , C(O)R hb , C(O)R hb ,
  • each of R hb and R ib independently is H or C 1 -C 6 alkyl
  • R S2b is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl
  • R S2b is optionally substituted with one or more–Q 5b -T 5b , wherein each Q 5b independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy, and each T 5b
  • R 10b is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy; and
  • R 11b and R 12b together with the carbon atom to which they are attached form a C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl.
  • the compounds of Formulae (I′′)-(III′′) may have one or more of the following features when applicable.
  • the EHMT2 inhibitor is a compound is of Formula (I′′).
  • At least one of X 1b , X 2b , X 3b and X 4b is N.
  • X 1b and X 3b are N.
  • X 1b and X 3b are N, X 2b is CR 3b and X 4b is CR 5b .
  • ring B is phenyl or 6-membered heteroaryl.
  • ring B is phenyl or pyridyl.
  • the EHMT2 inhibitor is a compound of Formula (Ia′′), (Ib′′), (Ic′′), or (Id′′):
  • At most one of R 3b and R 5b is not H.
  • At least one of R 3b and R 5b is not H.
  • R 3b is H or halo.
  • the EHMT2 inhibitor is a compound of Formula (Ie′′), (If′′), (Ig′′), or (Ih′′):
  • At most one of R 4b and R 5b is not H.
  • At least one of R 4b and R 5b is not H.
  • R 4b is H, C 1 -C 6 alkyl, or halo.
  • the EHMT2 inhibitor is a compound of Formula (Ii′′), (Ij′′), (Ik′′), or (Il′′):
  • At most one of R 2b and R 5b is not H.
  • At least one of R 2b and R 5b is not H.
  • R 2b is H, C 1 -C 6 alkyl, or halo.
  • R 5b is C1-C6 alkyl.
  • the EHMT2 inhibitor is a compound is of Formula (II′′).
  • each of X 5b , X 6b and X 7b is CH.
  • At least one of X 5b , X 6b and X 7b is N.
  • At most one of X 5b , X 6b and X 7b is N.
  • R 10b is optionally substituted 4- to 7-membered
  • heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.
  • R 10b is connected to the bicyclic group of Formula (II′′) via a carbon-carbon bond. [0313] In some embodiments, R 10b is connected to the bicyclic group of Formula (II′′) via a carbon-nitrogen bond.
  • the compound is of Formula (III′′).
  • R 11b and R 12b together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl.
  • R 11b and R 12b together with the carbon atom to which they are attached form a C4-C8 cycloalkyl which is optionally substituted with one or more of halo, C1- C 6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl.
  • each of X 5b and X 6b is CH.
  • each of X 5b and X 6b is N.
  • one of X 5b and X 6b is CH and the other is CH.
  • R 6b is–Q 1b -T 1b , in which Q 1b is a bond or C 1 -C 6 alkylene linker optionally substituted with one or more of halo, and T 1b is H, halo, cyano, or R S1b , in which R S1b is C 3 -C 8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1b is optionally substituted with one or more of halo, C 1 -C 6 alkyl, hydroxyl, oxo, NR cb R db , or C 1 -C 6 alkoxyl.
  • R 6b is C1-C6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl.
  • R 6b is unsubstituted C 1 -C 6 alkyl.
  • R 7b is–Q 2b -T 2b , in which Q 2b is a bond or C(O)NR eb , and T 2b is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl, wherein the 5- to 10- membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more–Q 3b -T 3b .
  • Q 2b is a bond
  • T 2b is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, which is optionally substituted with one or more–Q 3b - T 3b .
  • T 2b is 8- to 12-membered bicyclic heterocycloalkyl that comprises a 5- or 6-membered aryl or heteroaryl ring fused with a non-aromatic ring.
  • T 2b is 8- to 12-membered bicyclic heterocycloalkyl that comprises a 5- or 6-membered aryl or heteroaryl ring fused with a non-aromatic ring, in which the 5- or 6-membered aryl or heteroaryl ring is connected to Q 2b .
  • T 2b is 5- to 10-membered heteroaryl.
  • T 2b is selected from , , , , ,
  • T 2b is selected from
  • each Q 3b independently is a bond or C 1 -C 3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy
  • each T 3b independently is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocycloalkyl, OR fb , C(O)R fb , C(O)OR fb , NR fb R gb , C(O)NR fb R gb , and NR fb C(O)R gb , in which the C 3 -C 8 cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, C1-C6 alkyl or C1-C6 alkoxy.
  • At least one of R 8b and R 9b is H.
  • each of R 8b and R 9b is H.
  • R 8b is H.
  • R 9b is–Q 4b -T 4b , in which Q 4b is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 4b is H, halo, OR hb , NR hb R ib , NR hb C(O)R ib , C(O)NR hb R ib , C(O)R hb , C(O)OR hb , or R S2b , in which R S2b is C3-C8 cycloalkyl or 4- to 7-membered heterocycloalkyl, and R S2b is optionally substituted with one or more–Q 5b -T 5b .
  • each Q 5b independently is a bond or C1-C3 alkylene linker.
  • each T 5b independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, OR jb , C(O)R jb , C(O)OR jb , NR jb R kb , C(O)NR jb R kb , and
  • R 9b is C1-C3 alkyl.
  • the EHMT2 inhibitor is of Formula (I'''), (II'''), or (III'''):
  • X 1c is N or CR 2c ;
  • X 2c is N or CR 3c ;
  • X 3c is N or CR 4c ;
  • X 4c is N or CR 5c ;
  • each of X 5c , X 6c and X 7c is independently N or CH;
  • X 8c is NR 13c or CR 11c R 12c ;
  • R 1c is H or C 1 -C 4 alkyl
  • each of R 2c , R 3c , R 4c , and R 5c independently is selected from the group consisting of H, halo, cyano, C1-C6 alkoxyl, C6-C10 aryl, OH, NR ac R bc , C(O)NR ac R bc , NR ac C(O)R bc , C(O)OR ac , OC(O)R ac , OC(O)NR ac R bc , NR ac C(O)OR bc , C 3 -C 8 cycloalkyl, 4- to 7- membered
  • heterocycloalkyl 5- to 6-membered heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, 4- to 7- membered heterocycloalkyl, 5- to 6- membered heteroaryl, C1-C6 alkoxyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, are each optionally substituted with one or more of halo, OR ac , or NR ac R bc , in which each of R ac and R bc independently is H or C1-C6 alkyl; R 6c is–Q 1c -T 1c , in which Q 1c is a bond, or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted
  • R 7c is–Q 2c -T 2c , in which Q 2c is a bond, C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, and T 2c is H, halo, cyano, OR ec , OR fc , C(O)R fc , NR ec R fc ,
  • each R ec independently is H or C1-C6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl;
  • each of R fc and R gc is–Q 6c -T 6c , in which Q 6c is a bond or C1-C6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 6c is H, halo, OR m1c , NR m1c R m2c , NR m1c C(O)R m2c , C(O)NR m1c R m2c , C(O)R m1c , C(O)OR m1c , NR m1c C(O)OR m2c ,
  • each of R m1c and R m2c independently is H or C 1 -C 6 alkyl
  • R S3c is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl
  • R S3c is optionally substituted with one or more–Q 7c -T 7c , wherein each Q 7c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy
  • each T 7c independently is selected from the group consisting of H, halo, cyano
  • R 8c is H or C1-C6 alkyl
  • R 9c is–Q 4c -T 4c , in which Q 4c is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1- C 6 alkoxyl, and T 4c is H, halo, OR hc , NR hc R ic , NR hc C(O)R ic , C(O)NR hc R ic , C(O)R hc , C(O)OR hc , NR hc C(O)OR ic , OC(O)NR hc R ic , S(O)2R hc , S(O)2NR hc R ic , or R S2c , in which each of R hc and R ic independently is H or C 1 -C 6 alkyl, and
  • R 10c is halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 4- to 12- membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NR jc R kc , or NR jc C(O)R kc ;
  • R 11c and R 12c together with the carbon atom to which they are attached form a C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C3-C12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C1-C6 alkoxyl;
  • R 13c is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 12 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; and
  • each of R 14c and R 15c is H, halo, cyano, C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano, C2-C6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • the compound is of Formula (I'''), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
  • R 1c is CH
  • R 7c is , one of R 8c and R 9c is H and the other one is CH 3
  • R 14c is OCH3, then
  • R 15c is H, halo, cyano, C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano, C2-C6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • R 1c is CH
  • R 7c is , one of R 8c and R 9c is H and the other one is CH 3
  • R 14c is OCH3, then
  • R 15c is H, Cl, Br, cyano, C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano, C2-C6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • R 15c is H, halo, cyano, C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano, C2-C6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C3-C8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • R 8c and R 9c is H and the other one is CH3, and R 14c is Cl, then
  • R 15c is halo, cyano, C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano, C2-C6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • the compound is not one of the following compounds:
  • the compound is of Formula (II''') or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
  • R 9c is H and the other one is CH3, R 10c is and R 14c is OCH3, then
  • R 15c is H, halo, cyano, C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano, C2-C6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • X 5c is CH
  • X 7c is CH
  • R 7c is , one of R 8c
  • R 9c is H and the other one is CH 3 , R 10c is , and R 14c is OCH 3 , then
  • R 15c is H, Cl, Br, cyano, C1-C6 alkyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkenyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkynyl optionally substituted with one or more of halo or cyano, C3-C8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • the compound is not ,
  • X 5c is CH
  • X 8c is CR 11c R 12c , in which R 11c and R 12c together with the carbon atom to which they are attached form a cyclobutyl
  • R 7c is one of R 8c and R 9c is H and the other one is CH3
  • R 14c is OCH3
  • R 15c is H, halo, cyano, C1-C6 alkyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkenyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkynyl optionally substituted with one or more of halo or cyano, C3-C8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • X 5c is CH
  • X 8c is CR 11c R 12c , in which R 11c and R 12c together with the carbon atom to which they are attached form a cyclobutyl
  • R 7c is one of R 8c and R 9c is H and the other one is CH 3
  • R 14c is OCH 3
  • R 15c is H, Cl, Br, cyano, C1-C6 alkyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkenyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkynyl optionally substituted with one or more of halo or cyano, C3-C8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • the compound is not
  • At least one of R 14c and R 15c is halo. In some embodiments, at least one of R 14c and R 15c is F. In some embodiments, at least one of R 14c and R 15c is Cl. In some embodiments, at least one of R 14c and R 15c is Br. In some embodiments, one of R 14c and R 15c is halo. In some embodiments, one of R 14c and R 15c is F. In some embodiments, one of R 14c and R 15c is Cl. In some embodiments, one of R 14c and R 15c is Br. In some embodiments, R 14c is halo. In some embodiments, R 14c is F. In some embodiments, R 14c is Cl.
  • R 14c is Br. In some embodiments, R 15c is halo. In some embodiments, R 15c is F. In some embodiments, R 15c is Cl. In some embodiments, R 15c is Br. In some embodiments, both of R 14c and R 15c are halo. In some embodiments, both of R 14c and R 15c are F. In some embodiments, both of R 14c and R 15c are Cl. In some embodiments, both of R 14c and R 15c are Br.
  • one of R 14c and R 15c is halo, and the other one is H, cyano, C1- C 6 alkyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • one of R 14c and R 15c is halo, and the other one is H, C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano, C3-C8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c , in which R 6c is C 1 -C 6 alkyl optionally substituted with one or more of halo or cyano.
  • one of R 14c and R 15c is halo, and the other one is H, C 1 -C 6 alkyl, C3-C8 cycloalkyl, or–OR 6c , in which R 6c is C1-C6 alkyl.
  • R 14c is halo, and R 15c is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or–OR 6c , in which R 6c is C 1 -C 6 alkyl.
  • R 14c is halo, and R 15c is H.
  • R 14c is halo, and R 15c is C1-C6 alkyl.
  • R 14c is halo, and R 15c is C3-C8 cycloalkyl. In some embodiments, R 14c is halo, and R 15c is–OR 6c , in which R 6c is C 1 -C 6 alkyl. In some embodiments, R 15c is halo, and R 14c is H, C1-C6 alkyl, C3-C8 cycloalkyl, or–OR 6c , in which R 6c is C1-C6 alkyl. In some embodiments, R 15c is halo, and R 14c is H. In some embodiments, R 15c is halo, and R 14c is C 1 -C 6 alkyl.
  • R 15c is halo, and R 14c is C3-C8 cycloalkyl. In some embodiments, R 15c is halo, and R 14c is–OR 6c , in which R 6c is C 1 -C 6 alkyl. In some embodiments, one of R 14c and R 15c is halo, and the other one is H, -CH3, cyclopropyl, or–OCH3. In some embodiments, one of R 14c and R 15c is halo, and the other one is H or–OCH 3 .
  • R 14c is halo, and R 15c is H or–OCH3. In some embodiments, R 14c is F, and R 15c is H. In some embodiments, R 14c is Cl, and R 15c is H. In some embodiments,
  • R 14c is Br, and R 15c is H. In some embodiments, R 14c is F, and R 15c is–OCH3. In some embodiments, R 14c is Cl, and R 15c is–OCH 3 . In some embodiments, R 14c is Br, and R 15c is–OCH3.
  • R 15c is halo, and R 14c is H or–OCH 3 . In some embodiments, R 15c is F, and R 14c is H. In some embodiments, R 15c is Cl, and R 14c is H. In some embodiments,
  • R 15c is Br, and R 14c is H. In some embodiments, R 15c is F, and R 14c is–OCH 3 . In some embodiments, R 15c is Cl, and R 14c is–OCH3. In some embodiments, R 15c is Br, and R 14c is–OCH 3 .
  • R 15c is H
  • R 14c is halo, cyano, C1-C6 alkyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano, or–OR 6c .
  • R 15c is H
  • R 14c is halo or–OR 6c .
  • R 15c is H, and R 14c is F, Cl, or Br.
  • R 15c is H
  • R 14c is–OCH3.
  • the compound is of any one of Formula (I'''-1), (I'''-2), (II'''-1), (II''-2), (III'''-1), or (III'''-2):
  • X 1c is N or CR 2c ;
  • X 2c is N or CR 3c ;
  • X 3c is N or CR 4c ;
  • X 4c is N or CR 5c ;
  • each of X 5c , X 6c and X 7c is independently N or CH;
  • R 1c is H or C1-C4 alkyl
  • each of R 2c , R 3c , R 4c , and R 5c independently is selected from the group consisting of H, halo, cyano, C c
  • R 6c is–Q 1c -T 1c , in which Q 1c is a bond, or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C 1 -C 6 alkoxyl, and T 1c is H, halo, cyano, or R S1c , in which R S1c is C 3 -C 8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1c is optionally substituted with one or more of halo, C 1 - C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, -C(O)R cc
  • R 7c is–Q 2c -T 2c , in which Q 2c is a bond, a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, and T 2c is H, halo, cyano, OR ec , OR fc , C(O)R fc , NR ec R fc , C(O)NR ec R fc , NR ec C(O)R fc , C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C3-C12 cycloalkyl,
  • each R ec independently is H or C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl;
  • each of R fc and R gc is–Q 6c -T 6c , in which Q 6c is a bond or C 1 -C 6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 6c is H, halo, OR m1c , NR m1c R m2c , NR m1c C(O)R m2c , C(O)NR m1c R m2c , C(O)R m1c , C(O)OR m1c , NR m1c C(O)OR m2c ,
  • each of R m1c and R m2c independently is H or C1-C6 alkyl
  • R S3c is C3-C8 cycloalkyl, C6-C10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl
  • R S3c is optionally substituted with one or more–Q 7c -T 7c , wherein each Q 7c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy
  • each T 7c independently is selected from the group consisting of H, halo, cyano, C
  • R 9c is–Q 4c -T 4c , in which Q 4c is a bond or C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 - C6 alkoxyl, and T 4c is H, halo, OR hc , NR hc R ic , NR hc C(O)R ic , C(O)NR hc R ic , C(O)R hc , C(O)OR hc , NR hc C(O)OR ic , OC(O)NR hc R ic , S(O) 2 R hc , S(O) 2 NR hc R ic , or R S2c , in which each of R hc and R ic independently is H or C1-C6 alkyl, and R S2c
  • R 10 is halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, or 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, and 4- to 12- membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, oxo, amino, mono- or di- alkylamino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C(O)NR jc R kc , or NR jc C(O)R
  • R 11c and R 12c together with the carbon atom to which they are attached form a C 3 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C 3 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl
  • each of R 14c and R 15c is H, halo, cyano, C1-C6 alkyl optionally substituted with one or more of halo or cyano, C 2 -C 6 alkenyl optionally substituted with one or more of halo or cyano, C2-C6 alkynyl optionally substituted with one or more of halo or cyano, or C 3 -C 8 cycloalkyl optionally substituted with one or more of halo or cyano.
  • the compound is of Formula (I'''-1) or (I'''-2), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
  • At least one of X 1c , X 2c , X 3c and X 4c is N.
  • X 1c and X 3c are N. In some embodiments, X 1c and X 3c are N, X 2c is CR 3c and X 4c is CR 5c .
  • the compound is of Formula (I'''-1a), (I'''-2a), (I''-1b), (I'''-2b), (I'''-1c), or (I'''-2c):
  • At most one of R 3c and R 5c is not H. In some embodiments, at least one of R 3c and R 5c is not H. In some embodiments, R 3c is H or halo.
  • the compound is of Formula (I'''-1d), (I''-2d), (I''-1e), (I'''-2e), (I'''-1f), or (I'''-2f):
  • R 4c and R 5c are not H. In some embodiments, at least one of R 4c and R 5c is not H. In some embodiments, R 4c is H, C1-C6 alkyl, or halo.
  • R 2c and R 5c are not H. In some embodiments, at least one of R 2c and R 5c is not H. In some embodiments, R 2c is H, C1-C6 alkyl, or halo. In some embodiments, R 5c is C 1 -C 6 alkyl.
  • the compound is of Formula (II'''-1) of (II'''-2), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
  • each of X 5c , X 6c and X 7c is CH. In some embodiments, at least one of X 5c , X 6c and X 7c is N. In some embodiments, at most one of X 5c , X 6c and X 7c is N.
  • R 10 is optionally substituted 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.
  • R 10 is connected to the bicyclic group of Formula (II'''-1) or (II'''-2) via a carbon-carbon bond.
  • R 10 is connected to the bicyclic group of Formula (II'''-1) or (II'''-2) via a carbon- nitrogen bond.
  • the compound is of Formula (III'''-1) or (III'''-2), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
  • R 11c and R 12c together with the carbon atom to which they are attached form a 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl.
  • R 11c and R 12c together with the carbon atom to which they are attached form azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6- tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro- 2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, or morpholinyl.
  • R 11c and R 12c together with the carbon atom to which they are attached form tetrahyrofuranyl.
  • R 11c and R 12c together with the carbon atom to which they are attached form a C4-C8 cycloalkyl which is optionally substituted with one or more of halo, C1- C 6 alkyl, hydroxyl, oxo, amino, mono- or di- alkylamino, or C 1 -C 6 alkoxyl.
  • R 11c and R 12c together with the carbon atom to which they are attached form a C 4 -C 8 cycloalkyl (e.g., cyclobutyl, cyclopentyl, or cyclohexyl).
  • a C 4 -C 8 cycloalkyl e.g., cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 11c and R 12c together with the carbon atom to which they are attached form cyclobutyl.
  • R 11c and R 12c together with the carbon atom to which they are attached form cyclopentyl.
  • R 11c and R 12c together with the carbon atom to which they are attached form cyclohexyl.
  • each of X 5c and X 6c is CH. In some embodiments, each of X 5c and X 6c is N. In some embodiments, one of X 5c and X 6c is CH and the other is CH.
  • R 6c is–Q 1c -T 1c , in which Q 1c is a bond or C 1 -C 6 alkylene linker optionally substituted with one or more of halo, and T 1c is H, halo, cyano, or R S1c , in which R S1c is C 3 -C 8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1c is optionally substituted with one or more of halo, C 1 -C 6 alkyl, hydroxyl, oxo, NR cc R dc , or C 1 -C 6 alkoxyl.
  • R 6c is C1-C6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl. In some embodiments, R 6c is C 1 -C 6 alkyl. In some embodiments, R 6c is–CH3.
  • R 7c is–Q 2c -T 2c , in which Q 2c is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, and T 2c is C(O)NR ec R fc .
  • Q 2c is a bond.
  • R ec is H.
  • R fc is–Q 6c -T 6c , in which Q 6c is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxyl, and T 6c is H, NR m1c R m2c , or R S3c , in which each of R m1c and R m2c independently is H or C 1 -C 6 alkyl, and R S3c is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 12- membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R S
  • T 6c is 8- to 12-membered bicyclic heterocycloalkyl that comprises a 5- or 6-membered aryl or heteroaryl ring fused with a non-aromatic ring. In some embodiments, T 6c is 8- to 12-membered bicyclic heterocycloalkyl that comprises a 5- or 6- membered aryl or heteroaryl ring fused with a non-aromatic ring, in which the 5- or 6- membered aryl or heteroaryl ring is connected to Q 2c . In some embodiments, T 6c is 5- to 10- membered heteroaryl. [0393] In some embodiments, T 6c is selected from
  • T 6c is selected from
  • each Q 7c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy
  • each T 7c independently is selected the group consisting of H, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 7-membered heterocycloalkyl containing 1- 4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR n1c , C(O)R n1c , C(O)OR n1c , OC(O)R n1c , S(O) 2 R n1c , NR n1c R n2c , OC(O)NR n1c R
  • each Q 7c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy
  • each T 7c independently is selected from the group consisting of H, halo, cyano, C1-C6 alkyl, and NR n1c R n2c , each of R n1c and R n2c independently being H or C 1 -C 6 alkyl.
  • R 7c is ,
  • R 7c is–Q 2c -T 2c , in which Q 2c is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C2-C6 alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, or C1-C6 alkoxyl, and each T 2c independently is H, OR ec , OR fc , NR ec R fc , C3-C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl.
  • R 7c is wherein T 2c is H, halo, cyano, OR ec , OR fc , C(O)R fc , NR ec R fc , C(O)NR ec R fc , NR ec C(O)R fc , C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 - C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, hydroxyl, cyano, C 1 -C 6 haloalkyl, -SO 2 R cc , C 1 -C 6 alk
  • R 7c is wherein T 2c is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl optionally substituted with one or more of halo, hydroxyl, C1-C6 alkoxyl or C1-C6 alkyl. [0401] In some embodiments, R 7c is , , , ,
  • R 7c is OR ec .
  • R 7c is OR fc .
  • R 7c is -CH 2 -T 2c , wherein T 2c is H, halo, cyano, OR ec , OR fc , C(O)R fc , NR 7c R fc , C(O)NR ec R fc , NR ec C(O)R fc , C6-C10 aryl, 5- to 10-membered heteroaryl, C3- C12 cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 12 cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, hydroxyl, cyano, C 1 -C 6 haloalkyl, -SO 2 R cc ,
  • R 7c is -CH 2 -OR 8 .
  • R 7c is -CH2-NR7R8. [0407] In some embodiments, R 7c is , , , [0408] In some embodiments, R 7c is , ,
  • R 7c is , ,
  • R 7c is
  • R 7c is [0412] In some embodiments, R 7c is is
  • R 7c is–Q 2c -T 2c , in which Q 2c is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, amino, mono- or di- alkylamino, and T 2c is 5- to 10-membered heteroaryl optionally substituted with one or more– Q 3c -T 3c .
  • R 7c is–Q 2c -T 2c , in which Q 2c is a bond and T 2c is 5- to 10- membered heteroaryl optionally substituted with one or more–Q 3c -T 3c .
  • T 2c is selected from
  • T 2c is selected from and tautomers thereof, each of which is optionally substituted with one or more–Q 3c -T 3c .
  • T 2c is optionally substituted with one or more–Q 3c -T 3c .
  • T 2c is optionally substituted with one or more–Q 3c - T 3c .
  • T 2c is [0419] In some embodiments, T 2c is [0420] In some embodiments, T 2c is optionally substituted with one or more–Q 3 - T 3 .
  • T 2 is , , [0422] In some embodiments, T 2 is optionally substituted with one or more–Q 3 -T 3 .
  • T 2 is
  • each Q 3c independently is a bond or C1-C3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C1-C6 alkoxy
  • each T 3c independently is selected from the group consisting of H, C6-C10 aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, and NR fc R gc .
  • each Q 3c independently is a C1-C3 alkylene linker
  • each T 3c independently is NR fc R gc , each of R fc and R gc independently being H or C 1 -C 6 alkyl.
  • each Q 3c independently is a C1-C3 alkylene linker
  • each T 3c independently is NR fc R gc , each of R fc and R gc independently being H or methyl.
  • each Q 3c independently is a C1-C3 alkylene linker, and each T 3c independently is NH 2 .
  • each Q 3c independently is methylene, and each T 3c
  • each Q 3c independently is a C1-C3 alkylene linker, and each T 3c independently is NHCH 3 .
  • each Q 3c independently is methylene, and each T 3c
  • R 7c is independently is NHCH 3 .
  • R 7c is independently is NHCH 3 .
  • each Q 3c independently is a bond
  • each T 3c independently is selected from the group consisting of 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.
  • each Q 3c independently is a bond
  • each T 3c independently is 5-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.
  • each Q 3c independently is a bond
  • each T 3c independently is selected from , ,
  • each Q 3c independently is a bond
  • each T 3c independently is selected from
  • each Q 3c independently is a bond, and each T 3c independently is . In some embodiments, each Q 3c independently is a bond, and each T 3c
  • each Q 3c independently is a bond
  • each T 3c independently is
  • each Q 3c independently is a bond, and each T 3c independently is . In some embodiments, each Q 3c independently is a bond, and each T 3c independently is In some embodiments, each Q 3c independently is a bond, and each T 3c independently is [0438] In some embodiments, R 7c is . In some embodiments, R 7c is o . In some embodiments, R 7c is . In some
  • R 7c is
  • R 7c is In some embodiments, R 7c is In some embodiments, R 7c is In some embodiments, R 7c is In
  • R 7c is
  • At least one of R 8c and R 9c is H. In some embodiments, each of R 8c and R 9c is H. In some embodiments, R 8c is H.
  • R 9c is–Q 4c -T 4c , in which Q 4c is a bond or C1-C6 alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 4c is H, halo, OR hc , NR hc R ic , NR hc C(O)R ic , C(O)NR hc R ic , C(O)R hc , C(O)OR hc , or R S2c , in which R S2c is C 3 -C 8 cycloalkyl or 4- to 7-membered heterocycloalkyl, and R S2c is optionally substituted with one or more–Q 5c -T 5c .
  • each Q 5c independently is a bond or C 1 -C 3 alkylene linker.
  • each T 5c independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, OR jc , C(O)R jc , C(O)OR jc , NR jc R kc , C(O)NR jc R kc , and
  • R 9c is C 1 -C 3 alkyl.
  • R 14c is H, halo, or C1-C6 alkyl.
  • the compound is selected from those in Tables 1-6, 6A, and 7, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound is selected from those in Table 1, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers. [0448] In some embodiments, the compound is selected from those in Table 2, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound is selected from those in Table 3, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound is selected from those in Table 4, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound is selected from those in Table 5, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound is selected from those in Table 6, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound is selected from those in Table 6A, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound is selected from those in Table 7, tautomers thereof, and pharmaceutically acceptable salts of the compounds and tautomers.
  • the compound of is a selective inhibitor of EHMT2.
  • the present disclosure also provides a method of preventing or treating a cancer via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, and a therapeutically effective amount of one or more additional therapeutic agent.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent are administered simultaneously, sequentially, or alternately.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent are administered simultaneously.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent are administered sequentially.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent are administered alternately.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent is administered prior to the administration of the compound of the present disclosure (e.g., the EHMT2 inhibitor).
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent are administered in temporal proximity.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent are administered in a co- formulation.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent are administered in separate formulations.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the compound of the present disclosure is administered with one or more drug holidays.
  • the compound of the present disclosure e.g., the EHMT2 inhibitor
  • the one or more additional therapeutic agent is administered with one or more drug holidays. In some embodiments, the one or more additional therapeutic agent is administered without any drug holiday.
  • the one or more additional therapeutic agent comprises:
  • ABT263 (4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1- yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3- (trifluoromethylsulfonyl)phenyl]sulfonylbenzamide),
  • AC-261066 (4-[4-(2-butoxyethoxy)-5-methyl-1,3-thiazol-2-yl]-2-fluorobenzoic acid
  • AC-55649 (4-(4-octylphenyl)benzoic acid)
  • acitretin ((2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona- 2,4,6,8-tetraenoic acid),
  • adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic acid), aldesleukin (proleukin),
  • AM-580 (4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]benzoic acid), ara-C (cytarbine; 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan- 2-yl] pyrimidin-2-one)),
  • azacitidine (4-Amino-1-( ⁇ -D-ribofuranosyl)-1,3,5-triazin-2(1H)-one),
  • AZD7762 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene- 2-carboxamide),
  • bevacizumab (avastin; CAS No.216974-75-3),
  • BI-78D3 (4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-1,3-thiazol-2-yl)sulfanyl]- 1H-1,2,4-triazol-5-one),
  • binimetinib (6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3- methylbenzimidazole-5-carboxamide),
  • bivanib (BI2536; 4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2- yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide),
  • bleomycin ((3- ⁇ [(2'- ⁇ (5S,8S,9S,10R,13S)-15- ⁇ 6-amino-2- [(1S)-3-amino-1- ⁇ [(2S)-2,3- diamino-3-oxopropyl]amino ⁇ -3-oxopropyl] -5-methylpyrimidin-4-yl ⁇ -13- [ ⁇ [(2R,3S,4S,5S,6S)-3- ⁇ [(2R,3S,4S,5R,6R)-4-(carbamoyloxy)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy ⁇ -4,5-dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl]oxy ⁇ (1H-imidazol-5-yl)methyl]-9-hydroxy-5-[(1R)-1-hydroxyethyl]-8,10- dimethyl-4
  • BMS-536924 ((3Z)-4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-methyl- 6-morpholin-4-yl-1,3-dihydrobenzimidazol-2-ylidene)pyridin-2-one), BMS-753 (4-[(1,1,3,3-tetramethyl-2-oxoindene-5-carbonyl)amino]benzoic acid), BMS-93559,
  • buparlisib (BKM120; 5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-amine),
  • CD-1530 (4-[7-(1-adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid),
  • CD-2314 (5-(5,5,8,8-tetramethyl-6,7-dihydroanthracen-2-yl)thiophene-3-carboxylic acid),
  • CD-437 (6-[3-(1-adamantyl)-4-hydroxyphenyl]naphthalene-2-carboxylic acid), cediranib (AZD-2171; 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3- pyrrolidin-1-ylpropoxy)quinazoline)
  • Ch-55 (4-[(E)-3-(3,5-ditert-butylphenyl)-3-oxoprop-1-enyl]benzoic acid),
  • cladribine (5-(6-Amino-2-chloro-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol), clofarabine (5-(6-amino-2-chloro-purin-9-yl) -4-fluoro-2- (hydroxymethyl)oxolan-3- ol),
  • cobimetinib (cotellic; [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3- [(2S)-piperidin-2-yl]azetidin-1-yl]methanone),
  • crizotinib (PF2341066; 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin- 4-ylpyrazol-4-yl)pyridin-2-amine),
  • dabrafenib (tafinlar; N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2- fluorophenyl]-2,6-difluorobenzenesulfonamide),
  • NDP-BEZ235 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5- c]quinolin-1-yl)phenyl]propanenitrile
  • daporinad (FK866; (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2- enamide),
  • daunorubicin ((8S,10S)-8-acetyl-10-[(2S,4S,5S,6S)-4-amino-5-hydroxy-6-methyl- oxan-2-yl]oxy-6,8,11-trihydroxy-1-methoxy-9,10-dihydro-7H-tetracene-5,12-dione),
  • decitabine (4-Amino-1-(2-deoxy- ⁇ -D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one), dinaciclib (2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3- yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol),
  • diphtheria toxin-Interleukin-2 fusion protein diphtheria toxin-Interleukin-2 fusion protein (denileukin diftitox; CAS No.173146-27- 5),
  • disulfiram diethylcarbamothioylsulfanyl N,N-diethylcarbamodithioate
  • docetaxel (1,7 ⁇ ,10 ⁇ -trihydroxy-9-oxo-5 ⁇ ,20-epoxytax-11-ene-2 ⁇ ,4,13 ⁇ -triyl 4-acetate 2-benzoate 13- ⁇ (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate ⁇ ), dorsomorphin (6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5- a]pyrimidine),
  • ENMD-2076 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2- phenylethenyl]pyrimidin-4-amine), enzastaurin (3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3- yl]pyrrole-2,5-dione),
  • etretinate ethyl (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7- dimethylnona-2,4,6,8-tetraenoate
  • everolimus ((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- Dihydroxy-12- ⁇ (2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl ⁇ - 19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0 4,9 ]- hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone),
  • FH535 (2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide
  • fotemustine (1-(2-chloroethyl)-3-(1-diethoxyphosphorylethyl)-1-nitrosourea
  • ganetespib ((5Z)-5-(4-hydroxy-6-oxo-3-propan-2-ylcyclohexa-2,4-dien-1-ylidene)-4- (1-methylindol-5-yl)-1,2,4-triazolidin-3-one)
  • gemcitabine (4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5- (hydroxymethyl)oxolan-2-yl]pyrimidin-2-one),
  • gilteritinib (6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]- 5-(oxan-4-ylamino)pyrazine-2-carboxamide),
  • GSK0660 methyl 3-[(4-anilino-2-methoxyphenyl)sulfamoyl]thiophene-2-carboxylate
  • GSK2132231A methyl 3-[(4-anilino-2-methoxyphenyl)sulfamoyl]thiophene-2-carboxylate
  • GSK650394 (2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid), guadecitabine ((2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)-2- (hydroxymethyl)-tetrahydrofuran-3-yl (((2S,3R,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3- hydroxytetrahydrofuran-2-yl)methyl) hydrogen phosphate),
  • GW2580 (5-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]pyrimidine- 2,4-diamine),
  • GW441756 ((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2- one),
  • idarubicin ((7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2- yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione),
  • IMD-0354 N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide), ImmuniCell ® ,
  • interferon alfa 2b (intron a; CAS No.98530-12-2),
  • IL-2 interleukin-2
  • isotretinoin ((2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona- 2,4,6,8-tetraenoic acid),
  • laromustine (1-[2-chloroethyl(methylsulfonyl)amino]-3-methyl-1-methylsulfonylurea), lenalidomide (3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione),
  • LFM-A13 ((Z)-2-cyano-N-(2,5-dibromophenyl)-3-hydroxybut-2-enamide), linsitinib (OSI906; 3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]- 1-methylcyclobutan-1-ol),
  • PLC-412 midostaurin
  • mitomycin (mitomycin A, mitomycin B, or mitomycin C),
  • MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4- f][1,6]naphthyridin-3-one),
  • MVax nilotinib (4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4- pyridin-3-ylpyrimidin-2-yl)amino]benzamide),
  • nimustine (3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-1-(2-chloroethyl)-1- nitrosourea),
  • nivolumab (opdivo; BMS-936558; CAS No.946414-94-4),
  • NVP-TAE684 (5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1- yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine),
  • paclitaxel ((2 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,13 ⁇ )-4,10-Bis(acetyloxy)-13- ⁇ [(2R,3S)-3- (benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy ⁇ -1,7-dihydroxy-9-oxo-5,20-epoxytax-11- en-2-yl benzoate),
  • panobinostat ((2E)-N-hydroxy-3-[4-( ⁇ [2-(2-methyl-1H-indol-3- yl)ethyl]amino ⁇ methyl)-phenyl]acrylamide),
  • pazopanib (5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2- methylbenzenesulfonamide),
  • PD173074 (1-tert-butyl-3-[2-[4-(diethylamino)butylamino]-6-(3,5- dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]urea),
  • pegylated interferon alfa-2b (sylatron; CAS No.99210-65-8),
  • pembrolizumab (keytruda; CAS No.1374853-91-4),
  • PF-562271 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), pictilisib (4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1- yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine),
  • PIM-14a (5-[[3-(trifluoromethyl)phenyl]methylidene]-1,3-thiazolidine-2,4-dione), pinometostat ((2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert- butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran- 3,4-diol),
  • pioglitazone (5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4- dione),
  • PLX-4720 N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluorophenyl]propane-1-sulfonamide),
  • retinoic acid ((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona- 2,4,6,8-tetraenoic acid),
  • retinol (vitamin A; (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1- yl)nona-2,4,6,8-tetraen-1-ol),
  • ribociclib (7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2- yl)amino]pyrrolo-[2,3-d]pyrimidine-6-carboxamide),
  • silmitasertib (CX4945; 5-(3-chloroanilino)benzo[c][2,6]naphthyridine-8-carboxylic acid),
  • SNS-032 N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2- yl]piperidine-4-carboxamide
  • SNS-314 (1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3- thiazol-2-yl]urea),
  • sorafenib (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N- methylpyridine-2-carboxamide),
  • sunitinib N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3- ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
  • T0901317 N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2- trifluoroethyl)benzenesulfonamide
  • tamibarotene (4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoic tanespimycin (17-AAG; (3R,5S,6R,7S,8E,10S,11S,12Z,14E)-6-hydroxy-5,11- dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-21-(prop-2-enylamino)-17- azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate),
  • TCS 401 (2-[(Carboxycarbonyl)amino]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylic acid),
  • TCS JNK5a N-(3-cyano-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)naphthalene-1- carboxamide
  • temozolomide (3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide), tideglusib (TZDZ-8; 4-benzyl-2-naphthalen-1-yl-1,2,4-thiadiazolidine-3,5-dione), Tie2i, tipifarnib (6-[(R)-amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3- chlorophenyl)-1-methylquinolin-2-one),
  • tozasertib (VX680; 4-benzyl-2-naphthalen-1-yl-1,2,4-thiadiazolidine-3,5-dione), trametinib (mekinist; N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl- 2,4,7-trioxopyrido-[4,3-d]pyrimidin-1-yl]phenyl]acetamide),
  • valspodar ((3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-1,4,7,10,12,15,19,25,28- nonamethyl-33-[(E,2R)-2-methylhex-4-enoyl]-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30- tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane- 2,5,8,11,14,17,20,23,26,29,32-undecone),
  • vasastrol (4-[(E)-4-(4-hydroxyphenyl)hex-3-en-3-yl]phenol),
  • vatalanib (PTK787; N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine), veliparib (ABT888; 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4- carboxamide),
  • vemurafenib N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluorophenyl]propane-1-sulfonamide),
  • vemurafenib (zelboraf; N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3- carbonyl]-2,4-difluorophenyl]propane-1-sulfonamide), venetoclax (4-(4- ⁇ [2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl ⁇ -1- piperazinyl)-N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ sulfonyl)-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzamide),
  • vinblastine (dimethyl (2 ⁇ ,3 ⁇ ,4 ⁇ ,5 ⁇ ,12 ⁇ ,19 ⁇ )-15-[(5S,9S)-5-ethyl-5-hydroxy-9- (methoxycarbonyl)-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indol- 9-yl]-3-hydroxy-16-methoxy-1-methyl-6,7-didehydroaspidospermidine-3,4-dicarboxylate), vincristine ((3aR,3a1R,4R,5S,5aR,10bR)-Methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5- ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]- azacyclounde
  • volasertib N-[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-4-[[(7R)-7-ethyl-5- methyl-6-oxo-8-propan-2-yl-7H-pteridin-2-yl]amino]-3-methoxybenzamide),
  • SAHA vorinostat
  • VX-702 (6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)pyridine-3- carboxamide),
  • ZM336372 (3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4- methylphenyl]benzamide),
  • the one or more additional therapeutic agent comprises a standard-of-care treatment modality for treating AML, a standard-of-care treatment modality for treating melanoma, an epigenetic drug, a targeted therapy, or any combination thereof.
  • the one or more additional therapeutic agent comprises an antimetabolite, a topoisomerase II inhibitor, DNA hypomethylating agent, a DNA methyltransferase (DNMT) inhibitor, an HDAC inhibitor, an EZH2 inhibitor, a DOT1L inhibitor, a differentiation agent, a FLT3 inhibitor, a BCL2 inhibitor, a glucocorticoid receptor agonist (GRag), a BCR inhibitor, a corticosteroid, or any combination thereof.
  • DNMT DNA methyltransferase
  • the one or more additional therapeutic agent comprises Ara-C, CHOP, Daunorubicin, Azacitidine, Decitabine, Pracinostat, Panobinostat, Tazemetostat, Pinometostat, All trans retinoic acid (ATRA), Gilteritinib, Midostaurin, Venetoclax, AG-120, AG-221, Cytarabine, Midostaurin, pembrolizumab, ipilimumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, Dexamethasone, Prednisolone, Pomalidomide, Lenalidomide,
  • Thalidomide Ixazomib, Bortezomib, Carfilzomib, Melphalan, Vincristine, Mafosfamide, Etoposide, Doxorubicin, Bendamustine, Trametinib, Idelalisib, Ibrutinib, Tamatinib, Alisertib, Enzastaurin, Ipatasertib, doxorubicin, cytarabine, vincristine, everolimus, alisertib, topotecan, etoposide, carboplatin, entinostat, panobinostat, romidepsin, palbociclib, abemaciclib, selumetinib, trametinib, MK-2206, Vorinostat, Navitoclax, Rituximab, Obatoclax, atezolizumab, ABT-199, Velcade, Dasatinib, GSK1070916, GSK69
  • the one or more additional therapeutic agent comprises an antimetabolite, a topoisomerase II inhibitor, a DNA hypomethylating agent, an HDAC inhibitor, an EZH2 inhibitor, a DOT1L inhibitor, a differentiation agent, an FLT3 inhibitor, or a BCL2 inhibitor.
  • the one or more additional therapeutic agent comprises cytarabine (Ara-C), daunorubicin, azacitidine, decitabine, pracinostat, panobinostat, tazemetostat, pinometostat, all-trans retinoic acid (ATRA), gilteritinib, midostaurin, venetoclax, pembrolizumab, ipilimumab, dacarbazine, temozolomide, interleukin-2, nivolumab, vemurafenib, dabrafenib, trametinib, carmustine, cisplatin, interferon alfa-2b, cobimetinib, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • ATRA all-trans retinoic acid
  • the cancer is a hematological cancer or a skin cancer.
  • the cancer is a skin cancer.
  • the skin cancer is melanoma.
  • the one or more additional therapeutic agent comprises an alkylating agent, a platinum agent, a vinca alkaloid, a taxane (e.g., paclitaxel, docetaxel or cabazitaxel), a RAS pathway inhibitor (e.g., an ERK inhibitor, a MEK1/2 inhibitor, or a BRAF V600E or V600K inhibitor), a Pi3K/Akt pathway inhibitor (e.g., a Pi3K inhibitor, an Akt inhibitor, or an mTOR inhibitor), an immune-oncology drug (e.g., a CTLA-4 inhibitor or a checkpoint inhibitor), a cell cycle checkpoint inhibitor, a cytokine (e.g., an interferon- ⁇ 2b (IFN- ⁇ 2b), an interferon- ⁇ 2b recombinant (e.g., IFN- ⁇ 2b recombinant), or an IL-2 analog), a tryptophan synthesis inhibitor (e.g., IFN- ⁇ 2b re
  • the one or more additional therapeutic agent comprises dacarbazine, temozolomide, fotemustine, nimustine, melphalan, cisplatin, carboplatin, vinblastine, vincristine, paclitaxel, docetaxel, ulixertib, trametinib, cobimetinib, binimetinib, selumetinib, dabrafenib, vemurafenib, encorafenib, pictilisib, buparlisib, MK-2206, ipatasertinib, everolimus, ipilimumab, pembrolizumab, PDR001, pegylated interferon alfa-2b, interferon alfa 2b, interleukin-2, aldesleukin, epacadostat, seviprotimut-L, MVax,
  • ImmuniCell ® pracinostat, panobinostat, tazemetostat, pinometostat, azacitidine, decitabine, guadecitabine, valspodar, dasatanib, barasertib, palbociclib, ribociclib, bevacizumab, bleomycin, nivolumab, BMS-93559, diphtheria toxin-Interleukin-2 fusion protein, DS-8273a, dasatanib, dinaciclib, disulfiram, elesclomol, GSK2132231A, imatinib, talimogene
  • the alkylating agent comprises dacarbazine, temozolomide, fotemustine, nimustine, melphalan, or a pharmaceutically acceptable salt thereof.
  • the platinum agent comprises cisplatin, carboplatin, or a pharmaceutically acceptable salt thereof.
  • the vinca alkaloid is vinblastine, vincristine, or a pharmaceutically acceptable salt thereof.
  • the taxane is paclitaxel, docetaxel, or a pharmaceutically acceptable salt thereof.
  • the ERK inhibitor is ulixertib or a pharmaceutically acceptable salt thereof.
  • the MEK1/2 inhibitor is trametinib, cobimetinib, binimetinib, selumetinib, or a pharmaceutically acceptable salt thereof.
  • the BRAF V600E or V600K inhibitor is dabrafenib, vemurafenib, sorafenib, encorafenib, or a pharmaceutically acceptable salt thereof.
  • the Pi3K inhibitor is pictilisib, buparlisib, or a pharmaceutically acceptable salt thereof.
  • the Akt inhibitor is MK-2206, ipatasertinib, or a pharmaceutically acceptable salt thereof.
  • the mTOR inhibitor is everolimus or a pharmaceutically acceptable salt thereof.
  • the CTLA-4 inhibitor is ipilimumab or a pharmaceutically acceptable salt thereof.
  • the checkpoint inhibitor is nivolumab, pembrolizumab, PDR001, or a pharmaceutically acceptable salt thereof.
  • the interferon alfa-2b is pegylated interferon alfa-2b.
  • the interferon alfa-2b recombinant is intron a or interleukin-2.
  • the IL-2 analog is aldesleukin.
  • the IDO-1 inhibitor is epacadostat.
  • the therapeutic vaccine is seviprotimut-L or MVax.
  • the T-cell-based therapy is ImmuniCell ® .
  • the HDAC inhibitor is pracinostat, panobinostat, or a pharmaceutically acceptable salt thereof.
  • the EZH2 inhibitor is tazemetostat or a pharmaceutically acceptable salt thereof.
  • the DOT1L inhibitor is pinometostat or a pharmaceutically acceptable salt thereof.
  • the DNA hypomethylating agent comprises azacitidine, decitabine, guadecitabine, or a pharmaceutically acceptable salt thereof.
  • the P-glycoprotein inhibitor is vaspodar or a pharmaceutically acceptable salt thereof.
  • the c-Kit inhibitor is dasatanib or a pharmaceutically acceptable salt thereof.
  • the aurora kinase inhibitor is barasertib or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is palbociclib, ribociclib, or a pharmaceutically acceptable salt thereof.
  • the VGEF inhibitor is bevacizumab, bleomycin, nivolumab, or a pharmaceutically acceptable salt thereof.
  • the PD-L1 inhibitor is BMS-93559 or a pharmaceutically acceptable salt thereof.
  • the engineered protein combining Interleukin-2 and diphtheria toxin is diphtheria toxin- Interleukin-2 fusion protein.
  • the antibody DR5 agonist is DS-8273a, dasatanib, or a pharmaceutically acceptable salt thereof.
  • the CDK1/5 inhibitor is dinaciclib or a pharmaceutically acceptable salt thereof.
  • the acetaldehyde dehydrogenase inhibitor is disulfiram or a pharmaceutically acceptable salt thereof.
  • the pro-apoptotic drug is elesclomol or a pharmaceutically acceptable salt thereof.
  • the melanoma-associated antigen 3 (MAGE- A3) targeting agent comprises GSK2132231A, imatinib, talimogene laherparepvec, or a pharmaceutically acceptable salt thereof.
  • the one or more additional therapeutic agent comprises melanoma vaccine, Allovectin-7 ® , autologous dendritic cell vaccine, autologous dendritic cell- allogeneic melanoma tumor cell lysate vaccine, autologous dendritic cells loaded with autologous tumor RNA, autologous dendritic cell-tumor cell immunotherapy (DC-TC), autologous dendritic cell-tumor fusion vaccine,autologous tumor cell vaccine, autologous DNP-modified vaccine (M-Vax), autologous lethally irradiated melanoma cells, BCD-100, BCG vaccine, BMS-936559 (Anti-PD-L1), CADI-05, CancerVax vaccine (CANVAXIN), CB- 10-01 (transgenic lymphocyte immunization), corynebacterium granulosum P40 extract, CSF470 vaccine, BCG, Molgramostim, CYT004-Mel
  • ISCOMATRIX ® vaccine oblimersen sodium, ofatumumab, OVA BiP peptide, PBMC re- infusion, PEG IFN alfa-2b, peptide vaccine, peptide-pulsed dendritic cells, pIL-12, POL-103A, recombinant CD40-ligand, recombinant human Hsp110-gp100 chaperone complex vaccine, recombinant interferon alfa, recombinant interferon alfa-2b, recombinant interferon alpha-1b, recombinant interferon beta, sargramostim, TBI-1401(HF10), therapeutic autologous lymphocytes, TriMix-DC, TriMix-DC and ipilimumab, TRX518, tyrosinase peptide, vaccine consisting of a peptide derived from the protein IDO, ziv-aflibercept, MelaFind(R), 4SC-202 in
  • tremelimumab vitamin D, vitamin D3 (colecalciferol), XL888, YM155, IGIMRT, ionizing radiation (IR) therapy, proton radiation therapy, radiotherapy, WBRT, whole brain radiation, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • the one or more additional therapeutic agent comprises a tyrosine kinase inhibitor (e.g., an Abl inhibitor or an AblT351I inhibitor), an AhR agonist, a Pi3K/Akt pathway inhibitor (e.g., an Akt inhibitor), an alkylating agent, an AMPK agonist, and AMPK antagonist, an androgen receptor, an antimetabolite, an ARFGAP inhibitor, an arsenic derivative, an indoleamine 2,3-dioxygenase inhibitor, a receptor tyrosine kinase inhibitor (e.g., an ALK inhibitor), a serine/threonine kinase inhibitor (e.g., an ATM inhibitor, an aurora kinase inhibitor (e.g., an aurora kinase A inhibitor, an aurora kinase B inhibitor, or an aurora kinase C inhibitor), or a Plk inhibitor), a BCR inhibitor, a BCR inhibitor, a BCR inhibitor,
  • the one or more additional therapeutic agent comprises ara-C, all trans retinoic acid (ATRA), bexarotene, bortezomib, cisplatin, tofacitinib, crizotinib, cytarabine, dasatanib, daunorubicin, decitabine, docetaxel, erlotinib, etoposide, enasidenib, everolimus, fingolimod, fludarabine, gemcitabine, gilteritinib, ivosidenib, ruxolitinib, lapatinib, lenalidomide, nilotinib, nilutamide, pazopanib, pioglitazone, PLX-4720, sorafenib, stibogluconate, sunitinib, temozolomide, vincristine, venetoclax, vismodegib, vorinostat
  • ATRA all trans reti
  • the RAR agonist is 9CDHRA, alitretinoin, AC-261066, AC- 55649, acitretin, adapalene, arotinoid acid, tretinoin, AM-580, BMS-493, BMS-753, BMS- 961, CD-1530, CD-2314, CD-437, Ch-55, EC 23, etretinate, fenretinide, isotretinoin, palovarotene, retinoic acid, retinol, tamibarotene, tazarotene, tazarotenic acid, a pharmarcutically acceptable salt thereof, or any combination thereof.
  • the cancer is a hematological cancer.
  • the hematological cancer is acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL).
  • the hematological cancer is acute myeloid leukemia (AML).
  • the one or more additional therapeutic agent comprises an antimetabolite, a topoisomerase inhibitor (e.g., a topoisomerase II inhibitor, a topoisomerase I inhibitor), a methyl transferase inhibitor (e.g., a DNA methylation inhibitor), a DNA hypomethylating agent, an histone deacetylase (HDAC) inhibitor, a histone methyltransferase inhibitor (e.g., an EZH2 inhibitor, a DOT1L inhibitor), a cellular differentiation agent, a tyrosine kinase inhibitor (e.g., an FLT3 inhibitor), an inhibitor of anti-apoptotic proteins (e.g., a BCL2 inhibitor), an inhibitor of an adaptive immune response protein (e.g., a CTLA-4 inhibitor), a cell surface receptor inhibitor (e.g., an anti-CD33 ADC), a sulfatase inhibitor (e.g., a IDH1 inhibitor or an antimetabolite, a top
  • a receptor tyrosine kinase pathway inhibitor e.g., a c-Kit inhibitor
  • a cyclin dependent kinase inhibitor e.g., a CDK4/6 inhibitor
  • a RAS pathway inhibitor e.g., an ERK inhibitor, a MEK1/2 inhibitor, or a BRAF V600E or V600K inhibitor
  • an PI3K/Akt pathway inhibitor e.g., an Akt inhibitor
  • a heat shock protein inhibitor e.g., an Hsp90 inhibitor
  • a farnesyl transferase inhibitor e.g., a Jak2 inhibitor
  • the one or more additional therapeutic agent comprises a humanized monoclonal anti-CD52 antibody, an IL-15 superagonist, a VGEF inhibitor, an anti- CD33 antibody, an allogeneic myeloid progenitor cell, a humanized antibody inhibitor of complement, an inhibitor of TNF alpha, an antibody that targets the extracellular domain of Fms-like tyrosine kinase (FLT3, CD135 or FLK2), an anti RSV antibody, an anti-CD20 antibody, an anti-CD200 antibody, an injectable bivalent DNA vaccine, a WT1/PRAME vaccination, an antimetabolite, an FLT3 inhibitor, an anthracycline, a XIAP antisense oligonucleotide, a VGFR inhibitor, a cKIT inhibitor, a PDGFR inhibitor, a TK inhibitor, an IL- 2 receptor agonist, an IL-15 agonist, a CDK9 inhibitor, a folate analog, a blocker
  • an anticholinergic an anti-CD38 antibody, a glucocorticoid receptor agonist, an anti-mitotic, a SYK inhibitor, an mTOR inhibitor, a G-CSF, a calcineurim inhibitor, an AKT inhibitor, a BTK inhibitor, a JAK/STAT inhibitor, an IDO inhibitor, a pan PIM inhibitor, an IDO inhibitor , a RARalpha specific agonist, an anti CD123 antibody, an anti-KIR antibody, an antiCD56 antibody-drug conjugate, a GSK-3 inhibitor, an aurora kinase inhibitor, a BCR-ABL tyrosine kinase inhibitor, a VEGFR/FGFR/PDGFR inhibitor, a BCL2 inhibitor, a bromodomain inhibitor, a CDK4/6 inhibitor, a multitarget receptor tyrosine kinase inhibitor, a PLK-1 inhibitor, an IMiD, a CBP/Beta-catenin
  • the second therapeutic agent comprises alemtuzumab, ALT- 803, bevacizumab, BI 836858, BPX-501 and AP1903, Campath-1H, CLT-008,
  • daclizumab daclizumab, eculizumab, etanercept, filgrastim, FLYSYN, Nivolumab, palivizumab, rituximab, Samalizumab, VCL-CB01, WT1/PRAME vaccination, 8-chloro-adenosine, AC220, aclacinomycin, AEG35156, AG-013736 (Axitinib), AKN-028, Aldesleukin, ALT- 803, Alvocidib, aminopterin, Amonafide + cytarabine, amsacrine, APR-246, ARGX-110 with AZA, ARRY-520, Arsenic Trioxide, AS101, ASP2215, Astarabine (BST-236), Atorvastatin, Avelumab, Axitinib, belinostat, bexarotene, BGB324, BKM120, BL-8040, Bortez
  • the cancer is myelodysplastic syndromes (MDS),
  • the one or more additional therapeutic agent comprises an immunomodulatory drug (IMiD), a methyl trasferase inhibitor (e.g., a DNA methylation inhibitor (e.g., a DNA hypomethylating agent)), an antimetabolite, a topoisomerase II inhibitor, or any combination thereof.
  • IMD immunomodulatory drug
  • a methyl trasferase inhibitor e.g., a DNA methylation inhibitor (e.g., a DNA hypomethylating agent)
  • an antimetabolite e.g., a topoisomerase II inhibitor, or any combination thereof.
  • the one or more additional therapeutic agent comprises lenalidomide, azacitidine, decitabine, guadecitabine, ara-C, daunorubicin, idarubicin, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • administering inhibits dimethylation of histone 3 at lysine residue 9 (i.e., H3K9me2).
  • the one or more additional therapeutic agent comprises an anticancer agents or a chemotherapeutic agent. In some embodiments, the one or more additional therapeutic agent comprises a glucocorticoid. In some embodiments, the one or more additional therapeutic agent comprises prednisone, prednisolone, cyclophosphamide, vincristine, doxorubicin, mafosfamide, cisplatin, AraC, everolimus, decitabine,
  • the one or more additional therapeutic agent comprises prednisone or its active metabolite (e.g., prednisolone).
  • the one or more additional therapeutic agent comprises a chemotherapeutic agent (also referred to as an anti-neoplastic agent or anti-proliferative agent), selected from the group including an alkylating agent; an antibiotic; an anti-metabolite; a detoxifying agent; an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; an MTOR inhibitor; a multi-kinase inhibitor; a serine/threonine kinase inhibitor; a tyrosine kinase inhibitors; a VEGF/VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, an inhibitor of a molecular target or enzyme (e.g., a kinase
  • the one or more additional therapeutic agent comprises an agent selected from CHOP (e.g., cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone or prednisolone) and R-CHOP (e.g., rituximab, cyclophosphamide,
  • CHOP e.g., cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone or prednisolone
  • R-CHOP e.g., rituximab, cyclophosphamide
  • the one or more additional therapeutic agent comprises prednisone or prednisolone.
  • the one or more additional therapeutic agent comprises an alkylating agent; an antibiotic; an anti-metabolite; a detoxifying agent; an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; an MTOR inhibitor; a multi-kinase inhibitor; a serine/threonine kinase inhibitor; a tyrosine kinase inhibitors; a VEGF/VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, an inhibitor of a molecular target or enzyme (e.g., a kinase or a protein methyltransferase), a cytidine analogue drug or any chemotherapeutic, anti-neo
  • Exemplary alkylating agents include, but are not limited to, cyclophosphamide
  • antibiotics include, but are not limited to, doxorubicin (Adriamycin);
  • doxorubicin liposomal Doxil
  • mitoxantrone Novantrone
  • bleomycin Blenoxane
  • daunorubicin (Cerubidine); daunorubicin liposomal (DaunoXome); dactinomycin (Cosmegen); epirubicin (Ellence); idarubicin (Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin (Nipent); or valrubicin (Valstar).
  • Exemplary anti-metabolites include, but are not limited to, fluorouracil (Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine (Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine (Arranon); cladribine (Cladribine Novaplus);
  • clofarabine (Clolar); cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposomal (DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); floxuridine (FUDR); gemcitabine (Gemzar); cladribine (Leustatin); fludarabine (Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall); thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS).
  • Exemplary detoxifying agents include, but are not limited to, amifostine (Ethyol) or mesna (Mesnex).
  • interferons include, but are not limited to, interferon alfa-2b (Intron A) or interferon alfa-2a (Roferon-A).
  • Exemplary polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab (Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab (Vectibix); tositumomab/iodine131 tositumomab (Bexxar); alemtuzumab (Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); gemtuzumab
  • Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva); panitumumab (Vectibix); PKI-166;
  • canertinib (CI-1033); matuzumab (Emd7200) or EKB-569.
  • Exemplary HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin); lapatinib (Tykerb) or AC-480.
  • Histone Deacetylase Inhibitors include, but are not limited to, vorinostat (Zolinza).
  • Exemplary hormones include, but are not limited to, tamoxifen (Soltamox; Nolvadex); raloxifene (Evista); megestrol (Megace); leuprolide (Lupron; Lupron Depot; Eligard; Viadur) ; fulvestrant (Faslodex); letrozole (Femara); triptorelin (Trelstar LA; Trelstar Depot) ;
  • exemestane (Aromasin) ; goserelin (Zoladex) ; bicalutamide (Casodex); anastrozole
  • mitotic inhibitors include, but are not limited to, paclitaxel (Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin; Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos; VePesid); teniposide (Vumon); ixabepilone (Ixempra);
  • nocodazole nocodazole
  • epothilone vinorelbine
  • Vinorelbine camptothecin
  • CPT camptothecin
  • irinotecan Camptosar
  • topotecan Hycamtin
  • amsacrine or lamellarin D LAM-D
  • Exemplary MTOR inhibitors include, but are not limited to, everolimus (Afinitor) or temsirolimus (Torisel); rapamune, ridaforolimus; or AP23573.
  • Exemplary multi-kinase inhibitors include, but are not limited to, sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474; PKC-412; motesanib; or AP24534.
  • Exemplary serine/threonine kinase inhibitors include, but are not limited to, ruboxistaurin; eril/easudil hydrochloride; flavopiridol; seliciclib (CYC202; Roscovitrine); SNS-032 (BMS-387032); Pkc412; bryostatin; KAI-9803;SF1126; VX-680; Azd1152; Arry- 142886 (AZD-6244); SCIO-469; GW681323; CC-401; CEP-1347 or PD 332991.
  • Exemplary tyrosine kinase inhibitors include, but are not limited to, erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath);
  • gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584); CEP-701; SU5614; MLN518; XL999; VX- 322; Azd0530; BMS-354825; SKI-606 CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.
  • VEGF/VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent); ranibizumab; pegaptanib; or vandetinib.
  • microtubule targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilones and navelbine.
  • topoisomerase poison drugs include, but are not limited to, teniposide, etoposide, adriamycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, epirubicin and idarubicin.
  • Exemplary taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxol.
  • Exemplary general chemotherapeutic, anti-neoplastic, anti-proliferative agents include, but are not limited to, altretamine (Hexalen); isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin (Vesanoid); azacitidine (Vidaza); bortezomib (Velcade) asparaginase (Elspar); levamisole (Ergamisol); mitotane (Lysodren); procarbazine (Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak); porfimer (Photofrin); aldesleukin (Proleukin);
  • lenalidomide lenalidomide
  • bexarotene Targretin
  • thalidomide Thalomid
  • temsirolimus Torisel
  • arsenic trioxide Trisenox
  • verteporfin Visudyne
  • mimosine Leucenol
  • the one or more additional therapeutic agent comprises a cytokine, e.g., G-CSF (granulocyte colony stimulating factor).
  • a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, is administered in combination with radiation therapy. Radiation therapy can also be administered in combination with a compound of the present disclosure and one or more additional therapeutic agent described herein as part of a multiple agent therapy.
  • a compound of the present disclosure is administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP), Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at a molar ratio of 1:0.4:1), Camptothecin-11 (CPT-11, Iri
  • CMF cyclophosphamide, methotrexate and 5-fluorouracil
  • the one or more additional therapeutic agent comprises an HDAC inhibitor.
  • the one or more additional therapeutic agent comprises chemotherapetics (such as 2CdA, 5-FU, 6-Mercaptopurine, 6-TG, AbraxaneTM, Accutane®, Actinomycin-D, Adriamycin®, Alimta®, all-trans retinoic acid, amethopterin, Ara-C, Azacitadine, BCNU, Blenoxane®, Camptosar®, CeeNU®, Clofarabine, ClolarTM, Cytoxan®, daunorubicin hydrochloride, DaunoXome®, Dacogen®, DIC, Doxil®, Ellence®, Eloxatin®, Emcyt®, etoposide phosphate, Fludara®, FUDR®, Gemzar®, Gleevec®, hexamethylmelamine, Hycamtin®, Hydrea®, Idamycin®,
  • chemotherapetics such as 2
  • Zanosar® biologics (such as Alpha Interferon, Bacillus Calmette-Guerin, Bexxar®,
  • Campath® Ergamisol®, Erlotinib, Herceptin®, Interleukin-2, Iressa®, lenalidomide, Mylotarg®, Ontak®, Pegasys®, Revlimid®, Rituxan®, TarcevaTM, Thalomid®, Velcade® and ZevalinTM); small molecules (such as Tykerb®); corticosteroids (such as dexamethasone sodium phosphate, DeltaSone® and Delta-Cortef®); hormonal therapies (such as Arimidex®, Aromasin®, Casodex®, Cytadren®, Eligard®, Eulexin®, Evista®, Faslodex®, Femara®, Halotestin®, Megace®, Nilandron®, Nolvadex®, PlenaxisTM and Zoladex®); or
  • radiopharmaceuticals such as Iodotope®, Metastron®, Phosphocol® and Samarium SM-153.
  • Representative compounds of the present disclosure include compounds listed in Tables 1-6, 6A, and 7, and tautomers and salts thereof.

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