Combination therapies with ehmt2 inhibitors

Abstract

The present disclosure relates to a method of preventing or treating a cancer via administering an EHMT2 inhibitor or a combination comprising an EHMT2 inhibitor compound and one or more additional therapeutic agent disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds or combinations for research or other non-therapeutic purposes.

1 . A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an EHMT2 inhibitor and one or more additional therapeutic agent. 
     
     
         2 . The method of  claim 1 , wherein 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, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, epithelioid sarcoma, renal medullary carcinoma, diffuse large B-cell lymphoma, follicular lymphoma, or not otherwise specified (NOS) sarcoma. 
     
     
         3 .- 6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the EHMT2 inhibitor and the one or more additional therapeutic agent are administered simultaneously, sequentially, or in alteration. 
     
     
         8 .- 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein 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. 
     
     
         14 . The method of  claim 1 , wherein 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. 
     
     
         15 .- 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the one or more additional therapeutic agent comprises an alkylating agent, a platinum agent, a vinca alkaloid, a taxane (paclitaxel, docetaxel or cabazitaxel), a RAS pathway inhibitor (an ERK inhibitor, a MEK1/2 inhibitor, or a BRAF V600E or V600K inhibitor), a Pi3K/Akt pathway inhibitor (a Pi3K inhibitor, an Akt inhibitor, or an mTOR inhibitor), an immune-oncology drug (a CTLA-4 inhibitor or a checkpoint inhibitor), a cell cycle checkpoint inhibitor, a cytokine (an interferon-α2b (IFN-α2b), an interferon-α2b recombinant (IFN-α2b recombinant), or an IL-2 analog), a tryptophan synthesis inhibitor (an IDO-1 inhibitor), a therapeutic vaccine, an adoptive cell therapy (T-cell-based therapy or CAR-T therapy), an epigenetic drug (an HDAC inhibitor, methyltransferase inhibitor, an EZH2 inhibitor, or a DOT1L inhibitor), a methyl transferase inhibitor (a DNA methylation inhibitor), a DNA hypomethylating agent, a P-glycoprotein inhibitor, a receptor tyrosine kinase pathway inhibitor (a c-Kit inhibitor), a serine/threonine kinase inhibitor (an aurora kinase inhibitor), a cyclin dependent kinase inhibitor (CDK4/6 inhibitor), a growth factor inhibitor (a VGEF inhibitor), an immune response protein inhibitor (a PD-L1 inhibitor), an engineered protein combining Interleukin-2 and diphtheria toxin, a tumor necrosis factor receptor signaling modulator (an antibody DR5 agonist), a cyclin dependent kinase inhibitor (a CDK1/5 inhibitor), an acetaldehyde dehydrogenase inhibitor, a pro-apoptotic drug, a melanoma-associated antigen 3 (MAGE-A3) targeting agent, a retinoic acid receptor (RAR) modulator (an RAR agonist (an RARα agonist, an RARβ agonist, or an RARγ agonist)), or any combination thereof. 
     
     
         19 .- 53 . (canceled) 
     
     
         54 . The method of  claim 1 , wherein 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-MelQbG10, combination of CYT004-MelQbG10 and montanide, D1/3-MAGE-3-His fusion protein, DC/Apo-Nec vaccine, dendritic cell application, dendritic cell therapy, Detox-B adjuvant, DS-8273a, GM2-KLH vaccine, GM-CSF DNA, NSC 683472, gp100 antigen, gp75 DNA vaccine, GRN-1201, HLA-A1-binding MAGE-1/MAGE-3 multipeptide-pulsed autologous dendritic cell vaccine, human gp100 plasmid DNA vaccine, human tyrosinase, IL15-DC vaccine, mouse TYRP2 DNA, veledimex (INXN-2001; N′-(3,5-dimethylbenzoyl)-N′-[(3R)-2,2-dimethylhexan-3-yl]-2-ethyl-3-methoxybenzohydrazide), KLH conjugates with GD2L and GD3L, liposomal interleukin-2, MART-1 antigen, MART-1, anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody, MDX-010, MDX-CTLA4 antibody, tyrosinase/gp100/MART-1 peptides melanoma vaccine, melanoma vaccine modified to express HLA A2/4-1BB ligand, MKC1106-MT, monoclonal antibody 4B5 anti-idiotype vaccine, combination of montanide and melan-A analogue peptide, mouse gp100 plasmid DNA vaccine, nDC vaccination, NY-ESO-1 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®, 4SC-202 in combination with pembrolizumab, ABI-007, acetaminophen, ACY-241, adjuvant chemotherapy by fotemustin, flibercept, anti-CD137 (4-1BB) (BMS-663513), anti-CTLA4 monoclonal antibody and HDI, APO866, atezolizumab, atorvastatin, combination of bevacizumab and ipilimumab cohort 1, combination of BKM120 and vemurafenib (PLX4032), BMS-936558 (MDX1106-04), boronophenylalanine-fructose complex, combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib, buthionine sulfoximine, CC 5013, cilengitide, combination of varlilumab and ipilimumab, CP 870,893, CPG 7909 injection, CR011-vcMMAE, cyclophosphamide, combination of dacarbazine and genasense, dasatinib, dendritic cell-gp100-MART-1 antigen vaccine, denosumab, depsipeptide, disulfiram (DSF), combination of E7050 and lenvatinib, elesclomol (STA-4783), fentanyl sublingual spray, gamma-secretase, notch signalling pathway inhibitor RO4929097, Genasense® (G3139, oblimersen sodium), granulocyte-macrophage colony-stimulating factor (GM-CSF), GSK 2132231A, GSK1120212, GSK2118436, HSPPC-96, oncophage, hu14.18-IL2, hydroxychloroquine, imexon, imiquimod, IMP321, INC280, indocyanine green, indoximod, INO-1001, L19IL2, combination of ipilimumab and interleukin-2, INXN-1001, irinotecan, isolated limb perfusion, combination of L19IL2 and L19TNF, lenvatinib, LGX818, lomustine, masitinib, MDX-010 (anti-CTLA4) monoclonal antibody, MEK162, methylphenidate, nilotinib, combination of nivolumab and ipilimumab, OBP-301, omaveloxolone, combination of pazopanib and paclitaxel, peginterferon alfa-2b, pegIntron, pegylated interferon alfa-2a, pegylated interferon-alfa 2b (PEG Intron), combination of pembrolizumab and epacadostat, combination of pembrolizumab and high dose interferon alfa-2b (HDI), combination of pembrolizumab and all-trans retinoic acid, PF-06688992, placebo, PLX3397, propranolol, PV-10 (10% rose bengal disodium), combination of ranibizumab and TTT (ICG based), ranibizumab, recombinant interleukin-21, resiquimod, riluzole, rituxan, RO5185426, RTA 402, saracatinib, combination of sorafenib (Nexavar) and dacarbazine, sorafenib (Nexavar; BAY43-9006), sorafenib tosylate, STA-9090, sunitinib malate, SX-682, tanespimycin, tasisulam, combination of TIL and IL2, combination of timolol and LCP, TLPLDC, TMZ, 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. 
     
     
         55 . The method of  claim 1 , wherein the one or more additional therapeutic agent comprises a tyrosine kinase inhibitor (an Abl inhibitor or an AblT351I inhibitor), an AhR agonist, a Pi3K/Akt pathway inhibitor (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 (an ALK inhibitor), a serine/threonine kinase inhibitor (an ATM inhibitor, an aurora kinase inhibitor (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-Abl inhibitor, an inhibitor of negative regulator of apoptosis (a BIRC5 inhibitor), a BMP signaling antagonist, a Wnt signaling inhibitor (a beta-catenin inhibitor), an inhibitor of a protein involved in apoptosis (a BCL2 inhibitor or a Bcl-x inhibitor), a non-receptor tyrosine kinase inhibitor (a BTK inhibitor), a cyclin dependent kinase inhibitor (a CDK inhibitor, a CDK2 inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, or a CDK9 inhibitor), a Chk inhibitor (a CHk1 inhibitor, or a Chk2 inhibitor), a receptor tyrosine kinase pathway inhibitor (a c-Kit inhibitor), a casein kinase inhibitor (a CK2a inhibitor), a CSF1R inhibitor (a c-fms inhibitor), an EAR inhibitor, a receptor tyrosine kinase inhibitor (a HER inhibitor (a HER2 inhibitor), an ErbB inhibitor (an ErbB-2 inhibitor, an ErbB-3 inhibitor, or an ErbB-4 inhibitor), an FAK inhibitor (an FAK1 inhibitor or an FAK2 inhibitor), a fatty acid synthase, an FGF signaling inhibitor (an FGFR1 inhibitor or an FGFR3 inhibitor), an FTI inhibitor, a growth factor signaling inhibitor (an FGF inhibitor, a VEGF inhibitor or an FLT inhibitor (an FLT1 inhibitor, an FLT2 inhibitor, an FLT3 inhibitor or an FLT4 inhibitor)), a protein-tyrosine kinase inhibitor (a Fyn inhibitor), a gamma secretase, a serine-threonine kinase inhibitor (a GSK-3 inhibitor), an HDAC inhibitor, an Hh pathway inhibitor, an HIFa inhibitor, an HSP inducer (an HSP70 inducer), an HSP inhibitor (an HSP90 inhibitor), a receptor tyrosine kinase inhibitor (an IGF-1R inhibitor), an IKK inhibitor, an InR inhibitor, a JAK/STAT signaling inhibitor (a JAK1 inhibitor, a JAK2 inhibitor, or a JAK3 inhibitor), a JNK signaling inhibitor (a JNK inhibitor), a KSP inhibitor, a LXR inhibitor, a tyrosine protein kinase inhibitor (a Lyn inhibitor), a lipase inhibitor (a MAGL inhibitor), a ubiquitin ligase inhibitor (an MDM2 inhibitor), a MAP Kinase signaling inhibitor (a MEK inhibitor), a receptor tyrosine kinase inhibitor (a MET inhibitor), a methyl transferase inhibitor (a DNA hypomethylating agent), a microtubule agent (a taxane or a vinca alkaloid), an mTOR kinase inhibitor, an NAMPRT inhibitor, a PAK inhibitor, a PARP inhibitor, a pyruvate dehydrogenase kinase inhibitor (a PDK1 inhibitor), a PDGF signaling inhibitor (a PDGFb inhibitor or a PDGFR inhibitor), a Pi3K inhibitor, a MAP kinase inhibitor (a p38 inhibitor), a tumor suppressor protein inhibitor (a p53 inhibitor), a serine/threonine kinase inhibitor (a PIM inhibitor), a PKC-beta inhibitor, a PLC inhibitor, a serine/threonine kinase inhibitor (a PLK1 inhibitor), a peroxisome proliferator-activated receptor agonist (a PPARd agonist or a PPARg agonist), a peroxisome proliferator-activated receptor antagonist (a PPARG antagonist), a PPARg antagonist, a proteasome inhibitor, protein tyrosine phosphatase inhibitor (a PTP-1B inhibitor), a Raf inhibitor (a BRAF V600E or V600K inhibitor, or a c-Raf inhibitor), a proto-oncogene inhibitor (a RET inhibitor), a ROCK inhibitor, an RSK inhibitor (an RSK1 inhibitor, an RSK2 inhibitor, an RSK3 inhibitor, an RSK5 inhibitor), a nuclear receptor inhibitor (an RXR inhibitor), a SGK inhibitor, an inisotal phosphatase inhibitor (a SHIP inhibitor (a SHIP1 inhibitor or a SHIP2 inhibitor), a SIRT1 inhibitor, a S1PR inhibitor, a Src inhibitor, a survivin inhibitor, a tyrosine kinase inhibitor (a Syk inhibitor), a tankyrase inhibitor (a tankyrase 1 inhibitor or a tankyrase 2 inhibitor), a receptor tyrosine kinase inhibitor (a TIE-2 inhibitor), a TORC inhibitor (a TORC1 inhibitor or a TORC2 inhibitor), a tumor necfrosis factor inhibitor (a TNFa inhibitor), a topoisomerase inhibitor, a receptor tyrosine kinase inhibitor (a TrkA inhibitor), a tyrosine kinase inhibitor (aTyk2 inhibitor), a VEGF signaling inhibitor (a VEGFR-1 inhibitor, a VEGFR-2 inhibitor, a VEGFR-3 inhibitor, or a VEGFR-4 inhibitor), a checkpoint kinase inhibitor (a Wee-1 inhibitor), proto-oncogene inhibitor (a Yes inhibitor), an inhibitor of a protein involved in apoptosis (a XIAP inhibitor), a retinoic acid receptor (RAR) modulator (an RAR agonist (an RARα agonist, an RARβ agonist, or an RARγ agonist)), or any combination thereof. 
     
     
         56 . The method of  claim 1 , wherein 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, AZD7762, CHIR265, IMD-0354, Nutlin-3, OSU-03012, PF-04217903, PF-562271, SNS-032, SNS-314, ABT263, bivanib, silmitasertib, darinaparsin, ENMD-2076, EX527, daporinad, indole-3-carbinol, lestaurtinib, MK-1775, MK-2206, Dactolisib, RKI983, selumetinib, tideglusib, tozasertib, veliparib, VX-702, XL147, YM155, cediranib, dovitinib, enzastaurin, midostaurin, linsitinib, palbociclib, perifosine ((1,1-dimethylpiperidin-1-ium-4-yl) octadecyl phosphate), elesclomol, tamatinib, tanespimycin, tipifarnib, vatalanib, A769662, AS252424, BI-78D3, BI-D1870, BMS-536924, C 75 , dorsomorphin, embelin, FH535, GSK0660, GSK650394, GW0742, GW2580, GW441756, GW9662, HIF-1i, IPA-3, TCS JNK5a, JZL184, KU0063794, KU-55933, L779450, LFM-A13, LSN415169, NVP-TAE684, PD173074, PIM-1 4a, QS11, Src-I1, SU6656, T 0901317 , TCS 401, Tie2i, U73122, vasastrol, Wnti, XAV939, ZM336372, a pharmaceutically acceptable salt thereof, or any combination thereof. 
     
     
         57 .- 58 . (canceled) 
     
     
         59 . The method of  claim 1 , wherein 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 IDH2 inhibitor), an alkylating agent, a serine/threonine protein kinase inhibitor (e.g., a PLK-1 inhibitor, an aurora inhibitor), a non-receptor tyrosine kinase inhibitor (e.g., a BTK inhibitor), an immunoglobulin like receptor inhibitor (e.g., an anti-KIR antibody), a Hedgehog pathway inhibitor, a P-glycoprotein inhibitor, an inhibitor of an immunomodulator, 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), an aminopeptidase inhibitor, a Jak/Stat pathway inhibitor (e.g., a Jak2 inhibitor), a farnesyl transferase inhibitor, or any combination thereof. 
     
     
         60 .- 61 . (canceled) 
     
     
         62 . The method of  claim 1 , wherein the one or more additional therapeutic agent comprises an immunomodulatory drug (IMiD), a methyl transferase inhibitor (a DNA methylation inhibitor (a DNA hypomethylating agent)), an antimetabolite, a topoisomerase II inhibitor, or any combination thereof. 
     
     
         63 . (canceled) 
     
     
         64 . 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. 
     
     
         65 . The method of  claim 64 , wherein 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%. 
     
     
         66 .- 67 . (canceled) 
     
     
         68 . The method of  claim 1 , wherein the EHMT2 inhibitor is a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein
 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 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, 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 C 1 -C 6  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 C 1 -C 4  alkyl; 
 each of R 2 , R 3 , and R 4 , independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkoxyl, C 6 -C 10  aryl, NR a R b , C(O)NR a R b , NR a C(O)R b , C 3 -C 8  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 -C 6  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 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, oxo, or C 1 -C 6  alkoxyl, and T 1  is H, halo, cyano, NR 8 R 9 , C(O)NR 8 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, C 1 -C 6  alkyl, hydroxyl, oxo, —C(O)R 9 , —SO 2 R 8 , —SO 2 N(R 8 ) 2 , —NR 8  C(O)R 9 , amino, mono- or di-alkylamino, or C 1 -C 6  alkoxyl; or when ring A is a 5-membered heteroaryl containing at least one N atom, R 4  is a spiro-fused 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S; 
 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, C 1 -C 6  alkoxyl, C 6 -C 10  aryl, NR a R b , C(O)NR a R b , NR a C(O)R b , C 3 -C 8  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 C 2 -C 6  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 C 1 -C 3  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 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, oxo, or C 1 -C 6  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, C 1 -C 6  alkyl, hydroxyl, oxo, —C(O)R 9 , —SO 2 R 8 , —SO 2 N(R 8 ) 2 , —NR 8  C(O)R 9 , NR 8 R 9 , or C 1 -C 6  alkoxyl; and R 6  is not NR 8 C(O)NR 12 R 13 ; or 
 R 6  and one of R 2  or R 3  together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R 6  and one of R 2 ′ or R 3 ′ 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, oxo (═O), C 1 -C 3  alkoxyl, or -Q 1 -T 1 ; 
 each R 7  is independently oxo (═O) or -Q 2 -T 2 , in which each Q 2  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 C 1 -C 6  alkoxyl, and each T 2  independently is H, halo, cyano, OR 10 , OR 11 , C(O)R 11 , NR 10 R 11 , C(O)NR 10 R 11 , NR 10 C(O)R 11 , 5- to 10-membered heteroaryl, C 3 -C 8  cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the 5- to 10-membered heteroaryl, C 3 -C 8  cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C 1 -C 6  alkyl optionally substituted with NR x R y , hydroxyl, oxo, N(R 8 ) 2 , cyano, C 1 -C 6  haloalkyl, —SO 2 R 8 , or C 1 -C 6  alkoxyl, each of R x  and R y  independently being H or C 1 -C 6  alkyl; and R 7  is not H or C(O)OR g ; 
 each R 8  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 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 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 , C(O)NR 12 R 13 , C(O)R 13 , S(O) 2 R 13 , S(O) 2 NR 12 R 13 , or R S2 , in which R S2  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 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 C 1 -C 6  alkoxy, and each T 4  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 c , C(O)R c , S(O) 2 R c , NR c R d , C(O)NR c R d , and NR c C(O)R d , each of R c  and R d  independently being H or C 1 -C 6  alkyl; or -Q 4 -T 4  is oxo; or 
 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 C 1 -C 6  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 , S(O) 2 R e , S(O) 2 NR e R f , NR e R f , C(O)NR e R f , and NR e C(O)R f , each of R e  and R f  independently being H or C 1 -C 6  alkyl; or -Q 5 -T 5  is oxo; 
 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 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, oxo, or C 1 -C 6  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) 2 R 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 C 3 -C 8  cycloalkyl, or R g  and R h  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, and R S3  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 S3  is optionally substituted with one or more -Q 7 -T 7 , wherein each Q 7  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 C 1 -C 6  alkoxy, and each T 7  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 j , C(O)R j , NR j R k , C(O)NR j R k , S(O) 2 R j , and NR j C(O)R k , each of R j  and R k  independently being H or C 1 -C 6  alkyl optionally substituted with one or more halo; or -Q 7 -T 7  is oxo; or 
 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 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 C 1 -C 6  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, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q 8 -T 8  is oxo; and 
 n is 0, 1, 2, 3, or 4, provided that 
 the compound of Formula (I) 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)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine. 
 
     
     
         69 .- 74 . (canceled) 
     
     
         75 . The method of  claim 68 , wherein the EHMT2 inhibitor is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 ring B is phenyl or pyridyl, 
 
       one or both of 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 ; and
 n is 1, 2, or 3. 
 
     
     
         76 .- 115 . (canceled) 
     
     
         116 . The method of  claim 75 , wherein the EHMT2 inhibitor is a compound of Formula (VIIIa): 
       
         
           
           
               
               
           
         
       
       wherein
 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; and 
 R 5  are independently 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 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, C 1 -C 3  alkyl, hydroxyl or C 1 -C 3  alkoxyl; and 
 wherein at least one of R 2  or R 5  are not H. 
 
     
     
         117 .- 132 . (canceled) 
     
     
         133 . The method of  claim 1 , wherein the EHMT2 inhibitor is a compound of Formula (I″), (II″), or (III″): 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein
 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 C 6 -C 10  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 , C 3 -C 8  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 C 6 -C 10  aryl, C 3 -C 8  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 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 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, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, —C(O)R cb , —C(O)OR cb , —SO 2 R cb , —SO 2 N(R cb ) 2 , —NR cb C(O)R db , —C(O)NR cb R db , —NR cb C(O)OR db , —OC(O)NR cb R db , —NR cb R db , or C 1 -C 6  alkoxyl, in which each of R cb  and R db  independently is H or C 1 -C 6  alkyl; 
 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 C 1 -C 6  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 C 1 -C 6  alkoxy, and each T 3b  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  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 fb , C(O)R fb , C(O)OR fb , OC(O)R fb , S(O) 2 R fb , NR fb R gb , OC(O)NR fb R gb , NR fb C(O)OR gb , C(O)NR fb R gb , and NR fb C(O)R gb , each of R fb  and R gb  independently being H or C 1 -C 6  alkyl, in which the C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy; or -Q 3b -T 3b  is oxo; 
 R 8b  is H or C 1 -C 6  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 C 1 -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)OR hb , NR hb C(O)OR ib , OC(O)NR hb R ib , S(O) 2 R hb , S(O) 2 NR hb R ib , or R S2b , in which each of R hb  and R ib  independently is H or C 1 -C 6  alkyl, and 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, and R S2b  is optionally substituted with one or more -Q 5b -T 5b , wherein each Q 5b  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 5b  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  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 jb , C(O)R jb , C(O)OR jb , OC(O)R jb , S(O) 2 R jb , NR jb R kb , OC(O)NR jb R kb , NR jb C(O)OR kb , C(O)NR jb R kb , and NR jb C(O)R kb , each of R jb  and R kb  independently being H or C 1 -C 6  alkyl; or -Q 5b -T 5b  is oxo; 
 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, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 1 -C 6  alkoxy; and 
 R 11b  and R 12b  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, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C 1 -C 6  alkoxyl. 
 
     
     
         134 .- 187 . (canceled) 
     
     
         188 . The method of  claim 1 , wherein the EHMT2 inhibitor is a compound of Formula (I′″), (II′″), or (III′″): 
       
         
           
           
               
               
           
         
       
       a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein
 X 1c  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, C 1 -C 6  alkoxyl, C 6 -C 10  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, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl, wherein the C 6 -C 10  aryl, C 3 -C 8  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 ac , or NR ac R bc , in which each of R ac  and R bc  independently is H or C 1 -C 6  alkyl; 
 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 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, —C(O)R cc , —C(O)OR cc , —SO 2 R cc , —SO 2 N(R cc ) 2 , —NR cc C(O)R dc , —C(O)NR cc R dc , —NR cc C(O)OR dc , —OC(O)NR cc R dc , NR cc R dc , or C 1 -C 6  alkoxyl, in which each of R cc  and R dc  independently is H or C 1 -C 6  alkyl; 
 R 7c  is -Q 2c -T 2c , in which Q 2c  is a bond, 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, 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 , C 6 -C 10  aryl, 5- to 10-membered heteroaryl, C 3 -C 12  cycloalkyl, or 4- to 12-membered heterocycloalkyl, 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 -Q 3c -T 3c , wherein each Q 3c  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 3c  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  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 ec , OR fc , C(O)R fc , C(O)OR fc , OC(O)R fc , S(O) 2 R fc , NR fc R gc , OC(O)NR fc R gc , NR fc C(O)OR gc , C(O)NR fc R gc , and NR fc C(O)R gc ; or -Q 3c -T 3c  is oxo; 
 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 C 1 -C 6  alkoxyl; 
 each of R fc  and R gc  independently, is -Q 6c -T 6c , in which Q 6c  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 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 , OC(O)NR m1c R m2c , S(O) 2 R m1c , S(O) 2 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 S3c  is optionally substituted with one or more -Q 7c -T 7c , wherein each Q 7c  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 7c  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  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 n2c , NR n1c C(O)OR n2c , C(O)NR n1c R n2c , and NR n1c C(O)R n2c , each of R n1c  and R n2c  independently being H or C 1 -C 6  alkyl; or -Q 7c -T 7c  is oxo; 
 R 8c  is H or C 1 -C 6  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 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 , 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 C 1 -C 6  alkyl, and R S2c  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 S2c  is optionally substituted with one or more -Q 5c -T 5c , wherein each Q 5c  independently is a bond or C 1 -C 3  alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6  alkoxy, and each T 5  independently is selected from the group consisting of H, halo, cyano, C 1 -C 6  alkyl, C 2 -C 6  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, C(O)R jc , C(O)OR jc , OC(O)R jc , S(O) 2 R jc , NR jc R kc , OC(O)NR jc R kc , NR jc C(O)OR kc , C(O)NR jc R kc , and NR jc C(O)R kc , each of R jc  and R kc  independently being H or C 1 -C 6  alkyl; or -Q 5c -T 5c  is oxo; 
 R 10c  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 kc ; 
 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, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C 1 -C 6  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 , independently, is H, halo, cyano, C 1 -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, C 2 -C 6  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 . 
 
     
     
         189 .- 199 . (canceled) 
     
     
         200 . A kit comprising an EHMT2 inhibitor, one or more additional therapeutic agent, and instructions directing use of the EHMT2 inhibitor and the one or more additional therapeutic agent in treating cancer. 
     
     
         201 .- 206 . (canceled)