METHODS OF USING EHMT2 INHIBITORS IN IMMUNOTHERAPIES

Abstract

The present disclosure relates to methods and compositions for treating immune-mediated diseases. In some aspects, the disclosure relates to methods for treating immune-mediated diseases by administering an EHMT2 inhibitor in combination with one or more treatment modalities (e.g. one or more therapeutic agents). In some aspects the immune-mediated disease is rheumatoid arthritis, multiple sclerosis, psoriasis, a psoriatic disorder, psoriatic arthritis, or an inflammatory bowel disease.

Description

BACKGROUND

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., euchromatic 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).

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.

SUMMARY

In some aspects, the present disclosure provides a method of preventing or treating a disease or disorder associated with overexpression of EHMT2, comprising administering to a subject in need thereof a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor. In some embodiments, the method further comprises administering to the subject one or more additional treatment modalities in a therapeutically effective amount, wherein the one or more additional treatment modalities comprises one or more second therapeutic agents.

In some aspects, the present disclosure provides a method of preventing treating an immune-mediated disease, comprising administering to a subject in need thereof a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor. In some embodiments, the method further comprises administering to the subject one or more additional treatment modalities in a therapeutically effective amount, wherein the one or more additional treatment modalities comprises one or more second therapeutic agents.

In some aspects, the disclosure is based upon the discovery that EHMT2 inhibitors and other treatment modalities can be used in combination to treat certain diseases with superior results than those achieved by treating these diseases with EHMT2 inhibitors or the other treatment modalities alone. Accordingly, the disclosure provides methods comprising administering an EHMT2 inhibitor and one or more other treatment modalities to a subject in need thereof. The disclosure also provides compositions and combinations comprising an EHMT2 inhibitor and one or more second therapeutic agents, and methods for their use to treat diseases the course of which can be influenced by modulating the methylation status of non-histone proteins, e.g., certain diseases involving the immune system, which are also referred to as immune-mediated diseases.

Some aspects of this disclosure provide methods, strategies, treatment modalities, compositions, and combinations, for the treatment of a disease or disorder associated with overexpression of EHMT2. In some aspects, the present disclosure provides a method of treating a disease or disorder associated with overexpression of EHMT2, comprising administering to a subject in need thereof (a) a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor, and (b) one or more additional treatment modalities, e.g., with one or more additional therapeutic agent, in a therapeutically effective amount.

Some aspects of this disclosure provide methods, strategies, treatment modalities, compositions, and combinations, for the treatment of an immune-mediated disease or disorder. In some aspects, the present disclosure provides methods of treating an immune-mediated disease or disorder, comprising administering to a subject in need thereof (a) a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor, and (b) one or more additional treatment modalities in a therapeutically effective amount.

In certain embodiments, the first agent and/or the second agent may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be the same for the first and second agents or may be distinct between the first and second agents.

In some embodiments, the one or more second agents comprise two or more second therapeutic agents (e.g., two, three, four, or five, or more, different second therapeutic agents).

In further aspects, the present disclosure provides an EHMT2 inhibitor for use as medicament in the treatment of an immune-mediated disease or disorder in a subject in need thereof, wherein the subject is also administered one or more second agents in a therapeutically effective amount.

In further aspects, the present disclosure provides an EHMT2 inhibitor for use in the treatment of an immune-mediated disease or disorder in a subject in need thereof, wherein the subject is also administered one or more second agents in a therapeutically effective amount.

In further aspects, the present disclosure provides the use of an EHMT2 inhibitor in the manufacture of a medicament for the treatment of an immune-mediated disease or disorder in a subject in need thereof, wherein the subject is also administered one or more second agents in a therapeutically effective amount.

In further aspects, the present disclosure provides an EHMT2 inhibitor for use as a medicament for combinational therapy with one or more second agents in a therapeutically effective amount, for the treatment of an immune-mediated disease or disorder in a subject in need thereof.

In further aspects, the present disclosure provides the use of an EHMT2 inhibitor in the manufacture of a medicament for combinational therapy with one or more second agents in a therapeutically effective amount, for the treatment of an immune-mediated disease or disorder in a subject in need thereof.

In further aspects, the disclosure provides an EHMT2 inhibitor for use in a combinational therapy with one or more second agents in a therapeutically effective amount, for the treatment of an immune-mediated disease or disorder in a in a subject in need thereof.

In some aspects, the disclosure provides pharmaceutical compositions comprising an EHMT2 inhibitor of the disclosure, and one or more second agents.

In some embodiments, the EHMT2 inhibitor is an EHMT2 inhibitor provided herein. For example, and without limitation, in some embodiments, the EHMT2 inhibitor is a compound of Formula (I), (I′), (I′), (II″), (III″), (III″), (I′″), (II′″), or (III′″), or a pharmaceutically acceptable salt or a tautomer thereof, or a pharmaceutically acceptable salt the tautomer thereof. In some embodiments, the EHMT2 inhibitor is a compound is selected from those in Tables 1A-1E, 2-4, 4A, and 5, or a pharmaceutically acceptable salt or a tautomer thereof, or a pharmaceutically acceptable salt the tautomer thereof.

In some embodiments, the EHMT2 inhibitor is a compound having the following structure:

or a pharmaceutically acceptable salt or a tautomer thereof, or a pharmaceutically acceptable salt the tautomer thereof.

In some embodiments, the EHMT2 inhibitor is a compound having the following structure:

or a pharmaceutically acceptable salt or a tautomer thereof, or a pharmaceutically acceptable salt the tautomer thereof.

In some embodiments, the EHMT2 inhibitor is

or a pharmaceutically acceptable salt or a tautomer thereof, or a pharmaceutically acceptable salt the tautomer thereof.

In some embodiments, the one or more additional treatment modalities comprises one or more second therapeutic agents.

In some embodiments, the immune-mediated disease is an autoimmune disease. In some embodiments, the immune-mediated disease is an inflammatory disease or is characterized or associated with acute or chronic inflammation. In some embodiments, the immune-related disease is selected from the group comprising rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic disorders, psoriatic arthritis, and inflammatory bowel disease. For example, in some embodiments, the disease is rheumatoid arthritis. For example, in some embodiments, the disease is multiple sclerosis. For example, in some embodiments, the disease is psoriasis. For example, in some embodiments, the disease is a psoriatic disorder. For example, in some embodiments, the disease is psoriatic arthritis. For example, in some embodiments, the disease is an inflammatory bowel disease. For example, in some embodiments, the disease is Crohn's disease. For example, in some embodiments, the disease is ulcerative colitis.

In some embodiments, the one or more second therapeutic agents is selected from the group comprising tocilizumab, leflunomide, sulfasalazine, valdecoxib, certolizumab pegol, ibuprofen, famotidine, a combination of ibuprofen and famotidine, iodine, adalimumab, sarilumab, anakinra, naproxen sodium, abatacept, infliximab, golimumab, rofecoxib, tofacitinib, canakinumab, mesalamine, balsalazide, olsalazine, prednisone, budesonide, azathioprine, mercaptopurine, cyclosporine, methotrexate, golimumab, natalizumab, vedolizumab, ustekinumab, pharmaceutically acceptable salts thereof, and combinations thereof. In some such embodiments, the immune-mediated disease is rheumatoid arthritis.

In some embodiments, the one or more second therapeutic agents is selected from the group comprising dalfampridine, teriflunomide, leflunomide, interferon beta-1a, interferon beta-1b, glatiramer acetate, fingolimod, alemtuzumab, mitoxantrone hydrochloride, ocrelizumab, pegylated interferon beta-1a, dimethyl fumarate, natalizumab, daclizumab, mesalamine, balsalazide, olsalazine, prednisone, budesonide, azathioprine, mercaptopurine, cyclosporine, methotrexate, infliximab, adalimumab, golimumab, natalizumab, vedolizumab, ustekinumab, pharmaceutically acceptable salts thereof, and combinations thereof. In some such embodiments, the disease is multiple sclerosis.

In some embodiments, the one or more second therapeutic agents is selected from the group comprising alefacept, secukinumab, calcipotriene, betamethasone dipropionate, a combination of calcipotriene and betamethasone dipropionate, apremilast, prednisone, brodalumab, ustekinumab, ixekizumab, tazarotene, guselkumab, etanercept, mesalamine, balsalazide, olsalazine, prednisone, budesonide, azathioprine, mercaptopurine, cyclosporine, methotrexate, infliximab, adalimumab, golimumab, natalizumab, vedolizumab, ustekinumab, pharmaceutically acceptable salts thereof, and combinations thereof. In some such embodiments, the immune-mediated disease is psoriasis, a psoriatic disorder, or psoriatic arthritis

In some embodiments, the one or more second therapeutic agents is selected from the group comprising linaclotide, mesalamine, balsalazide, olsalazine, prednisone, budesonide, azathioprine, mercaptopurine, cyclosporine, methotrexate, infliximab, adalimumab, golimumab, natalizumab, vedolizumab, ustekinumab, pharmaceutically acceptable salts thereof, and combinations thereof. In some such embodiments, the immune-mediated disease is an inflammatory bowel disease.

In some embodiments, the one or more second therapeutic agents is an anti-inflammatory drug. For example, in some embodiments, the anti-inflammatory drug is selected from the group comprising aspirin, diflunisal, salsalate, diclofenac, ibuprofen, naproxen sodium, meloxicam, rofecoxib, valdecoxib, acetaminophen, lodine, mesalamine, balsalazide, olsalazine, betamethasone dipropionate, prednisone, sulfasalazine budesonide, interferon beta 1-b, pegylated interferon beta-1a, canakinumab, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the anti-inflammatory drug is a nonsteroidal anti-inflammatory drug. For example, in some embodiments, the nonsteroidal anti-inflammatory drug is selected from the group comprising aspirin, diflunisal, salsalate, diclofenac, ibuprofen, dexibuprofen, ketoprofen, naproxen sodium, meloxicam, rofecoxib, valdecoxib, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the anti-inflammatory drug is an aminosalicylate. For example, in some embodiments, the aminosalicylate is selected from the group comprising melamine, balsalazide, olsalazine, aspirin, diflunisal, salsalate, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the anti-inflammatory drug is a corticosteroid. For example, in some embodiments, the corticosteroid is selected from the group comprising triamcinolone, cortisone, dexamethasone, prednisone, prednisolone, methylprednisolone, cyclophosphamide, vincristine, doxorubicin, mafosfamide, cisplatin, AraC, everolimus, decitabine, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the anti-inflammatory drug is a biologic. In some embodiments, the biologic is a cytokine or a monoclonal antibody.

In some embodiments, the one or more second therapeutic agents is an immunomodulatory drug. In some embodiments, the immunomodulatory drug is a biologic. In some embodiments, the biologic is a monoclonal antibody or a dimeric fusion protein. In some embodiments, the immunomodulatory drug is an immunosuppressant. In some embodiments, the immunomodulatory drug is a phosphodiesterase (PDE) inhibitor. For example, in some embodiments, the immunomodulatory drug is selected from the group comprising pomalidomide, lenalidomide, thalidomide, apremilast, fingolimod, azathioprine, mercaptopurine, cyclosporine, methotrexate, alefacept, natalizumab, tocilizumab, golimumab interferon beta 1-b, glatiramer acetate, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the one or more second therapeutic agents is a biologic. In some embodiments, the biologic is a monoclonal antibody. For example, in some embodiments, the monoclonal antibody is drug is selected from the group comprising a human IgG1 monoclonal antibody, a human IgG1k monoclonal antibody, an anti α₄β₇ integrin antibody, an anti-IL-12/23 antibody, and an anti-alpha-4 integrin antibody.

In some embodiments, biologic is a protein. In some embodiments, the biologic is a cytokine or a dimeric fusion protein.

In some embodiments, the biologic is a interleukin 1 (IL1) receptor antagonist, an antibody that binds to CD20, an interleukin-17A (IL-17A) inhibitor, a TNFa inhibitor, a human interleukin-17 receptor A (IL-17RA) antagonist, an interleukin 12 (IL-12) and interleukin 23 (IL-23) antagonist, an antibody that targets the IL-23 subunit alpha, an antibody that blocks interleukin-23 but not IL-12, an agonist of guanylate cyclase 2C, or an interleukin-6 receptor agonist.

In some embodiments, the biologic is selected from the group comprising alefacept, tocilizumab, golimumab, certolizumab pegol, interferon beta 1-b, glatiramer acetate, anakinra, ocrelizumab, pegylated interferon beta-1a, natalizumab, daclizumab, secukinumab, infliximab, vedolizumab, ustekinumab, brodalumab, ixekizumab, guselkumab, etanercept, linaclotide, adalimumab, sarilumab, abatacept, canakinumab, alemtuzumab, and combinations thereof.

In some embodiments, the one or more second therapeutic agent is a disease-modifying antirheumatic drug. In some embodiments, the disease-modifying antirheumatic drug is a biologic or an immunosuppressant. For example, in some embodiments, the disease-modifying antirheumatic drug is selected from the group comprising leflunomide, teriflunomide, sulfasalazine, azathioprine, methotrexate, anakinra, etanercept, tocilizumab, adalimumab, abatacept, infliximab, golimumab, tofacitinib, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the one or more second therapeutic agent is a kinase inhibitor, a potassium channel blocker, a nicotinic acid receptor agonist, an antacid, an antihistamine, an antineoplastic agent, a synthetic vitamin D₃ derivative, a retinoid, or a combination thereof. For example, in some embodiments, the one or more therapeutic agents is selected from the group comprising tofacitinib, dalfampridine, dimethyl fumarate, famotidine, mitoxantrone, hydrochloride, calcipotriene, tazarotene, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the one or more second therapeutic agent is an HDAC inhibitor. For example, in some embodiments, the HDAC inhibitor is selected from the group comprising vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, SB939, resminostat, givinostat, quisinostat, HBI-8000, kevetrin, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, LAQ824, CI994, pharmaceutically acceptable salts thereof, and combinations thereof.

In certain embodiments, the EHMT2 inhibitor is a compound of any one of Formulae (I), (I′), (I′), (II″), (III″), (I′″), (II′″), and (III′″).

and a tautomer thereof, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer, wherein the variables are as defined herein.

In certain embodiments, the one or more second agents comprises a standard-of-care treatment modality for treating rheumatoid arthritis, a standard-of-care treatment modality for treating multiple sclerosis, a standard-of-care treatment modality for treating psoriasis, psoriatic disorders, or psoriatic arthritis or a standard-of-care treatment modality for treating inflammatory bowel disease.

In certain embodiments, the EHMT2 inhibitor and the one or more additional treatment modalities are administered simultaneously. For example, in certain embodiments, the EHMT2 inhibitor and the one or more second agents are administered simultaneously.

In certain embodiments, the EHMT2 inhibitor and the one or more additional treatment modalities are administered sequentially. For example, in certain embodiments, the EHMT2 inhibitor and the one or more second agents are administered sequentially.

In certain embodiments, the EHMT2 inhibitor and the one or more additional treatment modalities are administered in alternation. For example, in certain embodiments, the EHMT2 inhibitor and the one or more second agents are administered in alternation.

In certain embodiments, the one or more additional treatment modalities administered prior to the EHMT2 inhibitor. For example, in certain embodiments, the one or more second agents is administered prior to the EHMT2 inhibitor.

In certain embodiments, the EHMT2 inhibitor is administered prior to the one or more additional treatment modalities. For example, in certain embodiments, the EHMT2 inhibitor is administered prior to the one or more second agents.

In certain embodiments, the therapeutically effective amount of the EHMT2 inhibitor is an amount sufficient to achieve a desired clinical effect, e.g., an alleviation of a symptom of the immune-mediated disease in the subject treated with the EHMT2 inhibitor, an inhibition of disease progression, a reversal of a symptom or of all symptoms, or an increase in symptom-free or progression-free time windows, or an elongation of symptom-free or progression-free time periods, a prevention of onset of symptoms, and other clinical effects known to those of skill in the art to be desirable in the treatment of immune-mediated diseases.

In certain embodiments, 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 treatment modalities, e.g., simultaneously with, subsequent to, or prior to the administration of the EHMT2 inhibitor. For example, in certain embodiments, 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 second agents, e.g., simultaneously with, subsequent to, or prior to the administration of the EHMT2 inhibitor.

In certain embodiments, 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 treatment modalities. For example, in certain embodiments, 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 second agents.

In certain embodiments, the amount of the one or more treatment modalities 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. For example, in certain embodiments, the amount of the one or more second agents 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.

In certain embodiments, the EHMT2 inhibitor is administered prior to the administration of a combination of the EHMT2 inhibitor and the one or more treatment modalities. For example, in certain embodiments, the EHMT2 inhibitor is administered prior to the administration of a combination of the EHMT2 inhibitor and the one or more second agents.

In certain embodiments, the EHMT2 inhibitor is administered after the administration of a combination of the EHMT2 inhibitor and the one or more treatment modalities. For example, in certain embodiments, the EHMT2 inhibitor is administered after the administration of a combination of the EHMT2 inhibitor and the one or more second agents.

In certain embodiments, 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 100 nM or greater, 1 μM or greater, 10 μM or greater, 100 μM or greater, or 1000 μM or greater.

In certain embodiments, 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.

In certain embodiments, 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 1 μM or greater, 2 μM or greater, 5 μM or greater, or 10 μM 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.

Also provided herein are pharmaceutical 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 a second agent.

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, 62/509,620, 62/436,139, 62/517,840, 62/573,442, 62/681,804, 62/746,252, and 62/746,495, and Ser. No. 15/601,888, and PCT Application Nos. PCT/US2017/027918, PCT/US2017/054468, PCT/US2017/067192, PCT/US2018/056333, and PCT/US2018/056428, the contents of each of which are incorporated herein by reference in their entireties

In some aspects, the present disclosure provides an EHMT2 inhibitor described herein for preventing or treating a disease or disorder associated with overexpression of EHMT2.

In some aspects, the present disclosure provides an EHMT2 inhibitor described hereinfor use in combination with one or more second therapeutic agents for preventing or treating a disease or disorder associated with overexpression of EHMT2.

In some aspects, the present disclosure provides an EHMT2 inhibitor described hereinfor preventing or treating an immune-mediated disease.

In some aspects, the present disclosure provides an EHMT2 inhibitor described herein for use in combination with one or more second therapeutic agents for preventing or treating an immune-mediated disease.

In some aspects, the present disclosure provides use of an EHMT2 inhibitor described herein in the manufacture of a medicament for preventing or treating a disease or disorder associated with overexpression of EHMT2.

In some aspects, the present disclosure provides use of an EHMT2 inhibitor described herein in the manufacture of a medicament for use in combination with one or more second therapeutic agents for preventing or treating a disease or disorder associated with overexpression of EHMT2.

In some aspects, the present disclosure provides use of an EHMT2 inhibitor described herein in the manufacture of a medicament for preventing or treating an immune-mediated disease.

In some aspects, the present disclosure provides use of an EHMT2 inhibitor described herein in the manufacture of a medicament for use in combination with one or more second therapeutic agents for preventing or treating an immune-mediated disease.

Unless otherwise stated, 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. For example, the disclosure also provides methods of identifying an inhibitor of EHMT1 or EHMT2 or both.

For example, 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.

In some embodiments, performing the assay to detect methylation of H3-K9 in the histone substrate comprises measuring incorporation of labeled methyl groups.

In some embodiments, the labeled methyl groups are isotopically labeled methyl groups.

In some embodiments, 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 a second agent, wherein the combination of the EHMT2 inhibitor and the second agent inhibits histone methyltransferase activity of EHMT, thereby inhibiting conversion of H3-K9 to dimethylated H3-K9.

Further, the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic purposes.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

Other features and advantages of the disclosure will be apparent from the following figures, detailed description and claims.

BRIEF DESCRIPTION OF DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

The above and further features will be more clearly appreciated from the following detailed description when taken in conjunction with the accompanying drawings.

FIG. 1 shows the effect of Compound 571 on cell polarization. Panel A shows the effect on T regulatory (Treg) cell polarization. Panel B shows the effect on TH17 cell polarization. In the Figure, the number 1-5 represent the following. Panel A 1:Treg in cell culture medium; 2: Treg in DMSO 3: Compound 571, 10 nM; 4: Compound 571, 100 nM; 5: Compound 571, 1 uM. Panel B 1:Th17 in cell culture medium; 2: Th17 in DMSO 3: Compound 571, 10 nM; 4: Compound 571, 100 nM; 5: Compound 571, 1 uM.

FIG. 2 shows the effect of Compound 205 on TH17 cell polarization. In the Figure, the number 1-7 represent the following: 1:Th17 in DMSO; 2: Compound 205, 62.5 nM; 3: Compound 205, 125 nM; 4: Compound 205, 250 nM; 5: Compound 205, 500 nM; 6: Compound 205, 1000 nM; 7: Compound 205, 2000 nM.

FIG. 3 is a graph showing the dose-dependent increase in Treg polarization and dose-dependent decrease in H3K9me2 upon treatment with G9a inhibitor Compound D6.

FIGS. 4A and 4B are a set of graphs showing increased Treg polarization and decreased H3K9me2 upon treatment with G9a inhibitors Compound A75, Compound D6, and Compound 205.

FIG. 5 is a graph showing dose-dependent increase in Th17 polarization and dose-dependent decrease in H3K9me2 upon treatment with G9a inhibitor Compound D6.

FIGS. 6A and 6B are a set of graphs showing Th17 polarization and decreased H3K9me2 upon treatment with G9a inhibitors Compound A75, Compound D6, and Compound 205.

DETAILED DESCRIPTION

In some aspects, the present disclosure provides a method of preventing or treating a disease or disorder associated with overexpression of EHMT2, comprising administering to a subject in need thereof a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor. In some embodiments, the method further comprises administering to the subject one or more additional treatment modalities in a therapeutically effective amount, wherein the one or more additional treatment modalities comprises one or more second therapeutic agents.

In some aspects, the present disclosure provides a method of preventing treating an immune-mediated disease, comprising administering to a subject in need thereof a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor. In some embodiments, the method further comprises administering to the subject one or more additional treatment modalities in a therapeutically effective amount, wherein the one or more additional treatment modalities comprises one or more second therapeutic agents.

In further aspects, the present disclosure provides method of treating a disease or disorder associated with overexpression of EHMT2 (e.g., an immune-mediated disease or disorder), comprising administering to a subject in need thereof (a) a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor, and (b) one or more second agents in a therapeutically effective amount.

In certain embodiments, the second agent comprises a standard-of-care treatment modality for rheumatoid arthritis, standard-of-care treatment modality for multiple sclerosis, standard-of-care treatment modality for psoriasis, standard-of-care treatment modality for psoriatic disorders, a standard-of-care treatment modality for psoriatic arthritis, a standard-of-care treatment modality for inflammatory bowel disease, or a combination thereof.

In certain embodiments, an immune-mediated disease is an immune-mediated inflammatory disease or an autoimmune disease or disorder. Non-limiting examples of such diseases or disorders include multiple sclerosis, psoriasis, inflammatory bowel disease, such as ulcerative colitis, Crohn's disease, microscopic colitis (collagenous colitis and lymphocytic colitis), diversion colitis, Behçet's disease, and indeterminate colitis, rheumatoid arthritis and polyarthritis, ankylosing spondylitis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, cutaneous lupus erythematosus including chilblain lupus erythematosus, lupus nephritis, discoid lupus, subacute cutaneous lupus erythematosus, dermatomyositis, polymyositis, idiopathic myxedema, Hashimoto's disease, Guillain-Barre' syndrome, Grave's disease, myasthenia gravis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, uveitis, autoimmune oophoritis, chronic immune thrombocytopenic purpura, colitis, diabetes, psoriasis, pemphigus vulgaris, proliferative glomerulonephritis, Wiskott-Aldrich syndrome, autoimmune lymphoproliferative syndrome, chronic arthritis, inflammatory chronic rhinosinusitis, colitis, celiac disease, inflammatory bowel disease, Barrett's esophagus, inflammatory gastritis, autoimmune nephritis, autoimmune vasculitis, autoimmune hepatitis, autoimmune carditis, autoimmune encephalitis, and autoimmune mediated hematological disease.

Some aspects of this disclosure provide methods for modulating T cell activity, e.g., in vitro or in vivo, by inhibiting EHMT2 activity in a target T cell or target T cell population. In some embodiments, the method comprises contacting a target T cell, e.g., a T regulatory (Treg) cell or a Th17 cell or cell population with an EHMT2 inhibitor, e.g., an EHMT2 inhibitor provided herein. In some embodiments, the method comprises contacting the target T cell or T cell population in vivo, e.g., by administering the EHMT2 inhibitor to a subject harboring the target T cell or T cell population. In some embodiments, the method comprises administering the EHMT2 inhibitor in an amount effective to induce or increase polarization and/or differentiation of a target T cell or T cell population, e.g., of Treg and/or Th17 cells in a subject having an immune-mediated disease. In some embodiments, the method comprises administering the EHMT2 inhibitor in an amount effective to reduce or the number of pathogenic T cells or to keep the number of pathogenic T cells below a threshold level associated with an immune-mediated disease.

Without wishing to be bound by any particular theory, it is believed that pathogenesis in certain immune-mediated diseases, e.g., in inflammatory diseases such as, for example, inflammatory bowel syndrome, is associated with dysregulated T cell responses, e.g., with dysregulated CD4⁺ Th cell responses. In addition, it is believed that pharmacological inhibition of EHMT2 expression, e.g., by an EHMT2 inhibitory compound provided herein, and the resulting decrease or loss in histone 3 lysine 9 dimethylation (H3K9me2), promotes differentiation of naive T cells to Treg and/or Th17 cells, and/or reduces the number of pathogenic T cells, e.g., T cells involved in the disease-associated, dysregulated T cell response. Accordingly, some aspects of the present disclosure provide methods for treating an immune-mediated disease characterized by a dysregulated T cell response, by administering to a subject having such a disease an amount of an EHMT2 inhibitor, e.g., an EHMT2 inhibitor provided herein, effective to promote differentiation of naïve T cells to Treg and/or Th17 cells, and/or to reduce the number of pathogenic T cells, e.g., T cells involved in the disease-associated, dysregulated T cell response. In some embodiments, the EHMT2 inhibitor is administered in combination with one or more second agents as described herein. Exemplary suitable methods for detecting pathogenic and non-pathogenic T cells are described herein, and additional suitable methods will be apparent to the skilled artisan based on the instant disclosure. The disclosure is not limited in this respect.

In certain embodiments, for the methods disclosed herein, the EHMT2 inhibitor is a compound of Formula (I) below:

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;
  • X¹ is N, CR², or NR^2′ as valency permits;
  • X² is N, CR³, or NR^3′ as valency permits;
  • X³ is N, CR⁴, or NR^4′ as valency permits;
  • X⁴ is N or CR⁵, or X⁴ is absent such that ring A is a 5-membered heteroaryl containing at least one N atom;
  • X⁵ is C or N as valency permits;
  • B is absent or a ring structure selected from the group consisting of C₆-C₁₀ aryl, C₃-C₁₀ 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 C₁-C₆ 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 (R⁷)_n when B is absent; or when B is absent, T and R¹ 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 (R⁷)_n;
  • R¹ is H or C₁-C₄ alkyl;
  • each of R², R³, and R⁴, independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkoxyl, C₆-C₁₀ aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C₁-C₆ alkyl, wherein C₁-C₆ alkoxyl and C₁-C₆ alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or C₁-C₆ alkyl, or R³ is -Q¹-T¹, in which Q¹ 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 T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C₃-C₈ 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 alkyl, hydroxyl, oxo, —C(O)R⁹, —SO₂R⁸, —SO₂N(R⁸)₂, —NR⁸C(O)R⁹, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl; or when ring A is a 5-membered heteroaryl containing at least one N atom, R⁴ 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 C₁-C₃ alkyl; R⁵ is selected from the group consisting of H, F, Br, cyano, C₁-C₆ alkoxyl, C₆-C₁₀ aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C₃-C₈ cycloalkyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, C₁-C₆ alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, and C₂-C₆ alkynyl optionally substituted with 4- to 12-membered heterocycloalkyl; wherein said C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl are optionally substituted with one or more of halo, C(O)R^a, OR^a, NR^aR^b, 4- to 7-membered heterocycloalkyl, —C₁-C₆ alkylene-4- to 7-membered heterocycloalkyl, or C₁-C₄ alkyl optionally substituted with one or more of halo, OR^a or NR^aR^b, in which each of R^a and R^b independently is H or C₁-C₆ alkyl; or
  • R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ 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;
  • R⁶ is absent when X⁵ is N and ring A is a 6-membered heteroaryl; or R⁶ is -Q¹-T¹, in which Q¹ 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 T¹ is H, halo, cyano, NR⁸R⁹, C(O)NR⁸R⁹, C(O)R⁹, OR⁸, OR⁹, or R^S1, in which R^S1 is C₃-C₈ 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 alkyl, hydroxyl, oxo, —C(O)R⁹, —SO₂R⁸, —SO₂N(R⁸)₂, —NR⁸C(O)R⁹, NR⁸R⁹, or C₁-C₆ alkoxyl; and R⁶ is not NR⁸C(O)NR¹²R¹³; or
  • R⁶ and one of R² or R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁶ 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, C₁-C₃ alkyl, hydroxyl, oxo (═O), C₁-C₃ alkoxyl, or -Q¹-T¹;
  • each R⁷ is independently oxo (═O) or -Q²-T², in which each Q² 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 T² independently is H, halo, cyano, OR¹⁰, OR¹¹, C(O)R¹¹, NR¹⁰R¹¹, C(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹¹, 5- to 10-membered heteroaryl, C₃-C₈ 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, C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C₁-C₆ alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)₂, cyano, C₁-C₆ haloalkyl, —SO₂R⁸, or C₁-C₆ alkoxyl, each of R^x and R^y independently being H or C₁-C₆ alkyl; and R₇ is not H or C(O)OR⁹;
  • each R⁸ independently is H or C₁-C₆ alkyl;
  • each R⁹ is independently -Q³-T³, in which Q³ 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 C₁-C₆ alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)₂R¹³, S(O)₂NR¹²R¹³, or R^S2, in which R^S2 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, and R^S2 is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ 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-C₆ alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^c, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or C₁-C₆ alkyl; or -Q⁴-T⁴ is oxo; or
  • R⁸ and R⁹ 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 -Q⁵-T⁵, wherein each Q⁵ 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-C₆ alkoxy, and each T⁵ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^e, S(O)₂NR^eR^f, NR^eR^f, C(O)NR^eR^f, and NR^eC(O)R^f, each of R^e and R^f independently being H or C₁-C₆ alkyl; or -Q⁵-T⁵ is oxo;
  • R¹⁰ is selected from the group consisting of H and C₁-C₆ alkyl;
  • R¹¹ is -Q⁶-T⁶, in which Q⁶ 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 T⁶ is H, halo, OR^g, NR^gR^h, NR^gC(O)R^h, C(O)NR^gR^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, C₃-C₈ cycloalkyl, or C₁-C₆ 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 heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and R^S3 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, and R^S3 is optionally substituted with one or more -Q⁷-T⁷, wherein each Q⁷ 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-C₆ alkoxy, and each T⁷ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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^jR^k, C(O)NR^jR^k, S(O)₂R^j, and NR^jC(O)R^k, each of R^j and R^k independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q⁷-T⁷ is oxo; or
  • R¹⁰ and R¹¹ 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, C₁-C₆ alkyl, hydroxyl, or C₁-C₆ alkoxyl;
  • R¹² is H or C₁-C₆ alkyl;
  • R¹³ 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 -Q⁸-T⁸, wherein each Q⁸ 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-C₆ alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q⁸-T⁸ is oxo; and n is 0, 1, 2, 3, or 4.

The compounds of Formula (I) may have one or more of the following features when applicable.

In some embodiments, the EHMT2-inhibitor is not a compound selected from the group consisting of:

• 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;
• 2-(4-isopropyl-1,4-diazepan-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine;
• 4-(((2-((1-acetylindolin-6-yl)amino)-6-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)benzenesulfonamide;
• 5-bromo-N⁴-(4-fluorophenyl)-N²-(4-methoxy-3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyrimidine-2,4-diamine;
• N²-(4-methoxy-3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(5-(tert-pentyl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;
• 4-((2,4-dichloro-5-methoxyphenyl)amino)-2-((3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidine-5-carbonitrile;
• N-(naphthalen-2-yl)-2-(piperidin-1-ylmethoxy)pyrimidin-4-amine;
• N-(3,5-difluorobenzyl)-2-(3-(pyrrolidin-1-yl)propyl)pyrimidin-4-amine;
• N-(((4-(3-(piperidin-1-yl)propyl)pyrimidin-2-yl)amino)methyl)benzamide;
• N-(2-((2-(3-(dimethylamino)propyl)pyrimidin-4-yl)amino)ethyl)benzamide; and
• 2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-6,7-dimethoxy-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine.

In some embodiments, when T is a bond, B is substituted phenyl, and R⁶ is NR⁸R⁹, in which R⁹ is -Q³-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) -Q²-OR¹¹ in which R¹¹ is -Q⁶-R^S3 and Q⁶ is optionally substituted C₂-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker and (ii) -Q²-NR¹⁰R¹¹ in which R¹¹ is -Q⁶-R^S3.

In some embodiments, when T is a bond and B is optionally substituted phenyl, then R⁶ is not OR⁹ or NR⁸R⁹ in which R⁹ is optionally substituted naphthyl.

In some embodiments, when T is a bond and B is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl, then R⁶ is not NR⁸R⁹ in which R⁹ is optionally substituted phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydronaphthyl.

In some embodiments, when T is a bond and B is optionally substituted phenyl or thiazolyl, then R⁶ is not optionally substituted imidazolyl, pyrazolyl, pyridyl, pyrimidyl, or NR⁸R⁹ in which R⁹ is optionally substituted imidazolyl or 6- to 10-membered heteroaryl.

In some embodiments, when T is a C₁-C₆ 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 C₃-C₁₀ cycloalkyl or 4- to 12-membered heterocycloalkyl, then R⁶ is not NR⁸C(O)R¹³.

In some embodiments, when X¹ and X³ are N, X² is CR³, X⁴ is CR⁵, X⁵ is C, R⁵ is 4- to 12-membered heterocycloalkyl substituted with one or more C₁-C₆ alkyl, and R⁶ and R³ together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C₁-C₃ alkoxyl, then B is absent, C₆-C₁₀ aryl, C₃-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl.

In some embodiments, when X² and X³ are N, X¹ is CR², X⁴ is CR⁵, X⁵ is C, R⁵ is C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more C₁-C₆ alkyl, and R⁶ and R² together with the atoms to which they are attached form phenyl which is substituted with one or more of optionally substituted C₁-C₃ alkoxyl, then B is absent, C₆-C₁₀ aryl, C₃-C₁₀ cycloalkyl, or 5- to 10-membered heteroaryl.

In some embodiments, ring A is a 6-membered heteroaryl, at least one of X¹, X², X³ and X⁴ is N and X⁵ is C.

In some embodiments, ring A is a 6-membered heteroaryl, two of X¹, X², X³ and X⁴ are N and X⁵ is C.

In some embodiments, R⁶ and one of R² or R³ together with the ring A to which they are attached form a 6,5-fused bicyclic heteroaryl; or R⁶ and one of R^2′ or R^3′ together the ring A to which they are attached form a 6,5-fused bicyclic heteroaryl.

In some embodiments, at least one of R⁶, R², R³, and R⁴ is not H.

In some embodiments, when one or more of R^2′, R^3′, and R^4′ are present, at least one of R⁶, R^2′, R^3′, and R^4′ is not H.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (II):

wherein

• • ring B is phenyl or pyridyl,
  • one or both of X¹ and X² are N while X³ is CR⁴ and X⁴ is CR⁵ or one or both of X¹ and X³ are N while X² is CR³ and X⁴ is CR⁵; and
  • n is 1, 2, or 3.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (IIa1), (IIa2), (IIa3), (IIa4), or (IIa5):

In some embodiments, at most one of R³ and R⁵ is not H.

In some embodiments, the EHMNT2 inhibitor is a compound of Formula (IIb1), (IIb2), (IIb3), (IIb4), or (IIb5).

In some embodiments, at most one of R³, R⁴ and R⁵ is not H.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (IIc1), (IIc2), (IIc3), (IIc4), or (IIc5):

In some embodiments, at most one of R⁴ and R⁵ is not H.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (IId1), (IId2), (IId3), (IId4), or (IId5):

In some embodiments, at most one of R², R⁴, and R⁵ is not H.

In some embodiments, ring A is a 5-membered heteroaryl.

In some embodiments, the EHMNT2 inhibitor is a compound of Formula (III):

wherein

• • ring B is phenyl or pyridyl,
  • at least one of X² and X³ is N; and
  • n is 1 or 2.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (IIIa):

In some embodiments, at most one of R^4′ and R² is not H.

In some embodiments, the optionally substituted 6,5-fused bicyclic heteroaryl contains 1-4 N atoms.

In some embodiments, T is a bond and ring B is phenyl or pyridyl.

In some embodiments, n is 1 or 2.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (IV):

wherein ring B is C₃-C₆ cycloalkyl;

• • each of R²⁰, R²¹, R²² and R²³ independently is H, halo, C₁-C₃ alkyl, hydroxyl, or C₁-C₃ alkoxyl; and
  • n is 1 or 2.

In some embodiments, ring B is cyclohexyl.

In some embodiments, R¹ is H or CH₃.

In some embodiments, n is 1 or 2, and at least one of R⁷ is -Q²-OR¹¹ in which R¹¹ is -Q⁶-R^S3 and Q⁶ is optionally substituted C₂-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker.

In some embodiments, n is 1 or 2, and at least one of R⁷ is -Q²-NR¹⁰R¹¹ in which R¹¹ is -Q⁶-R^S3.

In some embodiments, Q⁶ is C₂-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with a hydroxyl and R^S3 is 4- to 7-membered heterocycloalkyl optionally substituted with one or more -Q⁷-T⁷.

In some embodiments, Q⁶ is C₁-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with a hydroxyl and R^S3 is C₃-C₆ cycloalkyl optionally substituted with one or more

• • -Q⁷-T⁷.

In some embodiments, each Q⁷ is independently a bond or a C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker and each T⁷ is independently H, halo, C₁-C₆ alkyl, or phenyl.

In some embodiments, Q² is a bond or a C₁-C₄ alkylene, C₂-C₄ alkenylene, or C₂-C₄ alkynylene linker.

In some embodiments, at least one of R⁷ is

In some embodiments, n is 2 and the compound further comprises another R′ selected from halo and methoxy.

In some embodiments, ring B is selected from phenyl, pyridyl, and cyclohexyl, and the halo or methoxy is at the para-position to NR¹.

In some embodiments, R⁶ is NR⁸R⁹.

In some embodiments, R⁹ is -Q³-T³, in which T³ is OR¹², NR¹²C(O)R¹³, C(O)R¹³, C(O)NR¹²R¹³, S(O)₂NR¹²R¹³, or R^S2.

In some embodiments, Q³ is C₁-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with a hydroxyl.

In some embodiments, R^S2 is C₃-C₆ cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, and R^S2 is optionally substituted with one or more -Q⁴-T⁴.

In some embodiments, each Q⁴ is independently a bond or C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker optionally substituted with one or more of hydroxyl and halo, and each T⁴ is independently H, halo, C₁-C₆ alkyl, or phenyl; or -Q⁴-T⁴ is oxo.

In some embodiments, R⁶ or NR⁸R⁹ is selected from the group consisting of:

In some embodiments, B is absent and T is unsubstituted C₁-C₆ alkyl or T is C₁-C₆ alkyl substituted with at least one R⁷.

In some embodiments, B is 4- to 12-membered heterocycloalkyl and T is unsubstituted C₁-C₆ alkyl.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (V):

wherein

• • ring B is absent or C₃-C₆ cycloalkyl;
  • X³ is N or CR⁴ in which R⁴ is H or C₁-C₄ alkyl;
  • R¹ is H or C₁-C₄ alkyl;
  • or when B is absent, T and R¹ 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 (R⁷)_n; or when B is absent, T is H and n is 0;
  • each R⁷ is independently oxo (═O) or -Q²-T², in which each Q² 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 T² independently is H, halo, OR¹⁰, OR¹¹, C(O)R¹¹, NR¹⁰R¹¹, C(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹¹, C₃-C₈ cycloalkyl, or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and wherein the C₃-C₈ cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of halo, C₁-C₆ alkyl optionally substituted with NR^xR^y, hydroxyl, oxo, N(R⁸)₂, cyano, C₁-C₆ haloalkyl, —SO₂R⁸, or C₁-C₆ alkoxyl, each of R^x and R^y independently being H or C₁-C₆ alkyl; and R₇ is not H or C(O)OR⁹;
  • R⁵ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₈ cycloalkyl and 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O and S, wherein the C₃-C₈ 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)C₁-C₆ alkyl or C₁-C₆ alkyl optionally substituted with one or more of halo or OR^a;
  • R⁹ is -Q³-T³, in which Q³ 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 C₁-C₆ alkoxyl, and T³ is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ 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-C₆ alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^c, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or C₁-C₆ alkyl; or -Q⁴-T⁴ is oxo; and
  • n is 0, 1 or 2.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (VI):

wherein

• • R⁵ and R⁶ are independently selected from the group consisting of C₁-C₆ alkyl and NR⁸R⁹, or R⁶ and R³ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl.

In some embodiments, R⁶ is methyl.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (VII):

wherein m is 1 or 2 and n is 0, 1, or 2.

In some embodiments, both of X¹ and X³ are N while X² is CR³ and X⁴ is CR⁵.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (VIIIa):

wherein

• • X¹ is N or CR²;
  • X² is N or CR³;
  • X³ is N or CR⁴;
  • X⁴ is N or CR⁵;
  • R² is selected from the group consisting of H, C₃-C₈ cycloalkyl, and C₁-C₆ alkyl optionally substituted with one or more of halo, OR^a, or NR^aR^b;
  • each of R³ and R⁴ is H; and
  • R⁵ are independently selected from the group consisting of H, C₃-C₈ cycloalkyl, and C₁-C₆ alkyl optionally substituted with one or more of halo or OR^a; or
  • R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ 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
  • wherein at least one of R₂ or R₅ are not H.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (VIIIb):

wherein

• • X¹ is N or CR²;
  • X² is N or CR³;
  • X³ is N or CR⁴;
  • X⁴ is N or CR⁵;
  • R² is selected from the group consisting of H, C₃-C₈ cycloalkyl, and C₁-C₆ alkyl each of R³ and R⁴ is H; and
  • R⁵ is selected from the group consisting of H, C₃-C₈ cycloalkyl, and C₁-C₆ alkyl; or
  • R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ 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
  • wherein at least one of R₂ or R₅ are not H.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (VIIIc):

wherein

• • X¹ is N or CR²;
  • X² is N or CR³;
  • X³ is N or CR⁴;
  • X⁴ is N or CR⁵;
  • R² is selected from the group consisting of H, C₃-C₈ cycloalkyl, and C₁-C₆ alkyl each of R³ and R⁴ is H; and
  • R⁵ is selected from the group consisting of H, C₃-C₈ cycloalkyl, and C₁-C₆ alkyl; or
  • R⁵ and one of R³ or R⁴ together with the atoms to which they are attached form phenyl or a 5- or 6-membered heteroaryl; or R⁵ 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
  • wherein at least one of R₂ or R₅ are not H.

In some embodiments, the EHMT2 inhibitor is a compound of (IX):

or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein

• • X⁶ is N or CH;
  • X⁷ is N or CH;
  • X³ is N or CR⁴;
  • R⁴, independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkoxyl, C₆-C₁₀ aryl, NR^aR^b, C(O)NR^aR^b, NR^aC(O)R^b, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C₁-C₆ alkyl, wherein C₁-C₆ alkoxyl and C₁-C₆ alkyl are optionally substituted with one or more of halo, OR^a, or NR^aR^b, in which each of R^a and R^b independently is H or C₁-C₆ alkyl;
  • each R⁹ is independently -Q³-T³, in which Q³ 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 C₁-C₆ alkoxyl, and T³ is H, halo, OR¹², OR¹³, NR¹²R¹³, NR¹²C(O)R¹³, C(O)NR¹²R¹³, C(O)R¹³, S(O)₂R¹³, S(O)₂NR¹²R¹³, or R^S2, in which R^S2 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, and R^S2 is optionally substituted with one or more -Q⁴-T⁴, wherein each Q⁴ 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-C₆ alkoxy, and each T⁴ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^c, NR^cR^d, C(O)NR^cR^d, and NR^cC(O)R^d, each of R^c and R^d independently being H or C₁-C₆ alkyl; or -Q⁴-T⁴ is oxo; or
  • R¹² is H or C₁-C₆ alkyl;
  • R¹³ 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 -Q⁸-T′, wherein each Q⁸ 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-C₆ alkoxy, and each T⁸ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q⁸-T⁸ is oxo;
  • R¹⁵ is C₁-C₆ alkyl, NHR¹⁷, 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 -Q⁹-T⁹, wherein each Q⁹ 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-C₆ alkoxy, and each T⁹ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q⁹-T⁹ is oxo;
  • R¹⁶ 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 -Q¹⁰-T¹⁰, wherein each Q¹⁰ 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-C₆ alkoxy, and each T¹⁰ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl; or -Q¹⁰-T¹⁰ is oxo;
  • R¹⁷ is H or C₁-C₆ alkyl; and
  • v is 0, 1, or 2.

In some embodiments, each T³ independently is OR¹² or OR¹³.

In some embodiments, each Q³ independently is a bond or C₁-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ alkynylene linker optionally substituted with a hydroxyl.

In some embodiments, R¹⁵ is C₁-C₆ alkyl, NHR¹⁷, or 4- to 12-membered heterocycloalkyl.

In some embodiments, R¹⁶ is C₁-C₆ alkyl or 4- to 12-membered heterocycloalkyl, each optionally substituted with one or more-Q¹⁰-T¹⁰.

In some embodiments, each T¹⁰ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, and 4- to 7-membered heterocycloalkyl.

In some embodiments, each Q¹⁰ independently is a bond or C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker optionally substituted with a hydroxyl.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (X):

wherein X³ is N or CR⁴, wherein R⁴ is selected from the group consisting of H, halo, and cyano.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), or (Xg):

In some embodiments, at least one of X¹, X², X³ and X⁴ is N.

In some embodiments, X² and X³ is CH, and X¹ and X⁴ is N.

In some embodiments, X² and X³ is N, X¹ is CR², and X⁴ is CR⁵.

In some embodiments, R⁶ is NR⁸R⁹ and R⁵ is C_1-6 alkyl or R⁵ and R³ together with the atoms to which they are attached form phenyl or a 5- to 6-membered heteroaryl ring.

In certain embodiments, for the methods disclosed herein, 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
  • X^1a is O, S, CR^1aR^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 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, independently, 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 C₁-C₆ alkoxyl, and each T^1a independently is H, halo, cyano, NR^5aR^6a, C(O)NR^5aR^6a, —OC(O)NR^5aR^6a, C(O)OR^5a, —OC(O)R^5a, C(O)R^5a, —NR^5aC(O)R^6a, —NR^5aC(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^S1a is optionally substituted with one or more of halo, C₁-C₆ alkyl, hydroxyl, oxo, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂—NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-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, C₁-C₆ 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, C₂-C₆ alkenylene, or C₂-C₆ 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, 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^S2a is optionally substituted with one or more of halo, C₁-C₆ alkyl, hydroxyl, oxo, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂—NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl;
  • R^3a is H, NR^aaR^ba, OR^aa, or R^S4a, in which R^S4a is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ 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^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, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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, or alternatively;
  • R^3a and one of R^1a′, R^2a′, R^1a, R^2a and R^11a, together with the atoms to which they are attached, form a 5- or 6-membered heteroaryl that is optionally substituted with one or more of halo, C₁-C₃ alkyl, hydroxyl or C₁-C₃ alkoxyl; or
  • 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, 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, cyano, OR^7a, OR^8a, C(O)R^8a, NR^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^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 C₁-C₆ 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 C₁-C₆ 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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^da, C(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^da independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo; and
  • n is 1, 2, 3, or 4.

In some embodiments, the compound is not

In some embodiments, when n is 2, X^1a is CR^1aR^11a, X^2a is N, X^3a is C, R^3a is NH₂, and at least one R^4a is OR^7a, then one of (1)-(4) below applies:

• • (1) at least one of R^1a and R^11a is -Q^1a-T^1a, in which Q^1a is a C₁-C₆ alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl, and T^1a is cyano, NR^5aR^6a, C(O)NR^5aR^6a, —OC(O)NR^5aR^6a, C(O)OR^5a, —OC(O)R^5a, C(O)R^5a, —NR^5aC(O)R^6a, —NR^5aC(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^S1a is optionally substituted with one or more of halo, C₁-C₆ alkyl, hydroxyl, oxo, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂—NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl; or
  • (2) at least one of R^1a and R^11a is -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 C₁-C₆ alkoxyl, and T^1a is H, halo, cyano, NR^5aR^6a, C(O)NR^5aR^6a, —OC(O)NR^5aR^6a, C(O)OR^5a, —OC(O)R^5a, C(O)R^5a, —NR^5aC(O)R^6a, —NR^5aC(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^S1a is optionally substituted with one or more of halo, C₁-C₆ alkyl, hydroxyl, oxo, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂, —NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl; or
  • (3) 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^5aR^6a, C(O)NR^5aR^6a, —OC(O)NR^5aR^6a, C(O)OR^5a, —OC(O)R^5a, C(O)R^5a, —NR^5aC(O)R^6a, —NR^5aC(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^S1a is optionally substituted with one or more of halo, C₁-C₆ alkyl, hydroxyl, oxo, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂—NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl; or
  • (4) R^1a and R^11a together with the carbon atom to which they are attached form a C₇-C₁₂ cycloalkyl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the C₇-C₁₂ 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 C₁-C₆ alkoxyl.

In some embodiments, at least one of X^2a and X^3a is N.

In some embodiments, at least two of X^1a, X^2a, and X^3a comprise N.

In some embodiments at least one of , and is a double bond.

In some embodiments, is a double bond.

In some embodiments, is a single bond.

In some embodiments, X^2a is NR^2a′ and R^3a is oxo.

In some embodiments, X^2a is N and X^3a is C.

In some embodiments, X^2a is CR^2a and X^3a is N.

In some embodiments, X^1a is S.

In some embodiments, X^1a is NR^1a′.

In some embodiments, X^1a is CR^1aR^11a.

In some embodiments, 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, C₁-C₆ alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, n is 1 or 2.

In some embodiments, n is 2.

In some embodiments, the compound is of Formula (IIa′), (IIb′), (IIc′), (IId′), (IIe′), (IIIa′), (IIIb′), (IIIc′), (IIId′), (IIIe′), (IIIf′), (IVa′), or (IVb′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, the compound is of Formula (IIf′), (IIg′), (IIh′), (IIIi′), (IIIj′), (IIIk′), or (IIIl′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein

• • R^3a is H, NR^aaR^ba, OR^aa, or R^S4a, in which R^S4a is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ 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^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, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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;
  • 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 C₁-C₆ alkoxyl, and each T^3a independently is H, halo, cyano, OR^7a, OR^8a, C(O)R^8a, NR^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^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 C₁-C₆ 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 C₁-C₆ 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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^da, C(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^da independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo.

In some embodiments, the compound is not one of those described in EP 0356234; U.S. Pat. Nos. 5,106,862; 6,025,379; 9,284,272; WO2002/059088; and/or WO2015/200329.

In some embodiments, when n is 2, X^1a is CR^1aR^11a, X^2a is N, X^3a is C, R^3a is NH₂, 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 C₁-C₆ alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl, and T^1a is cyano, NR^5aR^6a, C(O)NR^5aR^6a, —OC(O)NR^5aR^6a, C(O)OR^5a, —OC(O)R^5a, C(O)R^5a, —NR^5aC(O)R^6a, —NR^5aC(O)OR^6a, OR^5a, or R^S1a, in which R^S1a is C₃-C₁₂ 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, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂, —NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, when n is 2, X^1a is CR^1aR^11a, X^2a is N, X^3a is C, R^3a is NH₂, 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 C₂-C₆ alkenylene or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl, and T^1a is H, halo, cyano, NR^5aR^6a, C(O)NR^5aR^6a, —OC(O)NR^5aR^6a, C(O)OR^5a, —OC(O)R^5a, C(O)R^5a, —NR^5aC(O)R^6a, —NR^5aC(O)OR^6a, OR^5a, or R^S1a, in which R^S1a is C₃-C₁₂ 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, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂—NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, when n is 2, X^1a is CR^1aR^11a, X^2a is N, X^3a is C, R^3a is NH₂, 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^5aR^6a, C(O)NR^5aR^6a, —OC(O)NR^5aR^6a, C(O)OR^5a, —OC(O)R^5a, C(O)R^5a, —NR^5aC(O)R^6a, —NR^5aC(O)OR^6a, OR^5a, or R^S1a, in which R^S1a is C₃-C₁₂ 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, —C(O)R^6a, —SO₂R^5a, —SO₂N(R^5a)₂, —NR^5aC(O)R^6a, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, when n is 2, X^1a is CR^1aR^11a, X^2a is N, X^3a is C, R^3a is NH₂, and at least one R^4a is OR^7a, then R^1a and R^11a together with the carbon atom to which they are attached form a C₇-C₁₂ 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 C₇-C₁₂ 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 C₁-C₆ alkoxyl.

In some embodiments, 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 C₁-C₆ alkoxyl, and 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, C₁-C₆ alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, R^2a is C₁-C₆ alkyl optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl. In some embodiments, R^2a is unsubstituted C₁-C₆ alkyl.

In some embodiments, Q^1a is a bond or C₁-C₆ alkylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl, and 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, C₁-C₆ alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, Q^1a is a C₂-C₆ alkenylene or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl, and 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, C₁-C₆ alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, R^1a′ is -Q^2a-T^2a, in which Q^2a 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 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, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, R^2a′ is -Q^2a-T^2a, in which Q^2a 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 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, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, 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, C₃-C₁₂ cycloalkyl (e.g., C₃-C₈ cycloalkyl), or a 4- to 7-membered heterocycloalkyl.

In some embodiments, each Q^2a independently is C₂-C₆ alkenylene or C₂-C₆ alkynylene linker optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl.

In some embodiments, R^2a′ is H or C₁-C₆ alkyl.

In some embodiments, R^3a is H.

In some embodiments, R^3a is NR^aaR^ba or OR^aa, wherein each of R^aa and R^ba independently is H or C₁-C₆ alkyl optionally substituted with one or more of halo, hydroxyl, CN, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, R^3a is NR^aaR^ba or OR^aa, wherein each of R^aa and R^ba independently is H or C₁-C₆ 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.

In some embodiments, R^3a is NR^aaR^ba.

In some embodiments, each of R^aa and R^ba independently is H or R^S5a.

In some embodiments, one of R^aa and R^ba is H and the other is R^S5a.

In some embodiments, 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, C₁-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).

In some embodiments, 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, C₁-C₆ alkyl, or C₁-C₆ alkoxyl.

In some embodiments, 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).

In some embodiments, 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, C₁-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).

In some embodiments, the compound is of Formulae (Va′), (Vb′), (Vc′), (Vd′), (Ve′), or (Vf′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein

• • R^3a is H, NR^aaR^ba, OR^aa, or R^S4a, in which R^S4a is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ 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^S4a, R^S5a, and the heterocycloalkyl formed by R^a and R^ba is independently optionally substituted with one or more of halo, hydroxyl, oxo, CN, amino, mono- or di-alkylamino, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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;
  • 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 C₁-C₆ alkoxyl, and each T^3a independently is H, halo, cyano, OR^7a, OR^8a, C(O)R^8a, NR^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^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 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 C₁-C₆ 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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^da, C(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^da independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo.

In some embodiments, when R^3a is —NH₂, then R^4a is not —OCH₃.

In some embodiments, when R^3a is —NH₂, and R^4a is not —OCH₃, then R^4a′ is not OR^8a.

In some embodiments, 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, oxo, CN, amino, mono- or di-alkylamino, C₁-C₆ alkyl, or C₁-C₆ alkoxyl.

In some embodiments, R^3a is C₃-C₁₂ 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 C₃-C₁₂ 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, C₁-C₆ alkyl, or C₁-C₆ alkoxyl.

In some embodiments, R^3a is

In some embodiments, R^3a is NH₂.

In some embodiments, R^3a is NR^aaR^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.

In some embodiments, R^3a is oxo and is a single bond.

In some embodiments, R^3a is OH.

In some embodiments, R^3a is C₁-C₆ alkoxyl.

In some embodiments, R^3a and one of R^1a′, R^2a′, R^1a, R^2a and R^11a, together with the atoms to which they are attached, form a 6-membered heteroaryl that is optionally substituted with one or more of halo, C₁-C₃ alkyl, hydroxyl or C₁-C₃ alkoxyl.

In some embodiments, R^3a and one of R^1a′, R^2a′, R^1a, R^2a and R^11a, together with the atoms to which they are attached, form a 5-membered heteroaryl that is optionally substituted with one or more of halo, C₁-C₃ alkyl, hydroxyl or C₁-C₃ alkoxyl.

In some embodiments, the compound is of Formulae (VIa′), (VIb′), (VIc′), (VId′), (VIe′), or (VIf′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, 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^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, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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, or alternatively; and
  • 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 C₁-C₆ alkoxyl, and each T^3a independently is H, halo, cyano, OR^7a, OR^8a, C(O)R^8a, NR^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^6a;
  • each of R^8a, 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 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 C₁-C₆ 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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^da, C(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^da independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo.

In some embodiments, at least one of R^aa and R^ba is R^S5a.

In some embodiments, when both of R^aa and R^ba are H, then R^4a is not —OCH₃.

In some embodiments, when both of R^aa and R^ba are H, and R^4a is —OCH₃, then R^4a′ is not OR^8a.

In some embodiments, 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^1a, NR^7aR^8a, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₂ cycloalkyl, or 4- to 12-membered heterocycloalkyl.

In some embodiments, 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, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl.

In some embodiments, R^4a′ is -Q^3a-T^3a in which 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, OR^7a, OR^8a, NR^7aR^8a, C₃-C₁₂ cycloalkyl, or 4- to 12-membered heterocycloalkyl.

In some embodiments, at least one of R^4a and R^4a′ is C₁-C₆ alkyl. In some embodiments, R^4a is C₁-C₆ alkyl.

In some embodiments, at least one of R^4a and R^4a′ is CH₃. In some embodiments, R^4a is CH₃.

In some embodiments, at least one of R^4a and R^4a′ is halo. In some embodiments, R^4a is halo.

In some embodiments, at least one of R^4a and R^4a′ is F or Cl. In some embodiments, R^4a is F or Cl.

In some embodiments, at least one of R^4a and R^4a′ is C₆-C₁₀ aryl. In some embodiments, R^4a is C₆-C₁₀ aryl.

In some embodiments, at least one of R^4a and R^4a′ is

In some embodiments, R^4a is

In some embodiments, 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.

In some embodiments, at least one of R^4a and R^4a′ is

In some embodiments, R^4a is

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^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^6a.

In some embodiments, R^4a′ is

wherein T^3a is H, halo, cyano, OR^7a, OR^8a, C(O)R^8a, NR^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^6a.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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, C₁-C₆ alkyl, or OR^7a. In some embodiments, R^7a is H or C₁-C₆ alkyl optionally substituted with one or more of hydroxyl, amino or mono- or di-alkylamino.

In some embodiments, at least one of R^4a and R^4a′ is —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂.

In some embodiments, 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 OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂.

In some embodiments, at least one of R^4a and R^4a′ is —OCH₃.

In some embodiments at least one of R^4a and R^4a′ is

In some embodiments, R^4a′ is

In some embodiments, at least one of R^4a and R^4a′ is OR^7a. In some embodiments, R^4a is OR^7a. In some embodiments, R^4a is OR^7a

In some embodiments, at least one of R^4a and R^4a′ is OR^8a. In some embodiments, R^4a′ is OR^8a.

In some embodiments, at least one of 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^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^6a.

In some embodiments, R^4a′ is —CH₂-T^3a, wherein T^3a is H, halo, cyano, OR^7a, OR^8a, C(O)R^8a, NR^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^6a.

In some embodiments, at least one of R^4a and R^4a′ is —CH₂—OR₈. In some embodiments, R^4a′ is —CH₂—OR₈.

In some embodiments, at least one of R^4a and R^4a′ is —CH₂—NR₇R₈. In some embodiments, R^4a′ is —CH₂—NR₇R⁸.

In some embodiments, at least one of R^4a and R^4a′ is halo, C₁-C₆ alkyl, or OR^7a. In some embodiments, R^4a is halo, C₁-C₆ alkyl, or OR⁷.

In some embodiments, at least one of R^4a and R^4a′ is C₁-C₆ alkoxyl. In some embodiments, R^4a is C₁-C₆ alkoxyl.

In some embodiments, at least one of R^4a and R^4a′ is —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂. In some embodiments, R^4a is —OCH₃, —OCH₂CH₃, or —OCH(CH₃)₂.

In some embodiments, at least one of R^4a and R^4a′ is —OCH₃. In some embodiments, R^4a is —OCH₃.

In some embodiments, R^7a is H or C₁-C₆ alkyl optionally substituted with one or more of hydroxyl, amino or mono- or di-alkylamino.

In some embodiments, R^8a is -Q^4a-T^4a in which Q^4a is a C₁-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆ 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.

In some embodiments, 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-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 3-azabicyclo[3.1.0]hexanyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like.

In some embodiments, R^8a is -Q^4a-R^S5a, in which Q^4a is a bond or a C₁-C₆ 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-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 3-azabicyclo[3.1.0]hexanyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like), which is optionally substituted with one or more -Q^5a-T^5a.

In some embodiments, Q^4a is C₁-C₆ alkylene linker optionally substituted with a hydroxyl and R^S3a is C₃-C₆ cycloalkyl optionally substituted with one or more -Q^5a-T^5a.

In some embodiments, 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, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, morpholinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 3-azabicyclo[3.1.0]hexanyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like), which is optionally substituted with one or more -Q^5a-T^5a.

In some embodiments, Q⁴ is an optionally substituted C₂-C₆ alkenylene or C₂-C₆ alkynylene linker and R^S3a is C₃-C₆ cycloalkyl optionally substituted with one or more -Q^5a-T^5a.

In some embodiments, each Q^a independently is a bond or C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T^5a independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₁₂cycloalkyl (e.g., C₃-C₈ cycloalkyl), or 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

In some embodiments, each Q^a independently is a C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T^5a independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₃-C₁₂cycloalkyl (e.g., C₃-C₈ cycloalkyl), or 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

In some embodiments, -Q^5a-T^5a is oxo.

In some embodiments, at least one of R^4a and R^4a′ is

In some embodiments, at least one of R^4a′ is

In some embodiments, at least one of R^4a and R^4a′ is

In some embodiments, R^4a′ is

In some embodiments, at least one of R^4a and R^4a′ is

In some embodiments, R^4a′ is

In some embodiments, at least one of R^4a and R^4a′ is

In some embodiments R^4a′ is

In some embodiments, wherein at least one of R^4a and R^4a′ is

In some embodiments, R^4a′ is

In some embodiments, wherein at least one of R^4a and R^4a′ is

In some embodiments, R^4a′ is

In some embodiments, one of R^4a and R^4a′ is halo, C₁-C₆ 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 C₁-C₆ alkyl.

In some embodiments, R^4a is halo, C₁-C₆ alkyl, or OR^7a, 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.

In some embodiments, 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 C₁-C₆ alkyl.

In some embodiments, R^4a is C₁-C₆ alkoxyl, 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.

In some embodiments, one of R^4a and R^4a′ is —OCH₃, and the other is

In some embodiments, R^4a is —OCH₃, and R^4a′ is

In some embodiments, and one of R^4a and R^4a′ is —OCH₃, and the other is

In some embodiments, R^4a is —OCH₃, and R^4a′ is

In some embodiments, the compound is of Formula (VIIa′), (VIIb′), (VIIc′), (VIId′), (VIIe′), or (VIIf′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, 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^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, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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, or alternatively; and
  • 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^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^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 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 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-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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^da, C(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^a independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo.

In some embodiments, R^4a is —OCH₃.

In some embodiments, 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.

In some embodiments, the compound is of Formula (VIIIa′), (VIIIb′), (VIIIc′), (VIIId′), (VIIIe′), or (VIIIf′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, 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^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, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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, or alternatively; and
  • 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^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^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 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 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-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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^da, C(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^da independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo.

In some embodiments, R^4a is halo, C₁-C₆ alkyl, or OR^7a. In some embodiments, R^4a is C₁-C₆ alkoxyl. In some embodiments, R^4a is —OCH₃.

In some embodiments, the compound is of Formulae (IXa′), (IXb′), (IXc′), (IXd′), (IXe′), or (IXf′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, 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^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, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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, or alternatively; and
  • 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^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^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 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 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-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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^da, C(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^da independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo.

In some embodiments, R^4a is halo, C₁-C₆ alkyl, or OR^7a. In some embodiments, R^4a is C₁-C₆ alkoxyl. In some embodiments, R^4a is —OCH₃.

In some embodiments, the compound is of Formula (Xa′), (Xb′), (Xc′), (Xd′), (Xe′), or (Xf′):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, 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^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, C₁-C₆ alkyl, C₁-C₆ alkoxyl, 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, or alternatively; and
  • 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^7aR^8a, C(O)NR^7aR^8a, NR^7aC(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- 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-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^5aR^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 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 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-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 C₁-C₃ alkylene, C₂-C₃ alkenylene, or C₂-C₃ alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ 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-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^ca, C(O)R^ca, NR^caR^daC(O)NR^caR^da, S(O)₂R^ca, and NR^caC(O)R^da, each of R^ca and R^a independently being H or C₁-C₆ alkyl optionally substituted with one or more halo; or -Q^5a-T^5a is oxo.

In some embodiments, R^4a is halo, C₁-C₆ alkyl, or OR^7a. In some embodiments, R^4a is C₁-C₆ alkoxyl. In some embodiments, R^4a is —OCH₃.

In certain embodiments, for the methods disclosed herein, 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 C₆-C₁₀ aryl or 5- to 10-membered heteroaryl;
  • R^1b is H or C₁-C₄ alkyl;
  • each of R^2b, R^3b, R^4b, and R^5b, independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkoxyl, C₆-C₁₀ aryl, OH, NR^abR^bb, C(O)NR^abR^bb, NR^abC(O)R^bb, C(O)OR^ab, OC(O)R^ab, OC(O)NR^abR^b, NR^abC(O)OR^bb, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl, wherein the C₆-C₁₀ aryl, C₃-C₈ 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^ab, or NR^abR^b in which each of R^ab and R^bb independently is H or C₁-C₆ 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 optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C₁-C₆ alkoxyl, and T^1b is H, halo, cyano, or R^S1b, in which R^S1b is C₃-C₈ 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, oxo, —C(O)R^cb, —C(O)OR^cb, —SO₂R^cb, —SO₂N(R^b)₂—NR^cbC(O)R^db, —C(O)NR^cbR^db, —NR^cbC(O)OR^db, —OC(O)NR^cbR^db, NR^cbR^db, or C₁-C₆ alkoxyl, in which each of R^cb and R^db independently is H or C₁-C₆ alkyl;
  • R^7b is -Q^2b-T^2b, in which Q^2b is a bond, C(O)NR^cb, or NR^cbC(O), R^cb 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 C₁-C₃ 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^fb, NR^fbR^gb, OC(O)NR^fbR^gb, NR^fbC(O)OR^gb, C(O)NR^fbR^gb, and NR^fbC(O)R^gb, each of R^fb and R^gb independently being H or C₁-C₆ alkyl, in which the C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ alkoxy; or -Q^3b-T^3b is oxo;
  • R^8b is H or C₁-C₆ alkyl;
  • R^9b is -Q^4b-T^4b, in which Q^4b 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 C₁-C₆ alkoxyl, and T^4b is H, halo, OR^hb, NR^hbR^ib, NR^hbC(O)R^ib, C(O)NR^hbR^ib, C(O)R^b, C(O)OR^hb, NR^hbC(O)OR^ib, OC(O)NR^hbR^ib, S(O)₂R^hb, S(O)₂NR^hbR^ib, or R^S2b, in which each of R^hb and R^ib independently is H or C₁-C₆ alkyl, and R^S2b 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, and 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 C₁-C₆ alkoxy, and each T^5b independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^b, NR^jbR^kb, OC(O)NR^jbR^kb, NR^jbC(O)OR^kb, C(O)NR^jbR^kb, and NR^jbC(O)R^kb, each of R^jb and R^kb independently being H or C₁-C₆ 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, 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ 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.

In some embodiments, the EHMT2 inhibitor is a compound is of Formula (I′).

In some embodiments, at least one of X^1b, X^2b, X^3b and X^4b is N.

In some embodiments, X^1b and X^3b are N.

In some embodiments, X^1b and X^3b are N, X^2b is CR^3b and X^4b is CR^5b.

In some embodiments,

is

In some embodiments,

is

In some embodiments, ring B is phenyl or 6-membered heteroaryl.

In some embodiments,

is

In some embodiments, ring B is phenyl or pyridyl.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (Ia″), (Ib″), (Ic″), or (Id″):

In some embodiments, at most one of R^3b and R^5b is not H.

In some embodiments, at least one of R^3b and R^5b is not H.

In some embodiments, R^3b is H or halo.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (Ie″), (If″), (Ig″), or (Ih″):

In some embodiments, at most one of R^4b and R^5b is not H.

In some embodiments, at least one of R^4b and R^5b is not H.

In some embodiments, R^4b is H, C₁-C₆ alkyl, or halo.

In some embodiments, the EHMT2 inhibitor is a compound of Formula (Ii″), (Ij″), (Ik″), or (Il″).

In some embodiments, at most one of R^2b and R^5b is not H.

In some embodiments, at least one of R^2b and R^5b is not H.

In some embodiments, R^2b is H, C₁-C₆ alkyl, or halo.

In some embodiments, R^5b is C₁-C₆ alkyl.

In some embodiments, the EHMT2 inhibitor is a compound is of Formula (II″).

In some embodiments, each of X^5b, X^6b and X^7b is CH.

In some embodiments, at least one of X^5b, X^6b and X^7b is N.

In some embodiments, at most one of X^5b, X^6b and X^7b is N.

In some embodiments, R^10b is optionally substituted 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

In some embodiments, R^10b is connected to the bicyclic group of Formula (II″) via a carbon-carbon bond.

In some embodiments, R^10b is connected to the bicyclic group of Formula (II″) via a carbon-nitrogen bond.

In some embodiments, the compound is of Formula (III″).

In some embodiments, 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.

In some embodiments, 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-C₆ alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, each of X^5b and X^6b is CH.

In some embodiments, each of X^5b and X^6b is N.

In some embodiments, one of X^5b and X^6b is CH and the other is CH.

In some embodiments, R^6b is -Q^1b-T^1b, in which Q^1b is a bond or C₁-C₆ 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 C₃-C₈ 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, C₁-C₆ alkyl, hydroxyl, oxo, NR^cbR^db, or C₁-C₆ alkoxyl.

In some embodiments, R^6b is C₁-C₆ alkyl optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl.

In some embodiments, R^6b is unsubstituted C₁-C₆ alkyl.

In some embodiments, R^7b is -Q^2b-T^2b, in which Q^2b is a bond or C(O)NR^cb, 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.

In some embodiments, Q^2b is a bond.

In some embodiments, 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.

In some embodiments, 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 some embodiments, 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.

In some embodiments, T^2b is 5- to 10-membered heteroaryl.

In some embodiments, T^2b is selected from

and tautomers thereof, each of which is optionally substituted with one or more -Q^3b-T^3b, wherein X^8b is NH, O, or S, each of X^9b, X^10b, X^11b, and X^12b is independently CH or N, and at least one of X^9b, X^10b, X^11b, and X^12b is N, and ring A is a C₅-C₈ cycloalkyl, phenyl, 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

In some embodiments, T^2b is selected from

and tautomers thereof, each of which is optionally substituted with one or more -Q^3b-T^3b.

In some embodiments, each Q^3b independently is a bond or C₁-C₃ 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, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl, OR^fb, C(O)R^fb, C(O)OR^fb, NR^fbR^gb, C(O)NR^fbR^gb, and NR^fbC(O)R^gb, in which the C₃-C₈ cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more halo, cyano, hydroxyl, C₁-C₆ alkyl or C₁-C₆ alkoxy.

In some embodiments, at least one of R^8b and R^9b is H.

In some embodiments, each of R^8b and R^9b is H.

In some embodiments, R^8b is H.

In some embodiments, 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^hbR^ib, NR^hbC(O)R^ib, C(O)NR^hbR^ib, C(O)R^b, 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.

In some embodiments, each Q^5b independently is a bond or C₁-C₃ alkylene linker.

In some embodiments, 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^jbR^kb, C(O)NR^jbR^kb, and NR^jbC(O)R^kb.

In some embodiments, R^9b is C₁-C₃ alkyl.

In some embodiments, for the methods disclosed herein, the EHMT2 inhibitor is of Formula (I′″), (II′″), or (III′″).

tautomers thereof, and pharmaceutically acceptable salts of the compounds and the tautomers, wherein

• • 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^11cR^12c;
  • 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, C₁-C₆ alkoxyl, C₆-C₁₀ aryl, OH, NR^acR^bc, C(O)NR^acR^bc, NR^acC(O)R^bc, C(O)OR^ac, OC(O)R^ae, OC(O)NR^acR^bc, NR^acC(O)OR^bc, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl, wherein the C₆-C₁₀ aryl, C₃-C₈ 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^acR^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 with one or more of halo, cyano, hydroxyl, oxo, or C₁-C₆ alkoxyl, and T^1c is H, halo, cyano, or R^S1c, in which R^S1c is C₃-C₈ 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, oxo, —C(O)R^cc, —C(O)OR^cc, —SO₂R^cc, —SO₂N(R^cc)₂, —NR^ccC(O)R^dc, —C(O)NR^ccR^dc, —NR^ccC(O)OR^dc, —OC(O)NR^ccR^dc, NR^ccR^dc, or C₁-C₆ alkoxyl, in which each of R^cc and R^dc independently is H or C₁-C₆ alkyl;
  • 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^ecR^fc, C(O)NR^ecR^fc, NR^ecC(O)R^fc, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₂ cycloalkyl, or 4- to 12-membered heterocycloalkyl, and wherein the C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₂ cycloalkyl, or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more -Q^3c-T³, wherein 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, and each T^3c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^fc, NR^fcR^gc, OC(O)NR^fcR^gc, NR^fcC(O)OR^gc, C(O)NR^fcR^gc, and NR^fcC(O)R^gc; or -Q^3c-T^3c is oxo;
  • 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 C₁-C₆ alkoxyl;
  • each of R^fc and R^gc, independently, is -Q^6c-T⁶, in which Q^6c 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 C₁-C₆ alkoxyl, and T⁶ is H, halo, OR^m1c, NR^m1cR^m2c, NR^m1cC(O)R^m2c, C(O)NR^m1cR^m2c, C(O)R^m1c, C(O)OR^m1c, NR^m1cC(O)OR^m2c, OC(O)NR^m1cR^m2c, S(O)₂R^m1c, S(O)₂NR^m1cR^m2c, or R^S3c, in which each of R^m1c and R^m2c independently is H, C₁-C₆ alkyl, or (C₁-C₆ alkyl)-R^S3c, and 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, and 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 C₁-C₆ alkoxy, and each T^7c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^n1c, NR^n1cR^n2c, OC(O)NR^n1cR^n2c, NR^n1cC(O)OR^n2c, C(O)NR^n1cR^n2c, and NR^n1cC(O)R^n2c, each of R^n1c and R^n2c independently being H or C₁-C₆ alkyl; or -Q^7c-T^7c is oxo;
  • R^8c is H or C₁-C₆ alkyl;
  • 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 C₁-C₆ alkoxyl, and T^4c is H, halo, OR^hc, NR^hcR^ic, NR^hcC(O)R^ic, C(O)NR^hcR^ic, C(O)R^hc, C(O)OR^hc, NR^hcC(O)OR^ic, OC(O)NR^hcR^ic, S(O)₂R^hc, S(O)₂NR^hcR^ic, or R^S2c, in which each of R^hc and R^ic independently is H or C₁-C₆ alkyl, and R^S2c 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, and R^S2c is optionally substituted with one or more -Q^5c-T⁵⁰ wherein each Q^5c independently is a bond or C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T^5c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^jc, C(O)R^jc, C(O)OR^jc, OC(O)R^jc, S(O)₂R^jc, NR^jcR^kc, OC(O)NR^jcR^kc, NR^jcC(O)OR^kc, C(O)NR^jcR^kc, and NR^jcC(O)R^kc, each of R^jc and R^kc independently being H or C₁-C₆ alkyl; or -Q^5c-T^5c is oxo;
  • 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^jcR^kc, or NR^jcC(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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl;
  • R^13c is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₂ 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, C₁-C₆ 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.

In some embodiments, for the methods disclosed herein, the EHMT2 inhibitor is of Formula (I′″), (II′″), or (III′″), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein

• • 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^11cR^12c;
  • 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, C₁-C₆ alkoxyl, C₆-C₁₀ aryl, OH, NR^acR^bc, C(O)NR^acR^bc, NR^acC(O)R^bc, C(O)OR^ac, OC(O)R^ac, OC(O)NR^acR^bc, NR^acC(O)OR^bc, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl, wherein the C₆-C₁₀ aryl, C₃-C₈ 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^acR^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 with one or more of halo, cyano, hydroxyl, oxo, or C₁-C₆ alkoxyl, and T^1c is H, halo, cyano, or R^S1c, in which R^S1c is C₃-C₈ 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, oxo, —C(O)R^cc, —C(O)OR^cc, —SO₂R^cc, —SO₂N(R^cc)₂, —NR^ccC(O)R^dc, —C(O)NR^ccR^dc, —NR^ccC(O)OR^dc, —OC(O)NR^ccR^dc, NR^ccR^dc, or C₁-C₆ alkoxyl, in which each of R^cc and R^dc independently is H or C₁-C₆ alkyl;
  • 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^ecR^fc, C(O)NR^ecR^fc, NR^ecC(O)R^fc, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₂ cycloalkyl, or 4- to 12-membered heterocycloalkyl, and wherein the C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₂ 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 C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T^3c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^fc, NR^fcR^gc, OC(O)NR^fcR^gc, NR^fcC(O)OR^gc, C(O)NR^fcR^gc, and NR^fcC(O)R^gc; or -Q^3c-T^3c is oxo;
  • 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 C₁-C₆ alkoxyl;
  • each of R^fc and R^gc, independently, is -Q^6c-T^6c in which Q^6c 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 C₁-C₆ alkoxyl, and T^6c is H, halo, OR^m1c, NR^m1cR^m2c, NR^m1cC(O)R^m2c, C(O)NR^m1cR^m2c, C(O)R^m1c, C(O)OR^m1c, NR^m1cC(O)OR^m2c, OC(O)NR^m1cR^m2c, S(O)₂R^m1c, S(O)₂NR^m1cR^m2c, or R^S3c, in which each of R^m1c and R^m2c independently is H or C₁-C₆ alkyl, and 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, and 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 C₁-C₆ alkoxy, and each T^7c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^n1c, NR^n1cR^2c, OC(O)NR^n1cR^n2c, NR^n1cC(O)OR^n2c, C(O)NR^n1cR^n2c, and NR^n1cC(O)R^n2c, each of R^n1c and R^n2c independently being H or C₁-C₆ alkyl; or -Q^7c-T^7c is oxo;
  • R^8c is H or C₁-C₆ alkyl;
  • 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 C₁-C₆ alkoxyl, and T^4c is H, halo, OR^hc, NR^hcR^ic, NR^hcC(O)R^ic, C(O)NR^hcR^ic, C(O)R^hc, C(O)OR^hc, NR^hcC(O)OR^ic, OC(O)NR^hcR^ic, S(O)₂R^hc, S(O)₂NR^hcR^ic, or R^S2c, in which each of R^hc and R^ic independently is H or C₁-C₆ alkyl, and R^S2c 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, and R^S2c is optionally substituted with one or more -Q^5c-T^5c wherein each Q^5c independently is a bond or C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T⁵ independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^jc, C(O)R^jc, C(O)OR^jc, OC(O)R^jc, S(O)₂R^jc, NR^jcR^kc, OC(O)NR^jcR^kc, NR^jcC(O)OR^kc, C(O)NR^jcR^kc, and NR^jcC(O)R^kc, each of R^jc and R^kc independently being H or C₁-C₆ alkyl; or -Q^5c-T^5c is oxo;
  • 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^jcR^kc, or NR^jcC(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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl;

• • R^13c is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₂ 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, C₁-C₆ 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.

In some embodiments, the compound is of Formula (I′″), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, when X^1c is N, X^2c is CH, X^3c is N, X^4c is CCH₃, X^5c is CH, X^6c is CH, R^1c is H, R^7c is

one of R^8c and R^9c is H and the other one is CH₃, and R^14c is OCH₃, then

• • R^15c is H, halo, cyano, C₁-C₆ 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.

In some embodiments, when X^1c is N, X^2c is CH, X^3c is N, X^4c is CCH₃, X^5c is CH, X^6c is CH, R^1c is H, R^7c is

one of R^8c and R^9c is H and the other one is CH₃, and R^14c is OCH₃, then

• • R^15c is H, Cl, Br, cyano, C₁-C₆ 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.

In some embodiments, wherein when X^1c is N, X^2c is CH, X^3c is N, X^4c is CCH₃, X^5c is CH, X^6c is CH, R^1c is H, R^7c is selected from the group consisting of

one of R^8c and R^9c is H and the other one is CH₃, and R^14c is Cl, then

R^15c is H, halo, cyano, C₁-C₆ 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.

In some embodiments, wherein when X^1c is N, X^2c is CH, X^3c is N, X^4c is CCH₃, X^5c is CH, X^6c is CH, R^1c is H, R^7c is selected from the group consisting of

one of R^8c and R^9c is H and the other one is CH₃, and R^14c is Cl, then

• • R^15c is halo, cyano, C₁-C₆ 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.

In some embodiments, the compound is not one of the following compounds:

In some embodiments, the compound is of Formula (II′″) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, when X^5c is CH, X^7c is CH, R^7c is

one of R^8c and 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, C₁-C₆ 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.

In some embodiments, when X^5c is CH, X^7c is CH, R^7c is

one of R^8c and R^9c is H and the other one is CH₃, R^10c is

and R^14c is OCH₃, then

• • R^15c is H, Cl, Br, cyano, C₁-C₆ 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.

In some embodiments, the compound is not

In some embodiments, the compound is of Formula (III′″) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, when X^5c is CH, X^8c is CR^11cR^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, and R^14c is OCH₃, then

• • R^15c is H, halo, cyano, C₁-C₆ 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.

In some embodiments, when X^5c is CH, X^8c is CR^11cR^12c, in which R^11c and R^12c to ether 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, and R^14c is OCH₃, then

• • R^15c is H, Cl, Br, cyano, C₁-C₆ 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.

In some embodiments, the compound is not

In some embodiments, 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. In some embodiments, R^14c is Br. In some embodiments, R^15c is halo. In some embodiments, R^15c is F. In some embodiments, R¹⁵, is Cl. In some embodiments, R^15c is Br. In some embodiments, both of R^14c and R^15c are halo.

In some embodiments, one of R^14c and R^15c is halo, and the other one is H, cyano, C₁-C₆ 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.

In some embodiments, one of R^14c and R^15c is halo, and the other one is H, C₁-C₆ 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 R⁶, is C₁-C₆ alkyl optionally substituted with one or more of halo or cyano.

In some embodiments, one of R^14c and R^15c is halo, and the other one is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, or —OR^6c, in which R^6c is C₁-C₆ alkyl. In some embodiments, R^14c is halo, and R^15c is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, or —OR^6c, in which R^6c is C₁-C₆ alkyl. In some embodiments, R^14c is halo, and R^15c is H. In some embodiments, R^14c is halo, and R^15c is C₁-C₆ alkyl. In some embodiments, 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 C₁-C₆ 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 C₁-C₆ alkyl. In some embodiments, 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 C₁-C₆ 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, the compound is of any of Formula (I′″-1), (I′″-2), (II′″-1), (II′″-2), (III′″-1), or (III′″-2).

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, wherein

• • 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, C₁-C₆ alkoxyl, C₆-C₁₀ aryl, OH, NR^acR^bc, C(O)NR^acR^bc, NR^acC(O)R^bc, C(O)OR^ac, OC(O)R^ac, OC(O)NR^acR^bc, NR^acC(O)OR^bc, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl, wherein the C₆-C₁₀ aryl, C₃-C₈ 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^acCR^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 with one or more of halo, cyano, hydroxyl, oxo, or C₁-C₆ alkoxyl, and T^1c is H, halo, cyano, or R^S1c, in which R^S1c is C₃-C₈ 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, oxo, —C(O)R^cc, —C(O)OR^cc, —SO₂R^cc, —SO₂N(R^cc)₂, —NR^ccC(O)R^dc, —C(O)NR^ccR^dc, —NR^ccC(O)OR^dc, —OC(O)NR^ccR^dc, NR^ccR^dc, or C₁-C₆ alkoxyl, in which each of R^cc and R^dc independently is H or C₁-C₆ alkyl;
  • R^7c is -Q^2c-T^2c, in which Q^2c is a bond, 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, and T^2c is H, halo, cyano, OR^ec, OR^fc, C(O)R^fc, NR^ecR^fc, C(O)NR^ecR^fc, NR^ecC(O)R^fc, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₂ cycloalkyl, or 4- to 12-membered heterocycloalkyl, and wherein the C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₂ 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 C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T^3c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^fc, NR^fcR^gc, OC(O)NR^fcR^gc, NR^fcC(O)OR^gc, C(O)NR^fcR^gc, and NR^fcC(O)R^gc; or -Q^3c-T^3c is oxo;
  • 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 C₁-C₆ alkoxyl;
  • each of R^fc and R^gc, independently, is -Q^6c-T^6c in which Q^6c 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 C₁-C₆ alkoxyl, and T^6c is H, halo, OR^m1c, NR^m1cR^m2c, NR^m1cC(O)R^m2c, C(O)NR^m1cR^m2c, C(O)R^m1c, C(O)OR^m1c, NR^m1cC(O)OR^m2c, OC(O)NR^m1cR^m2c, S(O)₂R^m1c, S(O)₂NR^m1cR^m2c, or R^S3c, in which each of R^m1c and R^m2c independently is H or C₁-C₆ alkyl, and 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, and 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 C₁-C₆ alkoxy, and each T^7c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^n1c, NR^n1cR^2c, OC(O)NR^n1cR^n2c, NR^n1cC(O)OR^n2c, C(O)NR^n1cR^n2c, and NR^n1cC(O)R^n2c, each of R^n1c and R^n2c independently being H or C₁-C₆ alkyl; or -Q⁷C-T^7c is oxo; R^8c is H or C₁-C₆ alkyl;
  • 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 C₁-C₆ alkoxyl, and T⁴C is H, halo, OR^hc NR^hcR^ic, NR^hcC(O)R^ic, C(O)NR^hcR^ic, C(O)R^hc, C(O)OR^hc, NR^hcC(O)OR^ic, OC(O)NR^hcR^ic, S(O)₂R^hc, S(O)₂NR^hcR^ic, or R^S2c, in which each of R^hc and R^ic independently is H or C₁-C₆ alkyl, and R^S2c 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, and R^S2c is optionally substituted with one or more -Q^5c-T^5c wherein each Q^5c independently is a bond or C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T^5c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR^jc, C(O)R^jc, C(O)OR^jc, OC(O)R^jc, S(O)₂R^jc, NR^jcR^kc, OC(O)NR^jcR^kc, NR^jcC(O)OR^kc, C(O)NR^jcR^kc, and NR^jcC(O)R^kc, each of R^jc and R^kc independently being H or C₁-C₆ alkyl; or -Q^5c-T^5c is oxo;
  • R¹⁰ 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^jcR^kc, or NR^jcC(O)R^kc; and
  • 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, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl
  • each of R^14c and R^15c, independently, is H, halo, cyano, C₁-C₆ 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, or C₃-C₈ cycloalkyl optionally substituted with one or more of halo or cyano.

In some embodiments, the compound is of Formula (I′″-1) or (I′″-2), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, at least one of X^1c, X^2c, X^3c and X^4c is N. In some embodiments, 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.

In some embodiments,

is

In some embodiments,

is

In some embodiments, the compound is of Formula (I′″-1a), (I′″-2a), (I′″-1b), (I′″-2b), (I′″-1c), or (I′″-2c):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, 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.

In some embodiments, the compound is of Formula (I′″-1d), (I′″-2d), (I′″-1e), (I′″-2e), (I′″-1f), or (I′″-2f):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, at most one of R^4c and R^5c is 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.

In some embodiments, the compound of Formula (I′″-1g), (I′″-2g), (I′″-1h), (I′″-2h), (I′″-1i), or (I′″-2i):

a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, at most one of R^2c and R^5c is 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 C₁-C₆ alkyl.

In some embodiments, the compound is of Formula (II′″-1) of (II′″-2), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, 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.

In some embodiments, R¹⁰ is optionally substituted 4- to 7-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S. In some embodiments, R^1c is connected to the bicyclic group of Formula (II′″-1) or (II′″-2) via a carbon-carbon bond. In some embodiments, R¹⁰ is connected to the bicyclic group of Formula (II′″-1) or (II′″-2) via a carbon-nitrogen bond.

In some embodiments, the compound is of Formula (III′″-1) or (III′″-2), a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

In some embodiments, 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, C₁-C₆ alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, 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-C₆ alkyl, hydroxyl, oxo, amino, mono- or di-alkylamino, or C₁-C₆ alkoxyl.

In some embodiments, 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.

In some embodiments, R^6c is -Q^1c-T^1c, in which Q^1c is a bond or C₁-C₆ 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 C₃-C₈ 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, C₁-C₆ alkyl, hydroxyl, oxo, NR^ccR^dc, or C₁-C₆ alkoxyl.

In some embodiments, wherein R^6c is C₁-C₆ alkyl optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxyl. In some embodiments, R^6c is C₁-C₆ alkyl. In some embodiments, R^6c is —CH₃.

In some embodiments, R^7c is -Q^2c-T^2c, in which Q^2c 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, and T^2c is C(O)NR^ecR^fc.

In some embodiments, Q^2c is a bond. In some embodiments, R^ec is H.

In some embodiments, R^fc is -Q^6c-T^6c in which Q^6c 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 C₁-C₆ alkoxyl, and T^6c is H, NR^m1cR^m2c or R^S3c, in which each of R^m1c and R^m2c independently is H, C₁-C₆ alkyl, or —(C₁-C₆ alkyl)-R^S3c, and 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, and R^S3c is optionally substituted with one or more -Q^7c-T^7c.

In some embodiments, R^fc is -Q^6c-T^6c in which Q^6c 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 C₁-C₆ alkoxyl, and T^6c is H, NR^m1cR^m2c or R^S3c, in which each of R^m1c and R^m2c independently is H or C₁-C₆ alkyl, and 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, and R^S3c is optionally substituted with one or more -Q⁷C-T^7c.

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 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.

and tautomers thereof, each of which is optionally substituted with one or more -Q^7c-T^7c, wherein X^8c is NH, O, or S, each of X^9c, X¹⁰, X^11c, and X^12c is independently CH or N, and at least one of X^9c, X¹⁰, X^11c, and X^12c is N, and ring A is a C₅-C₈ cycloalkyl, phenyl, 6-membered heteroaryl, or 4- to 8-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S.

In some embodiments T^6c is selected from

and tautomers thereof, each of which is optionally substituted with one or more -Q^7c-T^7c.

In some embodiments, each Q^7c independently is a bond or C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T⁷, independently is selected the group consisting of H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ 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)₂R^n1c, NR^n1cR^n2c, OC(O)NR^n1cR^n2c, NR^n1cC(O)OR^n2c, C(O)NR^n1cR^n2c, and NR^n1cC(O)R^n2c, each of R^n1c and R^n2c independently being H or C₁-C₆ alkyl; or -Q^7c-T^7c is oxo.

In some embodiments, each Q^7c independently is a bond or C₁-C₃ alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C₁-C₆ alkoxy, and each T^7c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, and NR^n1cR^n2c, each of R^n1c and R^n2c independently being H or C₁-C₆ alkyl.

In some embodiments, R^7c is -Q^2c-T^2c, in which Q^2c 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^2c independently is H, OR^ec, OR^fc, NR^ecR^fc, C₃-C₁₂ cycloalkyl, or 4- to 12-membered heterocycloalkyl.

In some embodiments, R^7c is

wherein T^2c is H, halo, cyano, OR^ec, OR^fc, C(O)R^fc, NR^ecR^fc, C(O)NR^ecR^fc, NR^ecC(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 C₆-C₁₀ 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^cc, C₁-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^ccR^dc.

In some embodiments, 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.

In some embodiments, R^7c is

In some embodiments, R^7c is OR^ec.

In some embodiments, R^7c is OR^fc.

In some embodiments, R^7c is O-Q^6e-NR^m1cR^m2c. In some embodiments, R^7c is O-Q^6c-NH—(C₁-C₆ alkyl)-R^S3c.

In some embodiments, R^7c is —CH₂-T^2c, wherein T^2c is H, halo, cyano, OR^ec, OR^fc, C(O)R^fc, NR^7cR^fc, C(O)NR^ecR^fc, NR^ecC(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 C₆-C₁₀ 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^cc, C₁-C₆ alkoxyl or C₁-C₆ alkyl optionally substituted with one or more of NR^ccR^dc.

In some embodiments, R^7c is —CH₂—OR₈.

In some embodiments, R^7c is —CH₂—NR₇R₈.

In some embodiments, R^7c is

In some embodiments, R⁷ is

In some embodiments, R^7c is

In some embodiments, R^7c is

In some embodiments, R^7c is

In some embodiments, R^7c is

In some embodiments, 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.

In some embodiments, 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 C₁-C₆ alkoxyl, and T^4c is H, halo, OR^hc, NR^hcR^ic, NR^hcC(O)R^ic, C(O)NR^hcR^ic, C(O)R^hc, C(O)OR^hc, or R^S2c, in which R^S2c is C₃-C₈ cycloalkyl or 4- to 7-membered heterocycloalkyl, and R^S2c is optionally substituted with one or more -Q^5c-T^5c.

In some embodiments, each Q^5c independently is a bond or C₁-C₃ alkylene linker.

In some embodiments, each T^5c independently is selected from the group consisting of H, halo, cyano, C₁-C₆ alkyl, OR^jc, C(O)R^jc, C(O)OR^jc, NR^jcR^kc, C(O)NR^jcR^kc, and NR^jcC(O)R^kc.

In some embodiments, R^9c is C₁-C₃ alkyl.

In some embodiments, R^14c is H, halo, or C₁-C₆ alkyl.

In some aspects, the present disclosure provides a compound of Formula (IA′″) or (IIA′″):

a tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:

• • R^8c is C₁-C₆ alkyl;
  • R^5c is C₁-C₆ alkyl;
  • R^11c and R^12c each independently is C₁-C₆ alkyl, or R^11c and R^12c together with the carbon atom to which they are attached form C₃-C₁₂ cycloalkyl;
  • R^14c and R^15c each independently is H, halogen, or C₁-C₆ alkoxyl; and
  • R^7c is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of R^7cS; each R^7cS independently is COOH, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or 4- to 12-membered heterocycloalkyl, wherein the C₁-C₆ alkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of oxo, C₁-C₆ alkyl, or NR^7cSaR^7cSb; R^7cSa and R^7cSb each independently is H or C₁-C₆ alkyl, or R^7cSa and R^7cSb together with the nitrogen atom to which they are attached form C₃-C₆ heterocycloalkyl.

In some embodiments, the compound is of Formula (IA′″) or (IIA′″), a tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:

• • R^8c is C₁-C₆ alkyl;
  • R^5c is C₁-C₆ alkyl;
  • R^11c and R^12c each independently is C₁-C₆ alkyl, or R^11c and R^12c together with the carbon atom to which they are attached form C₃-C₁₂ cycloalkyl;
  • R^14c and R^15c each independently is H, halogen, or C₁-C₆ alkoxyl; and
  • R^7c is 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heteroaryl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of R^7cS; each R^7cS independently is C₁-C₆ alkyl or 4- to 12-membered heterocycloalkyl, wherein the C₁-C₆ alkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of NR^7cSaR^7cSb; R^7cSa and R^7cSb each independently is H or C₁-C₆ alkyl, or R^7cSa and R^7cSb together with the nitrogen atom to which they are attached form C₃-C₆ heterocycloalkyl.

In some embodiments, R^8c is methyl or ethyl. In some embodiments, R^8c is methyl.

In some embodiments, R^5c is methyl, ethyl, n-propyl, or i-propyl. In some embodiments, R^5c is methyl. In some embodiments, R^5c is i-propyl.

In some embodiments, R^11c and R^12c each independently is C₁-C₆ alkyl. In some embodiments, R^11c and R^12c each independently is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl. In some embodiments, R^11c and R^12c each independently is methyl, ethyl, n-propyl, or i-propyl.

In some embodiments, R^11c and R^12c together with the carbon atom to which they are attached form C₃-C₁₂ cycloalkyl. In some embodiments, R^11c and R^12c together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R^11c and R^12c together with the carbon atom to which they are attached form cyclobutyl.

In some embodiments, at least one of R^14c and R^15c is halogen. In some embodiments, at least one of R^14c and R^15c is F or Cl. 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, R^14c is halogen. In some embodiments, R^14c is F or Cl. In some embodiments, R^14c is F. In some embodiments, R^3c is Cl.

In some embodiments, R^15c is halogen. In some embodiments, R^15c is F or Cl. In some embodiments, R^15c is F. In some embodiments, R^15c is Cl.

In some embodiments, one of R^14c and R^15c is halogen, and the other one is H or C₁-C₆ alkoxyl. In some embodiments, at least one of R^14c and R^15c is F or Cl, and the other one is H or C₁-C₆ alkoxyl. In some embodiments, at least one of R^14c and R^15c is F or Cl, and the other one is H. In some embodiments, at least one of R^14c and R^15c is F or Cl, and the other one is methoxy.

In some embodiments, R^14c is halogen, and R^15c is H or C₁-C₆ alkoxyl. In some embodiments, R^14c is F or Cl, and R^15c is H or C₁-C₆ alkoxyl. In some embodiments, R^14c is F or Cl, and R^15c is H. In some embodiments, R^14c is F or Cl, and R^15c is methoxy.

In some embodiments, R^15c is halogen, and R^14c is H or C₁-C₆ alkoxyl. In some embodiments, R^15c is F or Cl, and R^14c is H or C₁-C₆ alkoxyl. In some embodiments, R^15c is F or Cl, and R^14c is H. In some embodiments, R^15c is F or Cl, and R^14c is methoxy.

In some embodiments, both R^14c and R^15c are halogen. In some embodiments, R^14c and R^15c each independently is F or Cl. In some embodiments, both R^14c and R^15c are F. In some embodiments, R^14c is F, and R^15c is Cl. In some embodiments, R^15c is F, and R^14c is Cl. In some embodiments, both R^14c and R^15c are Cl.

In some embodiments, R^7c is 5- to 10-membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more of R^7cS.

In some embodiments, R^7c is 5-membered heteroaryl containing 3 of N, wherein the 5-membered heteroaryl is optionally substituted with one or more of R^7cS.

In some embodiments, R^7c is

wherein n is 0, 1, or 2.

In some embodiments, R^7c is

wherein n is 0, 1, or 2.

In some embodiments, the compound is of Formula (IAa′″) or (IIAa′″):

a tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer.

In some embodiments, the compound is of Formula (IAb′″) or (IIAb)′″:

a tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer.

In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, R^7c is 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, wherein the 4- to 12-membered heterocycloalkyl is optionally substituted with one or more of R^7cS.

In some embodiments, at least one R^7cS is COOH.

In some embodiments, at least one R^7cS is oxo.

In some embodiments, at least one R^7cS is C₁-C₆ haloalkyl (e.g., methyl, ethyl, propyl, butyl, pental, or hexyl in which at least one H is substituted with a halogen (e.g., F, Cl, Br, or I)). In some embodiments, at least one R^7cS is CH₂F, CHF₂, or CF₃. In some embodiments, at least one R^7cS is CF₃.

In some embodiments, at least one R^7cS is C₁-C₆ alkyl optionally substituted with one or more of oxo or NR^7cSaR^7cSb. In some embodiments, at least one R^7cS is C₁-C₆ alkyl substituted with one oxo and one NR^7cSaR^7cSb.

In some embodiments, at least one R^7cS is C₁-C₆ alkyl optionally substituted with one or more of NR^7cSaR^7cSb. In some embodiments, at least one R^7cS is methyl optionally substituted with one or more of NR^7cSaR^7cSb. In some embodiments, at least one R^7cS is

In some embodiments, at least one R^7cS is.

In some embodiments, at least one R^7cS is 4- to 12-membered heterocycloalkyl optionally substituted with one or more of oxo, C₁-C₆ alkyl, or NR^7cSaR^7cSb. In some embodiments, at least one R^7cS is 4- to 12-membered heterocycloalkyl optionally substituted with one or more of C₁-C₆ alkyl.

In some embodiments, at least one R^7cS is 4- to 12-membered heterocycloalkyl optionally substituted with one or more of NR^7cSaR^7cSb. In some embodiments, at least one R^7cS is 5-membered heterocycloalkyl optionally substituted with one or more of NR^7cSaR^7cSb. In some embodiments, at least one R^7cS is pyrrolidinyl optionally substituted with one or more of NR^7cSaR^7cSb. In some embodiments, at least one R^7cS is pyrrolidinyl. In some embodiments, at least one R^7cS is

In some embodiments, at least one R^7cS is

H In some embodiments, at least one R^7cS is

In some embodiments, both of R^7cSa and R^7cSb are H. In some embodiments, one of R^7cSa and R^7cSb is H, and the other is C₁-C₆ alkyl. In some embodiments, one of R^7cSa and R^7cSb is H, and the other is methyl. In some embodiments, both of R^7cSa and R^7cSb are C₁-C₆ alkyl. In some embodiments, both of R^7cSa and R^7cSb are methyl.

In some embodiments, R^7cSa and R^7cSb together with the nitrogen atom to which they are attached form C₃-C₆ heterocycloalkyl. In some embodiments, R^7cSa and R^7cSb together with the nitrogen atom to which they are attached form C₄ heterocycloalkyl. In some embodiments, R^7cSa and R^7cSb together with the nitrogen atom to which they are attached form

In some embodiments, R^7c is

Exemplary EHMNT2 inhibitory compounds suitable for use in the methods of the present disclosure include, without limitation, compounds listed in Tables 1A-1E, 2-4, 4A, and 5, and tautomers and salts thereof.

The compounds of Tables 1A-1E are the compounds found in U.S. Application Nos. 62/323,602, 62/348,837, 62/402,997, and Ser. No. 15/601,888, and PCT Application No. PCT/US2017/027918, the entire contents of which are incorporated herein by reference.

TABLE 1A
Compound
No. Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
190
191
192
193
194
195
196
197
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262a
262b
263
264
265
266
267
268
269
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337

TABLE 1B
Cmpd.
No. Structure
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
494a
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517a
517b

TABLE 1C
Comd.
No. Structure
270
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
699
700
701
702
703
704
705
706
707
708
709
710
711
712
713
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
749
750
751
752
753
754
755
756
757
758
759
760
761
762
763
764
765

TABLE 1D
Cmpd.
No. Structure
784
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
820
821
822
823
824
825
826
827
828
832
833
834
836
837
838
839
840
841
842
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
868
869
870
871
872
873
874
875
876
877
878
879
881
882
883
884
885
886
887
888
890
891
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
921
922
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
961
962
963
964
965
966
967
968
969
970
971
972
974
975
976
977
983
985
986
989
990
991
992
993
994
997
998
999
1000
1001
1002
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
1023
1024
1025
1026
1027
1028
1029
1030
1031
1032
1033
1034
1035
1036
1037
1038
1039
1040
1041
1042

TABLE 1E
Cmpd.
No. Structure
1043
1044
1045
1046
1047
1048
1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
1070
1071
1072
1073
1074
1075
1076
1077
1078
1079
1080
1081
1082
1083
1084
1085
1086
1087
1088
1089
1090
1091
1092
1093
1094
1095
1096
1097
1098
1099
1100
1101
1102
1103
1104
1105
1106
1107
1108
1109
1110
1111
1112
1113
1114
1115
1116
1117
1118

TABLE 2
Compound
No. Structure
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
A30
A31
A32
A33
A34
A35
A36
A37
A38
A39
A40
A41
A42
A43
A44
A45
A46
A47
A48
A49
A50
A51
A52
A53
A54
A55
A56
A57
A58
A59
A60
A61
A62
A63
A64
A65
A66
A67
A68
A69
A70
A71
A72
A73
A74
A75
A76
A77
A78
A79
A80
A81
A82
A83
A84
A85
A86
A87
A88
A89
A90
A91
A92
A93
A94
A95
A96
A97
A98
A99
A100
A101
A106
A107
A110
A111
A112
A113
A114
A115
A116
A117
A118
A119
A120
A121
A122
A123
A124
A125
A126
A127
A128
A129
A130
A131
A132
A133
A134
A135
A136
A137
A138
A139
A140
A141

The compounds of Table 4 are the compounds found in U.S. Application Nos. 62/402,863 and 62/509,620, and PCT Appl'n No. PCT/US2017/054468, the entire contents of which are incorporated herein by reference.

TABLE 3
Cmpd.
No. Structure
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
B22
B23
B24
B25
B26
B27
B28
B29
B30
B31
B32
B33
B34
B35
B36
B37
B38
B39
B40
B41
B42
B43
B44
B45
B46
B47
B48
B49
B50
B51
B52
B53
B54
B55
B56
B57
B58
B59
B60
B61
B62
B63
B64
B65
B66
B67
B68
B69
B70
B71
B72
B73
B74
B75
B76
B77
B78
B79
B80
B81
B82
B83
B84
B85
B86
B87
B88
B89
B90
B91
B92
B93
B94
B95
B96
B97
B98
B99
B100
B101
B102
B103
B104
B105
B106
B107
B108
B109
B110
B111
B112
B113
B114
B115
B116
B117
B118
B119
B120
B121
B122
B123
B124
B125
B126
B127
B128
B129
B130
B131
B132
B133
B134
B135
B136
B137
B138
B139
B140
B141
B142
B143
B144
B145
B146
B147
B148
B149
B150
B151
B152
B153
B154
B155
B156
B157
B158
B159
B160
B161
B162
B163
B164
B165
B166
B167
B168
B169
B170
B171
B172
B173
B174
B175
B176
B177
B178
B179
B180
B181
B182
B183
B184
B185
B186
B187
B188
B191
B192
B193
B194
B195
B196
B197
B198
B199
B200
B201
B202
B203
B204
B205
B206
B207
B208
B209
B210
B211
B212
B213
B214
B215
B216
B217
B218
B219
B220
B221
B222
B223
B224
B225
B226
B227
B228
B229
B230
B231
B232
B233
B234
B235
B236
B237
B238
B239
B240
B241
B242
B243
B244
B245
B246
B247
B248
B249
B250
B251
B252
B253
B254
B255
B256
B257
B258
B259
B260
B261
B262
B269
B271
B274
B276
B277
B278
B279
B280
B281
B282
B283
B284
B285
B286
B287
B288
B289
B290
B291

The compounds of Table 3 are the compounds found in U.S. Application Nos. 62/436,139 and 62/517,840, and PCT Application No. PCT/US20170067192, the entire contents of which are incorporated herein by reference.

TABLE 4
Compound
No. Structure
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
C25
C26
C27
C28
C29
C30
C31
C32
C33
C34
C35
C36
C37
C38
C39
C40
C41
C42
C43
C44
C45
C46
C47
C48
C49
C50
C51
C52
C53
C54
C55
C56
C57
C58
C59
C60
C61
C62
C63
C64
C65
C66
C67
C68
C69
C70
C71
C72
C73
C74
C75
C76
C77
C78
C79
C79S
C79R
C80
C80S
C80R

The compounds of Table 4 are the compounds found in U.S. Application No. 62/573,442 and 62/746,495, and PCT Application No. PCT/US2018/056333, the entire contents of which are incorporated herein by reference

TABLE 4A
Cmpd.
No. Structure
CA1
CA2
CA2S
CA2R
CA3
CA4
CA4S
CA4R
CA5
CA6
CA7
CA8
CA9
CA10
CA11
CA12
CA13
CA14
CA15
CA16
CA17
CA18
CA19
CA20
CA21
CA22
CA23
CA24
CA25
CA26
CA27
CA27R
CA27S
CA28
CA28R
CA28S
CA29
CA30
CA31
CA31S
CA31R
CA32
CA33
CA33S
CA33R
CA34
CA35
CA35S
CA35R
CA36
CA37
CA38
CA39
CA39S
CA39R
CA40
CA40S
CA40R
CA41
CA41S
CA41R
CA42
CA43
CA43S
CA43R
CA44
CA45
CA46
CA46S
CA46R
CA47
CA48
CA49
CA50
CA51
CA52
CA52S
CA52R
CA53
CA53S
CA53R
CA54
CA55
CA56
CA57
CA58
CA59
CA59S
CA59R
CA60
CA61
CA62
CA63
CA64
CA65
CA66
CA67
CA68
CA69
CA70
CA71
CA72
CA72S
CA72R
CA73
CA73S
CA73R
CA74
CA75
CA76

The compounds of Table 4A are the compounds found in U.S. Application Nos. 62/681,804, 62/746,252, and 62/746,495, and PCT Application No. PCT/US2018/056333, the entire contents of which are incorporated herein by reference.

TABLE 5
Compound No. Structure
D1
D1R
D1S
D2
D3
D4
D4R
D4S
D5
D5R
D5S
D6
D7

The compounds of Table 5 are the compounds found in U.S. Application No. 62/573,917, and PCT Application No. PCT/US2018/056428, the entire contents of which are incorporated herein by reference.

In some embodiments, the EHMT2 inhibitor is a compound selected from Compound Nos. A75, CA51, CA70, D1R, D2, D3, D4R, D5R, D6, and D7, tautomers thereof, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts of the tautomers.

In some embodiments, the EHMT2 inhibitor is a compound selected from Compound Nos. A75, CA51, CA70, D1R, D2, D3, D4R, D5R, D6, and D7, and pharmaceutically acceptable salts thereof.

In some embodiments, the EHMT2 inhibitor is a compound selected from Compound Nos. A75, CA51, CA70, D1R, D2, D3, D4R, D5R, D6, and D7.

In some embodiments, the EHMT2 inhibitor is Compound No. A75 or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. A75.

In some embodiments, the EHMT2 inhibitor is Compound No. CA51 or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. CA51.

In some embodiments, the EHMT2 inhibitor is Compound No. CA70 or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. CA70.

In some embodiments, the EHMT2 inhibitor is Compound No. D1R or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. D1R.

In some embodiments, the EHMT2 inhibitor is Compound No. D2 or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. D2

In some embodiments, the EHMT2 inhibitor is Compound No. D3 or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. D3.

In some embodiments, the EHMT2 inhibitor is Compound No. D4R or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. D4R.

In some embodiments, the EHMT2 inhibitor is Compound No. D5R or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. D5R.

In some embodiments, the EHMT2 inhibitor is Compound No. D6 or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. D6.

In some embodiments, the EHMT2 inhibitor is Compound No. D7 or a pharmaceutically acceptable salt thereof.

In some embodiments, the EHMT2 inhibitor is Compound No. D7.

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆ alkyl” or “C₁-C₆ alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆ alkyl is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C₁-C₆ for straight chain, C₃-C₆ for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

As used herein, the term “cycloalkyl” refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C₃-C₁₂, C₃-C₁₀, or C₃-C₈). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.

The term “heterocycloalkyl” refers to a saturated, partially unsaturated, or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-yl, 7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-yl, 3′H-spiro[cyclohexane-1,1′-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic non-aromatic rings, only one of the rings needs to be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydroindole).

The term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, “alkyl linker” or “alkylene linker” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆ alkylene linker is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkylene linker groups. Examples of alkylene linker include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (—CH₂—), ethyl (—CH₂CH₂—), n-propyl (—CH₂CH₂CH₂—), i-propyl (—CHCH₃CH₂—), n-butyl (—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl (—C(CH₃)₂CH₂—), n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl (—CHCH₃CH₂CH₂CH₂—) or n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₂—).

“Alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.

In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆” includes alkenyl groups containing two to six carbon atoms. The term “C₃-C₆” includes alkenyl groups containing three to six carbon atoms.

The term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

“Alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆” includes alkynyl groups containing two to six carbon atoms. The term “C₃-C₆” includes alkynyl groups containing three to six carbon atoms. As used herein, “C₂-C₆ alkenylene linker” or “C₂-C₆ alkynylene linker” is intended to include C₂, C₃, C₄, C₅ or C₆ chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C₂-C₆ alkenylene linker is intended to include C₂, C₃, C₄, C₅ and C₆ alkenylene linker groups.

The term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

“Aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. Examples include phenyl, naphthalenyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics.” As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)_p, where p=1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).

As used herein, “carbocycle” or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. Carbocycle includes cycloalkyl and aryl. For example, a C₃-C₁₄ carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, and [4.4.0] bicyclodecane and [2.2.2] bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In some embodiments, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included.

As used herein, “heterocycle” or “heterocyclic group” includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., 1-4 heteroatoms selected from N, O and S). Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][1,3]dioxole-5-yl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted,” as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., ═O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. The term “perhalogenated” generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms. The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

The term “carbonyl” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term “carboxyl” refers to —COOH or its C₁-C₆ alkyl ester.

“Acyl” includes moieties that contain the acyl radical (R—C(O)—) or a carbonyl group. “Substituted acyl” includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

“Aroyl” includes moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.

“Alkoxyalkyl,” “alkylaminoalkyl,” and “thioalkoxyalkyl” include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “ether” or “alkoxy” includes compounds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms. For example, the term includes “alkoxyalkyl,” which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to an alkyl group.

The term “ester” includes compounds or moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term “ester” includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.

The term “thioalkyl” includes compounds or moieties which contain an alkyl group connected with a sulfur atom. The thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.

The term “thioether” includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” include moieties with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term “alkthioalkenyls” refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group; and alkthioalkynyls” refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

As used herein, “amine” or “amino” refers to —NH₂. “Alkylamino” includes groups of compounds wherein the nitrogen of —NH₂ is bound to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, etc. “Dialkylamino” includes groups wherein the nitrogen of —NH₂ is bound to two alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. “Arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. “Aminoaryl” and “aminoaryloxy” refer to aryl and aryloxy substituted with amino. “Alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group. “Alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. “Acylamino” includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The term “amide” or “aminocarboxy” includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes “alkaminocarboxy” groups that include alkyl, alkenyl or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. It also includes “arylaminocarboxy” groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group. The terms “alkylaminocarboxy”, “alkenylaminocarboxy”, “alkynylaminocarboxy” and “arylaminocarboxy” include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on amide groups may be further substituted.

Compounds of the present disclosure that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the present disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N→O or N⁺—O⁻). Furthermore, in other instances, the nitrogens in the compounds of the present disclosure can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R is substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like, it being understood that not all isomers may have the same level of activity. In addition, a crystal polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present disclosure.

“Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

A carbon atom bonded to four nonidentical substituents is termed a “chiral center.”

“Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It should also be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

Furthermore, the structures and other compounds discussed in this disclosure include all atropic isomers thereof, it being understood that not all atropic isomers may have the same level of activity. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

“Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (—CHO) in a sugar chain molecule reacting with one of the hydroxy groups (—OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine. Examples of lactam-lactim tautomerism are as shown below.

It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

The compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The substituted benzene compounds also include those salts containing quaternary nitrogen atoms.

Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H₂O.

As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

As defined herein, the term “derivative” refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all of the compounds represented by Formula (II) are substituted bi-heterocyclic compounds, and have Formula (II) as a common core.

The term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

The present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the respective method or process remains operable. Moreover, two or more steps or actions can be conducted simultaneously. In some embodiments, the one or more additional therapeutic agent is a therapeutic agent for the treatment of rheumatoid arthritis selected form the group comprising Actemra® (tocilizumab; immunosuppressant), Arava® (leflunomide; immunosuppressant), Azulfidine® (sulfasalazine; anti-inflammatory), Valdecoxib® (bextra; anti-inflammatory), Cimzia® (certolizumab pegol; anti-inflammatory), Duexis® (ibuprofen; nonsteroidal anti-inflammatory drug, and famotidine; antacid and antihistamine), Etodolac® (lodine; nonsteroidal anti-inflammatory drug), Humira® (adalimumab; immunosupressant), Kevzara® (sarilumab; monoclonal antibody), Kineret® (anakinra; immunosuperssant), Lodine® (etodolac; nonsteroidal anti-inflammatory drug), Naprelan® (naproxen sodium; nonsteroidal anti-inflammatory drug), Orencia® (abatacept; modified antibody), Rayos® (prednisone; steroid) delayed-release tablets, Remicade® (infliximab; chimeric monoclonal antibody), Simponi® (golimumab; immunosupressabt), Vioxx® (rofecoxib; nonsteroidal anti-inflammatory drug), Xeljanz® (Tofacitinib; JAK inhibitor), Ilaris® (canakinumab; anti-inflammatory), Asacol HD®/Delzicol® (mesalamine), Colazal® (balsalazide), Dipentum® (olsalazine), Deltasone® (prednisone), Entocort® (budesonide), Gengraf®, Neoral®, Sandimmune® (cyclosporine), Trexall® (methotraxate), Remicade® (Infliximib), Humira® (Adalimumab), Uceris® (Budesonide-MMX®), Azasan®, Imuran® (Azathioprine), Purinethol®/Purixan® (Mercaptopurine), Simponi® (Golimumab), Tysabri® (Natalizumab), Entyvio® (Vedolizumab), and Stelara® (Ustekinumab).

In some embodiments, the one or more additional therapeutic agent is a therapeutic agent for the treatment of multiple sclerosis selected form the group comprising Ampyra® (dalfampridine; potassium channel blocker), Arvara® (leflunomide; immunosuppressant) Aubagio® (teriflunomide; acive metabolite of leflunomide), Avonex®; Rebif® (Interferon beta 1-b; anti-inflammatory), Copaxone® (glatiramer acetate; immunomodulator drug), Extavia® (Interferon beta-1 b; immunosuppressant), Gilenya® (fingolimod; immunosuppressant), Lemtrada® (alemtuzumab; monochlonal antibody), Novantrone® (mitoxantrone hydrochloride; chemotherapy), Ocrevus™ (ocrelizumab; monochlonal antibody), Plegridy® (pegylated interferon beta-1a; anti-inflammatory), Tecfidera® (dimethyl fumarate; immunomodulatory drug), Tysabri® (natalizumab; immunosuppressant), Zinbryta® (daclizumab; monoclonal antibody), Asacol HD®/Delzicol® (mesalamine), Colazal® (balsalazide), Dipentum® (olsalazine), Deltasone® (prednisone), Entocort® (budesonide), Gengraf®, Neoral®, Sandimmune® (cyclosporine), Trexall® (methotraxate), Remicade® (Infliximib), Humira® (Adalimumab), Uceris® (Budesonide-MMX®), Azasan®, Imuran® (Azathioprine), Purinethol®/Purixan® (Mercaptopurine), Simponi® (Golimumab), Tysabri® (Natalizumab), Entyvio® (Vedolizumab), and Stelara® (Ustekinumab).

In some embodiments, the one or more additional therapeutic agent is a therapeutic agent for the treatment of psoriasis, a psoriatic disorders, or psoriatic arthritis selected from the group comprising Amevive® (alefacept; immunosupressant), Cosentyx® (secukinumab; human IgG1 monoclonal antibody), Dovonex®/Sorilux®/Calcitrene® (calcipotriene; Vitamin), Diprolene® (betamethasone dipropionate; glucocorticoid steroid), Enstilar® (calcipotriene and betamethasone dipropionate), Otezla® (apremilast; inhibitor of phosphodiesterase 4), Rayos® (prednisone delayed-release tablets; corticosteroid), Siliq® (brodalumab; human interleukin-17 receptor A (IL-17RA) antagonist), Stelara® (ustekinumab, human IgG1k monoclonal antibody), Taltz® (ixekizumab, humanized interleukin-17A antagonist), Tazorac® topical gel (tazarotene), Tremfya® (guselkumab, interleukin-23 blocker), Enbrel® (etanercept; TNF inhibitor), Asacol HD®/Delzicol® (mesalamine), Colazal® (balsalazide), Dipentum® (olsalazine), Deltasone® (prednisone), Entocort® (budesonide), Gengraf®, Neoral®, Sandimmune® (cyclosporine), Trexall® (methotraxate), Remicade® (Infliximib), Humira® (Adalimumab), Uceris® (Budesonide-MMX®), Azasan®, Imuran® (Azathioprine), Purinethol®/Purixan® (Mercaptopurine), Simponi® (Golimumab), Tysabri® (Natalizumab), Entyvio® (Vedolizumab), and Stelara® (Ustekinumab).

In some embodiments, the one or more additional therapeutic agent is a therapeutic agent for the treatment of inflammatory bowel syndrome, such as Linzess® (linaclotide; agonist of guanylate cyclase 2C), Asacol HD®/Delzicol® (mesalamine), Colazal® (balsalazide), Dipentum® (olsalazine), Deltasone® (prednisone), Entocort® (budesonide), Gengraf®, Neoral®, Sandimmune® (cyclosporine), Trexall® (methotraxate), Remicade® (Infliximib), Humira® (Adalimumab), Uceris® (Budesonide-MMX®), Azasan®, Imuran® (Azathioprine), Purinethol®/Purixan® (Mercaptopurine), Simponi® (Golimumab), Tysabri® (Natalizumab), Entyvio® (Vedolizumab), and Stelara® (Ustekinumab).

Second therapeutic agents of the disclosure are further described in Tables 8-16.

TABLE 8
Anti-Inflammatory Agents - Nonsteroidal Anti-Inflammatory Drugs
Generic Name	Trade Name	IUPAC Name
valdecoxib	Bextra ®	4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-
		Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide
ibuprofen		2-(4-isobutylphenyl)propanoic acid
lodine	Etodolac ®	2-(1,8-diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl)acetic
		acid
naproxen	Naprelan ®	sodium 2-(6-methoxy-2-naphthyl)propanoate
sodium
rofecoxib	Vioxx ®	4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone
mesalamine	Asacol ® HD	5-amino-2-hydroxybenzoic acid
	Delzicol ®
aspirin	Aspirin ®	2-acetoxybenzoic acid
diflunisal	Dolobid ®	2′,4′-Difluoro-4-hydroxy-3-biphenylcarboxylic acid
salsalate	Disalcid ®	2-((2-hydroxybenzoyl)oxy)benzoic acid
diclofenac	Cataflam ®	2-(2-((2,6-dichlorophenyl)amino)phenyl)acetic acid
	Voltaren ®
meloxicam	Mobic ®	4-hydroxy-2-methyl-N-(5-methylthiazol-2-yl)-2H-
	Vivlodex ®	benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide

TABLE 9
Anti-Inflammatory Agents - Aminosalicylates
Generic Name	Trade Name	IUPAC Name
mesalamine	Asacol ® HD	5-amino-2-hydroxybenzoic acid
	Delzicol ®
balsalazide	Colazal ®	5-[(E)-{4-[(2-carboxyethyl)carbamoyl]phenyl}diazenyl]-2-
		hydroxybenzoic acid
olsalazine	Dipentum ®	5-[(2Z)-2-(3-carboxy-4-oxocyclohexa-2,5-dien-1-
		ylidene)hydrazinyl]-2-hydroxybenzoic acid
aspirin	Aspirin ®	2-acetoxybenzoic acid
diflunisal	Dolobid ®	2′,4′-Difluoro-4-hydroxy-3-biphenylcarboxylic acid
salsalate	Disalcid ®	2-((2-hydroxybenzoyl)oxy)benzoic acid

TABLE 10
Anti-Inflammatory Agents - Corticosteroids
Generic Name	Trade Name	IUPAC Name
betamethasone	Diprolene ®	(8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11,17-
dipropionate		dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-
		6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-
		3-one
prednisone	Rayos ®	(8S,9S,10R,13S,14S,17R)-17-hydroxy-17-
	(delayed-	(hydroxyacetyl)-10,13-dimethyl-
	release tablets)	7,8,9,10,12,13,14,15,16,17-decahydro-3H-
	Deltasone ®	cyclopenta[a]phenanthrene-3,11(6H)-dione
prednisolone	Omnipred ®	(8S,9S,10R,13S,14S,17R)-11,17-dihydroxy-17-(2-
	Pediapred ®	hydroxyacetyl)-10,13-dimethyl-
	Pred Mild ®	6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
		cyclopenta[a]phenanthren-3-one
methylprednisolone	Medrol ®,	(6S,8S,9S,10R,13S,14S,17R)-11,17-dihydroxy-17-(2-
	Solu-Medrol ®	hydroxyacetyl)-6,10,13-trimethyl-
	Depo-Medrol ®	6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
		cyclopenta[a]phenanthren-3-one
budesonide	Entocort ®	(6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-
	Budesonide	hydroxyacetyl)-6a,8a-dimethyl-10-propyl-
	MMX ®	1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-
	Uceris ®	naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-4-one
triamcinolone	Aristocort ®	(8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-
	Kenacort ®	trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-
	Triaderm ®	6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
		cyclopenta[a]phenanthren-3-one
Triamcinolone	Kenalog  ®	9α-Fluoro-11β,21-dihydroxy-16α,17α-
acetonide	(topical)	isopropylidenedioxypregna-1,4-diene,3,20-dione
	Volon A ®
	(injection)
	Nasacort ®
	(nasal)
cortisone	Ala-Cort  ®	dimethyl-1,2,6,7,8,9,12,14,15,16-
	Cortone ®	decahydrocyclopenta[a]phenanthrene-3,11-dione
dexamethasone	Ozurdex ®	(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-
		dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-
		6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
		cyclopenta[a]phenanthren-3-one
cyclophosphamide	Endoxan ®	2-(bis(2-chloroethyl)amino)-1,3,2-oxazaphosphinane 2-
	Cytoxan ®	oxide
	Revimmune ®
vincristine	Marqibo ®	methyl (3aR,3a1R,4R,5S,5aR,10bR)-4-acetoxy-3a-ethyl-
	Vincasar ®	9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-
	Oncovin ®	1,4,5,6,7,8,9,10-octahydro-2H-3,7-
		methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-
		5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-
		1H-indolizino[8,1-cd]carbazole-5-carboxylate
doxorubicin	Adriamycin ®	(8S,10S)-10-(((2R,4S,5R,6S)-4-amino-5-hydroxy-6-
	Doxil ®	methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-
		8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-
		tetrahydrotetracene-5,12-dione
mafosfamide		2-{(2-[bis(2-chloroethyl)amino]-2-oxido-1,3,2-
		oxazaphosphinan-4-yl}thio)ethanesulfonic acid
cisplatin		cis-diamminedichloridoplatinum(II)
Cytarabine (AraC)	Cytosar-U ®	4-amino-1-((2R,3S,4S,5R)-3,4-dihydroxy-5-
	Depocyt ®	(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-
		one
everolimus	Zortress ®	42-O-(2-hydroxyethyl)rapamycin
	Afinitor ®
decitabine	Dacogen ®	5-aza-2′-deoxycytidine

TABLE 11
Anti-Inflammatory Agents - Others
acetaminophen
sulfasalazine	Azulfidine ®	2-hydroxy-5-{[4-(2-
		pyridinylsulfamoyl)phenyl]diazenyl}benzoic acid
certolizumab	Cimzia ®	monoclonal antibody
pegol
interferon beta 1-b	Avonex ®;	cytokine
	Rebif ®;
	Extavia ®
pegylated	Plegridy ®	cytokine
interferon beta-1a
canakinumab	Ilaris ®	monoclonal antibody

TABLE 12
Immuno-modulatory drugs
Generic Name	Trade Name	IUPAC Name	Mechanism of action
fingolimod	Gilenya ®	2-amino-2-[2-(4-	immunosuppressant
		octylphenyl)ethyl]propane-1,3-diol
azathioprine	Azasan ®	6-[(1-methyl-4-nitro-1H-imidazol-5-	immunosuppressant
	Imuran ®	yl)sulfanyl]-1H-purine
mercaptopurine	Purinethol ®	1,7-dihydro-6H-purine-6-thione	immunosuppressant
	Purixan ®
cyclosporine	Gengraf ®	(3S,6S,9S,12R,15S,18S,21S,24S,30S,33	immunosuppressant
	Neoral ®	S)-30-Ethyl-33-[(1R,2R,4E)-1-hydroxy-
	Sandimmune ®	2-methyl-4-hexen-1-yl]-6,9,18,24-
		tetraisobutyl-3,21-diisopropyl-
		1,4,7,10,12,15,19,25,28-nonamethyl-
		1,4,7,10,13,16,19,22,25,28,3 1-
		undecaazacyclotritriacontane-
		2,5,8,11,14,17,20,23,26,29,32-undecone
methotrexate	Trexall ®	N-(4-([(2,4-Diamino-6-	immunosuppressant
		pteridinyl)methyl](methyl)amino}benzo
		yl)-L-glutamic acid
alefacept	Amevive ®	dimeric fusion protein	Immunosuppressant
tocilizumab	Actemra ®	monoclonal antibody	Immunosuppressant
golimumab	Simponi ®	monoclonal antibody	TNFa inhibitor
interferon beta	Avonex ®;	cytokine (protein)	anti-inflammatory;
1-b	Rebif ®;		immunosuppressant
	Extavia ®
glatiramer	Copaxone ®	mixture of random-sized peptides	immunomodulator
acetate
natalizumab	Tysabri ®	monochlonal antibody	immunosuppressant
pomalidomide	Pomalyst ®	4-amino-2-(2,6-dioxopiperidin-3-	immunomodulator
		yl)isoindoline-1,3-dione
lenalidomide	Revlimid ®	3-(4-amino-1-oxoisoindolin-2-	immunomodulator
		yl)piperidine-2,6-dione
thalidomide	Thalomid ®	2-(2,6-dioxopiperidin-3-yl)isoindoline-	immunomodulator
	Immunoprin ®	1,3-dione
apremilast	Otezla ®	(S)-N-(2-(1-(3-ethoxy-4-	phosphodiesterase 4
		methoxyphenyl)-2-	(PDE4) inhibitor
		(methylsulfonyl)ethyl)-1,3-
		dioxoisoindolin-4-yl)acetamide

TABLE 13
Biologics
Generic Name	Trade Name	Type	Mechanism of action
alefacept	Amevive ®	dimeric fusion protein	immunosuppressant
tocilizumab	Actemra ®	monoclonal antibody	immunosuppressant
golimumab	Simponi ®	monoclonal antibody	immunosuppressant;
			TNFa inhibitor
certolizumab	Cimzia ®	monoclonal antibody	anti-inflammatory
pegol
interferon beta 1-b	Avonex ®;	cytokine	anti-inflammatory;
	Rebif ®;		immunosuppressant
	Extavia ®
glatiramer acetate	Copaxone ®	mixture of random-sized peptides	immunomodulator
anakinra	Kineret ®	recombinant protein	interleukin 1 (IL1)
			receptor antagonist
ocrelizumab	Ocrevus ™	monochlonal antibody	binds to CD20
pegylated	Plegridy ®	cytokine	anti-inflammatory
interferon beta-1a
natalizumab	Tysabri ®	monochlonal antibody	immunosuppressant
daclizumab	Zinbryta ®	monoclonal antibody	binds to CD25
secukinumab	Cosentyx ®	human IgG1 monoclonal antibody	interleukin-17A (IL-
			17A) inhibitor
infliximab	Remicade ®	monoclonal antibody	TNFa inhibitor
vedolizumab	Entyvio	monoclonal antibody	anti α4β7 integrin
			antibody
brodalumab	Siliq ®	monoclonal antibody	human interleukin-17
			receptor A (IL-17RA)
			antagonist
ustekinumab	Stelara ®	monoclonal antibody	interleukin 12 (IL-12)
			and interleukin 23 (IL-
			23) antagonist
ixekizumab	Taltz ®	monoclonal antibody	human interleukin-17A
			antagonist
guselkumab	Tremfya ®	monoclonal antibody	targets the IL-23 subunit
			alpha; blocks interleukin-
			23 but not IL-12
etanercept	Enbrel ®	fusion protein	TNF inhibitor
linaclotide	Linzess ®	oligo-peptide	guanylate cyclase 2C
			agonist
adalimumab	Humira ®	monoclonal antibody	TNFa inhibitor
sarilumab	Kevzara ®	monoclonal antibody	interleukin-6 receptor
			agonist
abatacept	Orencia ®	soluble fusion protein	modified antibody
canakinumab	Ilaris ®	monoclonal antibody	anti-inflammatory
alemtuzumab	Lemtrada ®	monochlonal antibody	binds to CD52

TABLE 14
Other second agents
	Generic Name	Trade Name	Type	Mechanism of action
kinase	tofacitinib	Xeljanz ®	3-{(3R,4R)-4-methyl-3-	inhibits (Janus
inhibitor			[methyl(7H-pyrrolo[2,3-	kinase (JAK)
			d]pyrimidin-4-
			yl)amino]piperidin-1-yl}-3-
			oxopropanenitrile
potassium	dalfampridine	Ampyra ®	4-aminopyridine	potassium
channel				channel blocker
blocker
nicotinic acid	dimethyl	Tecfidera ®	dimethyl (E)-but-2-enedioate	activates
receptor	fumarate			erythroid-derived
agonist				2-like 2 (Nrf2)
				pathway
antacid and	famotidine	Pepcid ®	3-(((2-	histamine H2
antihistamine			((aminoiminomethyl)amino)-	receptor
			4-thiazolyl)methyl)thio)-N-	antagonist
			(aminosulfonyl)propanimidamide
antineoplastic	mitoxantrone	Novantrone ®	1,4-dihydroxy-5,8-bis({2-[(2-	topoisomerase
agent	hydrochloride		hydroxyethyl)amino]ethyl}amino)-	inhibitor
			9,10-anthraquinone
			dihydrochloride
synthetic	calcipotriene	Dovonex ®	1,4-dihydroxy-5,8-bis[2-(2-
vitamin D3		Sorilux ®	hydroxyethylamino)ethylami-
derivative		Calcitrene ®	no]anthracene-9,10-
			dione; dihydrochloride
retinoid	tazarotene	Tazorac ®	ethyl 6-[(4,4-dimethyl-3,4-	binds at retinoid
		(topical gel)	dihydro-2H-thiochromen-6-	acid receptors
			yl)ethynyl]nicotinate	RARβ and RARγ

TABLE 15
Disease-Modifying Antirheumatic Drugs
Generic Name	Trade Name	Type/IUPAC Name	Mechanism of Action
leflunomide	Arava ®	5-methyl-N-(4-	immunosuppressant
		(trifluoromethyl)phenyl)isoxazole-
		4-carboxamide
teriflunomide	Aubagio ®	(2Z)-2-cyano-3-hydroxy-N-[4-	active metabolite of
		(trifluorotnethyl)phenyl]-2-	leflunomide
		butenamide
sulfasalazine	Azulfidine ®	2-hydroxy-5-{[4-(2-	anti-inflammatory;
		pyridinylsulfamoyl)phe-	immunosuppressant
		nyl]diazenyl}benzoic acid
azathioprine	Azasan ®	6-[(1-methyl-4-nitro-1H-	immunosuppressant
	Imuran ®	imidazol-5-yl)sulfanyl]-1H-
		purine
methotrexate	Trexall ®	N-(4-{[(2,4-Diamino-6-	immunosuppressant
		pteridinyl)methyl](methyl)amino}benzoyl)-
		L-glutamic acid
anakinra	Kineret ®	recombinant protein	interleukin 1 (IL1) receptor
			antagonist
etanercept	Enbrel ®	fusion protein	TNF inhibitor
tocilizumab	Actemra ®	monoclonal antibody	Immunosuppressant;
adalimumab	Humira ®	whole antibody	TNFa inhibitor
abatacept	Orencia ®	soluble fusion protein
infliximab	Remicade ®	monoclonal antibody
golimumab	Simponi ®	monoclonal antibody	immunosuppressant
tofacitinib	Xeljanz ®	3-{(3R,4R)-4-methyl-3-	Janus kinase (JAK)
		[methyl(7H-pyrrolo[2,3-	inhibitor
		d]pyrimidin-4-
		yl)amino]piperidin-1-yl}-3-
		oxopropanenitrile

TABLE 16
HDAC Inhibitors
vorinostat	Zolinza ®	N1-hydroxy-N8-phenyloctanediamide
romidepsin	Istodax ®	(1S,4S,7E,10S,16E,21R)-7-ethylidene-4,21-diisopropyl-2-oxa-12,13-
		dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-
		pentaone
chidamide	Epidaza	(E)-N-(2-amino-5-fluorophenyl)-4-((3-(pyridin-3-
		yl)acrylamido)methyl)benzamide
panobinostat	Farydak ®	(E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-
		yl)ethyl)amino)methyl)phenyl)acrylamide
belinostat	Beleodaq	(E)-N-hydroxy-3-(3-(N-phenylsulfamoyl)phenyl)acrylamide
valproic acid	Valproic	2-propylpentanoic acid
mocetinostat	—	N-(2-aminophenyl)-4-(((4-(pyridin-3-yl)pyrimidin-2-
		yl)amino)methyl)benzamide
abexinostat	—	3-((dimethylamino)methyl)-N-(2-(4-
		(hydroxycarbamoyl)phenoxy)ethyl)benzofuran-2-carboxamide
entinostat	—	pyridin-3-ylmethyl (4-((2-aminophenyl)carbamoyl)benzyl)carbamate
Pracinostat	—	(E)-3-(2-butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-
(SB939)		N-hydroxyacrylamide
resminostat	—	(E)-3-(1-((4-((dimethylamino)methyl)phenyl)sulfonyl)-1H-pyrrol-3-
		yl)-N-hydroxyacrylamide
givinostat	—	(6-((diethylamino)methyl)naphthalen-2-yl)methyl (4-
		(hydroxycarbamoyl)phenyl)carbamate
quisinostat	—	N-hydroxy-2-(4-((((1-methyl-1H-indol-3-
		yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide
Chidamide	Epidaza ®
(HBI-8000)
kevetrin	—	3-cyanopropyl carbamimidothioate
CUDC-101	—	7-((4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-
		hydroxyheptanamide
AR-42	—	(S)-N-hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide
tefinostat	—	cyclopentyl (S)-2-((4-(8-(hydroxyamino)-8-
(CHR-2845)		oxooctanamido)benzyl)amino)-2-phenyl acetate
CHR-3996	—	2-[(1R,5S)-6-[(6-fluoroquinolin-2-yl)methylamino]-3-
		azabicyclo[3.1.0]hexan-3-yl]-N-hydroxypyrimidine-5-carboxamide
4SC-202	—	(E)-N-(2-aminophenyl)-3-[1-[4-(1-methylpyrazol-4-
		yl)phenyl]sulfonylpyrrol-3-yl]prop-2-enamide; 4-
		methylbenzenesulfonic acid
CG200745	—	(E)-N(1)-(3-(dimethylamino)propyl)-N(8)-hydroxy-2-((naphthalene-
		1-loxy)methyl)oct-2-enediamide
Rocilinostat	—	2-(Diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-
(ACY-1215)		carboxamide
ME-344	—	4,4′-(7-hydroxy-8-methylchroman-3,4-diyl)diphenol
sulforaphane	—	1-isothiocyanato-4-(methylsulfinyl)butane
Dacinostat	—	(E)-3-(4-(((2-(1H-indol-3-yl)ethyl)(2-
(LAQ824)		hydroxyethyl)amino)methyl)phenyl)-N-hydroxyacrylamide
Tacedinaline	—	4-(Acetylamino)-N-(2-aminophenyl)benzamide
(CI994)

The synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

Compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th edition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3^rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

Compounds of the present disclosure can be conveniently prepared by a variety of methods familiar to those skilled in the art.

One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups.

One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3^rd edition, John Wiley & Sons: New York, 1999.

Compounds of the present disclosure inhibit the histone methyltransferase activity of G9a, also known as KMT1C (lysine methyltransferase 1C) or EHMT2 (euchromatic histone methyltransferase 2), or a mutant thereof and, accordingly, in one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders in which EHMT2 plays a role. The present disclosure provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomer thereof.

Unless otherwise stated, 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.

In still another aspect, this disclosure relates to a method of modulating the activity of EHMT2, which catalyzes the dimethylation of lysine 9 on histone H3 (H3K9) in a subject in need thereof.

The compound(s) of the present disclosure inhibit the histone methyltransferase activity of EHMT2 or a mutant thereof and, accordingly, the present disclosure also provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EHMT2. In one aspect of the disclosure, certain compounds disclosed herein are candidates for treating, or preventing certain conditions, diseases, and disorders. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present disclosure.

In still another aspect, this disclosure relates to a method of modulating the activity of EHMT2, which catalyzes the dimethylation of lysine 9 on histone H3 (H3K9) in a subject in need thereof. For example, the method comprises the step of administering to a subject having a cancer expressing a mutant EHMT2 a therapeutically effective amount of a composition comprising a compound described herein and a second agent, wherein the combination inhibits histone methyltransferase activity of EHMT2, thereby treating the cancer.

For example, the EHMT2-mediated cancer is selected from the group consisting of leukemia, prostate carcinoma, hepatocellular carcinoma, lung cancer, and skin cancer.

For example, the compounds disclosed herein can be used for treating cancer. For example, the cancer is a hematological cancer. For example, the cancer is a skin cancer.

For example, the cancer is selected from the group consisting of 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, and skin cancer. In some embodiments, a subject in need thereof is one who had, is having or is predisposed to developing brain and CNS cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lymphoma, myeloma, skin cancer, and/or sarcoma. Exemplary brain and central CNS cancer includes medulloblastoma, oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, and pineoblastoma. Exemplary ovarian cancer includes ovarian clear cell adenocarcinoma, ovarian endometrioid adenocarcinoma, and ovarian serous adenocarcinoma. Exemplary pancreatic cancer includes pancreatic ductal adenocarcinoma and pancreatic endocrine tumor. Exemplary skin cancer includes basal cell carcinoma, squamous cell carcinoma, melanoma, Kaposi's sarcoma, Merkel cell carcinoma, and sebaceous gland carcinoma. Exemplary sarcoma includes chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. In some embodiments, cancers to be treated by the compounds of the present invention are non NHL cancers.

For example, the cancer is selected from the group consisting of acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), medulloblastoma, 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, and not otherwise specified (NOS) sarcoma. In some embodiments, the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), medulloblastoma, ovarian clear cell adenocarcinoma, ovarian endometrioid adenocarcinoma, pancreatic ductal adenocarcinoma, malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma, pineoblastoma, carcinosarcoma, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, melanoma, chondrosarcoma, ewing sarcoma, epithelioid sarcoma, renal medullary carcinoma, diffuse large B-cell lymphoma, follicular lymphoma and/or NOS sarcoma.

As used herein, a “subject” is interchangeable with a “subject in need thereof”, both of which refer to a subject having a cancer or a disorder in which EHMT2-mediated protein methylation plays a part, or a subject having an increased risk of developing such cancer or disorder relative to the population at large. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having cancer or a precancerous condition. A subject in need thereof can also be one who has (e.g., is suffering from) cancer or a precancerous condition. In some embodiments, a subject in need thereof can be one who has an increased risk of developing such disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a precancerous condition. A subject in need thereof can have refractory or resistant cancer (i.e., cancer that doesn't respond or hasn't yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof has cancer recurrence following remission on most recent therapy. In some embodiments, the subject in need thereof received and failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In some embodiments, the subject has cancer or a cancerous condition. For example, the cancer is leukemia, prostate carcinoma, hepatocellular carcinoma, lung cancer, or melanoma.

As used herein, “candidate compound” refers to a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, that has been or will be tested in one or more in vitro or in vivo biological assays, in order to determine if that compound is likely to elicit a desired biological or medical response in a cell, tissue, system, animal or human that is being sought by a researcher or clinician. A candidate compound is a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof. The biological or medical response can be the treatment of cancer. The biological or medical response can be treatment or prevention of a cell proliferative disorder. The biological response or effect can also include a change in cell proliferation or growth that occurs in vitro or in an animal model, as well as other biological changes that are observable in vitro. In vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

For example, an in vitro biological assay that can be used includes the steps of (1) mixing a histone substrate (e.g., an isolated histone sample or an isolated histone peptide representative of human histone H3 residues 1-15) with recombinant EHMT2 enzymes; (2) adding a compound of the disclosure to this mixture; (3) adding non-radioactive and ³H-labeled S-Adenosyl methionine (SAM) to start the reaction; (4) adding excessive amount of non-radioactive SAM to stop the reaction; (4) washing off the free non-incorporated ³H-SAM; and (5) detecting the quantity of ³H-labeled histone substrate by any methods known in the art (e.g., by a PerkinElmer TopCount platereader).

For example, an in vitro study that can be used includes the steps of (1) treating cancer cells (e.g., breast cancer cells) with a compound of this disclosure; (2) incubating the cells for a set period of time; (3) fixing the cells; (4) treating the cells with primary antibodies that bind to dimethylated histone substrates; (5) treating the cells with a secondary antibody (e.g. an antibody conjugated to an infrared dye); (6) detecting the quantity of bound antibody by any methods known in the art (e.g., by a Licor Odyssey Infrared Scanner).

As used herein, “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

A compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. As used herein, “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3^rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18^th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

As used herein, “combination therapy” or “co-therapy” includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.

The present disclosure also provides pharmaceutical compositions comprising a compound of any of the Formulae described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

A “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

The term “therapeutically effective amount”, as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder.

For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m², and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

The compounds of the present disclosure are capable of further forming salts. All of these forms are also contemplated within the scope of the claimed disclosure.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

The compounds of the present disclosure can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate or other ester.

The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.

The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19^th edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

Example 1: Synthesis of EHMT2 Inhibitor Compounds

EHMT2 inhibitor compounds useful for the treatment of blood disorders as provided herein were synthesized or may be synthesized by, e.g., methods described in U.S. Application Nos. 62/323,602, 62/348,837, 62/402,997, 62/402,863, 62/509,620, 62/436,139, 62/517,840, 62/573,442, 62/681,804, 62/746,252, and 62/746,495, and Ser. No. 15/601,888, and PCT Application Nos. PCT/US2017/027918, PCT/US2017/054468, PCT/US2017/067192, PCT/US2018/056333, and PCT/US2018/056428, the contents of each of which are incorporated herein by reference in their entireties.

Example 2: The Effect of EHMT2 Inhibitor Compounds on Cell Polarization In Vitro

To evaluate the effects of Compounds on T regulatory (Treg) and Th17 cell polarization, naive CD4 T cells were isolated from human peripheral blood mononuclear cells (PBMCs) using magnetic bead separation and cultured with or without compound in the presence of Treg or Th17 polarizing cytokines. For Treg polarization, naive cells were cultured for five days with anti-CD3, anti-CD28, TL-2 and TGFβ. After five days, the cells were then evaluated for CD25 and Foxp3 expression by flow cytometry. For Th17 polarization, naive cells were cultured for 10-11 days with anti-CD3, anti-CD28, IL-10, IL-6, IL-23, TGFβ, anti-IFNγ antibody and anti-IL-4 antibody. After 10-11 days cells were stimulated and then evaluated for IL-17 and IFNγ by flow cytometry.

To evaluate the effects of Compounds 205 and 571 on Th17 cell polarization, naive cells were isolated from human peripheral blood mononuclear cells (PBMCs), stimulated with coated CD3 antibody and soluble CD28 antibody, and cultured with or without compound in the presence of Th17 polarizing cytokines for 11 days as described in [0601]. Compound was replenished at either day three or day four. After 11 days of treatment, cells were stimulated with PMA, ionomycin, brefeldin A and monensin, and then evaluated for IL-17 and IFNγ by flow cytometry. Treatment with Compounds 205 and 571 resulted in a dose-dependent increase in the percentage of polarized Th17 cells in vitro.

To evaluate the effects of Compound 571 on Treg cell polarization, naive cells were isolated from human peripheral blood mononuclear cells (PBMCs), stimulated with coated CD3 antibody and soluble CD28 antibody, and cultured with or without compound in the presence of Treg polarizing cytokines for five days, as described in [0601]. Compound was replenished at either day three or day four. Treatment with Compound 571 resulted in anin polarized Treg cells in vitro. The results of the studies are summarized in FIGS. 1 and 2.

Example 3. The Effect of EHMT2 Inhibitor Compounds on T Regulatory Cell Polarization

Naive CD4 T cells were isolated from healthy donor PBMCs using magnetic bead separation and were incubated for six days with cytokine cocktail to promote polarization to T regulatory cells, as described in [0601]. Cells were simultaneously treated with various concentrations of G9a inhibitors, with compound replenishment occurring at either day three or day four. Polarization to T regulatory cells was assessed by flow cytometry using Foxp3 and CD25. Methyl mark (H3K9me2) was also assessed by flow cytometry. The results of the study are summarized in FIGS. 3 and 4A-4B.

Example 4. The Effect of EHMT2 Inhibitor Compounds on Th17 Cell Polarization

Naive CD4 T cells were isolated from healthy donor PBMCs using magnetic bead separation and were incubated with cytokine cocktail to promote polarization to Th17 cells, as described in [0601]. Cells were simultaneously treated with various concentrations of G9a inhibitors, with compound replenishment occurring at day three or four. Polarization to Th17 cells was assessed by flow cytometry using IL-17A and IFNy. Methyl mark (H3K9me2) was also assessed by flow cytometry. The results of the study are summarized in FIGS. 5 and 6A-6B.

Claims

1. A method of preventing or treating a disease or disorder associated with overexpression of EHMT2, comprising administering to a subject in need thereof a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor.

2. (canceled)

3. A method of preventing or treating an immune-mediated disease, comprising administering to a subject in need thereof a first agent in a therapeutically effective amount, wherein the first agent comprises an EHMT2 inhibitor.

4. The method of claim 1, further comprising administering to the subject one or more additional treatment modalities in a therapeutically effective amount, wherein the one or more additional treatment modalities comprises one or more second therapeutic agents.

5. The method of claim 3, wherein the immune-mediated disease is selected from the group comprising rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic disorders, psoriatic arthritis, and inflammatory bowel disease.

6-58. (canceled)

59. The method of claim 3, wherein the EHMT2 inhibitor is a compound of Formula (I):

60-65. (canceled)

66. The method of claim 59, wherein the EHMT2 inhibitor is a compound of Formula (II):

67. The method of claim 66, wherein the EHMT2 inhibitor is a compound of Formula (IIa1), (IIa2), (IIa3), (IIa4), or (IIa5):

68-75. (canceled)

76. The method of claim 59, wherein the EHMT2 inhibitor is a compound of Formula (III):

77-81. (canceled)

82. The method of claim 59, wherein the EHMT2 inhibitor is a compound of Formula (IV):

83-101. (canceled)

102. The method of claim 3, wherein the EHMT2 inhibitor is a compound of Formula (V):

103-104. (canceled)

105. The method of claim 59, wherein the EHMT2 inhibitor is a compound of Formula (VII):

106. (canceled)

107. The method of claim 59, wherein the EHMT2 inhibitor is a compound of Formula (VIIIa):

108. (canceled)

109. The method of claim 59, wherein the EHMT2 inhibitor is a compound of Formula (VIIIc):

110. The method of claim 3, wherein the EHMT2 inhibitor is a compound of (IX):

111-122. (canceled)

123. The method of claim 3, wherein the EHMT2 inhibitor is a compound of Formula (I′):

124. The method of claim 3, wherein the EHMT2 inhibitor is a compound of Formula (I′), (II″), or (III″):

125-178. (canceled)

179. The method of claim 3, wherein the EHMT2 inhibitor is a compound of Formula (I′″), (II′″), or (III′″):

180-203. (canceled)

204. The method of claim 3, wherein EHMT2 inhibitor is selected from those in Tables 1A-1E, 2-4, 4A, and 5, and pharmaceutically acceptable salts thereof.

205. The method of claim 3, wherein the EHMT2 inhibitor is a compound selected from Compound Nos. A75, CA51, CA70, D1R, D2, D3, D4R, D5R, D6, and D7, tautomers thereof, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts of the tautomers.

206-230. (canceled)

231. A pharmaceutical composition comprising an EHMT2 inhibitor of claim 59, and one or more second agents.

232-269. (canceled)