Methods of treating hematologic cancer

Abstract

The present invention relates to methods and compositions for the treatment of BAF-related disorders such as cancer.

Description

[0001] METHODS OF TREATING HEMATOLOGIC CANCER

[0002] Background

[0003] Disorders can be affected by the BAF complex. BRD9 is a component of the BAF complex. The present invention relates to useful methods and compositions for the treatment of BAF-related disorders, such as cancer.

[0004] Summary of the Invention

[0005] Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of the BAF (BRG1- or BRM-associated factors) complex, a SWI / SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomaincontaining proteins. BRD9 is present in several SWI / SNF ATPase chromatin remodeling complexes and is upregulated in multiple cancer cell lines. Accordingly, agents that reduce the levels and / or activity of BRD9 may provide new methods for the treatment of disease and disorders, such as cancer and infection. The inventors have found that hematologic cancer cell lines (e.g., acute myeloid lymphoma (AML) and diffuse large B cell lymphoma (DLBCL) that have high IRF8 expression) are sensitive to treatment with a compound that reduces the level and / or activity of BRD9. Thus, agents that degrade BRD9 (e.g., compounds) are useful in the treatment of disorders (e.g., cancers or infections) related to BAF and / or BRD9.

[0006] Hematologic cancers, also known as blood cancers, are cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system, e.g., leukemias, lymphomas, and myelomas. Leukemias are cancers found in blood and bone marrow which are caused by rapid production of abnormal white blood cells. Lymphomas are cancers which affect the lymphatic system. Myelomas are cancers of the plasma cells. In most hematologic cancers, normal blood cell development is interrupted by uncontrolled growth of an abnormal type of blood cell. The abnormal blood cells prevent the blood from performing many of its functions. Hematologic cancers account for about 10% of all new cancer diagnoses. The 5-year relative survival rates for hematologic cancers range from about 50% to about 90%.AML is a cancer of the myeloid line of blood cells. Without wishing to be bound by theory, it is believed that depleting or inhibiting BRD9 results in the treatment of hematologic cancers with high IRF8 expression.

[0007] In one aspect, the present disclosure provides methods of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments of any of the aspects disclosed herein, the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B- cell lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments of any of the aspects disclosed herein, the hematologic cancer is diffuse large B cell lymphoma (DLBCL). In some embodiments of any of the aspects disclosed herein, the hematologic cancer is acute myeloid leukemia (AML). In some embodiments of any of the aspects disclosed herein, the AML is acute promyelocytic leukemia, arises from a pre-existing myelodysplastic syndrome or myeloproliferative disease, treatment-related AML, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, myeloid sarcoma, myeloid proliferations related to Down syndrome, blastic plasmacytoid dendritic cell neoplasm, AML minimally differentiated, AML without maturation, AML with granulocytic maturation, myelomonocytic together with bone marrow eosinophilia, acute monoblastic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, or acute basophilic leukemia. In some embodiments of any of the aspects disclosed herein, the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, or a combination thereof.

[0009] In another aspect, the present disclosure provides methods of treating MLL rearrangement (MLL- r) acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects disclosed herein, the MLL-r AML harbors high IRF8 expression.

[0010] In another aspect, the present disclosure provides methods of treating inv(16) acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects disclosed herein, the inv(16) is a CBFB-MYH11 fusion. In some embodiments of any of the aspects disclosed herein, the inv(16) AML harbors high IRF8 expression.

[0011] In another aspect, the present disclosure provides methods of inducing differentiation of common myeloid progenitor (CMP) cells into monocyte precursor cells in a subject that has hematologic cancer with determined high IRF8 expression, the method comprising administering to a subject in need thereof an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments of any of the aspects disclosed herein, the method slows progression of a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments of any of the aspects disclosed herein, the method reduces recurrence of a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments of any of the aspects disclosed herein, the method increases myeloid cell differentiation in a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments of any of the aspects disclosed herein, the method increases myeloid cell maturation in a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments of any of the aspects disclosed herein, the method increases myeloid cell proliferation in a hematologic cancer with high IRF8 expression in a subject in need thereof.

[0013] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of an agent that reduces the level and / or activity of BRD9 in the cell. In some embodiments of any of the aspects disclosed herein, the cell is an AML cell. In some embodiments of any of the aspects disclosed herein, the cell is a diffuse large B cell lymphoma cell. In some embodiments of any of the aspects disclosed herein, the cell is in a subject.

[0014] In some embodiments of any of the aspects disclosed herein, the IRF8 expression of the subject in need thereof is high relative to IRF8 expression in a subject without a hematologic cancer. In some embodiments of any of the aspects disclosed herein, the IRF8 expression of the subject in need thereof is high relative to a reference. In some embodiments of any of the aspects disclosed herein, the IRF8 expression of the subject in need thereof is high relative to standard levels of IRF8. In some embodiments of any of the aspects disclosed herein, the subject in need thereof has increased expression of myeloid peroxidase (MPO) relative to standard levels of MPO.

[0015] In some embodiments of any of the aspects disclosed herein, the subject in need thereof has low DNA methylation of the IRF8 genomic loci relative to a subject without a hematologic cancer. In some embodiments of any of the aspects disclosed herein, the subject in need thereof has low DNA methylation of the IRF8 genomic loci relative to a reference. In some embodiments of any of the aspects disclosed herein, the low DNA methylation is measured as a mean beta value of less than 0.20.

[0016] In some embodiments of any of the aspects disclosed herein, the compound that reduces the level and / or activity of BRD9 is 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2-dihydro-2,7- naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1- oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0017] In some embodiments of any of the aspects disclosed herein, the compound is 3-(6-(7-((1-(4-(6- (azetidin-1-yl)-2-methyl-1 -oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione having the structure: or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments of any of the aspects disclosed herein, the compound that reduces the level and / or activity of BRD9 is 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-1 ,6-dihydropyridin-3- y I) benzyl)-3,3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)piperidine-2, 6-dione.

[0019] In some embodiments of any of the aspects disclosed herein, the compound is 3-((4-(4-(1-(2,6- dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-1 ,6-dihydropyridin-3-yl)benzyl)-3,3-difluoropiperidin-4-yl)piperazin-1 - yl)-3-fluorophenyl)amino)piperidine-2, 6-dione having the structure: or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments of any of the aspects disclosed herein, the subject is further administered at least one additional anti-cancer therapy. In some embodiments of any of the aspects disclosed herein, the additional anti-cancer therapy is administered prior to the administering of the compound or pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects disclosed herein, the additional anti-cancer therapy is administered in addition to the administering of the compound or pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects disclosed herein, the additional anti-cancer therapy is administered subsequent to the administering of the compound or pharmaceutically acceptable salt thereof.

[0021] In some embodiments of any of the aspects disclosed herein, the additional cancer therapy is a menin inhibitor, abemaciclib, all-trans-retinoic acid, arsenic trioxide, azacitidine, cedazuridine, cobimetinib, CPX-351 , cytarabine, daunorubicin, decitabine, enasidenib, etoposide, gemtuzumab, gilteritinib, glasdegib, hemopoietic stem cell transplant, ivosidenib, midostaurin, olutasidenib, ozogamicin, venetoclax, or combinations thereof. In some embodiments of any of the aspects disclosed herein, the additional cancer therapy is a menin inhibitor. In some embodiments of any of the aspects disclosed herein, the menin inhibitor is BMF-219, DS-1594a, DS-1594b, JNJ-75276617, revumenib, SNDX-50469, ziftomenib, or combinations thereof. In some embodiments of any of the aspects disclosed herein, the hematologic cancer is resistant to treatment with a menin inhibitor. In some embodiments of any of the aspects disclosed herein, the hematologic cancer harbors an MEN1 mutation. In some embodiments of any of the aspects disclosed herein, the hematologic cancer has failed to respond to prior treatment with a menin inhibitor. In some embodiments of any of the aspects disclosed herein, the hematologic cancer has relapsed after prior treatment with a menin inhibitor. In some embodiments of any of the aspects disclosed herein, the hematologic cancer is refractory to prior treatment with a menin inhibitor.

[0022] In some embodiments of any of the aspects disclosed herein, the method further comprises administering induction chemotherapy. In some embodiments of any of the aspects disclosed herein, the induction chemotherapy comprises cytarabine, an anthracycline such as daunorubicin, arsenic trioxide, all-trans-retinoic acid, or combinations thereof.

[0023] In some embodiments of any of the aspects disclosed herein, the method further comprises administering consolidation therapy. In some embodiments of any of the aspects disclosed herein, the consolidation therapy comprises an allogenic stem cell transplantation and / or immunotherapy.

[0024] In some embodiments of any of the aspects disclosed herein, the method further comprises administering a hemopoietic stem cell transplant, gemtuzumab ozogamicin, or a combination thereof.

[0025] In some embodiments of any of the aspects disclosed herein, the subject or cancer has and / or has been identified as having increased BRD9 expression.

[0026] In some embodiments of any of the aspects disclosed herein of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-120 mg / kg (e.g., 20-60 mg / kg, 20-40 mg / kg, 40-80 mg / kg, 40-60 mg / kg, 60- 80 mg / kg, or 80-120 mg / kg).

[0027] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-80 mg / kg. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-60 mg / kg. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-40 mg / kg.

[0028] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20 mg / kg. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 40 mg / kg. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg / kg. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 60 mg / kg. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg / kg. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 120 mg / kg.

[0029] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered to the subject at least once per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered to the subject at least twice per week.

[0030] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20 mg / kg once per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20 mg / kg twice per week.

[0031] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 40 mg / kg once per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 40 mg / kg twice per week.

[0032] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg / kg once per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg / kg twice per week.

[0033] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 60 mg / kg once per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 60 mg / kg twice per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg / kg once per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg / kg twice per week.

[0034] In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 120 mg / kg once per week. In some embodiments of any of the aspects disclosed herein, the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 120 mg / kg twice per week.

[0035] In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 14-day dosing cycle. In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 21-day dosing cycle. In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 28-day dosing cycle.

[0036] In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof, is administered to the subject intravenously. In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof, is administered to the subject subcutaneously. In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof, is administered to the subject intramuscularly.

[0037] In one aspect, the present disclosure provides methods of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2- dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0038] In one aspect, the present disclosure provides methods of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1- oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0039] In one aspect, the present disclosure provides methods of treating acute myeloid leukemia with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2- dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0040] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2-dihydro-2,7-naphthyridin-4- yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2- y I) pi peridine-2, 6-dione.

[0041] In one aspect, the present disclosure provides methods of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0042] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0043] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0044] In one aspect, the present disclosure provides methods of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5- trimethyl-6-oxo-1 , 6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3- fluorophenyl)amino)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0045] In one aspect, the present disclosure provides methods of treating acute myeloid leukemia with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0046] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0047] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0048] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-1 ,6-dihydropy ridin-3- y I) benzyl)-3,3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-2, 6-dione.

[0049] In one aspect, the present disclosure provides methods of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0050] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0051] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0052] In one aspect, the present disclosure provides methods of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5- trimethyl-6-oxo-1 , 6-dihydro pyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3- fluorophenyl)amino)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0053] In one aspect, the present disclosure provides methods of treating acute myeloid leukemia with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0054] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0055] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0056] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-1 ,6-dihydropyridin-3- y I) benzyl)-3,3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-2, 6-dione. In one aspect, the present disclosure provides methods of determining hematologic cancer and / or monitoring a hematologic cancer in a subject in need thereof, the method comprising determining the DNA methylation status for the IRF8 gene in the subject.

[0057] In some embodiments of any of the aspects disclosed herein, the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B- cell lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments of any of the aspects disclosed herein, the hematologic cancer is diffuse large B cell lymphoma (DLBCL). In some embodiments of any of the aspects disclosed herein, the hematologic cancer is acute myeloid leukemia (AML). In some embodiments of any of the aspects disclosed herein, the AML is acute promyelocytic leukemia, arises from a pre-existing myelodysplastic syndrome or myeloproliferative disease, treatment-related AML, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, myeloid sarcoma, myeloid proliferations related to Down syndrome, blastic plasmacytoid dendritic cell neoplasm, AML minimally differentiated, AML without maturation, AML with granulocytic maturation, myelomonocytic together with bone marrow eosinophilia, acute monoblastic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, or acute basophilic leukemia. In some embodiments of any of the aspects disclosed herein, the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, or a combination thereof. In some embodiments of any of the aspects disclosed herein, the DNA methylation status for IRF8 is low. In some embodiments of any of the aspects disclosed herein, the low DNA methylation status is a mean beta value of less than 0.20. In some embodiments of any of the aspects disclosed herein, the subject determined to have a hematologic cancer is administered an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects disclosed herein, the compound that reduces the level and / or activity of BRD9 is 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2-dihydro- 2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1- oxoisoindolin-2-yl)piperidine-2, 6-dione. In some embodiments of any of the aspects disclosed herein, the compound that reduces the level and / or activity of BRD9 is 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl- 6-oxo-1 ,6-dihydropyridin-3-yl)benzyl)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)-3- fluorophenyl)amino)piperidine-2, 6-dione.

[0058] Chemical Terms

[0059] The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0060] For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as H atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

[0061] The term “acyl,” as used herein, represents a H or an alkyl group that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e. , a carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11 , or from 1 to 21 carbons.

[0062] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0063] An alkylene is a divalent alkyl group. The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0064] The term “alky ny I,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0065] The term “amino,” as used herein, represents -N(RN1)2, wherein each RN1is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an A / -protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1groups can be optionally substituted; or two RN1combine to form an alkylene or heteroalkylene, and wherein each RN2is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1)2).

[0066] The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.

[0067] The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl, or C1-C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.

[0068] The term “azido,” as used herein, represents a -N3 group.

[0069] The term “bridged polycycloalkyl,” as used herein, refers to a bridged polycyclic group of 5 to 20 carbons, containing from 1 to 3 bridges.

[0070] The term “cyano,” as used herein, represents a -CN group.

[0071] The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.

[0072] The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, and monovalent mono- or polycarbocyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0073] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl-O- A heteroalkenylene is a divalent heteroalkenyl group. The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl-O-. A heteroalkynylene is a divalent heteroalkynyl group.

[0074] The term “heteroaryl,” as used herein, refers to a mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring and containing 1 , 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[0075] The term “heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci-Ce alkyl C2-C9 heteroaryl, C1-C10 alkyl C2-C9 heteroaryl, or C1-C20 alkyl C2-C9 heteroaryl). In some embodiments, the alkyl and the heteroaryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.

[0076] The term “heterocyclyl,” as used herein, refers a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing 1 , 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetra hydrofuranyl, and 1 ,3-dioxanyl.

[0077] The term “heterocyclylalkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci-Ce alkyl C2-C9 heterocyclyl, C1-C10 alkyl C2-C9 heterocyclyl, or C1-C20 alkyl C2-C9 heterocyclyl). In some embodiments, the alkyl and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.

[0078] The term “hydroxyalkyl,” as used herein, represents alkyl group substituted with an -OH group.

[0079] The term “hydroxyl,” as used herein, represents an -OH group.

[0080] The term “A / -protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used A / -protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rdEdition (John Wiley & Sons, New York, 1999). A / -protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L, or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- 20 dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-bi ph e ny ly I)- 1 -methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred A / -protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t- butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0081] The term “nitro,” as used herein, represents an -NO2 group.

[0082] The term “thiol,” as used herein, represents an -SH group.

[0083] The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Another exemplary substituent is oxo. For example, a carbonyl group is a carbon (e.g., alkyl carbon, alkenyl carbon, alkynyl carbon, heteroalkyl carbon, heteroalkenyl carbon, heteroalkynyl carbon, carbocyclyl carbon, etc.) substituted with oxo. Alternatively, sulfur may be substituted with one or two oxo groups (e.g., -SO- or -SO2- within a substituted heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl group). Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)). In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from the group consisting of aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, thiol, and oxo. In some embodiments, the substituents are themselves unsubstituted.

[0084] Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and / or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. “Racemate” or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0085] Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.

[0086] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36CI,123l and125L Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. 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 invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0087] Definitions

[0088] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.

[0089] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 Nm” indicates a range of from 4.5 to 5.5 Nm.

[0090] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.

[0091] As used herein, the term “BAF complex” refers to the BRG1 - or HRBM-associated factors complex in a human cell.

[0092] As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.

[0093] As used herein, the term “BRD9” refers to bromodomain-containing protein 9, a component of the BAF (BRG1- or BRM-associated factors) complex, a SWI / SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomain-containing proteins. BRD9 is encoded by the BRD9 gene, the nucleic acid sequence of which is set forth in SEQ ID NO: 1 . The term “BRD9” also refers to natural variants of the wild-type BRD9 protein, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) to the amino acid sequence of wild-type BRD9, which is set forth in SEQ ID NO: 2.

[0094] SEQ ID NO: 1 atgggcaagaagcacaagaagcacaaggccgagtggcgctcgtcctacgaggattatgcc gacaagcccctggagaagcctctaaagctagtcctgaaggtcggaggaagtgaagtgact gaactctcaggatccggccacgactccagttactatgatgacaggtcagaccatgagcga gagaggcacaaagaaaagaaaaagaagaagaagaagaagtccgagaaggagaagcatctg gacgatgaggaaagaaggaagcgaaaggaagagaagaagcggaagcgagagagggagcac tgtgacacggagggagaggctgacgactttgatcctgggaagaaggtggaggtggagccg cccccagatcggccagtccgagcgtgccggacacagccagccgaaaatgagagcacacct attcagcaactcctggaacacttcctccgccagcttcagagaaaagatccccatggattt tttgcttttcctgtcacggatgcaattgctcctggatattcaatgataataaaacatccc atggattttggcaccatgaaagacaaaattgtagctaatgaatacaagtcagttacggaa tttaaggcagatttcaagctgatgtgtgataatgcaatgacatacaataggccagatacc gtgtactacaagttggcgaagaagatccttcacgcaggctttaagatgatgagcaaacag gcagctcttttgggcaatgaagatacagctgttgaggaacctgtccctgaagttgtacca gtacaagtagaaactgccaagaaatccaaaaagccgagtagagaagttatcagctgcatg tttgagcctgaagggaatgcctgcagcttgacggacagtaccgcagaggagcacgtgctg gcgctggtggagcacgcagctgacgaagctcgggacaggatcaaccggttcctcccaggc ggcaagatgggctatctgaagaggaacggggacgggagcctgctctacagcgtggtcaac acggccgagccggacgctgatgaggaggagacccacccggtggacttgagctcgctctcc agtaagctactcccaggcttcaccacgctgggcttcaaagacgagagaagaaacaaagtc acctttctctccagtgccactactgcgctttcgatgcagaataattcagtatttggcgac ttgaagtcggacgagatggagctgctctactcagcctacggagatgagacaggcgtgcag tgtgcgctgagcctgcaggagtttgtgaaggatgctgggagctacagcaagaaagtggtg gacgacctcctggaccagatcacaggcggagaccactctaggacgctcttccagctgaag cagagaagaaatgttcccatgaagcctccagatgaagccaaggttggggacaccctagga gacagcagcagctctgttctggagttcatgtcgatgaagtcctatcccgacgtttctgtg gatatctccatgctcagctctctggggaaggtgaagaaggagctggaccctgacgacagc catttgaacttggatgagacgacgaagctcctgcaggacctgcacgaagcacaggcggag cgcggcggctctcggccgtcgtccaacctcagctccctgtccaacgcctccgagagggac cagcaccacctgggaagcccttctcgcctgagtgtcggggagcagccagacgtcacccac gacccctatgagtttcttcagtctccagagcctgcggcctctgccaagacctaa

[0095] SEQ ID NO: 2:

[0096] MGKKHKKHKAEWRSSYEDYADKPLEKPLKLVLKVGGSEVTELSGSGHDSSYYDDRSDHER ERHKEKKKKKKKKSEKEKHLDDEERRKRKEEKKRKREREHCDTEGEADDFDPGKKVEVEP PPDRPVRACRTQPAENESTPIQQLLEHFLRQLQRKDPHGFFAFPVTDAIAPGYSMI IKHP MDFGTMKDKIVANEYKSVTEFKADFKLMCDNAMTYNRPDTVYYKLAKKILHAGFKMMSKQ AALLGNEDTAVEEPVPEVVPVQVETAKKSKKPSREVISCMFEPEGNACSLTDSTAEEHVL ALVEHAADEARDRINRFLPGGKMGYLKRNGDGSLLYSVVNTAEPDADEEETHPVDLSSLS SKLLPGFTTLGFKDERRNKVTFLSSATTALSMQNNSVFGDLKSDEMELLYSAYGDETGVQ CALSLQEFVKDAGSYSKKVVDDLLDQITGGDHSRTLFQLKQRRNVPMKPPDEAKVGDTLG DSSSSVLEFMSMKSYPDVSVDISMLSSLGKVKKELDPDDSHLNLDETTKLLQDLHEAQAE RGGSRPSSNLSSLSNASERDQHHLGSPSRLSVGEQPDVTHDPYEFLQSPEPAASAKT

[0097] As used herein, the term “BRD9-related disorder” refers to a disorder that is caused or affected by the level and / or activity of BRD9.

[0098] As used herein, the term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0099] As used herein, the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., BRD9) in a way which results in degradation of the protein, e.g., binding ofthe compound results in at least 5% reduction ofthe level of the protein, e.g., in a cell or subject.

[0100] As used herein, the term “degradation moiety” refers to a moiety whose binding results in degradation of a protein, e.g., BRD9. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., BRD9.

[0101] By “determining the level of a protein” is meant the detection of a protein, or an Mrna encoding the protein, by methods known in the art either directly or indirectly. “Directly determining” means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix -assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure Mrna levels are known in the art.

[0102] By “modulating the activity of a BAF complex,” is meant altering the level of an activity related to a BAF complex (e.g., GBAF), or a related downstream effect. The activity level of a BAF complex may be measured using any method known in the art, e.g., the methods described in Kadoch et al, Cell 153:71 - 85 (2013), the methods of which are herein incorporated by reference.

[0103] By “reducing the activity of BRD9,” is meant decreasing the level of an activity related to an BRD9, or a related downstream effect. A non-limiting example of inhibition of an activity of BRD9 is decreasing the level of a BAF complex (e.g., GBAF) in a cell. The activity level of BRD9 may be measured using any method known in the art. In some embodiments, an agent which reduces the activity of BRD9 is a small molecule BRD9 inhibitor. In some embodiments, an agent which reduces the activity of BRD9 is a small molecule BRD9 degrader.

[0104] By “reducing the level of BRD9,” is meant decreasing the level of BRD9 in a cell or subject. The level of BRD9 may be measured using any method known in the art.

[0105] By “level” is meant a level of a protein, or Mrna encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein is meant a decrease or increase in protein level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1 .2-fold, about 1 .4-fold, about 1 .5-fold, about 1 .8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass / vol (e.g., g / DI, mg / MI, pg / MI, ng / MI) or percentage relative to total protein or Mrna in a sample.

[0106] As used herein, the term “inhibitor” refers to any agent which reduces the level and / or activity of a protein (e.g., BRD9). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA).

[0107] As used herein, the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and / or activity of BRD9 (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and / or activity of BRD9 sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and / or activity of BRD9. The amount of a given agent that reduces the level and / or activity of BRD9 described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and / or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a “therapeutically effective amount” of an agent that reduces the level and / or activity of BRD9 of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and / or activity of BRD9 of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.

[0108] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0109] A “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a subject. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0110] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of any of the compounds described herein. For example, pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.

[0111] The compounds described herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds described herein, be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0112] By a “reference” is meant any useful reference used to compare protein, Mrna, DNA, or gene expression levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound described herein. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference.

[0113] As used herein, the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[0114] As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the subject; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0115] As used herein, the term “undetectable” refers to a measurement and / or observation that is not able to be obtained either due to insufficient presence of the substance in question or complete lack thereof. Instrumentation limitations can contribute to an undetectable measurement.

[0116] As used herein, the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material.

[0117] A used herein, the terms “relapse” and “recur” are used interchangeably and refer to cancer that has returned after prior treatment. Return can be in the form of symptoms and / or detectable cancer cells. As used herein, the terms “refractory” and “resistant” are used interchangeably and refer to cancer that does not respond to treatment. Cancer may be resistant or refractory at the beginning of treatment or it may become so during the course of treatment.

[0118] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0119] Brief Description of the Drawings

[0120] FIG. 1 is a graph depicting CpG sites whose DNA methylation status correlates with Compound 1 sensitivity.

[0121] FIG. 2 is a graph depicting example CpG sites whose DNA methylation status correlates with Compound 1 sensitivity.

[0122] FIG. 3 shows transcription factor motifs enriched in 500 CpG sites predicting Compound 1 sensitivity.

[0123] FIG. 4 is a graph depicting the IRF8 gene locus and corresponding DNA methylation status in AML cell lines.

[0124] FIG. 5 is a graph of AML cell lines and their IRF8 expression (log2(FPKM) vs. their notable genetic mutations such as MLL-r, NPM1-mut, and inv(16).

[0125] FIG. 6 is a graph depicting hCD45% (of total CD45) of two AML PDX cell lines treated with Compound 1 or vehicle.

[0126] FIG. 7 is a graph depicting inhibition percentage of a DLBCL cell line treated with increasing concentrations of Compound 1.

[0127] Detailed Description

[0128] The present inventors have discovered that hematologic cancers with high IRF8 expression may be treated with compounds that reduce the level and / or activity of bromodomain containing protein 9 (BRD9). Accordingly, the present invention features methods of treating hematologic cancer (e.g., acute myeloid lymphoma (AML) and / or diffuse large B cell lymphoma (DLBCL) that have high IRF8 expression) with compounds that reduce the level and / or activity of BRD9.

[0129] BRD9 inhibitors

[0130] Compounds that reduce the level of an activity related to BRD9, or a related downstream effect, or reduce the level of BRD9 in a cell or subject, may be used in accordance with the methods of the invention. BRD9 inhibitors are disclosed in US 20220098190, US 20220048906, US 20210230190, US 20210009568, US 20190247509, US 20180044335, WO 2020051235, WO 2020160192, WO 2020160193, WO 2020160198, WO 2021055295, and WO 2021178920, the BRD9 inhibitors of which are incorporated by reference into the present application. In some embodiments of the method of the invention, the BRD9 inhibitors are BRD9 degraders.

[0131] In a preferred embodiment of the methods of the present invention, the BRD9 inhibitor has the structure of Compound 1 , or a pharmaceutically acceptable salt thereof.

[0132]

[0133] Compound 1

[0134] Methods for synthesizing compound 1 are disclosed in US 2021-0230190 A1 , the synthetic methods of which are incorporated by reference into the present application. The BRD9 inhibitor may be, e.g., a compound of Formula I: where

[0135] R1is H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted Ci-Ce heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0136] Z1is CR2or N;

[0137] R2is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Cs-Cio carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted

[0138] Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl; each of R3a, R3b, R3c, and R3dis, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted Ci- Ce acyl, thiol, optionally substituted sulfone, optionally substituted sulfonamide, or optionally substituted amino, or R3aand R4b, R4aand R3b, R4band R4a, R3band R4c, R4band R4c, R3cand R4b, R3cand R4d, R4cand R4d, and / or R3dand R4c, together with the atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl; each of R4a, R4b, R4c, and R4dis, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted Ci- Ce acyl, thiol, optionally substituted sulfone, or optionally substituted amino, or R3aand R4b, R4aand R3b, R4band R4a, R3band R4c, R4band R4c, R3cand R4b, R3cand R4d, R4cand R4d, and / or R3dand R4c, together with the atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl; each of R5a, R5b, R5c, and R5dis, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; each of R3e, R3f, R3s, and R3his, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted Ci- Ce acyl, thiol, optionally substituted sulfone, optionally substituted sulfonamide, or optionally substituted amino, or R3eand R4for R4eand R3f, together with the atoms to which each is attached, combine to form optionally substituted heterocyclycl; each of R4e, R4f, R4s, and R4his, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted Ci- Ce acyl, thiol, optionally substituted sulfone, optionally substituted sulfonamide, or optionally substituted amino, or R3eand R4for R4eand R3f, together with the atoms to which each is attached, combine to form optionally substituted heterocyclycl; each of R5e, R5f, R5s, and R5his, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; and

[0139] G is optionally substituted Ce-C-io aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0140] The BRD9 inhibitor may be, e.g., a compound of Formula I:

[0141] Formula I, where

[0142] R1is H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted Ci-Ce heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0143] Z1is CR2or N;

[0144] R2is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl;

[0145] X1is a bond, O, NR3a, or CR4aR5a;

[0146] X2is O, NR3b, or CR4bR5b;

[0147] X3is O, NR3c, or CR4cR5c;

[0148] X4is a bond, O, NR3d, or CR4dR5d; each of R3a, R3b, R3c, and R3dis, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted Ci- Ce acyl, thiol, optionally substituted sulfone, optionally substituted sulfonamide, or optionally substituted amino, or R3aand R4b, R4aand R3b, R4band R4a, R3band R4c, R4band R4c, R3cand R4b, R3cand R4d, R4cand R4d, and / or R3dand R4c, together with the atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl; each of R4a, R4b, R4c, and R4dis, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted Ci- Ce acyl, thiol, optionally substituted sulfone, or optionally substituted amino, or R3aand R4b, R4aand R3b, R4band R4a, R3band R4c, R4band R4c, R3cand R4b, R3cand R4d, R4cand R4d, and / or R3dand R4c, together with the atoms to which each is attached, combine to form optionally substituted C2-C9 heterocyclyl; each of R5a, R5b, R5c, and R5dis, independently, H, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; and G is optionally substituted Ce-Cio aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0149] The BRD9 inhibitor may be, e.g., a compound of Formula II:

[0150] Formula II, where

[0151] R1is H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted Ci-Ce heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0152] Z1is CR2or N;

[0153] R2is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl; X1is CRX1or N;

[0154] X2is O or S;

[0155] RX1is H or optionally substituted Ci-Ce alkyl;

[0156] R3is H, cyano, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted amino, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C3-C10 heterocyclyl, or optionally substituted C2- C9 heteroaryl; and

[0157] G is optionally substituted C3-C10 carbocyclyl, C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, or optionally substituted C2-C9 heteroaryl, or a pharmaceutically acceptable salt thereof.

[0158] The BRD9 inhibitor may be, e.g., a compound of Formula III:

[0159] A-L-B

[0160] Formula III, where

[0161] A is a BRD9 binding moiety;

[0162] B is a degradation moiety; and

[0163] L has the structure of Formula II:

[0164] A1-(E1)-(F1)-(C3)m-(E3)n-(F2)oi-(F3)o2-(E2)P-A2,

[0165] Formula IDA where

[0166] A1is a bond between the linker and A;

[0167] A2is a bond between B and the linker; each of m, n, o1 , o2, and p is, independently, 0 or 1 ; each of E1and E2is, independently, O, S, NRN, optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, optionally substituted C2-10 alkynylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkylene;

[0168] E3is optionally substituted Ci-Ce alkylene, optionally substituted Ci-Ce heteroalkylene, O, S, or NRN; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alky ny I, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl;

[0169] C3is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and each of F1, F2, and F3is, independently, optionally substituted C3-C10 carbocyclylene, optionally substituted C2-10 heterocyclylene, optionally substituted Ce-C-io arylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the linker has the structure of Formula IIA-a:

[0171] Ai-(E1)-(F1)-(C3)m-(E2)P-A2.

[0172] Formula IIA-a

[0173] In some embodiments, the linker has the structure of Formula IIA-b:

[0174] A1-(E1)-(F1)-(E2)P-A2.

[0175] Formula IIA-b In some embodiments, the linker has the structure of Formula IIA-c: A1-(E1)-(F1)-A2.

[0176] Formula IIA-c

[0177] In some embodiments, the linker has the structure of Formula IIA-d: A1-(E1)-(F1)-(C3)m-(F2)oi-A2.

[0178] Formula IIA-d

[0179] In some embodiments, the linker has the structure of Formula IIA-e:

[0180] Ai-(E1)-(F1)-(E3)n-(F2)oi-(E2)P-A2.

[0181] Formula IIA-e

[0182] In some embodiments, the linker has the structure of Formula IIA-f: Ai-(E1)-(F1) -(C3)m-(E3)n-(F2)oi-(E2)p-A2.

[0183] Formula IIA-f

[0184] In some embodiments, the linker has the structure of Formula IIA-g:

[0185] A1-(E1)-(F1)-(E3)n-(F2)oi-A,

[0186] Formula IIA-g

[0187] The BRD9 inhibitor may be, e.g., a compound of Formula IV:

[0188] Formula IV, where

[0189] R1is H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0190] Z1is CR2or N;

[0191] R2is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl;

[0192] X1is N or CH, and X2is C-R7; or X1is C-R7, and X2is N or CH;

[0193] R7is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;

[0194] X3is N or CH;

[0195] X4is N or CH;

[0196] G is optionally substituted C3-C10 carbocyclyl, C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, or optionally substituted C2-C9 heteroaryl, or a pharmaceutically acceptable salt thereof.

[0197] The BRD9 inhibitor may be, e.g., a compound of Formula V:

[0198] Formula V wherein,

[0199] R1is Ci-salkyl or -cyclopropyl;

[0200] R2is selected from halogen, — Ci-salkyi, — Ci shaloalkyi, — NH?, — NHCi salkyl and — OH,

[0201] Xi is N or CR3

[0202] X2 is N or CR4wherein Xi and X? cannot be both N in the same molecule

[0203] R3is H or — Ci-salkyi;

[0204] R4is H or — Ci-salkyi; wherein R3and R4cannot be both — Ci-salkyi in the same molecule; alternatively, R2and R3taken together form a benzene ring or a 5-6 membered heteroarene ring, each of which rings can be optionally and independently substituted 'with one or more groups selected from halogen, — OH, — NH2, — NH — Ci-salkyl and — Ci salkyi, wherein the — Ci salkyl group can be optionally substituted 'with 5-6 membered heteroaryl or phenyl,

[0205] R5and Racan be the same or different and are independently selected from — H, — O — Ci salkyi and — Ci salkyl;

[0206] R6and Racan be the same or different and are independently selected from — H, — OH, halogen, — NH2, — Ci-salkyl, — O— C saikyi —O— Ci shaloalkyi, — Ci salkyl-O— Ci-salkyl, 4-7 membered heterocycloalkyl, — Ci-3alkyl-SO2 — Ci-salkyl, — Ci-salkyl-NHs, — Ci-?,alkyl-N( — Ci-salkyi)2, — NfCi-saikyl)?, — NH— R13;

[0207] R13is selected from — SO2 — Ci-salkyl and — Ci-saikyl, wherein the — Ci-salkyi groups can be optionally substituted with 5 to 6 membered heteroaryl; alternatively, R5and R6taken together form a benzene ring; alternatively, R7and R6or R7and R3taken together form a 5-7 membered heterocycloalkyl optionally substituted with — Ci-salkyl;

[0208] R?is selected from — H, — NHs, — Y — R12, — Ci-salkyl and 4-7 membered heterocycloalkyl;

[0209] Y is selected from — CR10R; |— , — SO2 — and — CO — ;

[0210] R13and R1' can be the same or different and are independently selected from — H or — Ci-salkyi; or R '° and R11taken together form a — Cs-icycloalkyl, R12is selected from NH?, OH, Ci-salkyl, N(R15,R16), O F?17, aryl 5-6 membered heteroaryl, wherein the aryl or heteroaryl is optionally and independently substituted with one or more halogen, 4-7 membered heterocycloalkyl, which heterocycloalkyl is optionally and independently substituted with one or more groups selected from halogen, OH, NH?, Ci-aalkyi, NHCi-salkyl, — N(Ci.3alky!)2, — O— Chalky! and — CH2— R14;

[0211] R14is selected from 5-10 membered mono- or bicyclic aryl or heteroaryl, which is optionally substituted with — NH2, — OH, halogen, — ON, Ci salkyl, — O — Ci-salkyl;

[0212] R15is — H or — Cioalkyl;

[0213] R15is selected from — Ci-salkyl, — C2-3alkyl-N(Ci-3alkyl)2, — C2-3alkyl-NHCi-3alkyl and 4-7 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with — C- saikyl;

[0214] R17is — C- -■alkyl or 4-7 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with C i-salky I; wherein when R7is Y — R12, R6and R3can be the same or different and are independently selected from — H, — OH, halogen, — NH2, — CN, — Ci-salkyl, — Ci-shaloalkyl, — O — Ci-salkyl, — O — Ci- shaloalkyl and — Ci salkyf-0 — Ci salkyi; wherein at least one of the substituents R5to Rsis not hydrogen; or a pharmaceutically acceptable salt thereof.

[0215] The BRD9 inhibitor may be, e.g., a compound of Formula VI, VII, or VIII: or a pharmaceutically acceptable salt thereof, wherein

[0216] Degron is selected from the group consisting of:

[0217] TL1 is a moiety that binds to BRD9 selected from the group consisting of:

[0218] TL2 is a moiety that binds to BROS selected from the group consisting of:

[0219]

[0220] X1, X2, X3, and X4are independently selected from CR4and N, wherein no more than two ef X1, X2, X3, and X4may be selected to be N;

[0221] X5and X6are independently selected from OR4and N;

[0222] Z2and Z3are selected from — CH2 — and — C(O) — wherein at least one of Z2and Z3is — C(O) — ; n is 0, 1 , 2. 3, 4, 5, 6, 7, 8, 9, or 10; is 1 , 2, 3, or 4; each Q is independently 0, S, or NR5;

[0223] R1is hydrogen or O-Cs alkyl;

[0224] R2, R3, and R3are independently selected from hydrogen and Ci-Csalkyl; each R4is independently selected from hydrogen, halogen, hydroxyl, Ci-Csaikyl. Ci-Caalkoxy, and Ci-Cshaioaikyl; each R5is independently hydrogen, Ci-Csaikyi, or — C(O)alkyl;

[0225] R7is selected from halogen, hydrogen, Ci-Csalkyl, Ci-Csalkoxy, and Ci-Cohaloalkyl; and each F?8is independently selected from hydrogen, Ci-Csalkyl, and C i -Cehaloalkyi; or two

[0226] R3groups together with the carbon to which they are attached form a cyclopropyl group.

[0227] The BRD9 inhibitor may be, e.g,, a compound of Formula IX:

[0228] Targeting Ligand Linker Targeting Ligase Binder

[0229] Formula IX where the Targeting Ligand is a group that is capable of binding to a brornodornain-containing protein, e.g., BRD9; the Linker is a group that covalently links the Targeting Ligand to the Targeting Ligase Binder; the Targeting Ligase Binder is a group that is capable of binding to a iigase (e.g., Cereblon E3 Ubiquitin ligase).

[0230] The Targeting Ligand may be, e.g.. a group Formula TL -I or TL-I I :

[0231] Formula TL-i Formula TL-II where n is 0, 1 , or 2;

[0232] R1 and R2 are independently selected from the group consisting of hydrogen and C1-6 alkyl; or R1 and R2 together with the atoms to which they are attached form an aryl or heteroaryl; each R3 may be independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, and halogen; and

[0233] R5 is selected from the group consisting of hydrogen and C1-6 alkyl.

[0234] The Linker may be, e.g., a group of Formula L-l:

[0235] -L1 -X1 -L2-X2-L3-,

[0236] Formula L-l where

[0237] L1 is selected from the group consisting of a bond, O, NR’, C(O), C1 -6 alkylene,

[0238] C1-6 heteroalkylene, *C(O)-C1-6 alkylene, C(O)-C1-6 alkenylene*, C1-6 alkenylene, and *C(O)-C1-6 heteroalkylene, where * denotes the point of attachment of L1 to the Targeting Ligand;

[0239] XI and X2 are each independently selected from the group consisting of a bond, carbocyclyl, and heterocyclyi, where the carbocyclyl and heterocyclyi are substituted 'with 0-4 occurrences of Ra, where each Ra is independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxyi, and halogen;

[0240] L2 is selected from the group consisting of a bond, O, NR’, C1-6 alkylene, and C1-6 heteroalkylene: or X1-L2-X2 form a spiroheterocyclyi; and

[0241] L3 is selected from the group consisting of a bond, O, C(O), Cl -5 alkylene, C1-6 heteroalkylene, *C(O)-C1-6 alkylene, *C(O)-C1-6 heteroalkylene, and *C(O)-C1-6 alkylene-O, where * denotes the point of attachment of L3 io X2; where no more than 2 of L1 , X1 , X2, L2, and L3 can simultaneously be a bond. The Targeting Ligase Binder may be, e.g., a compound of Formula TLB-I:

[0242] Formula TLB-I where

[0243] R4 is selected from the group consisting of C1-6 alkyl, C1 -6 alkoxyl, and halogen; and m is 0. 1.

[0244] The Targeting Ligase Binder may be, e.g., a oompound of Formula TLB-I’:

[0245] Formula TLB-I' where

[0246] Rdf and Rd2 are each independently selected from the group consisting of H, G1 -6 alkyl,

[0247] Cl -6 aikoxyi, C1-6 haloalkyl, and C1-6 heteroaikyi;

[0248] Rd3 is H: Rd4 is selected from the group consisting of H, Cl -6 alkyl, halo, C1 -6 haloalkyl, and Cl -6 heteroalkyl; and

[0249] Rd5 is selected from the group consisting of H, C1 -6 alkyl, halo, C1 -6 haloalkyl, and Ci -6 heteroalkyl.

[0250] The BRD9 inhibitor may be, e.g,, a compound of Formula Ixa:

[0251] Formula IX-a or a pharmaceutically acceptable salt thereof, where

[0252] L1 is selected from the group consisting of a bond, O, NR’, C(O), C1-6 alkylene,

[0253] C1-6 heteroaikylene, *C(O)-C1-6 alkylene, C(O)-C1-6 alkenylene*, C1-6 aikenylene, and *C(O)-C1-6 heteroalkylene, where * denotes the point of attachment of L1 to the Targeting Ligand; XI and X2 are each independently selected from the group consisting of a bond, carbocyclyl, and heterocyclyl, where the carbocyclyl and heterocyciyl are substituted with 0-4 occurrences of Ra, where each Ra is independently selected from the group consisting of C1 -6 alkyl, Cl -6 alkoxyl, and halogen;

[0254] L2 is selected from the group consisting of a bond, O, NR1, C1-6 alkylene, and C1-6 heteroalkylene; or X1-L2-X2 form a spiroheterocyciyl; and

[0255] L3 is selected from the group consisting of a bond, O, C(O), C1-6 alkylene, C1-6 heteroalkylene, *C(O)-C1-6 alkylene, *C(O)-C1-6 heteroalkylene, and *C(O)-C1-6 alkylene-O, where * denotes the point of attachment of L3 to X2. in some embodiments, no more than 2 of L1 , X1 , X2, L2, and L3 can simultaneously be a bond.

[0256] The BRD9 inhibitor may be, e.g., a compound of Formula X, XI, XII, XIII , XIV, or XV:

[0257] Formula XIV Formula XV or a pharmaceutically acceptable salt thereof, each a is independently 0. 1 , or 2; each y is independently 0, 1 , or 2; X3, X4, X5, and X6, are selected from the group consisting of N, GH and CR3, wherein no more than 3 of X3, X4. X5, and X6 are N;

[0258] X7 is N or CH;

[0259] X8 and X9 are each independently at each occurrence selected from the group consisting of N and CH; wherein at least one of X8 or X9 is CH;

[0260] X12 is a 5-membered heteroaryl group with 1 , 2, or 3 atoms independently selected from N, O, and S, wherein X12 is optionally substituted with 1 , 2, or 3 groups independently selected from R3;

[0261] X17 is aryl, heteroaryl, bicycle, or cycloalkyl, each of which is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R3;

[0262] Q1 is independently at each occurrence selected from the group consisting of NH, N(alkyi), N(haloalkyi), CH2, O, and S; wherein if X7 is N. then Q1 is CH2; R is independently at each occurrence selected from the group consisting of hydrogen, C1-C4haloalkyl, C1-C4aikyi, fluorine, chlorine, bromine, iodine, CH2F, CHF2, CF3, CH2CI, CHCI2, CCI3, CH2Br, CHBr2, and CBr3;

[0263] R1 is hydrogen, Ci -4 alkyl, C1-4 haloalkyl, or cycloalkyl;

[0264] R3 is independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, alkoxy, Ci -4 alkyl, Ci -4 haloalkyi, cycloalkyl, fluorine, chlorine, bromine, and iodine;

[0265] B is selected from B1 and B2;

[0266] Bl is selected from the group consisting of: B2 is selected from the group consisting of:

[0267] X10 is C(R7)2, C(0), or O; X1 1 is heterocycle, heteroaryl, aryl, cycloalkyl, or a bicycle, each of which X11 groups is optionally substituted with 1 , 2, 3, or 4 groups independently selected from R3; or

[0268] X13, X14, X15, and X16, are independently selected from the group consisting of N, CH and CR4, wherein no more than 3 of X13, X14, X15, and XI 6 are N; each R4 is independently selected from hydrogen, aryl, heteroaryi, C1 -4 alkoxy, C1 -4 haloalkyi, C1-4 haloalkoxy, C1-4 alkyl, fluorine, chlorine, bromine, and iodine; wherein two R4 groups on adjacent carbon atoms may optionally combine to form a fused cycle, wherein the fused cycle is optionally

[0269] R4

[0270] RV / \A

[0271] TJ substituted with 1 , 2, or 3 R substituents, thus, non-limiting examples of ' include wherein two R4 groups combined to form a pyrrole;

[0272] R5 is hydrogen, C1 -C4aiky I, allyl, crotyl, alkenyl, aikynyi, haloalkyi, or cycloalkyl; each R6 is independently selected from hydrogen, C1-4 alkoxy, C1 -4 alkyl, C1-4 haloalkyi, fluorine, chlorine, bromine, and iodine; each R7 is independently hydrogen or C1 -4 alkyl;

[0273] R8 is hydrogen, C1 -C4aiky I, allyl, crotyl, alkenyl, aikynyi, haloalkyi, or cycloalkyl; and L is a bivalent linking group.

[0274] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0275] or a pharmaceutically acceptable salt thereof.

[0276] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0277] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0278]

[0279] or a pharmaceutically acceptable salt thereof.

[0280] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292] or a pharmaceutically acceptable salt thereof.

[0293] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0294]

[0295]

[0296]

[0297]

[0298]

[0299] WO2021178920 compounds

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] or a pharmaceutically acceptable salt thereof.

[0342] Any suitable BRD9 inhibitor, e.g., a BRD9 inhibitor with an ionizable functional group, may be administered as a pharmaceutically acceptable salt, e.g., a salt of an acid selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, ciitric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and boric acid.

[0343] Hematologic Cancer

[0344] As used herein, “hematologic cancer” refers to a cancer of the blood, and includes leukemia, lymphoma and myeloma among others. “Leukemia” refers to a cancer of the blood, in which too many white blood cells that are ineffective in fighting infection are made, thus crowding out the other parts that make up the blood, such as platelets and red blood cells. It is understood that cases of leukemia are classified as acute or chronic. Certain forms of leukemia may be, by way of example, acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); Myeloproliferative disorder / neoplasm (MPDS); and myelodysplastic syndrome. “Lymphoma” may refer to a Hodgkin’s lymphoma, both indolent and aggressive non-Hodgkin’s lymphoma, Burkitt’s lymphoma, and follicular lymphoma (small cell and large cell), among others. Myeloma may refer to multiple myeloma (MM), giant cell myeloma, heavy-chain myeloma, and light chain or Bence-Jones myeloma.

[0345] In one aspect, the present disclosure provides a method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments, the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B- cell lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments, the hematologic cancer is AML. In some embodiments, the hematologic cancer is DLBCL.

[0346] In some embodiments, the methods disclosed herein slow progression of a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments, the methods disclosed herein reduce recurrence of a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments, the methods disclosed herein increase myeloid cell differentiation in a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments, the methods disclosed herein increase myeloid cell maturation in a hematologic cancer with high IRF8 expression in a subject in need thereof. In some embodiments, the methods disclosed herein increase myeloid cell proliferation in a hematologic cancer with high IRF8 expression in a subject in need thereof.

[0347] In another aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of an agent that reduces the level and / or activity of BRD9 in the cell. In some embodiments, the cell is an AML cell. In some embodiments, the cell is a diffuse large B cell lymphoma cell. In some embodiments, the cell is in a subject. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to IRF8 expression in a subject without a hematologic cancer. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to a reference. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to standard levels of IRF8. In some embodiments, the subject in need thereof has increased expression of myeloid peroxidase (MPO) relative to standard levels of MPO.

[0348] In one aspect, the present disclosure provides methods of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2- dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0349] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2-dihydro-2,7-naphthyridin-4- yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2- y I) pi peridine-2, 6-dione.

[0350] In one aspect, the present disclosure provides methods of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0351] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0352] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0353] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-1 ,6-dihydropy ridin-3- y I) benzyl)-3,3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-2, 6-dione.

[0354] In one aspect, the present disclosure provides methods of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0355] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0356] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0357] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-1 ,6-dihydropyridin-3- y I) benzyl)-3,3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-2, 6-dione.

[0358] Acute Myeloid Leukemia (AML)

[0359] AML is characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells. AML is generally considered incurable in about 65% of subjects under 60 years old and about 90% of subjects over 60 years old. Typical survival of older subjects with health too poor for intensive chemotherapy is 5- to 10-months. The five-year survival rate for AML is about 25% overall. The chemotherapy standard of care, a combination of cytarabine and an anthracycline, remains unchanged for more than 40 years, highlighting an unmet need for new therapies.

[0360] In one aspect, the present disclosure provides a method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments, the hematologic cancer is acute myeloid lymphoma (AML). In some embodiments, the AML is acute promyelocytic leukemia, arises from a pre-existing myelodysplastic syndrome or myeloproliferative disease, treatment-related AML, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, myeloid sarcoma, myeloid proliferations related to Down syndrome, blastic plasmacytoid dendritic cell neoplasm, AML minimally differentiated, AML without maturation, AML with granulocytic maturation, myelomonocytic together with bone marrow eosinophilia, acute monoblastic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, or acute basophilic leukemia.

[0361] In some embodiments, the AML is primary AML. In some embodiments, the AML is secondary AML. In some embodiments, the AML is therapy-related AML. In some embodiments, the AML harbors an MLL-r mutation. In some embodiments, the AML harbors an MLL PTD (partial tandem duplication) mutation. In some embodiments, the AML harbors a splicing factor mutation. In some embodiments, the AML harbors an AML-ETO fusion. In some embodiments, the AML harbors a DNMT mutation. In some embodiments, the AML harbors an FLT3 mutation. In some embodiments, the AML harbors an internal tandem duplication (ITD) mutation. In some embodiments, the AML harbors an FTL3-ITD mutation. In some embodiments, the AML harbors a tyrosine kinase domain mutation (TKD). n some embodiments, the AML harbors an FTL3-TKD mutation. In some embodiments, the AML harbors an NMP1 mutation. In some embodiments, the AML harbors a TP53 mutation. In some embodiments, the AML harbors a CEBPA mutation. In some embodiments, the AML harbors a DNMT3A mutation. In some embodiments, the AML harbors an IDH1 mutation. In some embodiments, the AML harbors an IDH2 mutation (e.g., IDH2-R140Q, IDH2-R172K). In some embodiments, the AML harbors an IDH1 mutation. In some embodiments, the AML harbors a JAK2 mutation. In some embodiments, the AML harbors a TET2 mutation. In some embodiments, the AML harbors a CBL mutation. In some embodiments, the AML harbors a MPL mutation. In some embodiments, the AML harbors a NRAS mutation. In some embodiments, the AML harbors a KRAS mutation. In some embodiments, the AML harbors a WT1 mutation. In some embodiments, the AML harbors an SF3B1 mutation. In some embodiments, the AML harbors an inv(16) mutation. In some embodiments, the AML harbors a RUNX1 mutation. In some embodiments, the AML harbors an ASXL3 mutation. In some embodiments, the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, an inv(16) mutation, or a combination thereof. In some embodiments, the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, an inv(16) mutation, a RUNX1 mutation, an ASXL3 mutation, or a combination thereof.

[0362] In some embodiments, the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3-ITD mutation, an FLT3-TKD mutation, an IDH1 mutation, an IDH2 mutation, a JAK2 mutation, a JAK2 mutation, a CBL mutation, an MPL mutation, an NRAS mutation, a KRAS mutation, a WT1 mutation, an SF3B1 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CBL mutation, an MPL mutation, a CEBPA mutation, an AML-ETO fusion mutation, an inv(16) mutation, a RUNX1 mutation, an ASXL3 mutation, or a combination thereof.

[0363] In some embodiments, the AML harbors an SRSF2 mutation, an SF3B1 mutation, a U2AF1 mutation, a ZRSR2 mutation, an ASXL1 mutation, a EZH2 mutation, a BCOR mutation, a STAG2 mutation, or a combination thereof.

[0364] In another aspect, the present disclosure provides a method of treating MLL rearrangement (MLL-r) acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments, the MLL-r AML harbors high IRF8 expression.

[0365] In another aspect, the present disclosure provides a method of treating inv(16) acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments, the inv(16) is a CBFB-MYH11 fusion. In some embodiments, the inv(16) AML harbors high IRF8 expression.

[0366] In one aspect, the present disclosure provides methods of treating acute myeloid leukemia with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2- dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)- 1-oxoisoindolin-2-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0367] In one aspect, the present disclosure provides methods of treating acute myeloid leukemia with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0368] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0369] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0370] In one aspect, the present disclosure provides methods of treating acute myeloid leukemia with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl-6-oxo-

[0371] 1 .6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)pi peridine-

[0372] 2.6-dione, or a pharmaceutically acceptable salt thereof.

[0373] Relapsed or Refractory AML

[0374] There is a large population of patients whose disease relapses after achieving first morphological complete remission. A 3-year study of 1 ,069 patients who did not undergo aSCT, conducted at MD Anderson Cancer Center, showed that the probability of relapse-free survival at 3 years was 29%. The patients had a median age of 55 years, included 22% with favorable cytogenetics, 64% with intermediate risk cytogenetics, and a 14% with adverse cytogenetics. Younger age and more favorable karyotype were associated with significantly increased rates of relapse-free survival at 1 year (Mangan, 2011). The prognosis of relapsed or refractory AML is poor and the median survival is approximately 6 months (Ferrara, 2004; Giles, 2005; Ritchie, 2013; Craddock, 2014; Plever, 2014).

[0375] For some patients with relapsed or refractory disease treated with chemotherapy alone, there is the potential for long-term disease-free survival, however this is most likely due to hematopoietic stem cell therapy (HSCT). HSCT in first relapse may be successful if a suitable donor can be identified, and the patient can proceed to transplant in a timely fashion. However, when treated patients with relapsed or refractory disease, challenges include accurately assessing the following: prognosis of disease, whether remission can be achieved, and the ability of patients to tolerate aggressive salvage therapies, choosing a successful salvage therapy, and ultimately identifying suitable patients for HSCT. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation. For patients potentially eligible for hematopoietic stem cell transplantation post-HSCT is frequent, and in spite of salvage attempts, less than 20% of these patients are alive after 5 years (Thol. F., Ganser, A., 2020). For those patients that are not eligible for HSCT, hypomethylating agents, low-dose AraC, and increasingly combination therapy of venetoclax with demethylating agents achieve encouraging response rates. However, there are patients that did not respond to one or more initial therapies (e.g. intensive chemotherapy, venetoclax, or hypomethylating agent, such as azacytidine).

[0376] DLBCL

[0377] Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of white blood cell responsible for producing antibodies. It is the most common type of non-Hodgkin lymphoma among adults, with an annual incidence of 7-8 cases per 100,000 people per year in the USA and the UK.

[0378] In one aspect, the present disclosure provides a method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments, the hematologic cancer is diffuse large B cell lymphoma (DLBCL).

[0379] In one aspect, the present disclosure provides methods of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1- oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0380] In one aspect, the present disclosure provides methods of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5- trimethyl-6-oxo-1 , 6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3- fluorophenyl)amino)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0381] In one aspect, the present disclosure provides methods of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5- trimethyl-6-oxo-1 , 6-dihydropyridin-3-yl) benzyl)-3, 3-difluoropiperidin-4-yl) pi perazin-1 -yl)-3- fluorophenyl)amino)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0382] IRF8

[0383] Interferon consensus sequence-binding protein (ICSBP), also known as interferon regulatory factor 8 (IRF8), is a transcription factor of the IRF family that plays a critical role in the regulation of lineage commitment, specifically in myeloid cell differentiation. IRF8 is expressed in bone marrow progenitor cells and controls cell growth and differentiation of myeloid cells at different developmental stages.

[0384] As used herein “IRF8” and “Interferon Regulatory Factor 8” are inclusive of all family members, mutants, alleles, fragments, species, coding and noncoding sequences, sense and antisense polynucleotide strands, etc.

[0385] As used herein, Interferon regulatory factor 8, IRF-8, IRF8, H-ICSBP, ICSBP, ICSBP1 , Interferon consensus sequence-binding protein, are considered the same in the literature and are used interchangeably herein. In one aspect, the present disclosure provides a method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to IRF8 expression in a subject without hematologic cancer. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to IRF8 expression in a subject without AML. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to IRF8 expression in a subject without DLBCL. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to a reference. In some embodiments, the IRF8 expression of the subject in need thereof is high relative to standard levels of IRF8.

[0386] In another aspect, the present disclosure provides a method of reducing differentiation of common myeloid progenitor (CMP) cells into monocyte precursor cells in a subject that has AML with determined high IRF8 expression, the method comprising administering to a subject in need thereof an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

[0387] IRF8 expression levels can be determined in a given sample by several different means. In some embodiments, IRF8 expression levels are measured in a blood sample from a subject. In some embodiments, IRF8 expression levels are measured in a bone marrow sample of a subject.

[0388] In some embodiments, IRF8 expression levels are measured by RNAseq. In some embodiments, IRF8 expression levels are measured as mRNA transcript per million (TPM). In some embodiments, a high IRF8 mRNA expression level is a level of greater than 6.0 TPM of log2(IRF8+1). In some embodiments, a high IRF8 mRNA expression level is a level of greater than or equal to 63 TPM. In some embodiments, TPM is measured by normalizing RNA-seq read counts mapping to IRF8 to all other RNA-seq counts in a given library that map to other genes. In some embodiments, IRF8 expression levels are measured as fragments per kilobase of transcript per million (FPKM). FPKM normalizes read count based on gene length and the total number of mapped reads. In some embodiments, IRF8 expression levels are measured as reads per kilobase of transcript per million (RPKM).

[0389] RT-qPCR (quantitative reverse transcription polymerase chain reaction) measures relative mRNA expression levels of a gene of interest (e.g., IRF8) against a panel of control genes with stable expression levels. In some embodiments, the panel of control genes has stable expression levels in CD34+and / or CD117+blasts. In some embodiments, CD34+and / or CD117+blasts are isolated from peripheral blood mononuclear cells of a subject. Samples of cancerous blast cells can be taken from subjects for RNA expression measurement and compared against subjects without hematologic cancer. In some embodiments, IRF8 expression levels in a subject are measured by RT-qPCR. In some embodiments, RNA is isolated from blast cells of a subject with hematologic cancer (e.g., AML, DBCLC). In some embodiments, RNA expression levels of IRF8 in a subject with hematologic cancer (e.g., AML, DBCLC) are compared to RNA expression levels of IRF8 in a subject without hematologic cancer.

[0390] In some embodiments, IRF8 expression levels are measured by RNA microarray.

[0391] In some embodiments, IRF8 protein levels are measured by flow cytometry. In some embodiments, protein expression is measured in peripheral and / or bone marrow blasts of a subject. In some embodiments, IRF8 protein levels are measured by immunohistochemistry. In some embodiments, IRF8 protein levels are measured by immunohistochemistry with an IRF8 antibody. In some embodiments, IRF8 protein levels are measured in subject bone marrow biopsies. In some embodiments, IRF8 protein levels in bone marrow of subjects with hematologic cancer (e.g., AML, DBCLC) are measured by immunohistochemistry and compared to bone marrow samples of subjects without hematologic cancer. In some embodiments, a high IRF8 protein level measured by immunohistochemistry is a percentage of IRF8 staining of greater than 50% of the sample.

[0392] DNA methylation is known to play a role in normal myeloid differentiation. During granulopoiesis there is an initial increase in DNA methylation at myeloid lineage enhancers, followed by removal of the repressive mark of DNA methylation as these cis-regulatory elements become active to turn on myeloid lineage genes. Regions containing differential DNA methylation are known to be enhancers and enriched with myeloid lineage transcription factor motifs (e.g., CEBP, IRF, MYB, AP-1). In some embodiments, DNA methylation with a mean beta value (e.g., proportion of CpG sites which are methylated) of less than 0.20 in those regions predicted sensitivity to compounds described herein.

[0393] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of an agent that reduces the level and / or activity of BRD9 in the cell.

[0394] In some embodiments of any of the aspects disclosed herein, the subject in need thereof has low DNA methylation of the IRF8 genomic loci relative to a subject without a hematologic cancer. In some embodiments of any of the aspects disclosed herein, the subject in need thereof has low DNA methylation of the IRF8 genomic loci relative to a reference. In some embodiments of any of the aspects disclosed herein, the low DNA methylation is measured as a mean beta value of less than 0.20.

[0395] In one aspect, the present disclosure provides methods of determining hematologic cancer and / or monitoring a hematologic cancer in a subject in need thereof, the method comprising determining the DNA methylation status for the IRF8 gene in the subject.

[0396] In some embodiments of any of the aspects disclosed herein, the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B- cell lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments of any of the aspects disclosed herein, the hematologic cancer is diffuse large B cell lymphoma (DLBCL). In some embodiments of any of the aspects disclosed herein, the hematologic cancer is acute myeloid leukemia (AML). In some embodiments of any of the aspects disclosed herein, the AML is acute promyelocytic leukemia, arises from a pre-existing myelodysplastic syndrome or myeloproliferative disease, treatment-related AML, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, myeloid sarcoma, myeloid proliferations related to Down syndrome, blastic plasmacytoid dendritic cell neoplasm, AML minimally differentiated, AML without maturation, AML with granulocytic maturation, myelomonocytic together with bone marrow eosinophilia, acute monoblastic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, or acute basophilic leukemia. In some embodiments of any of the aspects disclosed herein, the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, or a combination thereof. In some embodiments of any of the aspects disclosed herein, the DNA methylation status for IRF8 is low. In some embodiments of any of the aspects disclosed herein, the low DNA methylation status is a mean beta value of less than 0.20. In some embodiments of any of the aspects disclosed herein, the subject determined to have a hematologic cancer is administered an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects disclosed herein, the compound that reduces the level and / or activity of BRD9 is 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1 ,2-dihydro- 2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1- oxoisoindolin-2-yl)piperidine-2, 6-dione. In some embodiments of any of the aspects disclosed herein, the compound that reduces the level and / or activity of BRD9 is 3-((4-(4-(1-(2,6-dimethoxy-4-(1 ,4,5-trimethyl- 6-oxo-1 ,6-dihydropyridin-3-yl)benzyl)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)-3- fluorophenyl)amino)piperidine-2, 6-dione.

[0397] Methods of Treatment

[0398] The present disclosure features methods of treating disorders related to BRD9 such as cancer, e.g., a hematologic cancer with high IRF8 expression, in a subject in need thereof.

[0399] Cancer is a group of diseases characterized by the harmful, abnormal, uncontrolled, and undesirable growth of cells. In some embodiments, the uncontrolled growth is due to cells that divide and proliferate in the absence of signals (e.g., growth factors) instructing them to do so. In some embodiments, the uncontrolled growth is due to cells which fail to respond to signals instructing them to stop growing and / or engage in programmed cell death (i.e., apoptosis). In some embodiments, cancer cells may spread throughout the body (i.e., metastasize). In some embodiments, cancer cells may form tumors. In some embodiments, cancer cells may form solid tumors.

[0400] In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of: (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, (i) increased progression free survival of a subject, (j) slowed progression of cancer, (k) reduced recurrence of cancer, (I) decreased rate of metastatic tumor seeding, (m) decreased metastatic tumor nodule formation, (n) decreased spread of metastatic tumor nodule formation, and (o) decreased metastatic colonization.

[0401] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor.

[0402] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0403] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, can result in a decrease in the spread of metastatic nodules, e.g., a decrease in the number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).

[0404] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, can result in a decrease in the level of acute myeloid leukemia with high IRF8 expression cells in the subject. For example, after treatment, the level of a hematologic cancer with high IRF8 expression, cells in the subject are reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to level prior to treatment. The level of a hematologic cancer with high IRF8 expression, cells may be measured by any reproducible means of measurement. For example, the level of a hematologic cancer with high IRF8 expression, cells may be measured by obtaining a sample of blood and / or bone marrow from a subject with a hematologic cancer with high IRF8 expression, and conducting cell sorting experiments to determine the proportion of the cells in the sample that are a hematologic cancer with high IRF8 expression.

[0405] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, can result in the treatment of a cancer that had previously failed to respond to an anti-cancer therapy, e.g., an anticancer therapy that did not target BRD9. For example, the methods of the present invention may result in the treatment of a cancer that had previously failed to respond to active surveillance, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), cryotherapy, hormone therapy, chemotherapy, immunotherapy, vaccine treatment, immune checkpoint inhibitors, targeted therapy drugs, or bone- directed treatment.

[0406] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

[0407] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

[0408] Treating cancer, e.g., treating a hematologic cancer with high IRF8 expression, with a compound that reduces the level and / or activity of BRD9, or a pharmaceutical salt thereof, may result in a reduced recurrence of cancer relative to the recurrence of cancer in a subject that has not been treated with a compound that reduces the level and / or activity of BRD9, or a pharmaceutical salt thereof. A decrease in the recurrence of cancer may be measured, for example, by monitoring the number of incidences of recurrence of cancer over a period of time (e.g., one week, one month, one year, five years) in a population of cancer subjects with cancer treated with a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, and comparing that number of incidences to the number of incidences of recurrence of cancer in a population of subjects with cancer who are not administered a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, over the same period of time.

[0409] Combination Therapies

[0410] A method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of therapies to treat cancer. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect.

[0411] In some embodiments, the hematologic cancer with high IRF8 expression has failed to respond to a previous treatment. In some embodiments, the previous treatment is a second therapeutic agent. In some embodiments the previous treatment is an anti-cancer therapy. In some embodiments, a subject is further administered an anti-cancer therapy. In some embodiments, the anti-cancer therapy is administered prior to the administering of a compound of the present disclosure. In some embodiments, the anti-cancer therapy is administered in addition to the administering of a compound of the present disclosure. In some embodiments, the anti-cancer therapy is administered subsequent to the administering of a compound of the present disclosure. In some embodiments, the anti-cancer therapy is active surveillance, surgery, radiation therapy, high-intensity focused ultrasound (HIFU), cryotherapy, hormone therapy, chemotherapy, immunotherapy, vaccine treatment, immune checkpoint inhibitors, targeted therapy drugs, or bone-directed treatment. In some embodiments, an anti-cancer therapy is abiraterone acetate, alendronate, apalutamide, bicalutamide, cabazitaxel, carboplatin, cisplatin, darolutamide, degarelix, denosumab, docetaxel, enzalutamide, etoposide, flutamide, goserelin acetate, ibandronate, leuprolide acetate, lynparza, mitoxantrone hydrochloride, nilutamide, olaparib, pamidronate, radium 223 dichloride, relugolix, risedronate, rucaparib camsylate, sipuleucel-T, or zoledronic acid, or combinations thereof.

[0412] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; or zoledronic acid and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209): 1041-1047 (2000).

[0413] In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-l- 131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado- trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates. In some embodiments, the second therapeutic agent is dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgplOO, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or LXS196).

[0414] In some embodiments, the second therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib) and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or LXS196).

[0415] In some embodiments, the second therapeutic agent is cytarabine, an anthracycline such as daunorubicin, arsenic trioxide, all-trans-retinoic acid, or a combination thereof. In some embodiments, the second agent is an immunotherapy such as histamine dihydrochloride and interleukin 2. In some embodiments, the second agent is gemtuzumab ozogamicin.

[0416] The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and / or surgical excision of tumor tissue.

[0417] The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab / YERVOY® or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; pidilizumab / CT-011). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / lg fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, a2aR, B-7 family ligands, or a combination thereof.

[0418] In some embodiments, the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art, may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466;

[0419] 6,905,681 ; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041 ; and U.S. Patent Application Publication No. 20060121005.

[0420] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.

[0421] In one aspect, the present disclosure provides a method of treating a hematologic cancer with high interferon regulatory factor 8 (JRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In some embodiments, the additional anticancer therapy is administered prior to the administering of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the additional anti-cancer therapy is administered in addition to the administering of the compound or pharmaceutically acceptable salt thereof. In some embodiments, the additional anti-cancer therapy is administered subsequent to the administering of the compound or pharmaceutically acceptable salt thereof.

[0422] In some embodiments, the additional cancer therapy is a menin inhibitor, abemaciclib, all-trans- retinoic acid, arsenic trioxide, azacitidine, cedazuridine, cobimetinib, CPX-351 , cytarabine, daunorubicin, decitabine, enasidenib, etoposide, gemtuzumab, gilteritinib, glasdegib, hemopoietic stem cell transplant, ivosidenib, midostaurin, olutasidenib, ozogamicin, venetoclax, or combinations thereof.

[0423] In some embodiments, the method further comprises administering induction chemotherapy. In some embodiments, the induction chemotherapy comprises cytarabine, an anthracycline such as daunorubicin, arsenic trioxide, all-trans-retinoic acid, or combinations thereof.

[0424] In some embodiments, the method further comprises administering consolidation therapy. In some embodiments, the consolidation therapy comprises an allogenic stem cell transplantation and / or immunotherapy.

[0425] In some embodiments, the method further comprises administering a hemopoietic stem cell transplant, gemtuzumab ozogamicin, or a combination thereof.

[0426] In some embodiments, the method further comprises administering chemotherapy, cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, or a combination thereof. In some embodiments, the method further comprises administering cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, or a combination thereof. Decitabine

[0427] Methods of treatment of decitabine are described in US Application No. US20050222076A1 , the content of which is incorporated herein by reference in its entirety. Decitabine is approved for use by the FDA under the name DACOGEN®. In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In some embodiments, the at least one additional anti-cancer therapy is decitabine.

[0428] Cytarabine

[0429] Methods of treatment of cytarabine are described in "Nicholas D. Reese, Gary J. Schiller; Curr Hematol Malig Rep. 2013, 141-148," and Methods of treatment of low dose cytarabine are described in “Jehn U, Goldel N, Vehling-Kaiser U. Low-dose cytosine arabinoside (LD-Ara C) treatment in dysmyelopoietic syndromes (DMPS) and acute myelogenous leukemia (AML). Anticancer Res. 1987. :505-8.” Cytarabine is approved for use by the FDA under the name Cytosar-U®. In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In some embodiments, the at least one additional anti-cancer therapy is cytarabine.

[0430] FLT3 Inhibitors

[0431] In one embodiment, the invention features a combination therapy including (i) , 3-(6-(7-((1-(4-(6- (azetidin-1-yl)-2-methyl-1 -oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione or pharmaceutically acceptable salt of, and (ii) a FLT3 inhibitor. The term "FLT3 pathway inhibitor" or "FLT3 targeting compound" or "FLT3 inhibitor" refers to a compound that specifically binds to and inhibits FLT3, which interferes with the activation of FLT3 -mediated signal transduction pathways and reduces cell proliferation in cancer cells that overexpress FLT3. In certain embodiments, a FLT3 inhibitor is a compound that specifically binds to and inhibits wild type FLT3. In certain embodiments, a FLT3 inhibitor is a compound that specifically binds to and inhibits mutant FLT3, for example, FLT3-ITD (an internal tandem duplication mutation in the JM domain-coding sequence of the FLT3 gene) and / or FLT3-KDM (a missense point mutation at the D835 residue and point mutations, deletions and insertions in the codons surrounding D835 within a TK domain of FLT3).

[0432] In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In some embodiments, the at least one additional anti-cancer therapy is an FLT3 inhibitor. Exemplary FLT3 inhibitors for use herein include, but are not limited to quizartinib (AC220), sunitinib (SU11248), sorafenib (BAY 43-9006), midostaurin (PKC412), lestaurtinib (CEP-701), crenolanib (CP-868596), PLX3397, E6201 , AKN-028, ponatinib (AP24534), ASP2215, KW- 2449, famitinib and DCC-2036.

[0433] Menin Inhibitors

[0434] In one embodiment, the invention features a combination therapy including (i) 3-(6-(7-((1-(4-(6- (azetidin-1-yl)-2-methyl-1 -oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione or pharmaceutically acceptable salt of, and (ii) a menin inhibitor. The term "menin pathway inhibitor" or "menin targeting compound" or "menin inhibitor" refers to a compound that specifically binds to and inhibits menin, which inhibits the protein-protein interaction of menin with an MLL protein (e.g. MLL1 , MLL2, or MLL fusion protein). In certain embodiments, a menin inhibitor is a compound that specifically binds to and inhibits wild type menin. In certain embodiments, a menin inhibitor is a compound that specifically binds to and inhibits mutant menin, for example, menin-NPM1 (a mutation in the NPM1 gene in exon 12 of the NPM1 gene or a frameshift mutation, where the mutation can be an insertion of two to nine bases or a deletion of nucleotides 965 through 969 (GGAGG)) and or menin-DNMT3A (a mutation in the DNMT3A gene in R882, a frameshift deletion, missense mutation, nonsense mutation, splice-site substitution, splice-site deletion, or whole-gene deletion). Exemplary menin inhibitors for use herein include, but are not limited to, KO-539, SNDX-5613, revumenib, and DS-1594a. In some embodiments, the additional cancer therapy is a menin inhibitor. In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In some embodiments, the at least one additional anti-cancer therapy is a menin inhibitor. In some embodiments, the menin inhibitor is BMF-219, DS-1594a, DS-1594b, JNJ- 75276617, revumenib, SNDX-50469, ziftomenib, or combinations thereof.

[0435] IDH1 Inhibitor

[0436] In one embodiment, the invention features a combination therapy including (i) 3-(6-(7-((1-(4-(6- (azetidin-1-yl)-2-methyl-1 -oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione or pharmaceutically acceptable salt of, and (ii) an IDH1 inhibitor. The term "IDH1 inhibitor" or "IDH1 targeting compound" refers to a compound that specifically binds to and inhibits wild-type or mutant IDH1 , which inhibits the formation of a dimer, e.g., a homodimer of IDH1 wild-type subunits, a homodimer of IDH1 mutant subunits, or a heterodimer of a mutant and wildtype subunit. In certain embodiments, an IDH1 inhibitor is a compound that specifically binds to inhibits mutant IDH1 , for example, mlDH1 (somatic mutation in IDH1). In certain embodiments, the IDH1 inhibitor also inhibits IDH2. In certain embodiments. IDH1 inhibitor binds to an IDH1 mutant subunit and inhibits neoactivitiy . in some embodiments, the neoactivity inhibition is at least about 60%. 70%, 80%, 90%, 95% or 99% as compared to the activity in the absence of the mutant IDH1 inhibitor. In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In some embodiments, the at least one additional anti-cancer therapy is an IDH1 inhibitor. Exemplary IDH1 inhibitors for use herein include, but are not limited to ivosidenib, enasidenib, olutasidenib, and AG-881.

[0437] / D / 2 inhibitor

[0438] In one embodiment, the invention features a combination therapy including (i) 3-(6-(7-((1-(4-(6-(azetidin-1- yl)-2-methyl-1 -oxo-1 ,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7- diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-dione or pharmaceutically acceptable salt of, and (ii) an IDH2 inhibitor. The term "IDH2 inhibitor" or "IDH2 targeting compound" refers to a compound that specifically binds to and inhibits wild-type or mutant IDH2, which inhibits the formation of a dimer, e.g., a homodimer of IDH2 wild-type subunits, a homodimer of IDH2 mutant subunits, or a heterodimer of a mutant and wildtype subunit. In certain embodiments, an IDH2 inhibitor is a compound that specifically binds to inhibits mutant IDH2, for example, mlDH2 (somatic mutation in I DH2). In certain embodiments, the IDH2 inhibitor also inhibits IDH1 . Jn certain embodiments, !DH2 inhibitor binds to an IDH2 mutant subunit and inhibits neoactivitiy. in some embodiments, the neoactivity inhibition is at least about 60%, 70%, 80%, 90%, 95% or 99% as compared to the activity in the absence of the mutant IDH1 inhibitor. In some embodiments, the subject is further administered at least one additional anti-cancer therapy. In some embodiments, the at least one additional anti-cancer therapy is an IDH2 inhibitor. Exemplary IDH2 inhibitors for use herein include, but are not limited to ivosidenib, enasidenib, olutasidenib, and AG-881.

[0439] Pharmaceutical Compositions

[0440] The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0441] The compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0442] A compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound described herein may also be administered parenterally. Solutions of a compound described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.

[0443] The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

[0444] Dosages

[0445] The dosage of the compounds described herein, and / or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg.

[0446] Alternatively, the dosage amount can be calculated using the body weight of the subject. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a subject may range from 0.1-100 mg / kg.

[0447] In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 20-120 mg / kg (e.g., 20-60 mg / kg, 20-40 mg / kg, 40-80 mg / kg, 40-60 mg / kg, 60-80 mg / kg, or 80-120 mg / kg).

[0448] In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 20 mg / kg. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 40 mg / kg. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 50 mg / kg. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 60 mg / kg. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 80 mg / kg. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 120 mg / kg.

[0449] In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered at least once per week.

[0450] In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered at least twice per week.

[0451] In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 20 mg / kg once per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 40 mg / kg once per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 50 mg / kg once per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 60 mg / kg once per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 80 mg / kg once per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 120 mg / kg once per week.

[0452] In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 20 mg / kg twice per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 40 mg / kg twice per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 50 mg / kg twice per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 60 mg / kg twice per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 80 mg / kg twice per week. In some embodiments, the effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered in a dose of 120 mg / kg twice per week.

[0453] In some embodiments, the effective amount of a compound of the present disclosure of a pharmaceutically acceptable salt thereof is administered to the subject in a 14-day dosing cycle.

[0454] In some embodiments, the effective amount of a compound of the present disclosure of a pharmaceutically acceptable salt thereof is administered to the subject in a 2 week dosing cycle.

[0455] In some embodiments, the effective amount of a compound of the present disclosure of a pharmaceutically acceptable salt thereof is administered to the subject in a 21 -day dosing cycle. In some embodiments, the effective amount of a compound of the present disclosure of a pharmaceutically acceptable salt thereof is administered to the subject in a 3 week dosing cycle.

[0456] In some embodiments, the effective amount of a compound of the present disclosure of a pharmaceutically acceptable salt thereof is administered to the subject in a 28-day dosing cycle.

[0457] In some embodiments, the effective amount of a compound of the present disclosure of a pharmaceutically acceptable salt thereof is administered to the subject in a 4 week dosing cycle.

[0458] In some embodiments, the effective amount of a compound of the present disclosure of a pharmaceutically acceptable salt thereof is administered to the subject in a one month dosing cycle.

[0459] In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 1 NG / mL of compound for at least 14 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 1 NG / mL of compound for at least 2 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 1 NG / mL of compound for at least 21 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 1 NG / mL of compound for at least 3 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 1 NG / mL of compound for at least 28 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 1 NG / mL of compound for at least 4 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 1 NG / mL of compound for at least 1 month after administration.

[0460] In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 2 NG / mL of compound for at least 14 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 2 NG / mL of compound for at least 2 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 2 NG / mL of compound for at least 21 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 2 NG / mL of compound for at least 3 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 2 NG / mL of compound for at least 28 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 2 NG / mL of compound for at least 4 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 2 NG / mL of compound for at least 1 month after administration.

[0461] In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 3 NG / mL of compound for at least 14 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 3 NG / mL of compound for at least 2 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 3 NG / mL of compound for at least 21 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 3 NG / mL of compound for at least 3 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 3 NG / mL of compound for at least 28 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 3 NG / mL of compound for at least 4 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 3 NG / mL of compound for at least 1 month after administration.

[0462] In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 5 NG / mL of compound for at least 14 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 5 NG / mL of compound for at least 2 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 5 NG / mL of compound for at least 21 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 5 NG / mL of compound for at least 3 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 5 NG / mL of compound for at least 28 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 5 NG / mL of compound for at least 4 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 5 NG / mL of compound for at least 1 month after administration.

[0463] In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 10 NG / mL of compound for at least 14 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 10 NG / mL of compound for at least 2 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 10 NG / mL of compound for at least 21 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 10 NG / mL of compound for at least 3 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 10 NG / mL of compound for at least 28 days after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 10 NG / mL of compound for at least 4 weeks after administration. In some embodiments, a formulation of the present disclosure is administered in an amount sufficient to maintain a concentration of at least 10 NG / mL of compound for at least 1 month after administration.

[0464] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to decrease a BRD9 immunohistochemistry score of the subject. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 14 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 21 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 28 days.

[0465] In one aspect, the present disclosure provides a method of decreasing a BRD9 immunohistochemistry score in a subject, the method comprising administering an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 14 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 21 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 28 days.

[0466] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to reduce the level of BRD9 expression in the subject. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 14 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 21 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 28 days.

[0467] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to cause a greater than or equal to 10% decrease in tumor size and / or a greater than or equal to 15% decrease in tumor attenuation. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 14 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 21 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 28 days.

[0468] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof, wherein the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 14 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 21 days. In some embodiments of any of the aspects disclosed herein, the effective amount is an amount sufficient to maintain a plasma concentration of 3 NG / mL of the compound in a subject, over at least 28 days.

[0469] Advantageously, a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) may exhibit prolonged efficacy at BRD9 degradation, thus allowing for intermittent dosing regimens. For example, a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) may be administered to the subject in need thereof twice weekly or less frequently (e.g., twice weekly to once bimonthly, twice weekly to once monthly, twice weekly to once biweekly, once weekly to once monthly, or once weekly to once biweekly; e.g., once weekly, once biweekly, once every three weeks, or once monthly).

[0470] A BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) may be administered in cycles (e.g., four- to eight-week-long cycles; e.g., four-week-long, six-week-long, or eight- week-long cycles). In some variants, the regimen may include once weekly dosages of an effective amount of a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof). For example, a total of two to three once weekly dosages may be administered per cycle, e.g., an effective amount of a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered on weeks 1 and 2 of the cycle, or an effective amount of a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered on weeks 1 , 2, and 3 of the cycle. For example, a once weekly dosing may be implemented as follows: the first dose of an effective amount of a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) may be administered on Day 1 of the cycle, and the second once weekly dose may be administered on Day 8 or 9 (preferably, Day 8) of the cycle. If a third dose is administration, the third dose may be administered on Day 15 or Day 16 (preferably, Day 15) of the cycle. Alternatively, the regimen may include once biweekly, once every three weeks, once monthly, or once bimonthly dosages of an effective amount of a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof). Typically, the first dose of a BRD9 inhibitor (e.g., compound 1 or a pharmaceutically acceptable salt thereof) is administered on week 1 of the cycle.

[0471] Kits

[0472] The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and / or activity of BRD9 in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent that reduces the level and / or activity of BRD9 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.

[0473] The following Examples are illustrative only and not intended to limit the invention in any way.

[0474] EXAMPLES

[0475] Example 1. AML cell lines with high IRF8 expression are sensitive to treatment with Compound 1.

[0476] Procedure: AML cell lines were cultured in the presence of a serial dilution of Compound 1 (ranging from 0.000003 pM to 0.05 pM and a 0.25% DMSO control) at either Chempartner or Pharmaron. GI50 values were calculated on day 10 at Chempartner or day 14 at Pharmaron. A subset of AML lines were determined to be sensitive to Compound 1 , in vitro (defined as >50% inhibition over DMSO at day 10 or day 14, with GI50<50nM). In order to identify genomic biomarkers possibly explaining sensitivity to Compound 1 , groups of sensitive and insensitive AML cell lines were compared using common AML mutations and RNA-seq data available from DepMap (Table 1). NAN indicates that cell line was not profiled by DepMap for RNA-seq, so IRF8 expression values are unknown.

[0477] Table 1 . AML cell line characterization

[0478] Results: Sets of AML mutations which are enriched in lines sensitive to Compound 1 include MLL- rearrangement (8 / 10 MLL-r lines were sensitive), NPM1-mutant (1 / 1 NPM1 mutant line was sensitive) and DNMT3A-mutant lines (3 / 3 DNMT3A mutant lines were sensitive). An analysis of the gene expression from RNA-seq identified expression of IRF8 to be more highly expressed in the AML lines sensitive to Compound 1 compared to those which were insensitive (Table 1). A threshold for high IRF8 expression of greater than 6.0 log2(TPMs+1), or 63.0 TPMs, results in prediction of Compound 1 sensitivity with 47% sensitivity (8 true positives and 9 false negatives) and specificity of 80% (4 false positives and 16 true negatives). Conclusion: Higher expression of IRF8 in the cell lines sensitive to Compound 1 suggests that the sensitive lines could be more differentiated into myeloid cells. IRF8 is a myeloid lineage transcription factor that is not expressed in hematopoietic stem cells, and its expression is turned on later in differentiation into myeloid cells. Compound 1 may be a suitable treatment for subjects with AML harboring high IRF8 expression. Furthermore, notable genetic background may be an indicator of sensitivity to Compound 1 , such as AML with high IRF8 and also harboring an MLL-r. NPM1 , and / or DNMT3A mutation. Example 2. AML cell lines sensitive to treatment with Compound 1 have lower DNA methylation.

[0479] Using the same AML cell lines from Example 1 (Table 1), an analysis of available CCLE DNA methylation datasets identified the 500 most variable CpG sites globally between AML cell lines. The datasets were profiled with reduced representation bisulfite sequencing (RRBBS), and CpG sites were not limited to transcription start sites. CpG sites with methylation status correlating to Compound 1 sensitivity were further analyzed, resulting in a DNA methylation signature that correlated sensitivity to Compound 1 with lower DNA methylation (e.g., negative “Effect Size” in FIG. 1) in AML cell lines. Example CpG sites and their corresponding methylation status and sensitivity to Compound 1 are shown in FIG. 2.

[0480] DNA methylation is known to play a role in normal myeloid differentiation. During granulopoiesis there is an initial increase in DNA methylation at myeloid lineage enhancers, followed by removal of the repressive mark of DNA methylation as these cis-regulatory elements become active to turn on myeloid lineage genes. Regions containing differential DNA methylation are known to be enhancers and enriched with myeloid lineage transcription factor motifs (e.g., CEBP, IRF, MYB, AP-1). Our results fit with the model that more differentiated AML samples are actively transcribing myeloid genes, and that the enhancers regulating them are unmethylated with an open chromatin status. On the other hand, less differentiated AML samples are not yet expressing myeloid genes and those same enhancers show closed chromatin and higher DNA methylation.

[0481] To confirm if myeloid transcription factor motifs are located in regions of differential methylation, we tested the 500 most variable CpG sites from our AML lines that predicted Compound 1 sensitivity (FIG. 3). HOMER, which is a bioinformatics tool for identifying motifs enriched in defined genomic loci, was used to check for enriched transcription factor motifs. We found known myeloid transcription factors IRF / IRF3 / AP1 motifs to be enriched in these locations, indicating that they were myeloid enhancers. Furthermore, genomic loci containing CpG’s whose methylation predicted sensitivity to Compound 1 included the region near the gene encoding the myeloid transcription factor IRF8 (chr16:85898631 -85899332) whose gene expression we found to be higher in lines sensitive to Compound 1 (FIG. 4). Table 2 shows the full list of Genomic loci (in hg38 genomic coordinates) with lower DNA methylation in AML lines sensitive to Compound 1 . DNA methylation with a mean beta value (e.g., proportion of CpG sites which are methylated) of less than 0.20 in those regions predicted sensitivity to Compound 1 .

[0482] Table 2. Genomic loci (in hg38 genomic coordinates) with lower DNA methylation in AML lines sensitive to Compound 1 .

[0483] Example 3. AML cell lines with high IRF8 expression have a high occurrence of MLL-r and / or inv(16) mutations

[0484] Procedure: In order to examine how the biomarker of high IRF8 expression overlaps with other genetic biomarkers that stratify AML, we used the BEAT-AML cohort via http: / / www.vizome.org / aml2 / which has a large number of primary AML samples with RNA-seq and Exome-seq data. Expression of IRF8 was compared between consensus gene fusions and common AML mutations.

[0485] Results: Two genetic mutations were enriched for high IRF8 expression: MLL-rearranged samples and inv(16) (i.e. CBFB-MYTH1 fusion) (FIG. 5). NPM1 mutated samples were not enriched for higher IRF8 expression.

[0486] Conclusion: MLL-rearranged and inv(16) are two genetic backgrounds which are enriched for the high IRF8 expression biomarker, and may be useful to help predict sensitivity to Compound 1 . Thus, Compound 1 may be useful to treat subjects with AML with high IRF8 expression and an MLL-r and / or inv(16) mutation.

[0487] Example 4. AML PDX model with high IRF8 expression and MLL-r mutation is sensitive to treatment with Compound 1.

[0488] Procedure: Two AML PDX models from Dana Farber (DFAM-68555 and DFAM-15354) were tested in Balb / c Nude mice. Compound 1 was administered interperitoneally (IP) at 3 mg / kg bi-weekly (BIW) in six mice, and seven mice were treated with vehicle (PBS administered intraperitoneally QID). In addition, standard-of-care treatments of decitabine (0.2 mg / kg, via IP, QD for 5 days on and 2 days off), azacitadine (1 mg / kg, via IP, BIW), and cytarabine (both 10 mg / kg and 40 mg / kg, via IP, QD for 5 days on and 2 days off) were administered both alone (7 mice per cohort) and in combination with Compound 1 (6 mice per cohort) for comparison (Table 3). Mice were monitored daily for weight loss and were euthanized if they showed signs of distress (e.g., 10% BWL or hind limb paralysis). To assess the efficacy of treatment, the tumor burden was measured as the proportion of human CD45 (corresponding the AML PDX cells) at day 15 by bleeding the mice and comparing treated mice relative to vehicle. Table 3. AML PDX Model Cohorts

[0489] Results: The PDX models had been previously profiled by RNA-seq analysis and Exome-seq and that data was accessed via Dana Farber’s cBioPortal for Pan-Cancer Patient Derived Models Database (Table 4). DFAM-68555 expressed IRF8 at a level of 276 TPMs (above the IRF8-high cutoff from Example 1), while DFAM-15354 expressed IRF8 at level of 37 TPMs (below the I RF8-high cutoff from Example 1). In addition, from the exome-seq analysis, DFAM-68555 harbors an MLL-rearrangement and FLT3-ITD, while DFAM-15354 had mutations in NPM1 and DNMT3A (Table 4). The effect of each treatment was compared to vehicle by bleeding the mice at day 15 and calculating the percentage of human CD45 (hCD45%). The results in FIG. 6 show the mean percentage and standard deviation of 7 mice for vehicle and standard-of-care treatments and 6 mice for Compound 1 and combination treatments.

[0490] Table 4. AML PDX model characterization

[0491] Conclusion: The DFAM-68555 (high IRF8, MLL-r) showed a demonstrably larger response to Compound 1 compared to DFAM-15354 (lower IRF8) both as a single agent. Compound 1 showed a statistically significant decrease in tumor burden for DFAM-68555 (p=2.8E-11), while it did not for DFAM- 15354 (p=0.145). Furthermore, Compound 1 in combination with standard of care also showed a statistically significant decrease in tumor burden for DFAM-68555 mice. Thus, Compound 1 may be useful to treat subjects with AML with high IRF8 expression and harboring an MLL rearrangement. Example 5. BRD9 degrader causes growth inhibition in vitro in a Diffuse Large B Cell Lymphoma (DLBCL) cell line that has high IRF8 expression.

[0492] Cell Seeding: KARPASS422 is a Diffuse Large B Cell Lymphoma cell line that harbors high IRF8 expression. KARPASS422 cells were harvested, counted, and diluted with culture medium to a density of 100 cells per 40 pL in each well of a 384 well plate. The 384 well plates were incubated at room temperature for 30 minutes, and then at 37°C 5% CO2 overnight without shaking.

[0493] Compound Preparation: 45 pL of 0.1 mM rac-Compound 1 in DMSO stock solution was transferred into each well of a 384 well plate. 3-fold dilutions were made by transferring 15 pL of stock solution from the 384 well plate into a second 384 well plate containing 30 pL of DMSO. This was repeated serially an additional 8 times to obtain 10 different serial dilutions ranging 100 nM to about 0.005 nM (FIG 7). Dilutions were performed by a TECAN (EVO200) liquid handler. 384 well plates containing serial dilutions of compound were spun at room temperature at 1 ,000 RPM for 1 minute and then transferred to a plate shaker for 2 minutes.

[0494] Treatment: 40 nL of serial diluted compound was transferred to the 384 well plates containing seeded cells. Plates were incubated at 37°C 5% CO2 overnight without shaking. On Day 3, plates were removed from the incubator and spun at room temperature at 1 ,000 RPM for 1 minute. Spent culture media was aspirated and fresh media was added. 40 nL of serial diluted compound was transferred to the 384 well plates containing seeded cells. Plates were spun at room temperature at 1 ,000 RPM for 1 minute and then returned to the incubator. On Day 6, all procedures performed on Day 3 as noted above were repeated.

[0495] Detection: On Day 10, CellTiter-Glo (CTG) detection was performed on the 384 well plates. Plates were removed from the incubator and allowed to equilibrate to room temperature for 15 minutes. 40 pL of CellTiter-Glo reagent was added to each well of each 384 well plate, creating a 1 :1 ratio of reagent to culture medium. Plates were incubated at room temperature for 30 minutes and then read by an EnVision instrument. The inhibition activity was calculated following the formula below:

[0496] Inhibition (%) = 100% x (Lumvehicle- Lumsample) / (Lumvehicle- Lumblank) and IC50 was determined by fitting the Curve using Xlfit (v5.3.1 .3), equation 201 :

[0497] Y = Bottom + (Top - Bottom) / (1 + 10A((LoglC50 - XfHillSlope)).

[0498] Results: KARPAS422 is a cell line that expresses a high RNA level of IRF8 based on DepMap (depmap.org) data. In a 10-day in vitro cell proliferation assay, rac-Compound 1 significantly impacts cell proliferation of KARPAS422, with maximal growth inhibition at 62% and IC50 at 0.8nM (FIG. 7).

[0499] Other Embodiments

[0500] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0501] Other embodiments are in the claims.

Claims

What is claimed is: Claims 1. A method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin’s lymphoma.

3. The method of claim 1, wherein the hematologic cancer is diffuse large B cell lymphoma (DLBCL).

4. The method of claim 1, wherein the hematologic cancer is acute myeloid leukemia (AML).

5. The method of claim 4, wherein the AML is acute promyelocytic leukemia, arises from a pre- existing myelodysplastic syndrome or myeloproliferative disease, treatment-related AML, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, myeloid sarcoma, myeloid proliferations related to Down syndrome, blastic plasmacytoid dendritic cell neoplasm, AML minimally differentiated, AML without maturation, AML with granulocytic maturation, myelomonocytic together with bone marrow eosinophilia, acute monoblastic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, or acute basophilic leukemia.

6. The method of any one of claims 4-5, wherein the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, or a combination thereof.

7. A method of treating MLL rearrangement (MLL-r) acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the MLL-r AML harbors high IRF8 expression.

9. A method of treating inv(16) acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof. 50210. The method of claim 9, wherein the inv(16) is a CBFB-MYH11 fusion.

11. The method of any one of claims 9-10, wherein the inv(16) AML harbors high IRF8 expression.

12. A method of inducing differentiation of common myeloid progenitor (CMP) cells into monocyte precursor cells in a subject that has hematologic cancer with determined high IRF8 expression, the method comprising administering to a subject in need thereof an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1-12, wherein the method slows progression of a hematologic cancer with high IRF8 expression in a subject in need thereof.

14. The method of any one of claims 1-12, wherein the method reduces recurrence of a hematologic cancer with high IRF8 expression in a subject in need thereof.

15. The method of any one of claims 1-12, wherein the method increases myeloid cell differentiation in a hematologic cancer with high IRF8 expression in a subject in need thereof.

16. The method of any one of claims 1-12, wherein the method increases myeloid cell maturation in a hematologic cancer with high IRF8 expression in a subject in need thereof.

17. The method of any one of claims 1-12, wherein the method increases myeloid cell proliferation in a hematologic cancer with high IRF8 expression in a subject in need thereof.

18. A method of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of an agent that reduces the level and / or activity of BRD9 in the cell.

19. The method of claim 18, wherein the cell is an AML cell.

20. The method of claim 18, wherein the cell is a diffuse large B cell lymphoma cell.

21. The method of any one of claims 18-20, wherein the cell is in a subject.

22. The method of any one of claims 1-21, wherein the IRF8 expression of the subject in need thereof is high relative to IRF8 expression in a subject without a hematologic cancer.

23. The method of any one of claims 1-21, wherein the IRF8 expression of the subject in need thereof is high relative to a reference. 50324. The method of any one of claims 1-21, wherein the IRF8 expression of the subject in need thereof is high relative to standard levels of IRF8.

25. The method of any one of claims 1-24, wherein the subject in need thereof has increased expression of myeloid peroxidase (MPO) relative to standard levels of MPO.

26. The method of any one of claims 1-25, wherein the subject in need thereof has low DNA methylation of the IRF8 genomic loci relative to a subject without a hematologic cancer.

27. The method of any one of claims 1-25, wherein the subject in need thereof has low DNA methylation of the IRF8 genomic loci relative to a reference.

28. The method of any one of claims 26-27, wherein the low DNA methylation is measured as a mean beta value of less than 0.

20.

29. The method of any one of claims 1-28, wherein the compound that reduces the level and / or activity of BRD9 is 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6- dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione.

30. The method of any one of claims 1-28, wherein the compound that reduces the level and / or activity of BRD9 is 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione.

31. The method of any one of claims 1 to 30, wherein the subject is further administered at least one additional anti-cancer therapy.

32. The method of claim 31, wherein the additional anti-cancer therapy is administered prior to the administering of the compound or pharmaceutically acceptable salt thereof.

33. The method of claim 31, wherein the additional anti-cancer therapy is administered in addition to the administering of the compound or pharmaceutically acceptable salt thereof.

34. The method of claim 31, wherein the additional anti-cancer therapy is administered subsequent to the administering of the compound or pharmaceutically acceptable salt thereof.

35. The method of any one of claims 31-34, wherein the additional cancer therapy is a menin inhibitor, abemaciclib, all-trans-retinoic acid, arsenic trioxide, azacitidine, cedazuridine, cobimetinib, CPX- 351, cytarabine, daunorubicin, decitabine, enasidenib, etoposide, gemtuzumab, gilteritinib, glasdegib, hemopoietic stem cell transplant, ivosidenib, midostaurin, olutasidenib, ozogamicin, venetoclax, or combinations thereof. 50436. The method of claim 35, wherein the additional cancer therapy is a menin inhibitor.

37. The method of claim 36, wherein the menin inhibitor is BMF-219, DS-1594a, DS-1594b, JNJ- 75276617, revumenib, SNDX-50469, ziftomenib, or combinations thereof.

38. The method of any one of claims 1-37, wherein the hematologic cancer is resistant to treatment with a menin inhibitor.

39. The method of claim 38, wherein the hematologic cancer harbors an MEN1 mutation.

40. The method of any one of claims 1-39, wherein the hematologic cancer has failed to respond to prior treatment with a menin inhibitor.

41. The method of any one of claims 1-40, wherein the hematologic cancer has relapsed after prior treatment with a menin inhibitor.

42. The method of any one of claims 1-41, wherein thehematologiccancer is refractory to priortreatment with a menin inhibitor.

43. The method of any one of claims 1 to 42, wherein the method further comprises administering induction chemotherapy.

44. The method of claim 43, wherein the induction chemotherapy comprises cytarabine, an anthracycline such as daunorubicin, arsenic trioxide, all-trans-retinoic acid, or combinations thereof.

45. The method of any one of claims 1 to 44, wherein the method further comprises administering consolidation therapy.

46. The method of claim 45, wherein the consolidation therapy comprises an allogenic stem cell transplantation and / or immunotherapy.

47. The method of any one of claims 1-46, wherein the method further comprises administering a hemopoietic stem cell transplant, gemtuzumab ozogamicin, or a combination thereof.

48. The method of any one of claims 1-47, wherein the subject or cancer has and / or has been identified as having increased BRD9 expression.

49. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-80 mg / kg. 50550. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-60 mg / kg.

51. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-40 mg / kg.

52. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20 mg / kg.

53. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 40 mg / kg.

54. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg / kg.

55. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 60 mg / kg.

56. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg / kg.

57. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 120 mg / kg.

58. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered to the subject at least once per week.

59. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered to the subject at least twice per week.

60. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20 mg / kg once per week.

61. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20 mg / kg twice per week.

62. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 40 mg / kg once per week. 50663. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 40 mg / kg twice per week.

64. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg / kg once per week.

65. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg / kg twice per week.

66. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 60 mg / kg once per week.

67. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 60 mg / kg twice per week.

68. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg / kg once per week.

69. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg / kg twice per week.

70. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 120 mg / kg once per week.

71. The method of any one of claims 1-48, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 120 mg / kg twice per week.

72. The method of any one of claims 1-71, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 14-day dosing cycle.

73. The method of any one of claims 1-71, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 21-day dosing cycle.

74. The method of any one of claims 1-71, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 28-day dosing cycle.

75. The method of any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof, is administered to the subject intravenously.

76. The method of any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof, is administered to the subject subcutaneously. 50777. The method of any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof, is administered to the subject intramuscularly.

78. A method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6- dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione, or a pharmaceutically acceptable salt thereof.

79. A method of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6- dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione, or a pharmaceutically acceptable salt thereof.

80. A method of treating acute myeloid leukemia with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6- dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione, or a pharmaceutically acceptable salt thereof.

81. A method of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of 3-(6-(7-((1-(4-(6- (azetidin-1-yl)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4- yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

82. A method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

83. A method of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

84. A method of treating acute myeloid leukemia with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject an effective 508amount of 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

85. A method of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with an effective amount of 3-((4-(4-(1-(2,6- dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3-difluoropiperidin-4-yl)piperazin-1- yl)-3-fluorophenyl)amino)piperidine-2,6-dione.

86. A method of treating a hematologic cancer with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

87. A method of treating diffuse large B cell lymphoma with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

88. A method of treating acute myeloid leukemia with high interferon regulatory factor 8 (IRF8) expression in a subject in need thereof, the method comprising administering to the subject at least 2 mg per day of 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof.

89. A method of reducing the level and / or activity of BRD9 in a hematologic cancer cell with high IRF8 expression, the method comprising contacting the cell with at least 2 mg per day of 3-((4-(4-(1-(2,6- dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3-difluoropiperidin-4-yl)piperazin-1- yl)-3-fluorophenyl)amino)piperidine-2,6-dione.

90. A method of determining hematologic cancer and / or monitoring a hematologic cancer in a subject in need thereof, the method comprising determining the DNA methylation status for the IRF8 gene in the subject.

91. The method of claim 90, wherein the hematologic cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, diffuse large B cell lymphoma, or non-Hodgkin’s lymphoma. 50992. The method of claim 91, wherein the hematologic cancer is diffuse large B cell lymphoma (DLBCL).

93. The method of claim 91, wherein the hematologic cancer is acute myeloid leukemia (AML).

94. The method of claim 93, wherein the AML is acute promyelocytic leukemia, arises from a pre- existing myelodysplastic syndrome or myeloproliferative disease, treatment-related AML, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, myeloid sarcoma, myeloid proliferations related to Down syndrome, blastic plasmacytoid dendritic cell neoplasm, AML minimally differentiated, AML without maturation, AML with granulocytic maturation, myelomonocytic together with bone marrow eosinophilia, acute monoblastic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, or acute basophilic leukemia.

95. The method of any one of claims 93-94, wherein the AML harbors an MLL-r mutation, an MLL PTD mutation, a DNMT3A mutation, an FLT3 mutation, an IDH1 mutation, an IDH2 mutation, an NPM1 mutation, a splicing factor mutation, a TP53 mutation, a CEBPA mutation, an AML-ETO fusion mutation, or a combination thereof.

96. The method of any one of claims 90-95, wherein the DNA methylation status for IRF8 is low.

97. The method of claim 96, wherein low DNA methylation status is a mean beta value of less than 0.

20.

98. The method of any one of claims 90-97, wherein the subject determined to have a hematologic cancer is administered an effective amount of a compound that reduces the level and / or activity of BRD9, or a pharmaceutically acceptable salt thereof.

99. The method of claim 98, wherein the compound that reduces the level and / or activity of BRD9 is 3-(6-(7-((1-(4-(6-(azetidin-1-yl)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6- dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione.

100. The method of claim 98, wherein the compound that reduces the level and / or activity of BRD9 is 3-((4-(4-(1-(2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-3,3-difluoropiperidin-4- yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione. 510

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