Methods of treating 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 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 several clear cell ovarian cancer cell lines and head and neck squamous cell cancer cell lines were sensitive to BRD9 degradation. 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. Without wishing to be bound by theory, it is believed that depleting or inhibiting BRD9 results in the treatment of clear cell ovarian cancer and / or head and neck squamous cell cancers.

[0006] In one aspect, the present disclosure provides methods of treating clear cell ovarian cancer 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.

[0007] In some embodiments of any of the aspects disclosed herein, the clear cell ovarian cancer harbors an ARID1A mutation. In some embodiments of any of the aspects disclosed herein, the clear cell ovarian cancer is epithelial ovarian cancer.

[0008] In some embodiments of any of the aspects disclosed herein, the clear cell ovarian cancer is advanced epithelial ovarian cancer. In some embodiments of any of the aspects disclosed herein, the clear cell ovarian cancer is stage III epithelial ovarian cancer. In some embodiments of any of the aspects disclosed herein, the clear cell ovarian cancer is stage IV epithelial ovarian cancer.

[0009] In some embodiments of any of the aspects disclosed herein, the subject has undergone debulking surgery prior to administration of a compound that reduces the level and / or activity of BRD9.

[0010] In some embodiments of any of the aspects disclosed herein, the compound that reduces the level and / or activity of BRD9 is administered to maintain treatment of a subject with clear cell ovarian cancer.

[0011] In some embodiments of any of the aspects disclosed herein, the subject has clear cell ovarian cancer that harbors a deleterious germline BRCA-mutation (gBRCAm). In some embodiments of any of the aspects disclosed herein, the subject has clear cell ovarian cancer that harbors a somatic germline BRCA-mutation (gBRCAm).

[0012] In some embodiments of any of the aspects disclosed herein, the subject has a complete response to platinum-based chemotherapy. In some embodiments of any of the aspects disclosed herein, the subject has a partial response to platinum-based chemotherapy. In some embodiments of any of the aspects disclosed herein, the subject is resistant to platinum-based chemotherapy. In some embodiments of any of the aspects disclosed herein, the subject is refractory to platinum-based chemotherapy.

[0013] In some embodiments of any of the aspects disclosed herein, the subject has recurrent clear cell ovarian cancer after treatment with at least one line of chemotherapy.

[0014] In some embodiments of any of the aspects disclosed herein, the subject has platinum-sensitive recurrent clear cell ovarian cancer.

[0015] In another aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, the method comprising contacting the cell with an effective amount of a compound 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 in a subject.

[0016] In one aspect, the present disclosure provides methods of treating head and neck squamous cell cancer 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.

[0017] In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is cancer of the oral cavity, pharynx, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses, nasal cavity, salivary glands, tongue, esophagus, or a combination thereof.

[0018] In some embodiments of any of the aspects disclosed herein, the head and neck cancer is pharyngeal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma, or tongue squamous cell carcinoma. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is pharyngeal squamous cell carcinoma. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is hypopharyngeal squamous cell carcinoma. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is esophageal squamous cell carcinoma. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is tongue squamous cell carcinoma.

[0019] In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is metastatic after prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is resistant to prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer has failed to respond to prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer has relapsed after prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is refractory to prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is locally advanced after prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is regionally advanced after prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is recurrent locoregional disease after prior treatment. In some embodiments of any of the aspects disclosed herein, the head and neck squamous cell cancer is recurrent after prior treatment. In some embodiments of any of the aspects disclosed herein, the prior treatment comprises cetuximab, radiation therapy, fluorouracil, platinum-based therapy, or a combination thereof.

[0020] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, the method comprising contacting the cell with an effective amount of a compound 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 a pharyngeal squamous cancer cell. In some embodiments of any of the aspects disclosed herein, the cell is a hypopharyngeal squamous cancer cell. In some embodiments of any of the aspects disclosed herein, the cell is an esophageal squamous cancer cell. In some embodiments of any of the aspects disclosed herein, the cell is a tongue squamous cancer cell. In some embodiments of any of the aspects disclosed herein, the cell is in a subject.

[0021] 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-(3zetidine-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.

[0022] In some embodiments, 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.

[0023] 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.

[0024] In some embodiments, 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.

[0025] 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.

[0026] In some embodiments of any of the aspects disclosed herein, the additional cancer therapy is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or a combination thereof.

[0027] In some embodiments of any of the aspects disclosed herein, the additional cancer therapy is altretamine, bevacizumab, bleomycin sulfate, capecitabine, carboplatin, cemiplimab, cetuximab, cisplatin, cyclophosphamide, docetaxel, dostarlimab, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, an EGFR inhibitor, entrectinib, etoposide, gemcitabine hydrochloride, hydroxyurea, ifosfamide, irinotecan, laparib, melphalan, methotrexate sodium, mirvetuximab soravtansine-gynx, niraparib tosylate monohydrate, nivolumab, olaparib, paclitaxel, pemetrexed, rucaparib camsylate, thiotepa, topotecan hydrochloride, vinorelbine, luteinizing hormone releasing hormone (LHRH) agonists, tamoxifen, aromatase inhibitors, larotrectinib, entrectinib, and pembrolizumab, or a combination thereof.

[0028] In some embodiments of any of the aspects disclosed herein, the additional cancer therapy is albumin bound paclitaxel, altretamine, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, paclitaxel, pemetrexed, topotecan, vinorelbine, or a combination thereof.

[0029] In some embodiments of any of the aspects disclosed herein, the surgery is laser technology, excision, lymph node dissection, neck dissection, debulking, or a combination thereof.

[0030] In some embodiments of any of the aspects disclosed herein, the radiation is external beam radiation therapy, intensity-modulated radiation therapy (IMRT), proton therapy, or a combination thereof.

[0031] 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.

[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 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).

[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 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. 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 (e.g., once 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 to the subject at least twice per week (e.g., twice per week).

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof, is administered to the subject intravenously.

[0047] In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof, is administered to the subject subcutaneously.

[0048] In some embodiments of any of the aspects disclosed herein, the compound or a pharmaceutically acceptable salt thereof, is administered to the subject intramuscularly.

[0049] In one aspect, the present disclosure provides methods of treating clear cell ovarian cancer 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.

[0050] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, 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.

[0051] In one aspect, the present disclosure provides methods of treating head and neck squamous cell cancer 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.

[0052] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, 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.

[0053] In one aspect, the present disclosure provides methods of treating clear cell ovarian cancer 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.

[0054] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, 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-yl)benzyl)-3,3- difluoropi peridin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)piperidine-2, 6-dione.

[0055] In one aspect, the present disclosure provides methods of treating head and neck squamous cell cancer 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-dihydropy ridin-3-y Ijbenzy l)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-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 head and neck squamous cell cancer cell, 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-yl)benzyl)-3,3- difluoropi peridin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)piperidine-2, 6-dione.

[0057] In one aspect, the present disclosure provides methods of treating clear cell ovarian cancer in a subject in need thereof, the method comprising administering to the subject at least 2mg 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.

[0058] In one aspect, the present disclosure provides methods of treating head and neck squamous cell cancer in a subject in need thereof, the method comprising administering to the subject at least 2mg 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.

[0059] Chemical Terms

[0060] The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0061] 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.

[0062] 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.

[0063] 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). 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.

[0073] The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0074] 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.

[0075] 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.

[0076] 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 C1-C6alkyl 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.

[0077] 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.

[0078] 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 C1-C6alkyl C2-C9 heterocyclyl, C1-C10 alkyl C2-C9 heterocyclyl, or C1-C20alkyl 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.

[0079] The term “hydroxyalkyl,” as used herein, represents alkyl group substituted with an -OH group.

[0080] The term “hydroxyl,” as used herein, represents an -OH group.

[0081] 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-biphenylyI)- 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).

[0082] The term “nitro,” as used herein, represents an -NO2 group.

[0083] The term “thiol,” as used herein, represents an -SH group.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] Definitions

[0090] 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. 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.

[0091] 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.

[0092] As used herein, the term “BAF complex” refers to the BRG1 - or HRBM-associated factors complex in a human cell.

[0093] 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.

[0094] 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.

[0095] SEQ ID NO: 1 :

[0096]

[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 of the 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.

[0118] 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.

[0119] As used herein the term “platinum-based chemotherapy” refers to chemical moieties in complex with platinum that are used to treat cancer. Common agents include cisplatin, oxaliplatin, carboplatin, nedaplatin, as well as triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

[0120] Detailed Description

[0121] Though intrinsically resistant to traditional platinum and taxane therapies, clear cell ovarian cancer is still treated similarly to other ovarian cancers. Thus, due to the limited success of traditional therapies, there is an urgent, unmet need for more effective treatments which are specific to clear cell ovarian cancer. The present inventors have discovered several clear cell ovarian cancer cell lines that are sensitive to treatment with a compound that reduces the level and / or activity of bromodomain containing protein 9 (BRD9). Additionally, the present inventors have discovered that several head and neck squamous cell cancer cell lines are also sensitive to treatment with a compound that reduces the level and / or activity of bromodomain containing protein 9 (BRD9). Accordingly, the present disclosure features methods of treating clear cell ovarian cancer and / or head and neck squamous cell cancer with compounds that reduce the level and / or activity of BRD9.

[0122] BRD9 inhibitors

[0123] 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.

[0124] 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.

[0125] Compound 1

[0126] 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.

[0127] The BRD9 inhibitor may be, e.g., a compound of Formula I:

[0128] Formula I, where R1is H, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0129] Z1is CR2or N;

[0130] R2is H, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, or optionally substituted C2-C9 heteroaryl; each of R3a, R3b, R3c, and R3dis, independently, H, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C1- C6acyl, 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 C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C1- C6acyl, 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 C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, 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 C1-C6 alkyl, optionally substituted C1-C6 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 C1- C6acyl, 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 C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C1- C6acyl, 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 C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; and

[0131] G is optionally substituted C6-C10aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0132] The BRD9 inhibitor may be, e.g., a compound of Formula I: where

[0133] R1is H, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0134] Z1is CR2or N;

[0135] R2is H, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, or optionally substituted C2-C9 heteroaryl;

[0136] X1is a bond, O, NR3a, or CR4aR5a;

[0137] X2is O, NR3b, or CR4bR5b;

[0138] X3is O, NR3c, or CR4cR5c;

[0139] X4is a bond, O, NR3d, or CR4dR5d; each of R3a, R3b, R3c, and R3dis, independently, H, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C1- C6acyl, 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 C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C1- C6acyl, 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 C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, 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 C6-C10aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, or a pharmaceutically acceptable salt thereof. The BRD9 inhibitor may be, e.g., a compound of Formula II: where

[0140] R1is H, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0141] Z1is CR2or N;

[0142] R2is H, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, or optionally substituted C2-C9 heteroaryl;

[0143] RX1is H or optionally substituted C1-C6alkyl;

[0144] R3is H, cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C1-C6alkoxy, optionally substituted amino, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10aryl, optionally substituted C3-C10 heterocyclyl, or optionally substituted C2- C9 heteroaryl; and

[0145] G is optionally substituted C3-C10 carbocyclyl, C2-C9 heterocyclyl, optionally substituted C6-C10aryl, or optionally substituted C2-C9 heteroaryl, or a pharmaceutically acceptable salt thereof.

[0146] The BRD9 inhibitor may be, e.g., a compound of Formula III:

[0147] A-L-B

[0148] Formula III, where

[0149] A is a BRD9 binding moiety;

[0150] B is a degradation moiety; and

[0151] L has the structure of Formula II: where A1is a bond between the linker and A;

[0152] 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;

[0153] E3is optionally substituted C1-C6 alkylene, optionally substituted C1-C6 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;

[0154] 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 C6-C-io arylene, or optionally substituted C2-C9 heteroarylene, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the linker has the structure of Formula IIA-a : The BRD9 inhibitor may be, e.g., a compound of Formula IV:

[0156] Formula IV, where

[0157] R1is H, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 carbocyclyl;

[0158] Z1is CR2or N;

[0159] R2is H, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10aryl, or optionally substituted C2-C9 heteroaryl;

[0160] X1is N or CH, and X2is C-R7; or X1is C-R7, and X2is N or CH;

[0161] R7is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C1-C6alkoxy, 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;

[0162] X3is N or CH;

[0163] X4is N or CH;

[0164] G is optionally substituted C3-C10 carbocyclyl, C2-C9 heterocyclyl, optionally substituted C6-C10aryl, or optionally substituted C2-C9 heteroaryl, or a pharmaceutically acceptable salt thereof.

[0165] The BRD9 inhibitor may be, e.g., a compound of Formula V: wherein,

[0166] R1is C1-salkyl or -cyclopropyl;

[0167] R2is selected from halogen, C1-saikyi, Ci shaloalkyl, NH2, NHC1-salkyl and OH,

[0168] Xi is N or CR3 The BRD9 inhibitor may be, e.g., a compound of Formula VI, VII, or VIII:

[0169] Formula VIII or a pharmaceutically acceptable salt thereof, wherein Degron is selected from the group consisting of:

[0170] TL2 is a moiety that binds to BRD9 selected from the group consisting of:

[0171]

[0172] where n Is 0. 1 , or 2;

[0173] R1 and R2 are Independently selected from the group consisting of hydrogen and Ct -6 alkyl; or F?1 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, Ct -6 alkoxy, and halogen; and

[0174] R5 is selected from the group consisting of hydrogen and C1 -6 alkyl.

[0175] The Linker may be, e.g., a group of Formula L-l:

[0176] -L1-X1-L2-X2-L3-.

[0177] Formula L-i where

[0178] L1 is selected from the group consisting of a bond, O, NR:, C(O). C1 -6 alkylene,

[0179] 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;

[0180] XI and X2 are each independently selected from the group consisting of a bond, carbocyclyl, and heterooyclyi, 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, CI-6 alkoxyl, and halogen;

[0181] 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 spiroheterocyolyl; and

[0182] L3 is selected from the group consisting of a bond, O, C(O), Ci -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 io X2; where no more than 2 of L1 , X1 , X2, L2, and L3 can simultaneously be a bond.

[0183] The Targeting Ligase Binder may be, e.g., a compound of Formula TLB-I:

[0184] Formula TLB-I where R4 is selected from the group consisting of Cl -6 alkyl, Ct -6 alkoxyi, and halogen; and m is 0, 1 .

[0185] The Targeting Ligase Binder may be, e.g., a compound of Formula TLB-!’:

[0186] Formula TLB-h where

[0187] Rd1 and Rd2 are each independently selected from the group consisting of H, C1 -6 alkyl, C1-6 alkoxyi, Cl -6 haioaikyi, and Cl -6 heteroalkyl;

[0188] Rd3 is H; Rd4 is selected from the group consisting of H. C1-6 alkyi, halo, C1-6 haioaikyi, and C1-6 heteroaikyl; and

[0189] Rd5 is selected from the group consisting of H. C1-6 alkyl, halo, C1-6 haioaikyi, and C1-6 heteroaikyl.

[0190] The BRD9 inhibitor may be, e.g., a compound of Formula Ixa:

[0191] Formula IX-a or a pharmaceutically acceptable salt thereof, where

[0192] L1 is selected from the group consisting of a bond, O, NR’, C(O), C1-6 alkylene,

[0193] C1-6 heteroalkylene, *C(O)-C1-6 alkylene, C(O)-C1-6 aikenylene*, C1-6 alkenylene, and *C(O)-C1-6 heteroalkyiene, where * denotes the point of attachment of L1 to the Targeting Ligand;

[0194] X1 and X2 are each independently selected from the group consisting of a bond, carbocyclyi, and heterocyclyl, where the carbocyclyi and heterocyclyl 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;

[0195] L2 is selected from the group consisting of a bond, O, NR’, Ci -6 alkylene, and Ci -6 heteroalkyiene; or X1-L2-X2 form a spiroheterocyciyl; and

[0196] L3 is selected from the group consisting of a bond, O, C(O), C1-6 alkylene, C1-6 heteroalkyiene, *C(O)-C1-6 alkylene, *C(O)-C1-6 heteroalkyiene, and *C(O)-C1-6 alkylene-O, where * denotes the point of attachment of L3 to X2.

[0197] In some embodiments, no more than 2 of L1 , X1 , X2, L2, and L3 can simultaneously be a bond. The BRD9 inhibitor may be, e.g., a compound of Formula X, XI, XII, XII I, XIV, or XV:

[0198] 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;

[0199] X3, X4, X5, and X6, are selected from the group consisting of N, CH and CR3, wherein no more than 3 of X3, X4. X5, and X6 are N;

[0200] X7 is N or CH;

[0201] 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 XS is CH;

[0202] 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;

[0203] X17 is aryl, heteroaryl, bicycle, or cycloalkyl, each of which is optionally substituted with 1 , 2, 3, or 4 substituents independently selected from R3; Q1 is independently at each occurrence seiected from the group consisting of NH, N(alkyi),

[0204] N(haloalkyl), CH2, O, and S: wherein if X7 is N. then Q1 is CH2; R is independently at each occurrence seiected from the group consisting of hydrogen, C1 C4haloalkyl, C1-C4aikyi, fluorine, chlorine, bromine, iodine, CH2F, CHF2, CF3, CH2CI, CHCI2, CCI3, CH2Br, CHBr2, and CBr3;

[0205] R1 is hydrogen, C1-4 alkyl, C1-4 haioaikyi, or cycloalkyl;

[0206] R3 is independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, alkoxy, C1-4 alkyl, C1-4 haioaikyi, cycloalkyl, fluorine, chlorine, bromine, and iodine;

[0207] B is seiected from B1 and B2; Bi is seiected from the group consisting of: XI 0 is C(R7)2, C(0), or O; X11 is heterocycle, heteroaryl, aryl, cycloalkyl, or a bicycle, each of which XI 1 groups is optionally substituted with 1 , 2, 3, or 4 groups independently selected from R3; or

[0208] 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 X16 are N; each R4 is independently selected from hydrogen, aryl, heteroaryl, C1 -4 alkoxy, C1 -4 haioalkyl, 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

[0209] R5 is hydrogen, C1 C4aikyl, allyl, crotyl, alkenyl, alkynyl. haioalkyl, or cycloalkyi; each RS is independently selected from hydrogen, C1-4 alkoxy, C1 -4 alkyl, Cl -4 haioalkyl, fluorine, chlorine, bromine, and iodine; each R7 is independently hydrogen or C 1 -4 alkyl;

[0210] R8 is hydrogen, C1-C4alkyl, allyl, crotyl, alkenyl, alkynyl, haioalkyl, or cycloalkyi; and L is a bivalent linking group.

[0211] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0212]

[0213] or a pharmaceutically acceptable salt thereof.

[0214] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0215] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0216]

[0217]

[0218]

[0219] or a pharmaceutically acceptable salt thereof.

[0220] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] or a pharmaceutically acceptable salt thereof.

[0232] The BRD9 inhibitor may be, e.g., a compound selected from the group consisting of:

[0233]

[0234]

[0235]

[0236]

[0237]

[0238] WO2021178920 compounds

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254] 

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] or a pharmaceutically acceptable salt thereof.

[0283] 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.

[0284] Clear Cell Ovarian Cancer

[0285] Ovarian cancers can be divided into subtypes based on their tumor cell types: epithelial, germ cell, and stromal cell. Epithelial ovarian cancer can be further divided into serous, endometrioid, clear cell, mucinous, undifferentiated / unclassified, primary peritoneal, and fallopian tube. Clear cell ovarian cancer subtype represents approximately 10% of all malignant ovarian tumors, with variation depending on geographic, ethnic, and racial factors. Subjects with clear cell ovarian cancer tend to be young in age, with the median age ranging from about 50 years old to about 56 years old. Though they are intrinsically resistant to traditional platinum and taxane therapies, clear cell ovarian cancer is still treated similarly to other ovarian cancers. Thus, due to the limited success of traditional therapies, there is an urgent, unmet need for more effective treatments which are specific to clear cell ovarian cancer.

[0286] Clear cell ovarian cancer cells are defined based on histopathological findings, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). Clear cell ovarian cancer cells comprise clear cytoplasm rich with glycogen, distinct from yolk sac tumor and mesonephric neoplasms. The most commonly mutated genes in clear cell ovarian cancer are PIK3CA, PIK3, and ARID1A. Clear cell ovarian cancer can also be associated with endometriosis.

[0287] Initial or first-line treatment for epithelial ovarian cancers (e.g., clear cell ovarian cancer) typically comprises surgery (e.g., debulking) and chemotherapy. Debulking as used herein refers to the removal of as much of a tumor as possible by surgical means. Debulking is especially important in later stages of ovarian cancer where the cancer has spread beyond the pelvic area. The goal of debulking is to remove as much of the tumor as possible, leaving behind no visible cancer and / or no tumors that are larger than 1 cm in size. In debulking, depending on the stage of the cancer, organs external to the pelvis may also be removed in whole or in part including but not limited to colon, small intestine, bladder, spleen, and gallbladder.

[0288] Typically, chemotherapy for ovarian cancer comprises a combination of a platinum compound (e.g., cisplatin or carboplatin) and a taxane (e.g., paclitaxel or docetaxel). Chemotherapy can be administered by IV, by mouth, or by intraperitoneal methods, depending on the drug or drugs being administered. Chemotherapy drugs used for ovarian cancer treatment include, but are not limited to, albumin bound paclitaxel (e.g., nab-paclitaxel, Abraxane®), altretamine (e.g., Hexalen®), capecitabine (e.g., Xeloda®), carboplatin, cisplatin, cyclophosphamide (e.g., Cytoxan®), docetaxel, etoposide (e.g., VP-16), gemcitabine (e.g., Gemzar®), ifosfamide (e.g., Ifex®), irinotecan (e.g., CPT-11 , Camptosar®), liposomal doxorubicin (e.g., Doxil®), melphalan, paclitaxel, pemetrexed (e.g., Alimta®), topotecan, vinorelbine (e.g., Navelbine®).

[0289] Radiation therapy is sometimes used to treat areas where the cancer has spread but is not as commonly used as chemotherapy to treat ovarian cancers. Radiation therapy uses high energy X-Rays or particles to kill the cancer cells. External beam radiation and brachytherapy are radiation treatments that can be used to treat ovarian cancers.

[0290] Other therapies for ovarian cancers include but are not limited to luteinizing hormone releasing hormone (LHRH) agonists, tamoxifen, aromatase inhibitors, bevacizumab, PARP inhibitors (e.g., olaparib, rucaparib, niraparib), mirvetuximab soravtansine, larotrectinib, entrectinib, and pembrolizumab.

[0291] In one aspect, the present disclosure provides a method of treating clear cell ovarian cancer 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 clear cell ovarian cancer harbors an ARID1A mutation. In some embodiments, the clear cell ovarian cancer harbors a dependency on ARID1B for survival. In some embodiments, the clear cell ovarian cancer harbors a PIK3CA mutation. In some embodiments, the clear cell ovarian cancer harbors a PIK3 mutation. In some embodiments, the subject has endometriosis.

[0292] In some embodiments, the clear cell ovarian cancer is epithelial ovarian cancer.

[0293] Ovarian cancer can be described by staging (Table 1). In some embodiments, the subject has undergone staging prior to administration of a compound that reduces the level and / or activity of BRD9. In some embodiments, the clear cell ovarian cancer is advanced epithelial ovarian cancer. In some embodiments, the clear cell ovarian cancer is stage I epithelial ovarian cancer. In some embodiments, the clear cell ovarian cancer is stage II epithelial ovarian cancer. In some embodiments, the clear cell ovarian cancer is stage III epithelial ovarian cancer. In some embodiments, the clear cell ovarian cancer is stage IV epithelial ovarian cancer. In some embodiments, the subject has undergone debulking surgery prior to administration of a compound that reduces the level and / or activity of BRD9.

[0294] In some embodiments, the compound that reduces the level and / or activity of BRD9 is administered to maintain treatment of a subject with clear cell ovarian cancer. In some embodiments, the subject has clear cell ovarian cancer that harbors a deleterious germline BRCA-mutation (gBRCAm). In some embodiments, the subject has clear cell ovarian cancer that harbors a somatic germline BRCA- mutation (gBRCAm). In some embodiments, the subject is in complete response to platinum-based chemotherapy. In some embodiments, the subject is in partial response to platinum-based chemotherapy. In some embodiments, the subject is resistant to platinum-based chemotherapy. In some embodiments, the subject is refractory to platinum-based chemotherapy. In some embodiments, the subject has recurrent clear cell ovarian cancer after treatment with at least one line of chemotherapy. In some embodiments, the subject has platinum-sensitive recurrent clear cell ovarian cancer.

[0295] Table 1. Stages of Ovarian Cancer (International Federation of Gynecology and Obstetrics (FIGO) System and American Joint Committee on Cancer (AJCC) Tumor Nodes Metastasis (TNM) System) In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, the method comprising contacting the cell with an effective amount of a compound that reduces the level and / or activity of BRD9 in the cell. In some embodiments, the cell is in a subject.

[0296] In one aspect, the present disclosure provides methods of treating clear cell ovarian cancer 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.

[0297] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, 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.

[0298] In one aspect, the present disclosure provides methods of treating clear cell ovarian cancer 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.

[0299] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, 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 Ijbenzy l)-3,3- difluoropi peridin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)piperidine-2, 6-dione.

[0300] In one aspect, the present disclosure provides methods of treating clear cell ovarian cancer in a subject in need thereof, the method comprising administering to the subject at least 2mg 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.

[0301] Head and Neck Squamous Cell Cancers

[0302] Globally, head and neck cancer accounts for about 650,000 new cases of cancer and 330,000 deaths annually on average. In 2018, it was the seventh most common cancer worldwide with about 890,000 new cases documented and 450,000 dying from the disease. In the United States, head and neck cancer makes up about 3% of all cancer cases (averaging 53,000 new diagnoses per year) and 1 .5% of cancer deaths.

[0303] Head and neck squamous cell cancer occurs in the outermost surface of the skin or certain tissues within the head and neck region which includes the throat, mouth, sinuses and nose. Squamous cell cancer makes up approximately 90 percent of all head and neck cancers, with the most common types of head and neck cancers occurring in the lip, mouth, and larynx. The majority of head and neck cancer is caused by the use of alcohol or tobacco, including an increasing number of cases attributed to the human papillomavirus (HPV). Other risk factors include Epstein-Barr virus, betel quid, radiation exposure, and other workplace exposures.

[0304] In one aspect, the present disclosure provides a method of treating head and neck squamous cell cancer 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.

[0305] In some embodiments, the head and neck squamous cell cancer is cancer of the oral cavity, pharynx, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses, nasal cavity, salivary glands, tongue, esophagus, or a combination thereof. In some embodiments, the head and neck squamous cell cancer is pharyngeal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma, or tongue squamous cell carcinoma. In some embodiments, the head and neck squamous cell cancer is pharyngeal squamous cell carcinoma. In some embodiments, the head and neck squamous cell cancer is hypopharyngeal squamous cell carcinoma. In some embodiments, the head and neck squamous cell cancer is esophageal squamous cell carcinoma. In some embodiments, the head and neck squamous cell cancer is tongue squamous cell carcinoma.

[0306] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, the method comprising contacting the cell with an effective amount of a compound that reduces the level and / or activity of BRD9 in the cell. In some embodiments, the cell is a pharyngeal squamous cancer cell. In some embodiments, the cell is a hypopharyngeal squamous cancer cell. In some embodiments, the cell is an esophageal squamous cancer cell. In some embodiments, the cell is a tongue squamous cancer cell. In some embodiments, the cell is in a subject.

[0307] In some embodiments, the head and neck squamous cell cancer is metastatic after prior treatment. In some embodiments, the head and neck squamous cell cancer is resistant to prior treatment. In some embodiments, the head and neck squamous cell cancer has failed to respond to prior treatment. In some embodiments, the head and neck squamous cell cancer has relapsed after prior treatment. In some embodiments, the head and neck squamous cell cancer is refractory to prior treatment. In some embodiments, the head and neck squamous cell cancer is locally advanced after prior treatment. In some embodiments, the head and neck squamous cell cancer is regionally advanced after prior treatment. In some embodiments, the head and neck squamous cell cancer is recurrent locoregional disease after prior treatment. In some embodiments, the head and neck squamous cell cancer is recurrent after prior treatment. In some embodiments, the prior treatment comprises cetuximab, radiation therapy, fluorouracil, platinum-based therapy, or a combination thereof.

[0308] In one aspect, the present disclosure provides methods of treating head and neck squamous cell cancer 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. In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, 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.

[0309] In one aspect, the present disclosure provides methods of treating head and neck squamous cell cancer 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-dihydropy ridin-3-y Ijbenzy l)-3,3- difluoropiperidin-4-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2, 6-dione, or a pharmaceutically acceptable salt thereof.

[0310] In one aspect, the present disclosure provides methods of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, 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-yl)benzyl)-3,3- difluoropi peridin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)piperidine-2, 6-dione.

[0311] In one aspect, the present disclosure provides methods of treating head and neck squamous cell cancer in a subject in need thereof, the method comprising administering to the subject at least 2mg 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.

[0312] Methods of Treatment

[0313] The present disclosure features methods of treating disorders related to BRD9 such as cancer, e.g., clear cell ovarian cancer and / or head and neck squamous cell cancer in a subject in need thereof.

[0314] 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.

[0315] 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. Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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.

[0316] Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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).

[0317] Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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).

[0318] Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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 clear cell ovarian cancer and / or head and neck squamous cell cancer cells in the subject. For example, after treatment, the level of clear cell ovarian cancer and / or head and neck squamous cell cancer, cells in the subject is 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 clear cell ovarian cancer and / or head and neck squamous cell cancer cells may be measured by any reproducible means of measurement. For example, the level of clear cell ovarian cancer and / or head and neck squamous cell cancer cells may be measured by obtaining a sample of tissue from a subject with clear cell ovarian cancer and / or head and neck squamous cell cancer cells.

[0319] Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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 anti-cancer 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.

[0320] Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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.

[0321] Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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.

[0322] Treating cancer, e.g., treating clear cell ovarian cancer and / or head and neck squamous cell cancer 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.

[0323] Combination Therapies

[0324] 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.

[0325] In some embodiments, the clear cell ovarian cancer and / or head and neck squamous cell cancer 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 anticancer 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 anticancer 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.

[0326] 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). 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.

[0327] 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.

[0328] 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. 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; 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.

[0329] 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.

[0330] In one aspect, the present disclosure provides a method of treating clear cell ovarian cancer 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 another aspect, the present disclosure provides a method of treating head and neck squamous cell cancer 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 anti-cancer 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.

[0331] In some embodiments, the additional cancer therapy is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or a combination thereof.

[0332] In some embodiments, the additional cancer therapy is is Alkeran (Melphalan), Alymsys (Bevacizumab), Avastin (Bevacizumab), Bevacizumab, Carboplatin, Cisplatin, Cyclophosphamide, Doxorubicin Hydrochloride, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride Liposome, Elahere (Mirvetuximab soravtansine-gynx), Gemcitabine Hydrochloride, Gemzar (Gemcitabine Hydrochloride), Hycamtin (Topotecan Hydrochloride), Infugem (Gemcitabine Hydrochloride), Lynparza (Olaparib), Melphalan, Mirvetuximab soravtansine-gynx, Mvasi (Bevacizumab), Niraparib Tosylate Monohydrate, Olaparib, Paclitaxel, Paraplatin (Carboplatin), Rubraca (Rucaparib Camsylate), Rucaparib Camsylate, Tepadina (Thiotepa), Thiotepa, Topotecan Hydrochloride, Zejula (Niraparib Tosylate Monohydrate), Zirabev (Bevacizumab), or a combination thereof, or combinations thereof.

[0333] In some embodiments, the additional cancer therapy is altretamine, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, etoposide, gemcitabine hydrochloride, ifosfamide, irinotecan, laparib, melphalan, mirvetuximab soravtansine-gynx, niraparib tosylate monohydrate, olaparib, paclitaxel, pemetrexed, rucaparib camsylate, thiotepa, topotecan hydrochloride, vinorelbine, luteinizing hormone releasing hormone (LHRH) agonists, tamoxifen, aromatase inhibitors, larotrectinib, entrectinib, and pembrolizumab. or a combination thereof.

[0334] In some embodiments, the additional cancer therapy is altretamine, bevacizumab, bleomycin sulfate, capecitabine, carboplatin, cemiplimab, cetuximab, cisplatin, cyclophosphamide, docetaxel, dostarlimab, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, an EGFR inhibitor, entrectinib, etoposide, gemcitabine hydrochloride, hydroxyurea, ifosfamide, irinotecan, laparib, melphalan, methotrexate sodium, mirvetuximab soravtansine-gynx, niraparib tosylate monohydrate, nivolumab, olaparib, paclitaxel, pemetrexed, rucaparib camsylate, thiotepa, topotecan hydrochloride, vinorelbine, luteinizing hormone releasing hormone (LHRH) agonists, tamoxifen, aromatase inhibitors, larotrectinib, entrectinib, and pembrolizumab, or a combination thereof.

[0335] In some embodiments, the additional cancer therapy is albumin bound paclitaxel, altretamine, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, paclitaxel, pemetrexed, topotecan, vinorelbine, or a combination thereof.

[0336] In some embodiments, the additional cancer therapy is an EGFR inhibitor, entrectinib, nivolumab, cetuximab, cemiplimab, dostarlimab, hydroxyurea, bleomycin sulfate, methotrexate sodium, pembrolizumab, or a combination thereof.

[0337] In some embodiments, the additional cancer therapy is pembrolizumab, nivolumab, camipimab, dostarlimab, or a combination thereof.

[0338] In some embodiments, the additional cancer therapy is cetuximab.

[0339] In some embodiments, the surgery is laser technology, excision, lymph node dissection, neck dissection, debulking, or a combination thereof.

[0340] In some embodiments, the radiation is external beam radiation therapy, intensity-modulated radiation therapy (IMRT), proton therapy, or a combination thereof.

[0341] 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. Pharmaceutical Compositions

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] Dosages

[0347] 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.

[0348] 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.

[0349] 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).

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] 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. 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.

[0363] 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.

[0364] 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.

[0365] 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.

[0366] 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.

[0367] 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.

[0368] 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.

[0369] 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. 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).

[0370] 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.

[0371] Kits

[0372] 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.

[0373] The following Examples are illustrative only and not intended to limit the invention in any way.

[0374] EXAMPLES Example 1 . Clear Cell Ovarian Cancer Cell Lines are Sensitive to Treatment with Compound 1 in 3D Cell Culture Assay

[0375] Procedure: Six clear cell ovarian cancer cell lines were tested in 3D cell culture for sensitivity to Compound 1 (Table 2). 5,000 cells per well were seeded in ultra-low attachment 96 well plates with 3% Geltrex scaffolding material. Plates were centrifuged for 5 minutes to pellet the cells and then incubated at 37°C and 5% CO2. After 24 hours of incubation, plates were removed and Compound 1 was added to the wells in a 10-step, 3-fold serial dilution, starting with a concentration of 100 nM. Media and Compound 1 were replenished every 3 days for a time period of 10 to 16 days. Growth of each spheroid was measured every 6 hours in an Incucyte S3 live-cell analysis instrument. At the end of the study, viability of the spheres was measured using PrestoBlue cell viability reagent, and IC50 was calculated as the concentration that causes 50% growth inhibition of the sphere. Conversely, in a typical 2D cell culture, a lower number of cells would be seeded per well (typically 100-500 cells per well), cells would be given 24 hours to attach, and compound would be added in the same manner with serial dilutions. Depending on the doubling time of the cells, confluency would be reached in 7-10 days and cell viability would then be measured. Key advantages of the 3D culture method include the ability to extend the time of the treatment beyond 10 days, improved recapitulation of in vivo tumor architecture, and increased cell heterogeneity due to a hypoxic core.

[0376] Results: In total, three out of the six cell lines tested showed sensitivity to Compound 1 , with IC50 < 4nM (Table 2). A 4thcell line showed weak sensitivity (IC50=315nM), while the remaining three cell lines showed little to no sensitivity to Compound 1 . Three out of four cell lines sensitive to Compound 1 harbored ARID1 A mutations. Table 2. Clear Cell Ovarian Cancer Cell Line Characterization

[0377] Conclusion: The majority of clear cell ovarian cancer cell lines with ARID1 A mutations are sensitive to treatment with Compound 1 . This suggests that Compound 1 may be especially useful for treatment of subjects with clear cell ovarian cancer that harbors an ARID1A mutation.

[0378] Example 2. Head and Neck Squamous Cell Cancer Cell Lines are Sensitive to Treatment with Compound 1 in 3D Cell Culture Assay

[0379] Procedure: Five head and neck squamous cell cancer cell lines were tested in 3D cell culture for sensitivity to Compound 1 (Table 3). 5,000 cells per well were seeded in ultra-low attachment 96 well plates with 4% Matrigel scaffolding material. Plates were centrifuged for 5 minutes to pellet the cells and then incubated at 37°C and 5% CO2. After 24 hours of incubation, plates were removed and Compound 1 was added to the wells in a 10-step, 3-fold serial dilution, starting with a concentration of 100 nM. Media and Compound 1 were replenished every 3 days for a time period of 10 days. At the end of the study, viability of the spheres was measured using CellTiter Gio cell viability reagent, and IC50 was calculated as the concentration that causes 50% growth inhibition of the sphere. Previously, the same five cell lines were tested for sensitivity to Compound 1 in 2D cell culture. Cells were seeded in a 384-well plate and incubated with compound for 10 days, with media and compound replenishment every 3 days. Viability was measured at the end point using a fluorescent nuclear dye, and IC50 values were calculated. The IC50 values for all five of the tested cell lines were >100nM.

[0380] Results: All five cell lines tested showed sensitivity to Compound 1 , with IC50 values ranging from 0.01 nM to 36.37 nM. The same five cell lines were not sensitive to Compound 1 in 2D cell culture with all IC50 values exceeding 100nM.

[0381] Table 3. Head and Neck Cancer Cell Line Characterization

[0382] Conclusion: 3D cell culture is a valuable tool that allows for cells to grow in a more physiologically relevant environment which can then provide more detailed and accurate information about a cell line’s response to treatment. All five head and neck squamous cell cancer lines were sensitive to treatment with Compound 1 , suggesting that Compound 1 may be useful for treatment of subjects with head and neck squamous cell cancers.

[0383] Other Embodiments

[0384] 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.

[0385] 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.

[0386] Other embodiments are in the claims.

Claims

What is claimed is:Claims1 . A method of treating clear cell ovarian cancer 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 clear cell ovarian cancer harbors an ARID1A mutation.

3. The method of any one of claims 1-2, wherein the clear cell ovarian cancer is epithelial ovarian cancer.

4. The method of any one of claims 1-3, wherein the clear cell ovarian cancer is advanced epithelial ovarian cancer.

5. The method of any one of claims 1-4, wherein the clear cell ovarian cancer is stage III epithelial ovarian cancer.

6. The method of any one of claims 1-4, wherein the clear cell ovarian cancer is stage IV epithelial ovarian cancer.

7. The method of any one of claims 1-6, wherein the subject has undergone debulking surgery prior to administration of a compound that reduces the level and / or activity of BRD9.

8. The method of any one of claims 1-7, wherein the compound that reduces the level and / or activity of BRD9 is administered to maintain treatment of a subject with clear cell ovarian cancer.

9. The method of any one of claims 1-8, wherein the subject has clear cell ovarian cancer that harbors a deleterious germline BRCA-mutation (gBRCAm).

10. The method of any one of claims 1-8, wherein the subject has clear cell ovarian cancer that harbors a somatic germline BRCA-mutation (gBRCAm).

11. The method of any one of claims 1-10, wherein the subject has a complete response to platinumbased chemotherapy.

12. The method of any one of claims 1-10, wherein the subject has a partial response to platinumbased chemotherapy.

13. The method of any one of claims 1-10, wherein the subject is resistant to platinum-based chemotherapy.

14. The method of any one of claims 1-10, wherein the subject is refractory to platinum-based chemotherapy.

15. The method of any one of claims 1-10, wherein the subject has recurrent clear cell ovarian cancer after treatment with at least one line of chemotherapy.

16. The method of any one of claims 1-10, wherein the subject has platinum-sensitive recurrent clear cell ovarian cancer.

17. A method of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, the method comprising contacting the cell with an effective amount of a compound that reduces the level and / or activity of BRD9 in the cell.

18. The method of claim 17, wherein the cell is in a subject.

19. A method of treating head and neck squamous cell cancer 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.

20. The method of claim 19, wherein the head and neck squamous cell cancer is cancer of the oral cavity, pharynx, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses, nasal cavity, salivary glands, tongue, esophagus, or a combination thereof.21 . The method of any one of claims 19-20, wherein the head and neck cancer is pharyngeal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma, or tongue squamous cell carcinoma.

22. The method of claim 21 , wherein the head and neck squamous cell cancer is pharyngeal squamous cell carcinoma.

23. The method of claim 21 , wherein the head and neck squamous cell cancer is hypopharyngeal squamous cell carcinoma.

24. The method of claim 21 , wherein the head and neck squamous cell cancer is esophageal squamous cell carcinoma.

25. The method of claim 21 , wherein the head and neck squamous cell cancer is tongue squamous cell carcinoma.

26. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer is metastatic after prior treatment.

27. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer is resistant to prior treatment.

28. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer has failed to respond to prior treatment.

29. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer has relapsed after prior treatment.

30. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer is refractory to prior treatment.31 . The method of any one of claims 19-25, wherein the head and neck squamous cell cancer is locally advanced after prior treatment.

32. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer is regionally advanced after prior treatment.

33. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer is recurrent locoregional disease after prior treatment.

34. The method of any one of claims 19-25, wherein the head and neck squamous cell cancer is recurrent after prior treatment.

35. The method of any one of claims 26-34, wherein the prior treatment comprises cetuximab, radiation therapy, fluorouracil, platinum-based therapy, or a combination thereof.

36. A method of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, the method comprising contacting the cell with an effective amount of a compound that reduces the level and / or activity of BRD9 in the cell.

37. The method of claim 36, wherein the cell is a pharyngeal squamous cancer cell.

38. The method of claim 36, wherein the cell is a hypopharyngeal squamous cancer cell.

39. The method of claim 36, wherein the cell is an esophageal squamous cancer cell.

40. The method of claim 36, wherein the cell is a tongue squamous cancer cell.41 . The method of any one of claims 36-40, wherein the cell is in a subject.

42. The method of any one of claims 1-41 , wherein the compound that reduces the level and / or activity of BRD9 is 3-(6-(7-((1-(4-(6-(485zetidine-1-yl)-2-methyl-1-oxo-1 ,2-dihydro-2,7-naphthyridin-4-y I)-2.6-dimethoxybenzyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl) piperidine-2.6-dione.

43. The method of any one of claims 1-41 , 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-y Ijbenzy l)-3,3- difluoropi peridin-4-yl) pi perazin-1 -yl)-3-fluorophenyl)amino)piperidine-2, 6-dione.

44. The method of any one of claims 1 to 43, wherein the subject is further administered at least one additional anti-cancer therapy.

45. The method of claim 44, wherein the additional anti-cancer therapy is administered prior to the administering of the compound or pharmaceutically acceptable salt thereof.

46. The method of claim 44, wherein the additional anti-cancer therapy is administered in addition to the administering of the compound or pharmaceutically acceptable salt thereof.

47. The method of claim 44, wherein the additional anti-cancer therapy is administered subsequent to the administering of the compound or pharmaceutically acceptable salt thereof.

48. The method of any one of claims 44-47, wherein the additional cancer therapy is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, or a combination thereof.

49. The method of any one of claims 44-48, wherein the additional cancer therapy is altretamine, bevacizumab, bleomycin sulfate, capecitabine, carboplatin, cemiplimab, cetuximab, cisplatin, cyclophosphamide, docetaxel, dostarlimab, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, an EGFR inhibitor, entrectinib, etoposide, gemcitabine hydrochloride, hydroxyurea, ifosfamide, irinotecan, laparib, melphalan, methotrexate sodium, mirvetuximab soravtansine-gynx, niraparib tosylate monohydrate, nivolumab, olaparib, paclitaxel, pemetrexed, rucaparib camsylate, thiotepa, topotecanhydrochloride, vinorelbine, luteinizing hormone releasing hormone (LHRH) agonists, tamoxifen, aromatase inhibitors, larotrectinib, entrectinib, and pembrolizumab, or a combination thereof.

50. The method of any one of claims 44-48, wherein the additional cancer therapy is albumin bound paclitaxel, altretamine, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, paclitaxel, pemetrexed, topotecan, vinorelbine, or a combination thereof.51 . The method of claim 48, wherein the surgery is laser technology, excision, lymph node dissection, neck dissection, debulking, or a combination thereof.

52. The method of claim 48, wherein the radiation is external beam radiation therapy, intensity- modulated radiation therapy (IMRT), proton therapy, or a combination thereof.

53. The method of any one of claims 1 to 52, wherein the subject or cancer has and / or has been identified as having increased BRD9 expression.

54. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-80 mg / kg.

55. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-60 mg / kg.

56. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20-40 mg / kg.

57. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 20 mg / kg.

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

59. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 50 mg / kg.

60. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 60 mg / kg.

61. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 80 mg / kg.

62. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered in a dose of 120 mg / kg.

63. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered to the subject at least once per week.

64. The method of any one of claims 1-53, wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof, is administered to the subject at least twice per week.

65. The method of any one of claims 1-53, 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.

66. The method of any one of claims 1-53, 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.

67. The method of any one of claims 1-53, 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.

68. The method of any one of claims 1-53, 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.

69. The method of any one of claims 1-53, 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.

70. The method of any one of claims 1-53, 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.

71. The method of any one of claims 1-53, 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.

72. The method of any one of claims 1-53, 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.

73. The method of any one of claims 1-53, 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.

74. The method of any one of claims 1-53, 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.

75. The method of any one of claims 1-53, 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.

76. The method of any one of claims 1-53, 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.

77. The method of any one of claims 1-76, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 14-day dosing cycle.

78. The method of any one of claims 1-76, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 21 -day dosing cycle.

79. The method of any one of claims 1-76, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the subject in a 28-day dosing cycle.

80. The method of any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof, is administered to the subject intravenously.81 . The method of any one of the preceding claims, wherein the compound or a pharmaceutically acceptable salt thereof, is administered to the subject subcutaneously.

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

83. A method of treating clear cell ovarian cancer 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.

84. A method of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, 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) pi peridine-2, 6-dione.

85. A method of treating head and neck squamous cell cancer 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.

86. A method of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, the method comprising contacting the cell with an effective amount of 3-(6-(7-((1-(4-(6-(azetidin-1-yl)- 2-methy 1-1 -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) pi peridine-2, 6-dione.

87. A method of treating clear cell ovarian cancer 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)pi peridine-2.6-dione, or a pharmaceutically acceptable salt thereof.

88. A method of reducing the level and / or activity of BRD9 in a clear cell ovarian cancer cell, 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) pi perazin-1 -yl)-3- fluorophenyl)amino)pi peridine-2, 6-dione.

89. A method of treating head and neck squamous cell cancer 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.

90. A method of reducing the level and / or activity of BRD9 in a head and neck squamous cell cancer cell, 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) pi perazin-1 -yl)-3- fluorophenyl)amino)pi peridine-2, 6-dione.91 . A method of treating clear cell ovarian cancer in a subject in need thereof, the method comprising administering to the subject at least 2mg 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)pi peridine-2.6-dione, or a pharmaceutically acceptable salt thereof.

92. A method of treating head and neck squamous cell cancer in a subject in need thereof, the method comprising administering to the subject at least 2mg 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.