JP2023535124A - how to treat cancer - Google Patents

Abstract

The present invention relates to methods and compositions for the treatment of BAF-related disorders such as acute myeloid leukemia. The present invention features methods of treating AML, eg, in a subject in need of treatment for AML. In one aspect, the invention features a method of treating AML in a subject in need thereof, comprising administering to the subject a therapeutically effective amount to reduce the level and/or activity of BRG1 and/or BRM. including administering an agent of [Selection drawing] Fig. 1

Description

The present invention relates to methods of modulating BRG1 or BRM-associated factor (BAF) complexes for use in the treatment of acute myeloid leukemia. In particular, the invention relates to methods for treating disorders associated with the function of the BAF complex.

Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. The human switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, also known as the BAF complex, comprises two SWI2 known as BRG1 (Brahma-related gene-1) and BRM (Brahma). have a similar ATPase. The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is required for cancer cell proliferation. BRM, also known as the likely global transcriptional activator SNF2L2 and/or the ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and is characterized by loss-of-function mutations in BRG1. It has been shown to be essential for tumor cell proliferation in cells. Deactivation of BRG and/or BRM leads to downstream effects in cells, including cell cycle arrest and tumor suppression.

AML is a cancer of the myeloid line of blood cells. AML is characterized by rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells. AML is generally considered incurable in about 65% of subjects under the age of 60 and about 90% of those over the age of 60. Typical survival for elderly subjects in very poor health to intensive chemotherapy is 5-10 months. Overall, the 5-year survival rate for AML is approximately 25%.

The invention features a method of treating AML (eg, in a subject in need thereof).

In one aspect, the invention features a method of treating AML in a subject in need thereof, comprising administering an effective amount of an agent that reduces the level and/or activity of BRG1 and/or BRM. Including administering to a subject.

In another aspect, the invention features a method of reducing the proliferation of AML in a subject in need thereof, which method reduces the level and/or activity of BRG1 and/or BRM in a tumor It includes administering (eg, orally administering) an effective amount of the agent to the subject.

In another aspect, the invention features a method of inhibiting metastatic progression of AML in a subject, comprising administering an effective amount of an agent that reduces the level and/or activity of BRG1 and/or BRM (e.g., , oral administration).

In another aspect, the invention features a method of inhibiting metastatic colonization of AML in a subject, comprising administering an effective amount of an agent that reduces the level and/or activity of BRG1 and/or BRM ( for example, oral administration).

In another aspect, the invention features a method of reducing the level and/or activity of BRG1 and/or BRM in an AML cell, the method comprising reducing the level and/or activity of BRG1 and/or BRM in the cell This includes contacting with an effective amount of an agent that reduces activity.

In some embodiments of any of the above aspects, the AML cell is within the subject.

In some embodiments of any of the above aspects, the effective amount of the agent reduces the level and/or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%) compared to the reference substance. %, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%). In some embodiments, the level and/or activity of BRG1 is reduced by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%) compared to a reference substance. , or 95%). In some embodiments, the level and/or activity of BRG1 is reduced by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) effective amount of the drug.

In some embodiments, an effective amount of an agent reduces BRG1 levels and/or activity by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% %) by at least 12 hours (eg, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, BRG1 levels and/or activity are reduced by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (eg, 5 days, 6 days, 7 days, 14 days, 28 days, or more) an effective amount of the agent.

In some embodiments of any of the above aspects, the effective amount of the agent reduces the level and/or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% , 85%, 90%, or 95%). In some embodiments, the level and/or activity of BRM is reduced by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) effective amount of the drug. In some embodiments, the level and/or activity of BRM is reduced by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) A reducing effective amount of the agent.

In some embodiments, an effective amount of an agent reduces BRM levels and/or activity by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% %) by at least 12 hours (eg, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the level and/or activity of BRM is reduced by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) for at least 4 days (eg, 5 days, 6 days, 7 days, 14 days, 28 days, or more) an effective amount of the agent.

In some embodiments, the AML expresses BRG1 and/or BRM proteins and/or the cell or subject has been identified as expressing BRG1 and/or BRM. Some embodiments have elevated expression of BRG1 and/or BRM. In some embodiments, the AML expresses BRG1 protein and/or the cell or subject has been identified as expressing BRG1. In some embodiments, the AML has elevated expression of BRG1. In some embodiments, the AML expresses a BRM protein and/or the cell or subject has been identified as expressing a BRM. In some embodiments, AML has elevated expression of BRM.

In some embodiments, the AML is acute promyelocytic leukemia (APL). In some embodiments, AML results from a pre-existing myelodysplastic syndrome or myeloproliferative disorder. In some embodiments, the AML is therapy-related AML, eg, AML that occurs after chemotherapy for another previous malignancy. In some embodiments, the AML is AML with recurrent genetic abnormalities. In some embodiments, the AML is AML with myelodysplasia-associated changes. In some embodiments, the AML is therapy-related myeloid neoplasia. In some embodiments, the AML is myelosarcoma. In some embodiments, the AML is myeloproliferation associated with Down's syndrome. In some embodiments, the AML is a blast plasmacytoid dendritic cell tumor. In some embodiments, the AML is minimally differentiated AML. In some embodiments, AML without AML maturation. In some embodiments, the AML is AML with a granulocyte mutation. In some embodiments, the AML is myelomonocytic with bone marrow eosinophils. In some embodiments, the AML is acute monoblastic leukemia. In some embodiments, the AML is acute erythrocytic leukemia, eg, erythroleukemia or pure cell leukemia. In some embodiments, the AML is acute megakaryoblastic leukemia. In some embodiments, the AML is acute basophilic leukemia.

In some embodiments, the AML cytogenetics is t(8;21), t(15;17), or inv(16). In some embodiments, the cytogenetics of AML is normal +8, +21, +22, del(7q), del(9q) or abnormal 11q23. In some embodiments, the AML cytogenetics is -5, -7, del(5q), abnormal 3q, or combined cytogenetics.

In some embodiments, the cancer is metastatic (eg, cancer has spread to the liver). Metastatic cancer may contain cells that exhibit migratory cell migration and/or invasion, and/or cells that exhibit endothelial recruitment and/or angiogenesis. In some embodiments, an effective amount of the agent to reduce BRG1 and/or BRM levels and/or activity is an amount effective to inhibit metastatic colonization of the liver with AML.

In some embodiments, the AML has a DNMT3A mutation. In some embodiments, the AML has a FLT3-ITD mutation. In some embodiments, the AML has an NPM1 mutation. In some embodiments, the AML has a CEBPA mutation (eg, biallelic CEBPA mutation). In some embodiments, the AML has a c-KIT mutation. In some embodiments, the AML has a RUNX1 mutation. In some embodiments, the AML has an ASXL1 mutation. In some embodiments, the AML has a TP53 mutation. In some embodiments, the AML has a DNMT3A mutation. In some embodiments, the AML has an IDH1 mutation. In some embodiments, the AML has an IDH2 mutation.

In some embodiments, the subject is over 60 years old. In some embodiments, the subject has elevated levels of lactate dehydrogenase.

In some embodiments, the anti-cancer therapies and agents that reduce the level and/or activity of BRG1 and/or BRM in cells are administered within 28 days of each other and each in an amount effective to treat the subject. administered at

In some embodiments, the subject or cancer has and/or has been identified as having a BRG1 loss-of-function mutation. In some embodiments, the subject or cancer has and/or has been identified as having a BRM loss-of-function mutation. In some embodiments, the cancer has a T910M mutation in BRG1.

In some embodiments, the method further comprises administering induction chemotherapy (eg, cytarabine, anthracyclines, eg, daunorubicin, arsenic trioxide, all-trans-retinoic acid, or combinations thereof). In some embodiments, the method comprises administering a 7-day infusion of cytarabine and a 3-day intravenous injection of an anthracycline, such as daunorubicin. In some embodiments, the method further comprises administering a consolidation therapy (eg, allogeneic stem cell transplantation, immunotherapy such as histamine dihydrochloride and interleukin-2, or a combination thereof). In some embodiments, the method further comprises administering a hematopoietic stem cell transplant, gemtuzumab ozogamicin, or a combination thereof. In some embodiments, the method further comprises administering venetoclax, gilteritinib, or a combination thereof.

In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to a chemotherapeutic or cytotoxic agent). (e.g., by genetic markers) or are likely to be resistant to chemotherapeutic or cytotoxic agents (e.g., cancers that have not responded to chemotherapeutic or cytotoxic agents). In some embodiments, the cancer failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is cytarabine, anthracyclines such as daunorubicin, arsenic trioxide, all-trans-retinoic acid, histamine dihydrochloride, interleukin 2, gemtuzumab ozogamicin, dacarbazine, temozolomide , cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (eg, ipilimumab), PD-1 inhibitors (eg, nivolumab or pembrolizumab), PD-L1 inhibitors (eg, atezolizumab, avelumab, or durvalumab) , mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and/or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or LXS196, aka IDE196) , or did not respond. In some embodiments, the cancer is treated with cytarabine, an anthracycline such as daunorubicin, arsenic trioxide, all-trans-retinoic acid, histamine dihydrochloride, interleukin-2, and/or gemtuzumab ozogamicin. tolerated or did not respond. In some embodiments, the cancer was resistant or did not respond to venetoclax, gilteritinib, or a combination thereof.

In some embodiments, agents that reduce BRG1 and/or BRM levels and/or activity in cells are small molecule compounds, antibodies, enzymes, and/or polynucleotides.

In some embodiments, the agent that reduces the level and/or activity of BRG1 and/or BRM in a cell is an enzyme, e.g., clustered regularly spaced short palindromic repeat (CRISPR)-related protein (CRISPR-related protein 9 (Cas9), CRISPR-associated protein 12a (Cas12a), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), or meganucleases).

In some embodiments, the agent that reduces the level and/or activity of BRG1 and/or BRM in a cell is a polynucleotide, e.g., an antisense nucleic acid, small interfering RNA (siRNA), short hairpin RNA (shRNA) , microRNAs (miRNAs), CRISPR/Cas9 nucleotides, or ribozymes.

In some embodiments, agents that reduce BRG1 and/or BRM levels and/or activity in cells are small molecule compounds (eg, small molecule BRG1 inhibitors and/or BRM inhibitors). In some embodiments, the agent that reduces BRG1 and/or BRM levels and/or activity in a cell is a small molecule compound (eg, a small molecule BRG1 inhibitor). In some embodiments, agents that reduce BRG1 and/or BRM levels and/or activity in cells are small molecule compounds (eg, small molecule BRM inhibitors or degradants).

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof,

wherein m is 0, 1, 2, 3, or 4;
X ¹ is N or CH,
Each R ¹ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ - C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally C ₂ -C ₆ alkenyl substituted with , optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula II or a pharmaceutically acceptable salt thereof,

wherein R ² is phenyl substituted with hydroxy, optionally independently the group consisting of halo, cyano, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, and C _1-3 alkoxy phenyl substituted with one or more groups selected from
R ³ is selected from the group consisting of -R ^a , -OR ^a , -N(R ^a )2, -S(O) ₂ R ^a , and -C(O)-N(R ^a ) ₂ ,
Each R ^a is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl; _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl are optionally and independently R ^b , oxo, halo, —NO2, —N(R ^b ) ₂ , —CN, —C(O)—N(R ^b ) ₂ , —S(O)—N(R ^b ) ₂ , —S(O) ₂ —N(R ^b ) ₂ , —O—R ^b , —S—R ^b , —O—C(O)—R ^b , —C(O)—R ^b , —C(O)—OR ^b , —S(O)—R ^b , -S(O)2-R ^b , -N(R ^b )-C(O)-R ^b , -N(R ^b )-S(O)-R ^b , -N(R ^b )-C( substituted with one or more groups selected from the group consisting of O)—N(R ^b ) ₂ and —N(R ^b )—S(O) ₂ —R ^b ;
the group in which each R ^b independently consists of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally independently are substituted with one or more groups selected from R ^c , or two R ^b , together with the nitrogen to which they are attached, are heterocyclyl (optionally, independently, substituted with one or more groups selected from the group consisting of oxo, halo and C _1-3 alkyl, wherein C _1-3 alkyl is optionally independently selected from the group consisting of oxo and halo is substituted with one or more groups that are
Each R ^c is independently oxo, halo, —NO2, —N(R ^d ) ₂ , —CN, —C(O)—N(R ^d ) ₂ , —S(O)—N(R ^d ) ₂ , —S(O) ₂ —N(R ^d ) ₂ , —SR ^d , —O—C(O)—R ^d , —C(O)—R ^d , —C(O)—OR ^d , -S(O)-R ^d , -S(O) _2- R ^d , -N(R ^d )-C(O)-R ^d , -N(R ^d )-S(O)-R ^d , —N(R ^d )—C(O)—N(R ^d ) ₂ , —N(R ^d )—S(O) _2- R ^d , C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, any C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally independently R ^d , oxo, halo, —NO ₂ , —N(R ^d ) ₂ , —CN, —C(O)—N(R ^d ) ₂ , -S(O)-N(R ^d ) ₂ , -S(O) ₂ -N(R ^d ) ₂ , -O-R ^d , -S-R ^d , -O-C(O)-R ^d , -C(O)-R ^d , -C(O)-R ^d , -S(O)R ^d , -S(O) ₂ -R ^d , -N(R ^d )-C(O)-R ^d , —N(R ^d )—S(O)—R ^d , —N(R ^d )—C(O)—N(R ^d ) ₂ , and —N(R ^d )—S(O) ₂ — substituted with one or more groups selected from the group consisting of R ^d ,
each R ^d is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, and carbocyclyl(C _1-3 alkyl)-;
R ⁴ is H, C _1-6 alkyl, or —C(=O)—C _1-6 alkyl;
R ⁵ is H or C _1-6 alkyl.

Compounds of Formula II can be synthesized by methods known in the art, such as those described in US Patent Publication No. 2018/0086720, which synthetic methods are incorporated by reference.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula III or a pharmaceutically acceptable salt thereof,

wherein R ⁶ is halo (e.g. fluoro or chloro),
R ⁷ is hydrogen, optionally substituted amino, or optionally substituted C _1-6 alkyl;
R ⁸ is optionally substituted C _6-10 aryl or optionally substituted C _2-9 heteroaryl.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of any one of compounds 1-16, or a pharmaceutically acceptable salt thereof.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula IV or a pharmaceutically acceptable salt thereof,

wherein R ¹ is absent or H, optionally substituted C ₁ -C ₆ acyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₂ -C ₉ heterocyclyl, or —SO ₂ R ⁶ ;

is 5- or 6-membered heteroarylene, each of R ² and R ⁵ is independently H or optionally substituted C ₁ -C ₆ alkyl, and R ³ is H or optionally substituted is C ₁ -C ₆ alkyl and R ⁴ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl, or R ³ and R ⁴ are , together with the carbon atom to which they are attached, form an optionally substituted C ₃ -C ₆ cycloalkyl, and R ⁶ is an optionally substituted C ₁ -C ₆ alkyl or —NR ⁷ R ⁸ , R ⁷ and R ⁸ are independently optionally substituted C ₁ -C ₆ alkyl, Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or

and A is optionally substituted C ₆ -C ₁₀ arylene, optionally substituted C ₂ -C ₉ heterocyclylene, or optionally substituted C ₂ -C ₉ heteroarylene, and L is , absent or —O—, optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₁ -C ₆ heteroalkylene, optionally substituted C ₂ -C ₆ alkenylene, optionally substituted C ₂ -C ₆ heteroalkenylene, optionally substituted C ₂ -C ₆ alkynylene, optionally substituted C ₂ -C ₆ heteroalkynylene, optionally substituted C ₂ -C ₉ heterocyclylene, optionally C ₂ -C ₉ heterocyclyl, C ₁ -C ₆ alkylene, optionally substituted C ₂ -C ₉ heteroarylene, or optionally substituted C ₂ -C ₉ heteroaryl C ₁ -C ₆ alkylene substituted with and B is H, halogen, cyano, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ cycloalkyl, optionally substituted C ₂ -C ₉ heterocyclyl, or optionally substituted C ₂ -C ₉ heteroaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments,

is a 6-membered heteroarylene. In some embodiments,

is a 5-membered heteroarylene.

In some embodiments,

but,

where each of X, Y, and Z is independently N or CH.

In some embodiments, the compound of Formula IV has the structure of Formula IVa,

wherein each of X, Y, and Z is independently N or CH, and R ¹ is H, optionally substituted C ₁ -C ₆ acyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₉ heterocyclyl, or —SO ₂ R ⁶ ; Each of R ² , R ³ , and R ⁵ is independently H or optionally substituted C ₁ -C ₆ alkyl, and R ⁴ is H, optionally substituted C ₁ -C ₆ alkyl , or optionally substituted C ₁ -C ₆ heteroalkyl, wherein R ⁶ is optionally substituted C ₁ -C ₆ alkyl or —NR ⁷ R ⁸ and each of R ⁷ and R ⁸ is independently optionally substituted C ₁ -C ₆ alkyl, and Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or

and A is optionally substituted C ₆ -C ₁₀ arylene, optionally substituted C ₂ -C ₉ heterocyclylene, or optionally substituted C ₂ -C ₉ heteroarylene, and L is , absent or —O—, optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₁ -C ₆ heteroalkylene, optionally substituted C ₂ -C ₆ alkenylene, optionally substituted C ₂ -C ₆ heteroalkenylene, optionally substituted C ₂ -C ₆ alkynylene, optionally substituted C ₂ -C ₆ heteroalkynylene, optionally substituted C ₂ -C ₉ heterocyclylene, optionally C ₂ -C ₉ heterocyclyl C ₁ -C ₆ heteroalkylene substituted with , optionally substituted C ₂ -C ₉ heteroarylene, or optionally substituted C ₂ -C ₉ heteroaryl C ₁ -C ₆ alkylene and B is H, halogen, cyano, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ cycloalkyl, optionally substituted C ₂ -C ₉ heterocyclyl, or optionally substituted C ₂ -C ₉ heteroaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, X, Y, and Z are CH; X is N, Y and Z are CH; Z is N, and X and Y are CH; Y is N, X and Z are CH; X is CH, Y and Z are N; Z is CH, X and Y are N; and Z is N; or X, Y and Z are N.

In some embodiments, the compound of Formula IV has Formula IVb:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, Formula IV is Formula IVc:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula IV has Formula Ic:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, Formula IV is Formula IVe:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments,

teeth,

where X' is O or S, Y' is N or CH, and Z' is N or CH.

In some embodiments, the compound of Formula IVa has the structure of Formula V,

wherein W′ is C or N, X′ is O, S or N—CH ₃ , Y′ is N or CH, Z′ is N or CH, R ¹ is absent or H, optionally substituted C ₁ -C ₆ acyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₉ heteroalkyl, or —SO ₂ R ⁶ and R ² , R ³ and R ⁵ are each independently H or optionally substituted C ₁ -C ₆ alkyl, R ⁴ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl, and R ⁶ is optionally substituted C ₁ -C ₆ alkyl, or —NR ⁷ R ⁸ , R ⁷ and R ⁸ are each independently optionally substituted C ₁ -C ₆ alkyl, and Het is optionally substituted 5-membered heteroarylene substituted with, optionally substituted 6-membered heteroarylene, or

and A is optionally substituted C ₆ -C ₁₀ arylene, optionally substituted C ₂ -C ₉ heterocyclylene, or optionally substituted C ₂ -C ₉ heteroarylene, and L is , absent or —O—, optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₁ -C ₆ heteroalkylene, optionally substituted C ₁ -C ₆ alkenylene, optionally substituted C ₂ -C ₆ heteroalkenylene, optionally substituted C ₂ -C ₆ alkynylene, optionally substituted C ₂ -C ₆ heteroalkynylene, optionally substituted C ₂ -C ₉ heterocyclylene, optionally C ₂ -C ₉ heterocyclyl C ₁ -C ₆ alkylene, optionally substituted C ₂ -C ₉ heteroarylene, or optionally substituted C ₂ -C ₉ heteroaryl C ₁ -C ₆ alkylene substituted with and B is H, halogen, cyano, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ cycloalkyl, optionally substituted C ₂ -C ₉ heterocyclyl, or optionally _or a _{pharmaceutically} acceptable salt thereof.

In some embodiments, X' is O, Y' is CH, Z' is N; X' is S, Y' is CH, Z' is N X' is O, Y' is N, Z' is CH; X' is S, Y' is N, Z' is CH; X' is O, Y' is N, and Z' is N; or X' is S, Y' is N, and Z' is N.

In some embodiments, Formula V is Formula Va:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, Formula II is Formula Vb:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, the small molecule compound, or a pharmaceutically acceptable salt thereof, is any one of compounds 17-20 having the structure below.

In some embodiments, the small molecule compound or pharmaceutically acceptable salt thereof is a degradant. In some embodiments, the degrading agent has the structure of Formula VI,
CL-D
Formula VI
wherein C is the binding moiety of BRG1 and/or BRM, L is the linker and D is the degrading moiety or a pharmaceutically acceptable salt thereof. In some embodiments, the degradation moiety is a ubiquitin ligase moiety. In some embodiments, the ubiquitin ligase binding moiety is a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homolog (MDM2), a hydrophobic tag, or a von Hippel-Lindau ligand, or Including derivatives or analogues.

In some embodiments, A comprises the structure of any one of Formulas IV or the structure of any one of compounds 1-20.

In some embodiments, the hydrophobic tag comprises diphenylmethane, adamantine, or tri-Boc arginine, ie the hydrophobic tag comprises the structure:

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula A,

wherein X ¹ is CH ₂ , O, S, or NR ¹ and R ¹ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ —C ₆ heteroalkyl and X ² is C═O, CH ₂ , or

and R ³ and R ⁴ are independently H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl, and m is , 0, 1, 2, 3, or 4, and each R ² is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted _C2 - _C9 heteroaryl, optionally substituted _C2 - _C6 alkenyl, optionally substituted _C2 - _C6 heteroalkenyl, hydroxy, thiol, or optionally substituted or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of formula B,

wherein each R ⁴ , R ⁴ ′, and R ⁷ is independently H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ hetero alkyl and R ⁵ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl , optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl, wherein R ⁶ is H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₆ - _{C10 aryl ,} optionally substituted _C1 - _C6 alkylC3- _C10 carbocyclyl, or optionally substituted _C1 - _C6 alkylC6- _C10 aryl, and n is 0, 1, 2, 3, or 4, and each R ⁸ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - _C6 heteroalkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally C ₂ -C ₉ heteroaryl substituted with , optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino wherein each R ⁹ and R ¹⁰ is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₆ -C ₁₀ is aryl and R ^4' or R ⁵ includes a bond to a linker, or is a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula C,

wherein each R ¹¹ , R ¹³ and R ¹⁵ is independently H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl and R ¹² is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl, wherein R ¹⁴ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl, p is 0, 1, 2, 3, or 4, each R ¹⁶ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl , optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino, wherein q is 0, 1, 2, 3, or 4 and each R ¹⁷ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ hetero aryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino; are legally acceptable salts.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula D,

wherein each R ¹⁸ and R ¹⁹ is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl and r1 is 0, 1, 2, 3, or 4, and each R ²⁰ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally optionally substituted amino, r2 is 0, 1, 2, 3, or 4, and each R ²¹ is independently halogen, optionally substituted C ₁ -C ₆ alkyl , optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ hetero alkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the linker has the structure of Formula V,
A ¹ -(B ¹ ) _f -(C ¹ ) _g -(B ² ) _h -(D)-(B ³ ) _i -(C ² ) _j -(B ⁴ ) _k -A ²
Formula V
wherein A ¹ is the bond between the linker and A, A ² is the bond between B and the linker, and B ¹ , B ² , B ³ and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, optionally substituted C ₁ -C ₃ heteroalkyl, O, S, S(O) ₂ , and NR ^{N ;} is hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _2-6 heterocyclyl, optionally substituted C _6-12 aryl, or optionally substituted C _1-7 heteroalkyl, wherein C ¹ and C ² are each independently carbonyl, f, g, h, i, j, and k are each independently 0 or 1 and D is optionally substituted C _1-10 selected from thiocarbonyl, sulfonyl, or phosphoryl alkyl, optionally substituted C _2-10 alkenyl, optionally substituted C _2-10 alkynyl, optionally substituted C _2-6 heterocyclyl, optionally substituted C _{6 -12} aryl, optionally substituted C ₂ -C ₁₀ polyethylene glycol, or optionally substituted C _1-10 heteroalkyl, or A ¹ -(B ¹ ) _f -(C ¹ ) _g -(B ² ) _h with -(B ³ ) _i -(C ² ) _j -(B ⁴ ) _k -A ² .

In some embodiments, D is optionally substituted C ₂ -C ₁₀ polyethylene glycol. In some embodiments, C ¹ and C ² are each independently carbonyl or sulfonyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, optionally substituted C ₁ - selected from C ₃ heteroalkyl, O, S, S(O) ₂ and NR ^N , where ^RN is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, or optionally substituted C _{1 —C3} heteroalkyl. In some embodiments, j is 0. In some embodiments, k is 0. In some embodiments, j and k are each independently zero. In some embodiments, f, g, h, and i are each independently 1.

In some embodiments, the linker of Formula VII has the structure of Formula VIIa,

where A ¹ is the bond between the linker and A and A ² is the bond between B and the linker.

In some embodiments, D is an optionally substituted C _1-10 alkyl. In some embodiments, C ¹ and C ² are each independently carbonyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, optionally substituted C ₁ - selected from C ₃ heteroalkyl, O, S, S(O) ₂ and NR ^N , where ^RN is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, O, S, S(O) ₂ , and NR ^N , where ^RN is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ¹ and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl. In some embodiments, B ¹ and B ⁴ are each independently C ₁ alkyl. In some embodiments, B ² and B ⁴ are each independently NR ^N and R ^N is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ² and B ⁴ are each independently NH. In some embodiments, f, g, h, i, j, and k are each independently 1.

In some embodiments, the linker of Formula VII has the structure of Formula VIIb,

where A ¹ is the bond between the linker and A and A ² is the bond between B and the linker.

Chemical Terminology In any of the chemical definitions below, the number following the atomic symbol indicates the total number of atoms of that element present in the particular chemical moiety. It will be appreciated that other atoms, such as hydrogen atoms, or substituent groups as described herein, may be present, if necessary, to satisfy the valences of the atoms. For example, an unsubstituted _C2 alkyl group has _the formula _-CH2CH3 . When used with groups defined herein, references to the number of carbon atoms include divalent carbons in acetal and ketal groups, but include carbonyl carbons in acyl, ester, carbonate, or carbamate groups. do not have. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group includes only those atoms that form part of the heterocyclic ring.

The term "acyl," as used herein, represents a hydrogen or alkyl group, as defined herein, attached to the parent molecular group through a carbonyl group, formyl (i.e., carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1-6, 1-11, or 1-21 carbons.

As used herein, the term "alkyl" refers to 1 to 20 carbon atoms, such as 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. ) refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical.

Alkylene is a divalent alkyl group. As used herein, the term “alkenyl,” alone or in combination with other groups, has a carbon-carbon double bond and has 2-20 carbon atoms (eg, 2-16 carbon atoms, 2-10 carbon atoms, 2-6, or 2 carbon atoms).

As used herein, the term “alkynyl,” alone or in combination with other groups, has a carbon-carbon triple bond and has 2-20 carbon atoms (eg, 2-16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

As used herein, the term “amino” represents —N(R ^N1 ) ₂ , where each R ^N1 is independently H, OH, NO ₂ , N(R ^N2 ) ₂ , SO ₂ OR ^N2 , SO ₂ R ^N2 , SOR ^N2 , N-protecting groups, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (eg, acetyl, trifluoroacetyl, or others described herein). ) and each of these indicated R ^N1 groups may be optionally substituted, or two R ^N1 together form an alkylene or heteroalkylene and each R ^N2 independently is H, alkyl, or aryl. The amino group of the compounds described herein can be unsubstituted amino (ie —NH ₂ ) or substituted amino (ie —N(R ^N1 ) ₂ ).

As used herein, the term "aryl" refers to an aromatic mono- or polycarbocyclic radical of 6-12 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 1H-indenyl.

As used herein, the term "arylalkyl" represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups have 7 to 30 carbons (eg, C ₁ -C ₆ alkyl C ₆ -C ₁₀ aryl, C ₁ -C ₁₀ alkyl C ₆ -C ₁₀ aryl, such as benzyl and phenethyl). , or 7-16 or 7-20 carbons, such as C ₁ -C ₂₀ alkyl C ₆ -C ₁₀ aryl). In some embodiments, each alkyl and aryl can be further substituted with 1, 2, 3, or 4 substituent groups, as defined herein for each group.

As used herein, the term "azido" represents a _-N3 group.

As used herein, the term "bridged cyclyl" refers to a bridged polycyclic group of 5-20 carbons containing 1-3 bridges.

As used herein, the term "cyano" represents a -CN group.

As used herein, the term “carbocyclyl” refers to a non-aromatic C ₃ -C ₁₂ monocyclic, bicyclic or tricyclic structure in which the ring is formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.

As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monovalent monocarbocyclic 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.

As used herein, the term "halogen" means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

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

As used herein, the term "heteroaryl" includes at least 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. It refers to an aromatic monocyclic or polycyclic radical of 5-12 atoms having one aromatic ring. One or two ring carbon atoms of a heteroaryl group can be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl and thiazolyl.

As used herein, the term "heteroarylalkyl" represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups have 7 to 30 carbons (eg, C ₁ -C ₆ alkyl C ₂ -C ₉ heteroaryl, C ₁ -C ₁₀ alkyl C ₂ -C ₉ heteroaryl, or C 7-16 or 7-20 carbons, such as ₁ -C ₂₀ alkyl C ₂ -C ₉ heteroaryl. In some embodiments, each alkyl and heteroaryl can be further substituted with 1, 2, 3, or 4 substituent groups, as defined herein for each group.

As used herein, the term “heterocyclyl” refers to a 3-12 ring having at least one ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S. refers to a monocyclic or polycyclic radical having atoms of and the rings are not aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.

As used herein, the term "heterocyclylalkyl" represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups have from 7 to 30 carbons (eg, C ₁ -C ₆ alkyl C ₂ -C ₉ heterocyclyl, C ₁ -C ₁₀ alkyl C ₂ -C ₉ heterocyclyl, or C ₁ -C 7-16 or 7-20 carbons, such as ₂₀ alkyl C ₂ -C ₉ heterocyclyl). In some embodiments, each alkyl and heterocyclyl can be further substituted with 1, 2, 3, or 4 substituent groups, as defined herein for each group.

As used herein, the term "hydroxyalkyl" represents an alkyl group substituted with an --OH group.

As used herein, the term "hydroxyl" represents a -OH group.

The term "N-protecting group," as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999). N-protecting groups include, but are not limited to, formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, chiral auxiliaries such as α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and 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; benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- Nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro -4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl 3,5-dimethoxybenzyloxycarbonyl , benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl , fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and trimethylsilyl. A silyl group can be mentioned. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein, the term "nitro" represents a _-NO2 group.

As used herein, the term "thiol" represents a -SH group.

Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (eg, cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. When substituted, there are generally 1-4 substituents present unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted; substituents include any group described herein, e.g., aryl, halo, hydroxyl), aryl (e.g., substituted and unsubstituted phenyl ), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., _NH2 or mono- or dialkylamino), azide, cyano, nitro, or thiol. Aryl, carbocyclyl (eg, cycloalkyl), heteroaryl, and heterocyclyl groups can also be substituted with alkyl (unsubstituted and substituted, such as arylalkyl (eg, substituted and unsubstituted benzyl)).

The compounds described herein can have one or more asymmetric carbon atoms, optically pure enantiomers, e.g. mixtures of enantiomers such as racemates, optically pure diastereomers, It can be present in the form of a mixture of diastereomers, a diastereomeric racemate, or a mixture of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, by asymmetric synthesis or by asymmetric chromatography (chromatography using chiral adsorbents or eluents). Thus, certain disclosed compounds can exist in different 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 functions 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 most commonly related as mirror images because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. It is a stereoisomer that does not Enantiomers of a compound can be prepared, for example, by separating the enantiomers from the racemate using one or more well-known techniques and methods, such as chiral chromatography and separation methods based thereon. Suitable techniques and/or methods for separating the enantiomers of the compounds described herein from their racemic mixtures can be readily determined by those skilled in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, such mixtures exhibit no optical activity, ie they do not rotate the plane of polarized light. "Geometric isomer" means isomers that differ in the orientation of substituent atoms with respect to a carbon-carbon double bond, cycloalkyl ring, or bridged bicyclic system. The atoms on each side of the carbon-carbon double bond (other than H) are in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. in placement. "R", "S", "S*", "R*", "E", "Z", "cis" and "trans" indicate the configuration relative to the core molecule. Certain disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about a single bond in which the steric strain barrier to rotation is sufficiently high to allow isolation of conformers. Compounds described herein may be prepared as individual isomers by isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include salt formation of the free base of each isomer of the isomer pair using an optically active acid (followed by fractional crystallization and regeneration of the free base); Forming a salt of the acid form of each isomer of the isomer pair using an amine that is active in isomeric pairs (followed by fractional crystallization and regeneration of the free acid), optically pure acids, amines, or Forming the respective esters or amides 35 of the isomers of the isomeric pair using an alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or starting using various well-known chromatographic methods. It involves resolving isomeric mixtures of either substances or final products. Where the stereochemistry of a disclosed compound is named or indicated by structure, the named or indicated stereoisomer is at least 60%, 70%, 80% by weight relative to the other stereoisomer. , 90% by weight, 99% by weight, or 99.9% by weight. Where a single enantiomer is named or named by structure, the named or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Wt % optically pure. Where a single diastereomer is named or named by structure, the named or named diastereomer is at least 60%, 70%, 80%, 90%, 99% by weight, or 99.9% pure by weight. Percent optical purity is the weight of an enantiomer, or the ratio of the weight of an enantiomer to the weight of its optical isomer. Diastereomeric purity by weight is the ratio to the weight of one diastereomer or the weight of all diastereomers. Where the stereochemistry of a disclosed compound is named or indicated by structure, the named or indicated stereoisomer is at least a 60%, 70%, 80% molar fraction relative to the other stereoisomer. %, 90%, 99%, or 99.9% pure. Where a single enantiomer is named or named by structure, the named or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% in mole fraction. Pure. Where a single diastereomer is named or named by structure, the named or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure. Percent purity by mole fraction is the ratio of moles of an enantiomer or moles of an enantiomer and its optical isomer to moles. Similarly, percent purity by mole fraction is the ratio of moles of diastereomers or moles of a diastereomer and its isomers to moles. When a disclosed compound is named or depicted by structure without indicating stereochemistry and the compound has at least one chiral center, the name or structure refers to the enantiomers of the compound without the corresponding optical isomers, the racemic mixture of the compound. , mixtures of compounds, or mixtures enriched in one enantiomer with respect to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and has two or more chiral centers, the name or structure refers to the diastereomer, excluding other diastereomers. Some diastereomers containing no mer pairs, mixtures of diastereomers, mixtures of diastereomer pairs, diastereomers enriched in one diastereomer with respect to the other diastereomer(s) or mixtures of diastereomers enriched in one or more diastereomers relative to other diastereomers. The present invention encompasses all of these forms.

Unless defined otherwise, 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 for use in the present disclosure are described herein. Other suitable methods and materials known in the art may 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.

DEFINITIONS In this application, unless the context clearly indicates otherwise, (i) the term "a" may be understood to mean "at least one" and (ii) the term "or" means "and/or and (iii) the terms "including" and "including" may be expressed by themselves or together with one or more additional components or steps. It may be understood to include itemized components or steps regardless of whether they are included.

As used herein, the terms "about" and "approximately" refer to values within 10% above and below the stated value. For example, the term "about 5 nM" indicates a range of 4.5-5.5 nM.

As used herein, the term "administration" refers to administration of a composition (eg, a compound or formulation comprising a compound as described herein) to a subject or system. Administration to animal subjects (eg, humans) can be by any suitable route. For example, in some embodiments, administration is bronchial (including by bronchial instillation), buccal, enteral, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intracerebroventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal , vagina, and vitreous.

As used herein, the term "BAF complex" refers to the BRG1 or HBRM-associated factor complex in human cells.

As used herein, the term "BRG1 loss-of-function mutation" refers to a reduction in activity (e.g., at least 1% reduction in BRG1 activity, e.g., 2%, 5%, 10%, 25% reduction in BRG1 activity). %, 50%, or 100% reduction) in BRG1. Exemplary BRG1 loss-of-function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

As used herein, the term "BRG1 loss-of-function disorder" refers to a reduction in BRG1 activity (e.g., a reduction in BRG1 activity of at least 1%, e.g., 2%, 5%, 10% of BRG1 activity, refers to a disorder (eg, cancer) that exhibits a 25%, 50%, or 100% reduction).

As used herein, the term "loss-of-function mutation of BRM" refers to a reduction in activity (e.g., a reduction in BRM activity of at least 1%, e.g., 2%, 5%, 10%, 25% of BRM activity, %, 50%, or 100% reduction) in the BRM. Exemplary BRM loss-of-function mutations include, but are not limited to, homozygous BRM mutations and deletions at the C-terminus of the BRM.

As used herein, the term "BRM loss-of-function disorder" refers to a reduction in BRM activity (e.g., a reduction in BRM activity of at least 1%, e.g., BRG1 activity of 2%, 5%, 10%, refers to a disorder (eg, cancer) that exhibits a 25%, 50%, or 100% reduction).

The terms "GBAF complex" and "GBAF" as used herein refer to the SWI/SNF ATPase chromatin remodeling complex in human cells. GBAF complex subunits include, but are not limited to, ACTB, ACTL6A, ACTL6B, BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2, SMARCD3, and SS18.

The term "cancer" refers to conditions caused by the growth of malignant cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

As used herein, "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are combined in one defined treatment regimen for a particular disease or condition. It is meant to be administered to a subject as a portion. A therapeutic regimen defines the dose and periodicity of administration of each agent such that the effects of the separate agents overlap on the subject. In some embodiments, delivery of two or more agents is simultaneous or concomitant, and the agents may be co-formulated. In some embodiments, two or more agents are not co-formulated and are administered in a sequential fashion as part of a prescribed regimen. In some embodiments, administration of two or more agents or combined treatments results in a reduction in symptoms, or other parameters associated with the disorder, either alone or in the absence of one agent or agent delivered. Such that it is greater than that observed with treatment. The effect of the two treatments can be partially additive, fully additive, or more than additive (eg, synergistic). Sequential or substantially simultaneous administration of each therapeutic agent may be effected by any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissue. obtain. 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.

As used herein, the term "BRG1" refers to the ATP-dependent chromatin remodeler SMARCA4. BRG1 is a component of the BAF complex, the SWI/SNF ATPase chromatin remodeling complex. Human BRG1 is encoded by the SMARCA4 gene on chromosome 19 and its nucleic acid sequence is shown in SEQ ID NO:1. (GenBank accession number: NM_001128849.1 (mRNA); www.ncbi.nlm.nih.gov/nuccore/NM_001128849.1?report=fasta)
GGCGGGGGAGGCGCCGGGAAGTCGACGGCGCCGGCGGCTCCTGCAGGAGGCCACTGTCTGCAGCTCCCGT
GAAGATGTCCACTCCAGACCCACCCCTGGGCGGAACTCCTCGGCCAGGTCCTTCCCCGGGCCCTGGCCCT
TCCCCTGGAGCCATGCTGGGCCCTAGGCCCCGGGTCCCTCGCCGGGCTCCGCCCACAGCATGATGGGGGCCCA
GCCCAGGGCCGCCCTCAGCAGGACACCCCATCCCCACCCAGGGGCCTGGAGGGTACCCTCAGGACAACAT
GCACCAGATGCACAAGCCCATGGAGTCCATGCATGAGAAGGGCATGTCGGACGACCCGCGCTACAACCAG
ATGAAAGGAATGGGGATGCGGTCAGGGGGCCATGCTGGGATGGGGCCCCCGCCCAGCCCCATGGACCAGC
ACTCCCAAGGTTACCCCCTCGCCCCTGGGTGGCTCTGAGCATGCCTCTAGGTCCAGTTCCAGCCAGTGGCCC
GTCTTCGGGGCCCCAGATGTCTTCCGGGCCAGGAGGTGCCCCGCTGGATGGTGCTGACCCCCAGGCCTTG
GGGCAGCAGAACCGGGGCCCAACCCCATTTAACCAGAACCAGCTGCACCAGCTCAGAGCTCAGATCATGG
CCTACAAGATGCTGGCCAGGGGGCAGCCCCTCCCCCGACCACCTGCAGATGGCGGTGGCAGGGCAAGCGGCC
GATGCCCGGGGATGCAGCAGCAGATGCCAACGCTACCTCCACCCTCGGTGTCCGCAACAGGACCCGGGCCCT
GGCCCTGGCCCTGGCCCCGGCCCGGGTCCCGGCCCCGGCACCTCAAATTACAGCAGGCCTCATGGTATGG
GAGGGCCCAACATGCCTCCCCCAGGACCCTCGGGCGTGCCCCCCGGGATGCCAGGCCCAGCCTCCTGGAGG
GCCTCCCAAGCCCTGGCCTGAAGGACCCATGGCGAATGCTGCTGCCCCCACGAGCACCCCTCAGAAGCTG
ATTCCCCCGCAGCCAACGGGCCGCCCTTCCCCCGCGCCCCCTGCCGTCCCCACCCGCCGCTCGCCCGTGA
TGCCACCGCAGACCCAGTCCCCCGGGCAGCCGGCCCAGCCCGCGCCCATGGTGCCACTGCACCAGAAGCA
GAGCCGCATCACCCCCATCCAGAAGCCGCGGGGCCTCGACCCTGTGGGAGATCCTGCAGGAGCGCGAGTAC
AGGCTGCAGGCTCGCATCGCACACCGAATTCAGGAACTTGAAAACCTTCCCGGGTCCCTGGCCGGGGATT
TGCGAACCAAAGCGACCATTGAGCCTCAAGGCCCTCAGGCTGCTGAACTTCCAGAGGCAGCTGCGCCAGGA
GGTGGTGGTGTGCATGCGGAGGGACACAGCGCTGGAGACAGCCCTCAATGCTAAGGCCTACAAGCGCAGC
AAGCGCCAGTCCCTGCGCGAGGCCCCGCATCACTGAGAAGCTGGAGAAGCAGCAGAAGATCGAGCAGGAGC
GCAAGCGCCGGCAGAAGCACCAGGAATACCTCAATAGCATTCTCCAGCATGCCAAGGATTTCAAGGAATA
TCACAGATCCGTCACAGGCAAATCCAGAAGCTGACCAAGGCAGTGGCCACGTACCATGCCAACACGGAG
CGGGAGCAGAAGAAAGAGAACGAGCGGATCGGAGAAGGAGCGCATGCGGAGGCTCCATGGCTGAAGATGAGG
AGGGGTACCGCAAGCTCCATCGACCAGAAGAAGGACAAGCGCCTGGCCTACCTCTTGCAGCAGACAGACGA
GTACGTGGCTAACCTCACGGAGCTGGTGCGGCAGCACAAGGCTGCCCAGGTCGCCAAGGAGAAAAGAAG
AAAAAAGAAAAGAAGAAGGCAGAAAATGCAGAAGGACAGACGCCTGCCATTGGGCCGGATGGCGAGCCTC
TGGACGAGACCAGCCAGATGAGCGACCTCCCGGTGGAAGGTGATCCACGTGGAGAGTGGGAAGATCCTCAC
AGGCACAGATGCCCCCAAAGCCCGGGCAGCTGGAGGCCTGGCTCGAGATGAACCCGGGGTATGAAGTAGCT
CCGAGGTCTGATAGTGAAGAAAGTGGCTCAGAAGAAGAGGAAGAGGAGGAGGAGGAAGAGCAGCCGCAGGG
CAGCACAGCCTCCCCCACCCTGCCCGTGGAGGAGAAGAAGAAGATTCCAGATCCAGACAGCGATGACGTCTC
TGAGGTGGACGCGCGGCACATCATTGAGAATGCCAAGCAAGATGTCGATGATGAATATGGCGTGTCCCAG
GCCCTTGCACGTGGCCTGCAGTCCTACTATGCCGTGGCCCATGCTGTCACTGAGAGAGTGGACAAGCAGT
CAGCGCTTATGGTCAATGGTGTCCTCAAACAGTACCAGATCAAAGGTTTGGAGTGGCTGGTGTCCCCTGTA
CAACAACAACCTGAACGGCATCCTGGCCGACGAGATGGGCCCTGGGGAAGACCATCCAGACCATCGCGCTC
ATCACGTACCTCATGGAGCACAAACGCATCAATGGGCCCTTCCTCCATCATCGTGCCTCTCTCCAACGCTGT
CCAACTGGGCGTACGAGTTTGACAAGTGGGCCCCCTCCGTGGTGAAGGTGTCTTACAAGGGATCCCCCAGC
AGCAAGACGGGCCTTTGTCCCCCAGCTCCGGAGTGGGAAGTTCAACGTCTTTGCTGACGACGTACGAGTAC
ATCATCAAAGACAAGCACATCCTCGCCAAGATCCGTTGGAAGTACATGATTGTGGACGAAGGTCACCGCCA
TGAAGAACCACCACTGCAAGCTGACGCAGGTGCTCAACACGCACTATGTGGCACCCCGCCGCCTGCTGCT
GACGGGCACACCGCTGCAGAACAAGCTTCCCGAGCTCTGGGGCGCTGCTCCAACTTCCTGCTGCCCACCATC
TTCAAGAGCTGCAGCACCTTCGAGCAGTGGTTTAACGCACCCTTTGCCATGACCGGGGAAAGGTGGGACC
TGAATGAGGAGGAAACCATTCTCATCATCCGGCGTCTCTCCAAAAGTGCTGCGGCCCTTCTTGCTCCGACG
ACTCAAGAAGGAAGTCGAGGCCCAGTTGCCCCGAAAAGGTGGAGTACGTCATCAAGTGCGGACATGTCTGCG
CTGCAGCGAGTGCTCTACCGCCACATGCAGGCCAAGGGCGTGCTGCTGACTGATGGCTCCGAGAAGGACA
AGAAGGGCAAAGGCGGCACCAAGACCCTGATGAACACCCATCATGCAGCTGCGGAAGATCTGCAACCACCC
CTACATGTTCCAGCCACATCGAGGAGTCCTTTTCCGAGCACTTGGGGTTCACTGGCGGCATTGTCCAAGGG
CTGGACCTGTACCGAGCCTTCGGGTAAATTTGAGCTTCTTGATAGAATTCTTCCCAAAACTCCGAGCAACCA
ACCACAAAGTGCTGCTGTTCTGCCAAATGACCTCCCTCCATGACCATCATGGAAGAATTACTTTGCGTATCG
CGGCTTAAATACCTCAGGCTTGATGGAACCACGAAGGCGGAGGACCGGGGCATGCTGCTGAAAAACCTTC
AACGAGCCCGGGCTCTGAGTACTTCATCTTCCTGCTCAGCACCCGGGCTGGGGGGCTCCGGCCTGAACCTCC
AGTCGGCAGACACTGTGATCATTTTTGACAGCGACTGGAATCCCACCAGGACCTGCAAGCGCAGGACCG
AGCCCACCGCATCGGGCAGCAGAACGAGGTGCGTGTGCTCCGCCTCTGCACCGTCAACAGCGTGGAGGAG
AAGATCCTAGCTGCAGCCAAGTACAAGCTCAACGTGGACCAGAAGGTGATCCAGGCCGGCATGTTCGACC
AGAAGTCCTCCAGCCATGAGCGGCGCGCCTTCCTGCAGGGCCATCCTGGAGCACGAGGAGCAGGATGAGAG
CAGACACTGCAGCACGGGCAGCGGCAGTGCCAGCTTCGCCCACACTGCCCCTCCGCCAGCGGGCGTCAAC
CCCGACTTGGAGGAGCCACCTCTAAAGGAGGAAGACGAGGTGCCCCGACGACGAGACCGTCAACCAGATGA
TCGCCCCGGCACGAGGAGGAGTTTGATCTGTTCATGCGCATGGACCTGGACCGCAGGCGCGAGGAGGCCCCG
CAACCCCCAAGCGGAAGCCGCGCCTCATGGAGGAGGACGAGCTCCCTCGTGGATCATCAAGGACGACGCCG
GAGGTGGAGCGGCTGACCTGTGAGGAGGAGGAGGGAGAAGATGTTCGGCCGTGGCTCCCGCCACCGCAAGG
AGGTGGACTACAGCGACTCACTGACGGAGAAGCAGTGGCTCAAGAAAATTACAGGAAAAGATATCCATGA
CACAGCCAGCAGTGTGGCACGTGGGCTACAATTCCAGCGTGGCCTTCAGTTCTGCACACGTGCGTCAAG
GCCATCGAGGAGGGCACGCTGGAGGAGATCGAAGAGGAGGTCCGGCAGAAGAAATCATCACGGAAGCGCA
AGCGAGACAGCGACGCCGGCTCCTCCCACCCCGACCACCAGCACCGCGCAGCCGCGACAAGGACGACGAGAG
CAAGAAGCAGAAGAAGCGCGGGCGGCCGCCTGCCGAGAAACTCTCCCCTAACCCACCCAACCTCACCAAG
AAGATGAAGAAGATTGTGGATGCCGTGATCAAGTACAAGGACAGCAGCAGTGGACGTCAGCTCAGCGAGGG
TCTTCATCCAGCTGCCCTCGCGAAAGGAGCTGCCCGAGTACTACGAGCTCCATCCGCAAGCCCGTGGACTT
CAAGAAGATAAAGGAGCGCATTCGCCAACCACAAGTACGCGCAGCCTCAACGACCTAGAGAAGGACGTCATG
CTCCTGTGCCAGAACGCACAGACCTTCAACCTGGAGGGCTCCCTGATCTATGAAGACTCCATCGTCTTGC
AGTCGGTCTTCACCAGCGTGCGGCAGAAATCGAGAAGGAGGATGACAGTGAAGGCGAGGGAGAGTGAGGA
GGAGGAAGAGGGCGCGGAGGAAGGCTCCGAATCCGAATCTCGGTCCGTCAAAGTGAAGATCAAGCTTGGC
CGGAAGGAGAAGGCACAGGACCGGCTGAAGGGCGGCCGGCGGCGGCCGAGCCGAGGTCCCGAGCCAAGC
CGGTCGTGAGTGACGATGACAGTGAGGAGGAACAAGAGGAGGACCGCTCAGGAAGTGGCAGCGAAGAAGA
CTGAGCCCCGACATTCCAGTCTCGACCCCGAGCCCCTCGTTCCAGAGCTGAGATGGCCATAGGCCTTAGCA
GTAACGGGTAGCAGCAGATGTAGTTTCAGACTTGGAGTAAAACTGTATAAAACAAAAGAATCTTCCATATT
TATACAGCAGAGAAGCTGTAGGACTGTTTGTGACTGGCCCTGTCCCTGGCATCAGTAGCATCTGTAACAGC
ATTAACTGTCTTAAAGAGAGAGAGAGAGAATTCCGAATTGGGGAACACACGATACCTGTTTTTCTTTTTCC
GTTGCTGGCAGTACTGTTGCGCCGCAGTTTGGAGTCACTGTAGTTAAGTGTGGATGCATGTGCGTCACCG
TCCACTCCTCCTACTGTATTTTATTGGACAGGTCAGACTCGCCGGGGGCCCGGCGGAGGGTATGTCAGTGT
CACTGGATGTCAAACAGTAAAATTAAAACCAACAACAAAACGCACAGCCAAAAAAAAA

The term "BRG1" also includes at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%, 85%, 86%, 87%, 88%, 89%, 90% %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) of the wild-type BRG1 protein. (UniProt accession number: P51532; www.uniprot.org/uniprot/P51532.fasta).
SEQ ID NO:2.
MSTPDPPLGGTPRPGPSPGPGPSPGAMLGPSPGPSPGSAHSMMGPSPGPPSAGHPIPTQG
PGGYPQDNMHQMHKPMESMHEKGMSDDPRYNQMKGMGMRSGGHAGMGPPPPSMDQHSQGY
PSPLGGSEHASSSPVPASGPSSGPQMSSGPGGAPLDGADPQALGQQNRGPTPFNQNQLHQL
RAQIMAYKMLARGQPLPDHLQMAVQGKRPMPGMQQMPTLPPPSVSATGPGPGPGPGPGP
GPGPAPPNYSRPHGMGGPNMPPPGPSGVPPGMPGQPPGGPPKPWPEGPMANAAAPTSTPQ
KLIPPQPTGRSPAPPAVPPAASPVMPPQTQSPGQPAQPAPMVPLHQKQSRITPIQKPRG
LDPVEILQEREYRLQARIAHRIQELENLPGSLAGDLRTKATIELKALRLLNFQRQLRQEV
VVCMRRDTALETALNAKAYKRSKRQSLREARITEKLEKQQKIEQERKRRQKHQEYLNSIL
QHAKDFKEYHRSVTGKIQKLTKAVATYHANTEREQKKENERIEKERMRRLMAEDEEGYRK
LIDQKKDKRLAYLLQQTDEYVANLTELVRQHKAAQVAKEKKKKKKKKKAENAEGQTPAIG
PDGEPLDETSQMSDLPVKVIHVESGKILTGTDAPKAGQLEAWLEMNPGYEVAPRSDSEES
GSEEEEEEEEEEEQPQAAQPPTLPVEEKKKIPPDPDSDDDVSEVDARHIIENAKQDVDDEYGV
SQALARGLQSYYAVAHAVTERVDKQSALMVNGVLKQYQIKGLEWLVSLYNNNLNGILADE
MGLGKTIQTIALITYLMEHKRINGPFLIIVPLSTTLSNWAYEFDKWAPSVVKVSYKGSPAA
RRAFVPQLRSGKFNVLLTTYEYIIKDKHILAKIRWKYMIVDEGHRMKNHHCKLTQVLNTH
YVAPRRLLTGTPLQNKLPELWALLNFLLPTIFKSCSTFEQWFNAPFAMTGEKVDLNEEE
TILIIRRLHKVLRPFLLRRLKKEVEAQLPEKVEYVIKCDMSALQRVLYRHMQAKGVLLTD
GSEKDKKGKGGTKTLMNTIMQLRKICNHPYMFQHIEESFSEHLGFTGGIVQGLDLYRASG
KFELLDRILPKLRATNHKVLLFCQMTSLMTIMEDYFAYRGFKYLRLDGTTKAEDRGMLLK
TFNEPGSEYFIFLLSTRAGGLGLNLQSADTVIFDSDWNPHQDLQAQDRAHRIGQQNEVR
VLRLCTVNSVEEKILAAAKYKLNVDQKVIQAGMFDQKSSSHERRAFLQAILEHEEQDESR
HCSTGSGSASFAHTAPPPAGVNPDLEEPPLKEEDEVPDDETVNQMIARHEEEFDLFMRMD
LDRRREEARNPKRKPRLMEEDELPSWIIKDDAEVERLTCEEEEEEKMFGRGSRHRKEVDYS
DSLTEKQWLKAIEEGTLEEIEEEVRQKKSSRKRKRDSDAGSSTPTTTSTRSRDKDDESKKQ
KKRGRPPAEKLSPNPPNLTKKMKKIVDAVIKYKDSSSGRQLSEVFIQLPSRKELPEYYEL
IRKPVDFKKIKERIRNHKYRSLNDLEKDVMLLCQNAQTFNLEGSLIYEDSIVLQSVFTSV
RQKIEKEDDSEGEEEEEEEGEEEGSESESRSVKVKIKLGRKEKAQDRLKGGRRRPSRGS
RAKPVVSDDDSEEEQEEDRSGSGSEED

As used herein, the term "BRM" refers to the likely global transcriptional activator SNF2L2. BRM is a component of the BAF complex, the SWI/SNF ATPase chromatin remodeling complex. Human BRM is encoded by the SMARCA2 gene on chromosome 9 and its nucleic acid sequence is shown in SEQ ID NO:3. (GenBank accession number: NM_003070.4 www.ncbi.nlm.nih.gov/nuccore/NM_003070.4?report=fasta)
SEQ ID NO:3.
GCGTCTTCCGGCGCCCCGCGGAGGAGGCGAGGGTGGGACGCTGGGCGGAGCCCGAGTTTAGGAAGAGGAGG
GGACGGCTGTCATCAATGAAGTCATATTCATAATCTAGTCCTCTCTCCCTCTGTTTCTGTACTCTGGGTG
ACTCAGAGAGGGAAGAGATTCAGCCAGCACACTCCTCGCGAGCAAGCATTACTCTACTGACTGGCAGAGA
CAGGAGAGGTAGATGTCCACGCCCACAGACCCTGGTGCGATGCCCCACCCAGGGGCCTTCGCCGGGGCCTG
GGCCTTCCCCTGGGCCAATTCTTGGGCCTAGTCCAGGACCAGGACCATCCCCAGGTTCCGTCCACAGCAT
GATGGGGCCAAGTCCTGGACCTCCAAGTGTCTCCCATCCTATGCCGACGATGGGGTCCACAGACTTCCCA
CAGGAAGGCATGCATCAAATGCATAAGCCCCATCGATGGTATACATGACAAGGGGATTGTAGAAGACATCC
ATTGTGGATCCATGAAGGGCACTGGTATGCGACCACCTCACCCAGGCATGGGCCCTCCCCAGAGTCCAAT
GGATCAACACAGCCAAGGTTATATGTCACCACACCCATCTCCATTAGGAGCCCCAGAGCACGTTCCCAGC
CCTATGTCTGGAGGAGGCCCAACTCCACCTCAGATGCCACCAAGCCAGCCGGGGCCCCTCCATCCCAGGTG
ATCCGCAGGCCATGAGCCAGCCCAACAGAGGTCCCTCACCTTTTCAGTCCTGTCCAGCTGCATCAGCTTCG
AGCTCAGATTTTAGCTTATAAAATGCTGGCCCGAGGCCAGCCCCTCCCCGAAAACGCTGCAGCTTGCAGTC
CAGGGGAAAGGACGTTGCCTGGCTTGCAGCAACAACAGCAGCAGCAACAGCAGCAGCAGCAGCAGCAGC
AGCAGCAGCAGCAGCAGCAACAGCAGCCGCAGCAGCAGCCGCCGCAACCACAGACGCAGCAACAACAGCA
GCCGGCCCTTGTTAACTACAACAGACCATCTGGCCCGGGGCCGGAGCTGAGCGGCCCGAGCACCCCGCAG
AAGCTGCCGGTGCCCCGCGCCCCGGCGGCCGGCCCCTCGCCCGCGCCCCCCCGCAGCCGCGCAGCCGCCCGCGG
CCGCAGTGCCCCGGGCCCTCAGTGCCGCAGCCGGCCCCGGGGCAGCCCTCGCCCGTCCTCCAGCTGCAGCA
GAAGCAGAGCCGCATCAGCCCCATCCAGAAACCGCAAGGCCTGGACCCCGTGGAAATTCTGCAAGAGCGG
GAATACAGACTTCAGGCCCGCTAGCTCATAGGATACAAGAACTGGAAATCTGCCTGGCTCTTTGCCAC
CAGATTTAAGAACCAAAGCCAACCGTGGAACTAAAAGCACTTCGGTTACTCAATTTCCAGCGTCAGCTGAG
ACAGGAGGTGGTGGCCTGCATGCGCAGGGACACGACCCTGGAGACGGCTCTCAACTCCAAAGCATACAAA
CGGAGCAAGCGCCAGACTCTGAGAGAAGCTCGCATGACCGAGAAGCTGGAGAAGCAGCAGCAGAAGATTGAGC
AGGAGAGGAAACGCCGTCAGAAACACCAGGAATACCTGAACAGTATTTTGCAACATGCAAAAGATTTTAA
GGAATATCATCGGTCTGTGGCCGGAAAGATCCAGAAGCTCTCAAAGCAGTGGCCAACTTGGCATGCCAAC
ACTGAAAGAGAGCAGAAGAAGGAGACAGAGCGGATTGAAAAGGGAGAGAATGCGGCGACTGATGGCTGAG
ATGAGGAGGGTTATAGAAAACTGATTGATCAAAGAAAGACAGGCGTTTAGCTTACCTTTTGCAGCAGAC
CGATGAGTATGTAGCCAATCTGACCAATCTGGTTTGGGAGCCAAGCAAGCCCCAGGCAGCCAAAGAGAGAG
AAGAAGAGGAGGAGGAGGAAGAAGAAGGCTGAGGAGAATGCAGAGGGTGGGGGGAGTCTGCCCTGGGACCGG
ATGGAGAGCCCATAGATGAGAGCAGCCAGATGAGTGACCTCCCTGTCAAAGTGACTCACACAGAAACCGG
CAAGGTTCTGTTCGGACCAGAAGCACCCAAAGCAAGTCAGCTGGACGCCTGGCTGGAAAATGAATCCTGGT
TATGAAGTTGCCCCTAGATCTGACAGTGAAGAGAGTGATTCTGATTATGAGGAAGAGGATGAGGAAGAAG
AGTCCAGTAGGCAGGAAACCGAAGAGAAAATACTCCTGGATCCAAAATAGCGAAGAAGTTTTCTGAGAAGGA
TGCTAAGCAGATCATTGAGACAGCTAAGCAAGACGTGGATGATGAATACAGCATGCAGTACAGTGCCAGG
GGCTCCCAGTCCTACTACACCGTGGCTCATGCCATCTCGGAGAGGGTGGAGAAAACAGTCTGCCCTCCTAA
TTAATGGGACCCTAAAGCATTACCAGCTCCAGGGCCTGGAATGGATGGTTTCCCTGTATAATAACAACTT
GAACGGAATCTTAGCCGATGAAATGGGGCTTGGAAAGACCATACAGACCATTGCACTCATCACTTATCTG
ATGGAGCACAAAAGACTCAATGGCCCCTATCTCCATCATTGTTCCCCTTTCGACTCTATCTAACTGGACAT
ATGAATTTGACAAATGGGCTCCTTCTGTGGTGAAGATTTCTTACAAGGGTACTCCTGCCATGCGTCGTCTC
CCTTGTCCCCCAGCTACGGAGTGGCAAATTCAATGTCCTCTTGACTACTTATGAGTATATTATAAAAGAC
AAGCACATTCTTGCAAAGATTCGGTGGAAACATATGATAGTGGACGAAGGCCACCGAATGAAGAATCACC
ACTGCAAGCTGACTCAGGTCTTGAACACTCACTATGTGGCCCCCAGAAGGATCCCTCTTGACTGGACCCC
GCTGCAGAATAAGCTCCCTGAACTCTGGGCCCTCCTCAACTTCCTCCTCCCCAACAATTTTTAAGAGCTGC
AGCACATTTGAACAATGGTTCAATGCTCCATTTGCCATGACTGGTGAAAGGGGTGGACTTAAAATGAAGAAG
AAAACTATATTGATCATCAGGCGTCTACATAAGGTGTTAAGACCATTTTTACTAAGGAGACTGAAGAAAGA
AGTTGAATCCCAGCTTCCGAAAAAGTGGAATATGTGATCAAGTGTGGACATGTCAGCTCTGCAGAAGATT
CTGTATCGCCATATGCAAGCCAAGGGGATCCTTCTCACAGATGGTTCTGAGAAAGATAAGAAGGGGGAAAG
GAGGTGCTAAGACACTTATGAACACTATTATGCAGTTGAGAAAATCTGCAACCACCCATATATGTTTCA
GCACATTGAGGAATCCTTTGCTGAACACCTAGGGCTATTCAAATGGGGTCATCAATGGGGCTGAACTGTAT
CGGGCCTCAGGGAAGTTTGAGCTGCTTTGATCGTATTCTGCCAAAATTGAGAGCGACTATCACCGAGTGC
TGCTTTTCTGCCAGATGACATCTCTCATGACCATCATGGAGGATTATTTTGCTTTTCGGAACTTCCTTTA
CCTACGCCTTGATGGCACCACCAAGTCTGAAGATCGTGCTGCTTTGCTGAAGAAAATTCAATGAACCTGGA
TCCCAGTATTTCATTTTTCTTGCTGAGCACAAGAGCTGGTGGCCTGGGGCTTAAATCTTCAGGCAGCTGATA
CAGTGGTCATCTTTGACAGCGACTGGAATCCTCATCAGGATCTGCAGGCCCAAGACCGAGCTCACCGCAT
CGGGCAGCAGAACGAGGTCCGGGTACTGAGGCTCTGTACCGTGAACAGCGTGGAGGAAAGATCCTCGCG
GCCGCAAAATACAAGCTGAACGTGGATCAGAAAGTGATCCAGGCGGGCATGTTTGACCAAAGTCTTCAA
GCCACGAGCGGAGGGCATTCCTGCAGGCCATCTTGGAGCATGAGGAGGAAAATGAGGAAGAAGATGAAGT
ACCGGACGATGAGACTCTGAACCAAATGATTGCTCGACGAGAAGAAGAATTTGACCTTTTTATGCGGATG
GACATGGACCGGCGGAGGGAAGATGCCCCGGAACCCGAAACGGAAGCCCCGTTTAATGGAGGAGGATGAGC
TGCCCTCCTGGATCATTAAGGATGACGCTGAAGTAGAAAGGCTCACCTGTGAAGAAGAGGAGGAGAAAAT
ATTTGGGAGGGGGTCCCCGCCAGCGCCGTGACGTGGACTACAGTGACGCCCTCACGGGAGAAGCAGTGGCTA
AGGGCCATCGAAGACGGCAATTTGGAGGAAATGGAAGAGGAAGTACGGCTTAAGAAGCGAAAAAAGACGAA
GAAATGTGGATAAAGATCCTGCAAAGAAGATGTGGAAAAAAGCTAAGAAGAGAAGAGGGCCGCCCTCCCGC
TGAGAAAACTGTCACCAAATCCCCCCAAAACTGACAAAGCAGATGAACGCTATCCATCGATACTGTGATAAAC
TACAAAGATAGGTGTAACGTGGGAGAAGGTGCCCAGTAATTCTCAGTTTGGAAATAGAAGGAAACAGTTCAG
GGCGACAGCTCAGTGAAGTCTTCATTCAGTTACCTTCAAGGAAAGAATTACCAGAATACTATGAATTAAT
TAGGAAGCCAGTGGATTTCAAAAAAAAAAGGAAAGGATTCGTAATCATAAGTACCGGAGCCTAGGCGAC
CTGGAGAAGGATGTCATGCTTCTCTGTCACAACGCTCAGACGTTCAACCTGGAGGATCCCAGATCTATG
AAGACTCCATCGTCTTACAGTCAGTGTTTAAGAGTGCCCGGCAGAAAAATTGCCCAAAGAGGAAGAGAGTGA
GGATGAAAGCAATGAAGAGGAGGAAGAGGAAGATGAAGAAGAGTCAGAGTCCGAGGCAAATCAGTCAAG
GTGAAAAATTAAGCTCAATAAAAAAAGATGACAAAGGCCGGGACAAAGGGGAAAGGCAAGAAAAGGCCAAAATC
GAGGAAAAGCCAAAACCTGTAGTGAGCGATTTTGACAGCGATGAGGAGCAGGATGAACGTGAACAGTCAGA
AGGAAGTGGGACGGATGATGATGATCAGTATGGACCTTTTTCCTTGGGTAGAACTGAATTCCTTCCTCCC
CTGTCTCATTTTCTACCCAGTGAGTTCATTTGTCATATAGGCACTGGGTTGTTTCTATATCATCATCGTCT
ATAAACTAGCTTTAGGATAGTGCCAGACAAACATATGATATCATGGTGTAAAAAAAACACACACATATACACAA
ATATTTGTAACATATTGTGACCAAATGGGCCTCAAAGATTCAGATTGAAAACAAAACAAAAGCTTTTGATG
GAAAATATGTGGGTGGATAGTATATTTCTATGGGTGGGTCTAATTTGGGTAACGGTTTGATTGTGCCTGGGT
TTTATCACCTGTTTCAGATGAGAAGATTTTTTGTCTTTTGTAGCACTGATAACCAGGAGAAGCCATTAAAG
CCACTGGTTATTTTATTTTTTCATCAGGCAATTTTCGAGGTTTTTATTTGTTCGGTATTGTTTTTTTTACAC
TGTGGTACATATAAGCAACTTTTAATAGGTGATAAATGTACAGTAGTTAGATTTCACCTGCATATACATTT
TTCCATTTTATGCTCTATGATCTGAACAAAAGCTTTTTGAATTGTATAAGATTTATGTCTACTGTAAACA
TTGCTTAATTTTTTTTGCTCTTGATTTAAAAAAAAGTTTTGTTGAAAGCGCTATTGAATATTGCAATCTAT
ATAGTGTATTGGATGGCTTCTTTTGTCACCCTGATCTCCTATGTTACCAATGTGTATCGTCTCCTTCTCC
CTAAAGTGTACTTAATCTTTGCTTTCTTTGCACAATGTCTTTGGTTGCAAGTCATAAGCCTGAGGCAAAT
AAAATTCCAGTAATTTCGAAGAATGTGGTGTTGGTGCTTTCCTAATAAAAGAAATAATTTAGCTTGACAAA
AAAAAAAAAAAAA

The term "BRM" also includes at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%, 85%, 86%, 87%, 88%, 89%, 90% %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) of a wild-type BRM protein. refers to variants. (Uniprot accession number: P51531; www.uniprot.org/uniprot/P51531.fasta)
SEQ ID NO:4.
MSTPTDPGAMPHPGPSPGPGPSPGPILGPSPGPGPSPGSVHSMMGPSPGPPSVSHPMPTM
GSTDFPQEGMHQMHKPIDGIHDKGIVEDIHCGSMKGTGMRPPHPGMGPPQSPMDQHSQGY
MSPHPSPLGAPEHVSSPMSGGGPTPPQMPPSQPGALIPGDPQAMSQPNRGPSSPFPVQLH
QLRAQILAYKMLARGQPLPETLQLAVQGKRTLPGLQQQQQQQQQQQQQQQQQQQQQPQ
QQPPQPQTQQQQPALVNYNRPSGPGPELSGPSTPQKLPVPAPGGRPSPAPPAAAQPPAA
AVPGPSVPQPAPGQPSPVLQLQQKQSRISPIQKPQGLDPVEILQEREYRLQARIAHRIQE
LENLPGSLPPDLRTKATVELKALRLLNFQRQLRQEVVACMRRDTTLETALNSKAYKRSKR
QTLREAARMTEKLEKQQKIEQERKRRQKHQEYLNSILQHAKDFKEYHRSVAGKIQKLSKAV
ATWHANTEREQKKETERIEKERMRRLMAEDEEGYRKLIDQKKDRRLLAYLLQQTDEYVANL
TNLVWEHKQAQAAKEKKKKRRRRKKKAEENAEGGESALGPDGEPIDESQMSDLPVKVTHT
ETGKVLFGPEAPKASQLDAWLEMNPGYEVAPRSDSEEDSDSDYEEEDEEEEESSSRQETEEKI
LLDPNSEEVSEKDAKQIIETAKQDVDDEYSMQYSARGSQSYYTVAHAISERVEKQSALLI
NGTLKHYQLQGLEWMVSLYNNNLNGILADEMGLGKTIQTIALITYLMEHKRLNGPYLIIV
PLSTLSNWTYEFDKWAPSVVKISYKGTPAMRRSLVPQLRSGKFNVLLTTYEYIIKDKHIL
AKIRWKYMIVDEGHRMKNHHCKLTQVLNTHYVAPRRILLTGTPLQNKLPELWALLNFLLP
TIFKSCSTFEQWFNAPFAMTGGERVDLNEEETILIIRRLHKVLRPFLLRRLKKEVESQLPE
KVEYVIKCDMSALQKILYRHMQAKGILLTDGSEKDKKGKGGAKTLMNTIMQLRKICNHPY
MFQHIEESFAEHLGYSNGVINGAELYRASGKFELLDRILLPKLRATNHRVLLFCQMTSLMT
IMEDYFAFRNFLYLRLDGTTKSEDRAALLKKFNEPGSQYFIFLLSTRAGGLGLNLQAADT
VVIFDSDWNPHQDLQAQDRAHRIGQQNEVRVLRLCTVNSVEEKILAAAKYKLNVDQKVIQ
AGMFDQKSSSHERRAFLQAILEHEEENEEEDEVPDDETLNQMIARREEEEFDLFMRMDMDR
RREDARNPKRKPRLMEEDELPSWIIKDDAEVERLTCEEEEEKIIFGRGSRQRRDVDYSDAL
TEKQWLRAIEDGNLEEMEEEVRLKKRKRRRNVDKDPAKEDVEKAKKRRGRPPAEKLSPNP
PKLTKQMNAIIDTVINYKDRCNVEKVPSNSSQLLEIEGNSSGRQLSEVFIQLPSRKELPEYY
ELIRKPVDFKKIKERIRNHKYRSLGDLEKDVMLLCHNAQTFNLEGSQIYEDSIVLQSVFK
SARQKIAKEEESEDESNEEEEEEEDEEESESEAKSVKVKIKLNKKDDKGRDKGKGKKRPNR
GKAKPVVSDFDSDEEQDEREQSEGSGTDDE

As used herein, the term "degrader" refers to a small molecule compound comprising a degrading moiety, wherein the compound results in protein degradation (e.g., binding of the compound may cause, e.g., cells or interacts with a protein (eg, BRG1 and/or BRM) in a manner that results in at least a 5% reduction in the level of the protein in the subject.

As used herein, the term "degradation moiety" refers to a moiety whose binding results in degradation of the protein (eg, BRG1 and/or BRM). In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes proteins (eg, BRG1 and/or BRM).

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

By "modulating the activity of the BAF complex" is meant altering the level of activity associated with the BAF complex (eg, GBAF) or associated downstream effects. The activity level of the BAF complex can be measured using any method known in the art, such as the method described in Kadoch et al, Cell 153:71-85 (2013), and the The method is incorporated herein by reference.

By "reducing the activity of BRG1 and/or BRM" is meant reducing the level of activity or associated downstream effects associated with BRG1 and/or BRM. A non-limiting example of inhibition of BRG1 and/or BRM activity is decreasing levels of BAF complexes (eg, GBAF) in cells. BRG1 and/or BRM activity levels can be measured using any method known in the art. In some embodiments, the agent that reduces BRG1 and/or BRM activity is a small molecule BRG1 and/or BRM inhibitor.

"Reducing the level of BRG1 and/or BRM" means reducing the level of BRG1 and/or BRM in a cell or subject. Levels of BRG1 and/or BRM can be measured using any method known in the art.

As used herein, the term "inhibit BRG and/or BRM" refers to blocking or reducing the level or activity of the protein's ATPase catalytic binding domain or bromodomain. Inhibition of BRG1 and/or BRM is determined using methods known in the art (e.g., BRG and/or BRM ATPase assay, Nano DSF assay, or BRG1 and/or BRM luciferase cell assay). obtain.

By "level" is meant the level of a protein, or mRNA encoding a protein, compared to a reference material. A reference material, as defined herein, can be any useful reference material. A "decreased level" or "increased level" of a protein means a decrease or increase in protein level when compared to a reference material (e.g., 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 decrease or increase, about A decrease or increase of more than 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, about 0.01-fold, about 0.02-fold, about 0.1-fold , about 0.3-fold, about 0.5-fold, less than about 0.8-fold, or less, or about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1. 8 times, about 2.0 times, about 3.0 times, about 3.5 times, about 4.5 times, about 5.0 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40-fold, about 50-fold, about 100-fold, about 1000-fold or greater increase). Protein levels can be expressed as mass/volume (eg, g/dL, mg/mL, μg/mL, ng/mL) or as a percentage of total protein or mRNA in the sample.

As used herein, the term "inhibitor" refers to any agent that reduces the level and/or activity of a protein (eg, BRG1 and/or BRM). Non-limiting examples of inhibitors include small molecule inhibitors, degradants, antibodies, enzymes, or polynucleotides (eg, siRNA).

As used herein, the term "LXS196" refers to a PKC inhibitor having the following structure:

or a pharmaceutically acceptable salt thereof.

As used herein, an "effective amount", "therapeutically effective amount" of an agent that reduces the level and/or activity (e.g., in a cell or subject) of BRG1 and/or BRM described herein , and the terms "sufficient amount" refer to an amount sufficient to produce beneficial or desired results, including clinical results, when administered to a subject, including humans; , depending on the context in which it applies. For example, in the context of treating cancer, it is sufficient to achieve a therapeutic response compared to the response obtained without administration of an agent that reduces the level and/or activity of BRG1 and/or BRM. The amount of agent that reduces the level and/or activity of BRG1 and/or BRM. Amounts of a given agent that reduce the level and/or activity of BRG1 and/or BRM described herein that would correspond to such amounts are given by the agent, pharmaceutical formulation, route of administration, Depending on a variety of factors, such as the type of disease or disorder, the identity of the subject (e.g., age, sex, and/or weight), or the host being treated, nevertheless routinely by those skilled in the art. can be determined. Also, as used herein, a "therapeutically effective amount" of an agent that reduces the level and/or activity of BRG1 and/or BRM of the present disclosure is a beneficial or desired result in a subject as compared to a control. is the amount that brings about A therapeutically effective amount of an agent that reduces the levels and/or activity of BRG1 and/or BRM of the present disclosure, as defined herein, can be readily determined by those skilled in the art by routine methods known in the art. can be determined to Dosage regimens may be adjusted to provide the optimum therapeutic response.

The term "inhibitory RNA agent" refers to an RNA or analog thereof that has sufficient sequence complementarity to a target RNA to induce RNA interference. Examples also include DNA, which can be used to make RNA. RNA interference (RNAi) refers to a sequence-specific or selective process by which a target molecule (eg, target gene, protein, or RNA) is downregulated. In general, an interfering RNA (“iRNA”) is a double-stranded small interfering RNA (siRNA), short hairpin RNA (shRNA), or single-stranded microRNA (miRNA) that leads to catalytic degradation of a specific mRNA. and can also be used to reduce or inhibit gene expression.

The terms "small interfering RNA" and "siRNA" (also known as "small interfering RNA") refer to an RNA agent, preferably double-stranded, of about 10-50 nucleotides in length, the strands optionally being For example, it has overhanging ends that include 1, 2, or 3 overhanging nucleotides (or nucleotide analogues) that are capable of inducing or mediating RNA interference. Naturally occurring siRNAs are produced from longer dsRNA molecules (eg, >25 nucleotides in length) by the cellular RNAi machinery (eg, Dicer or its homologues).

As used herein, the term "shRNA" refers to an RNA agent having a stem-loop structure comprising first and second regions of complementary sequence, wherein the degree of complementarity and orientation of the regions are Sufficient for pairing to occur between the regions, the first and second regions being joined by a loop region, the loop resulting from the lack of base pairing between nucleotides (or nucleotide analogues) within the loop region. occur.

The terms "miRNA" and "microRNA" refer to RNA agents, preferably single-stranded agents, about 10-50 nucleotides in length, preferably about 15-25 nucleotides in length, which are capable of inducing or mediating RNA interference. . Naturally occurring miRNAs are generated from stem-loop precursor RNAs (ie, pre-miRNAs) by Dicer. As used herein, the term "Dicer" includes Dicer as well as any Dicer orthologs or homologs that can process dsRNA structures into siRNA, miRNA, siRNA-like or miRNA-like molecules. The term microRNA (“miRNA”) was coined from “small RNA” (“ stRNA") are used interchangeably.

As used herein, the term "antisense" refers to any gene, primary transcript, or mRNA processed so as to interfere with the expression of an endogenous gene (eg, BRG1 and/or BRM). Or refers to a nucleic acid comprising a polynucleotide that is sufficiently complementary to a portion. "Complementary" polynucleotides are those that are capable of base pairing according to the standard Watson-Crick complementarity rules. Specifically, purines base-pair with pyrimidines, guanine paired with cytosine (G:C) for DNA, adenine paired with either thymine (A:T), or for RNA Forms adenine (A:U) combinations paired with uracil. It is understood that two polynucleotides can hybridize to each other, provided they each have at least one region that is substantially complementary to each other, even if they are not completely complementary to each other.

The term "antisense nucleic acid" includes single-stranded RNA as well as double-stranded DNA expression cassettes that can be transcribed to produce antisense RNA. An "active" antisense nucleic acid has at least 80% sequence identity (e.g., 80%, 85%, 86%, 87%, 88%) with a targeting polypeptide sequence (e.g., BRG1 and/or BRM polypeptide sequences). %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% or more identity) An antisense RNA molecule capable of selectively hybridizing to a primary transcript or mRNA encoding a peptide. An antisense nucleic acid can be complementary to an entire coding strand, or only a portion thereof. In another embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleic acid sequence. The term "coding region" refers to a region of a nucleotide sequence that contains codons translated into amino acid residues. In another embodiment, an antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleic acid sequence. The term "noncoding region" refers to the 5' and 3' sequences that flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions). An antisense nucleic acid molecule can be complementary to an entire coding region of an mRNA or can be antisense to only a portion of the coding or noncoding region of an mRNA. For example, an antisense oligonucleotide can be complementary to the region surrounding the translation initiation site. Antisense oligonucleotides can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length.

A "percent (%) sequence identity" relative to a reference polynucleotide or polypeptide sequence is obtained by aligning the sequences, introducing gaps, if necessary, to achieve a maximum percent sequence identity, and then determining the identity of the reference polynucleotide or polypeptide. Defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to nucleic acids or amino acids in the sequence. Alignments for purposes of determining percent nucleic acid or amino acid sequence identity may be performed in a variety of ways within the capabilities of those of skill in the art, such as publicly available BLAST, BLAST-2, or Megalign software. It can be accomplished using computer software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, percent sequence identity values can be generated using the sequence comparison computer program BLAST. As an example, the percent sequence identity of a given nucleic acid or amino acid sequence A relative to, with, or relative to a given nucleic acid or amino acid sequence B (alternatively, for a given nucleic acid or amino acid sequence B) (which can be expressed as a given nucleic acid or amino acid sequence A having a certain percent sequence identity of, or relative to, A) is calculated as follows:
100 x (Fractional X/Y)
X is the number of nucleotides or amino acids that were scored as identical matches by a sequence alignment program (eg, BLAST) in the programmatic alignment of A and B, and Y is the total number of B nucleic acids. It is understood that the percent sequence identity of A to B is not equal to the percent sequence identity of B to A if the length of the nucleic acid or amino acid sequence A is not equal to the length of the nucleic acid or amino acid sequence B. be.

As used herein, the term "pharmaceutical composition" refers to a composition comprising a compound described herein, formulated with pharmaceutically acceptable excipients, and administered to a mammal. Manufactured or marketed with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in animals. The pharmaceutical compositions are, for example, for oral administration in unit dosage form (eg, tablets, capsules, caplets, gelcaps, or syrups), for topical administration (eg, as creams, gels, lotions, or ointments). , for intravenous administration (e.g., as a sterile solution free of embolic particulate emboli and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation can be done.

As used herein, "pharmaceutically acceptable excipient" means a vehicle other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound). , refers to any ingredient that has the properties of being substantially non-toxic and non-inflammatory in the patient. Excipients include, for example, antiadherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers. Or they may include coating agents, flavors, fragrances, lubricants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, Cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, alpha starch, propylparaben, Retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of any of the compounds described herein. . For example, pharmaceutically acceptable salts of any of the compounds described herein are used in contact with human and animal tissue without undue toxicity, irritation, or allergic response. and within the scope of sound medical judgment and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are known in the art. For example, pharmaceutically acceptable salts are described in Berge et al. , J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

The compounds described herein may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts, including inorganic or organic acids, or salts, for the acid forms of the compounds described herein, may be prepared from inorganic or organic bases. Often compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing suitable salts are known in the art. Salts can 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, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexane hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate acid, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate are mentioned. Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, and ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and non-toxic ammonium, quaternary ammonium, and amine cations, including ethylamine.

By "reference material" is meant any useful reference material used to compare protein or mRNA levels. A reference material can be any sample, standard, standard curve, or level used for comparison purposes. A reference material can be a regular reference sample or a reference standard or level. A "reference sample" is defined, e.g., as a control, e.g., a predetermined negative control value, such as a "normal control," or a previous sample taken from the same subject; samples (e.g., cells or tissues) from subjects who do not have the disease; samples from subjects who have been diagnosed with the disease but have not yet been treated with a compound described herein; It may be a sample from a subject being treated with a compound described herein; or a sample of purified protein (eg, any described herein) of 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 predetermined value indicative of a non-disease condition, eg, the value expected in a healthy control subject. Typically, normal control values are expressed as a range (“between X and Y”), a high threshold (“less than or equal to X”), or a low threshold (“greater than or equal to X”). Subjects with measurements within normal control values for a particular biomarker are typically referred to as being "within the normal range" for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject who does not have a disease or disorder (eg, cancer); a subject being 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, gender, disease stage, and general health. A standard curve of levels of purified protein within the normal reference range, eg, any of those described herein, can also be used as a reference.

As used herein, the term "subject" refers to any organism to which compositions according to the invention can be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Point. Typical subjects include any animal (eg, mice, rats, rabbits, non-human primates, and mammals such as humans). A subject is seeking or in need of treatment, is requesting treatment, is undergoing treatment, is undergoing treatment in the future, or is being treated by a professional trained in a particular disease or condition. It can be a human or animal recipient.

As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to To prevent or slow (alleviate) a physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; reduction in the extent of a condition, disease, disorder, or disease; stabilization of a condition, disorder, or disease; delayed or slowed onset of progression of a condition, disorder, or disease; improvement or remission (partial or complete) of a condition, disorder, or disease state; not always discernible by the patient improvement in at least one measurable physical parameter; or enhancement or amelioration of a 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.

As used herein, the terms "variants" and "derivatives" are used interchangeably and include naturally occurring, synthetic, and synthetic forms of the compounds, peptides, proteins, or other substances described herein. Refers to semi-synthetic analogues. Variants or derivatives of compounds, peptides, proteins, or other substances described herein may retain or improve the biological activity of the original material.

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

FIG. 10 is a graph showing inhibition of cell proliferation of several cancer cell lines by a BRG1/BRM inhibitor (compound 17). FIG. 10 is a graph showing inhibition of cell proliferation of several cancer cell lines by the BRG1/BRM inhibitor, compound 18. FIG. FIG. 10 is a graph showing area under the curve (AUC) calculated from dose-response curves of cancer cell lines treated with BRG1/BRM inhibitors. Graph showing in vivo inhibition of AML proliferation by BRG1/BRM inhibitors. FIG. 10 is a graph showing in vivo inhibition of AML proliferation by BRG1/BRM inhibitors. Graph showing in vivo inhibition of AML proliferation by BRG1/BRM inhibitors.

The inventors have found that depletion of BRG1 and/or BRM in AML results in decreased proliferation of cancer cells.

Accordingly, the present invention features methods and compositions useful for inhibiting BRG1 and/or BRM activity, eg, for the treatment of AML. The invention further features methods and compositions useful for inhibiting BRG1 and/or BRM protein activity, eg, in a subject in need thereof, eg, for the treatment of AML. Exemplary methods are described herein.

BRG1 and/or BRM Reducing Agents Agents described herein that reduce the level and/or activity of BRG1 and/or BRM in cells are antibodies, proteins (such as enzymes), polynucleotides, or small molecule compounds. obtain. The agent reduces the level of BRG1 and/or BRM associated activity or associated downstream effects, or reduces the level of BRG1 and/or BRM in a cell or subject.

In some embodiments, the agent that reduces BRG1 and/or BRM levels and/or activity in a cell is an enzyme, polynucleotide, or small molecule compound (such as a small molecule BRG1 and/or BRM inhibitor).

Antibodies Agents that reduce BRG1 and/or BRM levels and/or activity can be antibodies or antigen-binding fragments thereof. For example, agents that reduce BRG1 and/or BRM levels and/or activity described herein reduce or block BRG1 and/or BRM activity and/or function through binding to BRG1 and/or BRM is an antibody.

The production and use of therapeutic antibodies against target antigens (eg, BRG1 and/or BRM) are known in the art. See, eg, the references cited herein above, and Zhiqiang An (Editor), Therapeutic Monoclonal Antibodies: From Bench to Clinic. 1st Edition. See Wiley 2009. Also, antibody engineering, use of degenerate oligonucleotides, 5'-RACE, phage display and mutagenesis, antibody testing and characterization, antibody pharmacokinetics and pharmacodynamics, antibody purification and storage, and screening and labeling techniques. See Greenfield (Ed.), Antibodies: A Laboratory Manual. See also (Second edition) Cold Spring Harbor Laboratory Press 2013.

Polynucleotides In some embodiments, the agent that reduces BRG1 and/or BRM levels and/or activity is a polynucleotide. In some embodiments, the polynucleotide is an inhibitory RNA molecule that acts, for example, through the RNA interference (RNAi) pathway. Inhibitory RNA molecules can decrease the expression level (eg, protein level or mRNA level) of BRG1 and/or BRM. For example, inhibitory RNA molecules include short interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), and/or microRNAs (miRNAs) that target full-length BRG1 and/or BRM. siRNAs are typically double-stranded RNA molecules having a length of about 19-25 base pairs. shRNAs are RNA molecules containing hairpin turns that reduce target gene expression via RNAi. MicroRNAs are non-coding RNA molecules typically about 22 nucleotides in length. miRNAs bind to target sites on mRNAs and silence mRNAs, eg, by causing mRNA cleavage, mRNA destabilization, or inhibition of mRNA translation. Degradation is caused by the enzymatic RNA-induced silencing complex (RISC).

In some embodiments, the agent that reduces BRG1 and/or BRM levels and/or activity is an antisense nucleic acid. Antisense nucleic acids include antisense RNA (asRNA) and antisense DNA (asDNA) molecules (typically about 10-30 nucleotides in length), which target sequences (eg, BRG1 and/or BRM). recognizes a polynucleotide target sequence or sequence portion through hydrogen bonding interactions with the nucleotide bases of . A target sequence can be single- or double-stranded RNA, or single- or double-stranded DNA.

In some embodiments, the polynucleotide reduces the level and/or activity of a negative regulator of function or a positive regulator of function. In other embodiments, the polynucleotide reduces the level and/or activity of an inhibitor of a positive regulator of function.

Polynucleotides of the present invention include, for example, modified nucleotides (eg, 2′-fluoro, 2′-o-methyl, 2′-deoxy, unlocked nucleic acid, 2′-hydroxy, phosphorothioate, 2 Without being bound by theory, certain modifications increase nuclease resistance and/or serum stability. Alternatively, the polynucleotides may be provided in specialized forms such as liposomes, microspheres, etc., or may be applied in gene therapy, or It can be provided in combination with a binding moiety, such as a polycation such as polylysine that acts as a charge neutralizer for the phosphate backbone, or a polycation that enhances interaction with cell membranes or increases nucleic acid uptake. Included are hydrophobic moieties such as lipids (e.g., phospholipids, cholesterol, etc.) These moieties may be attached to nucleic acids at their 3' or 5' ends, via bases, sugars, or intramolecular nucleoside linkages. Other moieties may be capping groups specifically placed at the 3′ or 5′ end of the nucleic acid to prevent degradation by nucleases such as exonucleases, ribonucleases and the like. Such capping groups include hydroxyl protecting groups known in the art and include glycols such as polyethylene glycol and tetraethylene glycol.The inhibitory effects of polynucleotides are in vivo and in vitro on the cell lines or animals of the present invention. In some embodiments, the polynucleotide reduces the level and/or activity or function of BRG1 and/or BRM.In embodiments, the polynucleotide comprises: Inhibits expression of BRG1 and/or BRM In other embodiments, the polynucleotide increases degradation of BRG1 and/or BRM and/or increases stability (i.e., half-life) of BRG1 and/or BRM. Polynucleotides can be chemically synthesized or transcribed in vitro.

Inhibitory polynucleotides can be designed by methods well known in the art and have sufficient homology to provide the sequence specificity necessary to uniquely degrade any RNA. , shRNA, and asRNA molecules can be obtained from programs known in the art, including, but not limited to, those maintained on the websites of Thermo Fisher Scientific, the German Cancer Research Center, and The Ohio State University Wexner Medical Center. can be designed using Several designed types of systematic tests for optimizing inhibitory polynucleotide sequences can be routinely performed by one skilled in the art. Considerations in designing interfering polynucleotides include, but are not limited to, biophysical, thermodynamic, and structural considerations, base preferences at particular positions of the sense strand, and homology. Also, the production and use of non-coding RNA-based inhibitory therapeutic agents such as ribozymes, ribonuclease P, siRNA, and miRNA are known in the art, see, for example, Sioud, RNA Therapeutics: Function, Design, and Delivery ( Methods in Molecular Biology). Humana Press 2010. Exemplary inhibitory polynucleotides for use in the methods of the invention are provided in Table 1 below. In some embodiments, the inhibitory polynucleotide is at least 50% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 85%) the inhibitory polynucleotide nucleic acid sequence of Table 1. , at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity. In some embodiments, the inhibitory polynucleotide has at least 70% sequence identity (e.g., 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% or more identity ).

Construction of vectors to express polynucleotides for use in the present invention can be accomplished using conventional techniques which do not require detailed description to those of ordinary skill in the art. Efficient expression vector generation requires having control sequences that control the expression of the polynucleotide. These regulatory sequences, including promoter and enhancer sequences, are influenced by specific cellular factors that interact with these sequences and are well known in the art.

Gene Editing In some embodiments, the agent that reduces the level and/or activity of BRG1 and/or BRM is a component of a gene editing system. For example, agents that reduce the level and/or activity of BRG1 and/or BRM may include alterations in BRG1 and/or BRM (e.g., insertions, deletions (e.g., knockouts), rearrangements, inversions, single point mutations, or other mutation). In some embodiments, the agent that reduces BRG1 and/or BRM levels and/or activity is a nuclease. Exemplary gene editing systems include zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALENs), and clustered regularly spaced short palindromic repeats (CRISPR) systems. ZFN, TALEN, and CRISPR-based methods are described, for example, in Gaj et al. , Trends Biotechnol. 31(7):397-405 (2013).

CRISPR refers to a set (or system of sets) of clustered regularly spaced short palindromic repeats. CRISPR system refers to systems derived from CRISPR and Cas (CRISPR-associated protein) or other nucleases that can be used to silence or mutate the genes described herein. The CRISPR system is a naturally occurring system and is found in the genomes of bacteria and archaea. The CRISPR locus is composed of alternating repeating sequences and spacer sequences. In naturally occurring CRISPR systems, spacers are typically sequences foreign to the bacterium (eg, plasmid or phage sequences). The CRISPR system has been modified for use in gene editing (eg, alteration, silencing, and/or enhancement of specific genes) in eukaryotes. For example, Wiedenheft et al. , Nature 482(7385):331-338 (2012). For example, such modification of the system involves introducing a plasmid containing a specifically designed CRISPR and one or more appropriate Cas proteins into eukaryotic cells. The CRISPR loci are transcribed into RNA and processed by Cas proteins into small RNAs containing repeated sequences flanked by spacers. RNA acts as a guide to induce Cas proteins to silence specific DNA/RNA sequences, depending on the spacer sequence. For example, Horvath et al. , Science 327(5962): 167-170 (2010), Makarova et al. , Biology Direct 1:7 (2006); Pennisi, Science 341(6148):833-836 (2013). In some examples, the CRISPR system includes a Cas9 protein, a nuclease that cuts both strands of DNA. See, for example, Ibid.

In some embodiments, in a CRISPR system for use as described herein (e.g., for use by one or more methods described herein), the CRISPR spacer is a sequence of the target gene (e.g. , BRG1 and/or BRM sequences). In some embodiments, in a CRISPR system for use as described herein (e.g., for use by one or more methods described herein), the CRISPR spacer is a sequence of the target gene (e.g. , the sequence of BRG1). In some embodiments, in a CRISPR system for use described herein (e.g., for use by one or more methods described herein), the CRISPR spacer is a sequence of the target gene ( For example, the sequence of BRM).

In some embodiments, agents that reduce BRG1 and/or BRM levels and/or activity include guide RNAs (gRNAs) for use in the CRISPR system for gene editing. Exemplary gRNAs for use in the methods of the invention are provided in Table 1 below. In embodiments, agents that reduce the level and/or activity of BRG1 and/or BRM are ZFNs that target (e.g., cleave) nucleic acid sequences (e.g., DNA sequences) of BRG1 and/or BRM, or ZFNs. Contains the encoding mRNA. In embodiments, agents that reduce the level and/or activity of BRG1 and/or BRM are TALENs that target (eg, cleave) nucleic acid sequences (eg, DNA sequences) of BRG1 and/or BRM, or TALENs Contains the encoding mRNA. In embodiments, agents that reduce the level and/or activity of BRG1 and/or BRM are TALENs that target (eg, cleave) nucleic acid sequences (eg, DNA sequences) of BRG1, or mRNAs encoding TALENs. include. In embodiments, an agent that reduces the level and/or activity of BRG1 and/or BRM is a TALEN that targets (e.g., cleaves) a nucleic acid sequence (e.g., a DNA sequence) of BRM, or an mRNA encoding a TALEN. include.

For example, gRNAs can be used in CRISPR systems to engineer alterations in genes (eg, BRG1 and/or BRM). In other examples, ZFNs and/or TALENs can be used to engineer alterations in genes (eg, BRG1 and/or BRM). Exemplary modifications include insertions, deletions (eg, knockouts), rearrangements, inversions, single point mutations, or other mutations. Modifications can be introduced into genes within cells, eg, in vitro, ex vivo, or in vivo. In some embodiments, the modification reduces (eg, knocks down or knocks out) the level and/or activity of BRG1 and/or BRM, eg, the modification is a negative regulator of function. In yet another example, the modification corrects a defect (eg, a mutation causing the defect) in BRG1 and/or BRM. In yet another example, the modification corrects a defect (eg, a mutation causing the defect) in BRG1. In yet another example, the modification corrects a defect in the BRM (eg, mutation causing the defect).

In certain embodiments, the CRISPR system is used to edit (eg, add or delete base pairs) a target gene, eg, BRG1 and/or BRM. In other embodiments, the CRISPR system is used to introduce premature stop codons (eg, thereby reducing target gene expression). In still other embodiments, the CRISPR system is used to turn off target genes in a reversible manner, eg, similar to RNA interference. In embodiments, a CRISPR system is used to direct Cas to the promoter of a target gene (eg, BRG1 and/or BRM), thereby sterically blocking RNA polymerase. In embodiments, the CRISPR system is used to direct Cas to the promoter of a target gene (eg, BRG1), thereby sterically blocking RNA polymerase. In embodiments, the CRISPR system is used to direct Cas to the promoter of a target gene (eg, BRM), thereby sterically blocking RNA polymerase.

In some embodiments, the CRISPR system is, for example, US Publication No. 20140068797, Cong et al. , Science 339(6121):819-823 (2013), Tsai, Nature Biotechnol. , 32(6):569-576 (2014), and U.S. Pat. , and US Pat. No. 8,697,359 to edit BRG1 and/or BRM.

In some embodiments, CRISPR interference (CRISPRi) technology can be used for transcriptional repression of specific genes (eg, genes encoding BRG1 and/or BRM). In CRISPRi, an engineered Cas9 protein (eg, nuclease-null dCas9, or a dCas9 fusion protein, eg, dCas9-KRAB or dCas9-SID4X fusion) can be paired with a sequence-specific guide RNA (sgRNA). The Cas9-gRNA complex can block RNA polymerase, thereby preventing transcription elongation. The complex can also block transcription initiation by preventing the binding of transcription factors. The CRISPRi method is specific, has minimal off-target effects, is multiplexable, and can suppress more than one gene at the same time (e.g., using multiple gRNAs). can be done. Also, the CRISPRi method allows for reversible gene silencing.

In some embodiments, CRISPR-mediated gene activation (CRISPRa) is, for example, for transcriptional activation of one or more genes described herein (e.g., genes that inhibit BRG1 and/or BRM). can be used. In CRISPRa technology, the dCas9 fusion protein recruits transcriptional activators. For example, dCas9 is used to recruit polypeptides (e.g., activation domains) such as VP64 or p65 activation domains (p65D) and used with sgRNAs (e.g., single sgRNA or multiple sgRNAs) to One or more genes, eg, endogenous gene(s), can be activated. Multiple activators can be recruited by using multiple sgRNAs, which can increase activation efficiency. Various activation domains and single or multiple activation domains can be used. In addition to manipulating dCas9 to recruit activators, sgRNAs can also be manipulated to recruit activators. For example, RNA aptamers can be incorporated into sgRNAs to recruit proteins such as VP64 (eg, activation domains). In some instances, synergistic activation mediator (SAM) systems can be used for transcriptional activation. In SAM, the MS2 aptamer is attached to the sgRNA. MS2 recruits the MS2 coat protein (MCP) fused to p65AD and heat shock factor 1 (HSF1). CRISPRi and CRISPRa techniques are described, for example, in Dominguez et al. , Nat. Rev. Mol. Cell Biol. 17(1):5-15 (2016), incorporated herein by reference.

Small Molecule Compounds In some embodiments of the invention, agents that reduce the level and/or activity of BRG1 and/or BRM in cells are small molecule compounds. In some embodiments, the small molecule compounds are structures of Formulas I-III.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof,

wherein m is 0, 1, 2, 3, or 4;
X ¹ is N or CH,
Each R ¹ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ - C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally C ₂ -C ₆ alkenyl substituted with , optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula II or a pharmaceutically acceptable salt thereof,

wherein R ² is phenyl substituted with hydroxy, optionally independently the group consisting of halo, cyano, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, and C _1-3 alkoxy phenyl substituted with one or more groups selected from
R ³ is selected from the group consisting of -R ^a , -OR ^a , -N(R ^a )2, -S(O) ₂ R ^a , and -C(O)-N(R ^a ) ₂ ,
Each R ^a is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl; _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl are optionally and independently R ^b , oxo, halo, —NO2, —N(R ^b ) ₂ , —CN, —C(O)—N(R ^b ) ₂ , —S(O)—N(R ^b ) ₂ , —S(O) ₂ —N(R ^b ) ₂ , —O—R ^b , —S—R ^b , —O—C(O)—R ^b , —C(O)—R ^b , —C(O)—OR ^b , —S(O)—R ^b , —S(O) ₂ —R ^b , —N(R ^b ) —C(O) —R ^b , —N(R ^b ) —S(O) —R ^b , —N(R ^b ) —C( substituted with one or more groups selected from the group consisting of O)—N(R ^b ) ₂ and —N(R ^b )—S(O) ₂ —R ^b ;
the group in which each R ^b independently consists of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally independently are substituted with one or more groups selected from R ^c , or two R ^b , together with the nitrogen to which they are attached, are heterocyclyl (optionally, independently, substituted with one or more groups selected from the group consisting of oxo, halo and C _1-3 alkyl, wherein C _1-3 alkyl is optionally independently selected from the group consisting of oxo and halo is substituted with one or more groups that are
Each R ^c is independently oxo, halo, —NO2, —N(R ^d ) ₂ , —CN, —C(O)—N(R ^d ) ₂ , —S(O)—N(R ^d ) ₂ , —S(O) _2- N(R ^d ) ₂ , —S—R ^d , —O—C(O)—R ^d , —C(O)—R ^d , —C(O)—OR ^d , -S(O)-R ^d , -S(O) _2- R ^d , -N(R ^d )-C(O)-R ^d , -N(R ^d )-S(O)-R ^d , —N(R ^d )—C(O)—N(R ^d ) ₂ , —N(R ^d )—S(O) _2- R ^d , C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, any C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally independently R ^d , oxo, halo, —NO ₂ , —N(R ^d ) ₂ , —CN, —C(O)—N(R ^d ) ₂ , -S(O)-N(R ^d ) ₂ , -S(O) ₂ -N(R ^d ) ₂ , -O-R ^d , -S-R ^d , -O-C(O)-R ^d , -C(O)-R ^d , -C(O)-R ^d , -S(O)-R ^d , -S(O) ₂ -R ^d , -N(R ^d )-C(O)- R ^d , —N(R ^d )—S(O)—R ^d , —N(R ^d )—C(O)—N(R ^d ) ₂ , and —N(R ^d )—S(O) ₂ substituted with one or more groups selected from the group consisting of -R ^d ;
each R ^d is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, and carbocyclyl(C _1-3 alkyl)-;
R ⁴ is H, C _1-6 alkyl, or —C(=O)—C _1-6 alkyl;
R ⁵ is H or C _1-6 alkyl.

Compounds of Formula II can be synthesized by methods known in the art, such as those described in US Patent Publication No. 2018/0086720, which synthetic methods are incorporated by reference.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula III or a pharmaceutically acceptable salt thereof,

wherein R ⁶ is halo (e.g. fluoro or chloro),
R ⁷ is hydrogen, optionally substituted amino, or optionally substituted C _1-6 alkyl;
R ⁸ is optionally substituted C _6-10 aryl or optionally substituted C _2-9 heteroaryl.

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of any one of Compounds 1-16, or a pharmaceutically acceptable salt thereof;

In some embodiments, the small molecule BRG1 and/or BRM inhibitor is a compound having the structure of Formula IV or a pharmaceutically acceptable salt thereof,

wherein R ¹ is absent or H, optionally substituted C ₁ -C ₆ acyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₂ -C ₉ heterocyclyl, or —SO ₂ R ⁶ ;

is a 5- or 6-membered heteroarylene,
each of R ² and R ⁵ is independently H or optionally substituted C ₁ -C ₆ alkyl;
R ³ is H or optionally substituted C ₁ -C ₆ alkyl and R ⁴ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ hetero alkyl, or R ³ and R ⁴ together with the carbon atom to which they are attached form an optionally substituted C ₃ -C ₆ cycloalkyl;
R ⁶ is optionally substituted C ₁ -C ₆ alkyl or —NR ⁷ R ⁸ ;
R ⁷ and R ⁸ are independently optionally substituted C ₁ -C ₆ alkyl;
Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or

and
A is optionally substituted C ₆ -C ₁₀ arylene, optionally substituted C ₂ -C ₉ heterocyclylene, or optionally substituted C ₂ -C ₉ heteroarylene;
L is absent or —O—, optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₁ -C ₆ heteroalkylene, optionally substituted C ₂ -C ₆ alkenylene, optionally substituted C ₂ -C ₆ heteroalkenylene, optionally substituted C ₂ -C ₆ alkynylene, optionally substituted C ₂ -C ₆ heteroalkynylene, optionally substituted C ₂ -C ₉ heterocyclylene , optionally substituted C ₂ -C ₉ heterocyclyl C ₁ -C ₆ alkylene, optionally substituted C ₂ -C ₉ heteroarylene, or optionally substituted C ₂ -C ₉ heteroaryl C ₁ -C ₆ is an alkylene;
B is H, halogen, cyano, optionally substituted _C6 - _C10 aryl, optionally substituted _C3 - _C10 cycloalkyl, optionally substituted _C2 - _C9 heterocyclyl, or optionally substituted C ₂ -C ₉ heteroaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments,

is a 6-membered heteroarylene. In some embodiments,

is a 5-membered heteroaryl.

In some embodiments,

but,

where each of X, Y, and Z is independently N or CH.

In some embodiments, the compound of Formula IV has the structure of Formula IVa,

wherein each of X, Y, and Z is independently N or CH;
R ¹ is H, optionally substituted C ₁ -C ₆ acyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C _{3 -C8} cycloalkyl, optionally substituted _C2 - _C9 heterocyclyl, ^or _-SO2R6 ;
each of R ² , R ³ , and R ⁵ is independently H or optionally substituted C ₁ -C ₆ alkyl;
R ⁴ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl;
R ⁶ is optionally substituted C ₁ -C ₆ alkyl or —NR ⁷ R ⁸ ;
each of R ⁷ and R ⁸ is independently optionally substituted C ₁ -C ₆ alkyl;
Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or

and
A is optionally substituted C ₆ -C ₁₀ arylene, optionally substituted C ₂ -C ₉ heterocyclylene, or optionally substituted C ₂ -C ₉ heteroarylene;
L is absent or —O—, optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₁ -C ₆ heteroalkylene, optionally substituted C ₂ -C ₆ alkenylene, optionally substituted C ₂ -C ₆ heteroalkenylene, optionally substituted C ₂ -C ₆ alkynylene, optionally substituted C ₂ -C ₆ heteroalkynylene, optionally substituted C ₂ -C ₉ heterocyclylene , optionally substituted C ₂ -C ₉ heterocyclyl C ₁ -C ₆ heteroalkylene, optionally substituted C ₂ -C ₉ heteroarylene, or optionally substituted C ₂ -C ₉ heteroaryl C ₁ -C is ₆ alkylene;
B is H, halogen, cyano, optionally substituted _C6 - _C10 aryl, optionally substituted _C3 - _C10 cycloalkyl, optionally substituted _C2 - _C9 heterocyclyl, or optionally substituted C ₂ -C ₉ heteroaryl, or a pharmaceutically acceptable salt thereof.

In some embodiments, X, Y, and Z are CH; X is N, Y and Z are CH; Z is N, and X and Y are CH; Y is N, X and Z are CH; X is CH, Y and Z are N; Z is CH, X and Y are N; and Z is N; or X, Y and Z are N.

In some embodiments, the compound of Formula IV has Formula IVb:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, Formula IV is Formula IVc:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula IV has Formula Ic:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, Formula IV is Formula IVe:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments,

teeth,

where X' is O or S, Y' is N or CH, and Z' is N or CH.

In some embodiments, the compound of Formula IVa has the structure of Formula V,

wherein W' is C or N;
X' is O, S or N- _CH3 ,
Y' is N or CH,
Z' is N or CH,
R ¹ is absent or H, optionally substituted C ₁ -C ₆ acyl, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₂ -C ₉ heteroalkyl, or —SO ₂ R ⁶ ;
R ² , R ³ , and R ⁵ are each independently H or optionally substituted C ₁ -C ₆ alkyl;
R ⁴ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl;
R ⁶ is optionally substituted C ₁ -C ₆ alkyl or —NR ⁷ R ⁸ ;
R ⁷ and R ⁸ are each independently optionally substituted C ₁ -C ₆ alkyl;
Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or

and
A is optionally substituted C ₆ -C ₁₀ arylene, optionally substituted C ₂ -C ₉ heterocyclylene, or optionally substituted C ₂ -C ₉ heteroarylene;
L is absent or —O—, optionally substituted C ₁ -C ₆ alkylene, optionally substituted C ₁ -C ₆ heteroalkylene, optionally substituted C ₁ -C ₆ alkenylene, optionally substituted C ₂ -C ₆ heteroalkenylene, optionally substituted C ₂ -C ₆ alkynylene, optionally substituted C ₂ -C ₆ heteroalkynylene, optionally substituted C ₂ -C ₉ heterocyclylene , optionally substituted C ₂ -C ₉ heterocyclyl C ₁ -C ₆ alkylene, optionally substituted C ₂ -C ₉ heteroarylene, or optionally substituted C ₂ -C ₉ heteroaryl C ₁ -C ₆ is an alkylene;
B is H, halogen, cyano, optionally substituted _C6 - _C10 aryl, optionally substituted _C3 - _C10 cycloalkyl, optionally substituted _C2 - _C9 heterocyclyl, or optionally substituted C ₂ -C ₉ heteroaryl,
Alternatively, they are pharmaceutically acceptable salts thereof.

In some embodiments, X' is O, Y' is CH, Z' is N; X' is S, Y' is CH, Z' is N X' is O, Y' is N, Z' is CH; X' is S, Y' is N, Z' is CH; X' is or X' is S, Y' is N and Z' is N.

In some embodiments, Formula V is Formula Va:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, Formula II is Formula Vb:

or has the structure of a pharmaceutically acceptable salt thereof.

In some embodiments, the small molecule compound, or a pharmaceutically acceptable salt thereof, is any one of compounds 17-20 having the structure below.

In some embodiments, the small molecule compound or pharmaceutically acceptable salt thereof is a degradant. In some embodiments, the degrading agent has the structure of Formula VI,
CL-D
Formula VI
wherein C is the binding moiety of BRG1 and/or BRM, L is the linker, and B is the degrading moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the degradation moiety is a ubiquitin ligase moiety. In some embodiments, the ubiquitin ligase binding moiety is a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homolog (MDM2), a hydrophobic tag, or a von Hippel-Lindau ligand, or Including derivatives or analogues.

In some embodiments, A comprises the structure of any one of Formulas IV or the structure of any one of compounds 1-20.

In some embodiments, the hydrophobic tag comprises diphenylmethane, adamantine, or tri-Boc arginine, ie the hydrophobic tag comprises the structure:

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula A,

wherein X ¹ is CH ₂ , O, S, or NR ¹ and R ¹ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ —C ₆ heteroalkyl and X ² is C═O, CH ₂ , or

and R ³ and R ⁴ are independently H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl, and m is , 0, 1, 2, 3, or 4, and each R ² is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted _C2 - _C9 heteroaryl, optionally substituted _C2 - _C6 alkenyl, optionally substituted _C2 - _C6 heteroalkenyl, hydroxy, thiol, or optionally substituted or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula B,

wherein each R ⁴ , R ⁴ ′, and R ⁷ is independently H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ hetero alkyl and R ⁵ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl , optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl, wherein R ⁶ is H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₆ - _{C10 aryl ,} optionally substituted _C1 - _C6 alkylC3- _C10 carbocyclyl, or optionally substituted _C1 - _C6 alkylC6- _C10 aryl, and n is 0, 1, 2, 3, or 4, and each R ⁸ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ - _C6 heteroalkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally C ₂ -C ₉ heteroaryl substituted with , optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino wherein each R ⁹ and R ¹⁰ is independently H, halogen, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₆ -C ₁₀ Aryl and R ^4′ or R ⁵ includes a bond to a linker or is a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula C,

wherein each R ¹¹ , R ¹³ and R ¹⁵ is independently H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₁ -C ₆ heteroalkyl and R ¹² is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl, wherein R ¹⁴ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl, p is 0, 1, 2, 3, or 4, each R ¹⁶ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl , optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino, wherein q is 0, 1, 2, 3, or 4 and each R ¹⁷ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ hetero aryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino; are legally acceptable salts.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure of Formula D,

wherein each R ¹⁸ and R ¹⁹ is independently H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₁ -C ₆ alkylC ₃ -C ₁₀ carbocyclyl, or optionally substituted C ₁ -C ₆ alkylC ₆ -C ₁₀ aryl and r1 is 0, 1, 2, 3, or 4, and each R ²⁰ is independently halogen, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, hydroxy, thiol, or optionally optionally substituted amino, r2 is 0, 1, 2, 3, or 4, and each R ²¹ is independently halogen, optionally substituted C ₁ -C ₆ alkyl , optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₂ -C ₉ heteroaryl, optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ hetero alkenyl, hydroxy, thiol, or optionally substituted amino, or a pharmaceutically acceptable salt thereof.

In some embodiments, the ubiquitin ligase binding moiety comprises the structure:

Alternatively, it is a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the linker has the structure of Formula VII,
A ¹ -(B ¹ ) _f -(C ¹ ) _g -(B ² ) _h -(D)-(B ³ ) _i -(C ² ) _j -(B ⁴ ) _k -A ²
Formula VII
wherein A ¹ is the bond between the linker and A, A ² is the bond between B and the linker, and B ¹ , B ² , B ³ and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, optionally substituted C ₁ -C ₃ heteroalkyl, O, S, S(O) ₂ , and NR ^{N ;} is hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _2-6 heterocyclyl, optionally substituted C _6-12 aryl, or optionally substituted C _1-7 heteroalkyl, wherein C ¹ and C ² are each independently carbonyl, f, g, h, i, j, and k are each independently 0 or 1 and D is optionally substituted C _1-10 selected from thiocarbonyl, sulfonyl, or phosphoryl alkyl, optionally substituted C _2-10 alkenyl, optionally substituted C _2-10 alkynyl, optionally substituted C _2-6 heterocyclyl, optionally substituted C _{6 -12} aryl, optionally substituted C ₂ -C ₁₀ polyethylene glycol, or optionally substituted C _1-10 heteroalkyl, or A ¹ -(B ¹ ) _f -(C ¹ ) _g -(B ² ) _h with -(B ³ ) _i -(C ² ) _j -(B ⁴ ) _k -A ² .

In some embodiments, D is optionally substituted C ₂ -C ₁₀ polyethylene glycol. In some embodiments, C ¹ and C ² are each independently carbonyl or sulfonyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, optionally substituted C ₁ - selected from C ₃ heteroalkyl, O, S, S(O) ₂ and NR ^N , where ^RN is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, or optionally substituted C _{1 —C3} heteroalkyl. In some embodiments, j is 0. In some embodiments, k is 0. In some embodiments, j and k are each independently zero. In some embodiments, f, g, h, and i are each independently 1.

In some embodiments, the linker of Formula VII has the structure of Formula VIIa,

where A ¹ is the bond between the linker and A and A ² is the bond between B and the linker.

In some embodiments, D is an optionally substituted C _1-10 alkyl. In some embodiments, C ¹ and C ² are each independently carbonyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, optionally substituted C ₁ - selected from C ₃ heteroalkyl, O, S, S(O) ₂ and NR ^N , where ^RN is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ¹ , B ² , B ³ , and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl, O, S, S(O) ₂ , and NR ^N , where ^RN is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ¹ and B ⁴ are each independently optionally substituted C ₁ -C ₂ alkyl. In some embodiments, B ¹ and B ⁴ are each independently C ₁ alkyl. In some embodiments, B ² and B ⁴ are each independently NR ^N and R ^N is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, B ² and B ⁴ are each independently NH. In some embodiments, f, g, h, i, j, and k are each independently 1.

In some embodiments, the linker of Formula V has the structure of Formula VIIb,

where A ¹ is the bond between the linker and A and A ² is the bond between B and the linker.

Pharmaceutical Uses The compounds described herein are useful in the methods of the present invention and, without being bound by theory, through their ability to modulate the level, status, and/or activity of the BAF complex. For example, they are believed to exert their desirable effects by inhibiting the activity or levels of intracellular BRG1 and/or BRM proteins within the BAF complex in mammals.

One aspect of the invention relates to methods of treating disorders associated with BRG1 and/or BRM proteins, such as AML, in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to effect one (or more, such as two or more, three or more, four or more) of: (a) reduced tumor size, (b) reduced tumor growth rate, (c) increased tumor cell death, (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced metastasis rate, (g) reduced tumor recurrence, (h) increased survival in a subject, and (i) increased progression-free survival in a subject.

Treatment of cancer may result in a reduction in tumor size or volume. For example, after treatment, the tumor size is 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more). Tumor size may be measured by any reproducible means of measurement. For example, tumor size can be measured as the diameter of the tumor.

Treatment of cancer may further result in a reduction in the number of tumors. For example, after treatment, the number of tumors is 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more) is reduced. The number of tumors may be measured by any reproducible means of measurement, for example, the number of tumors may be visible to the naked eye or at a particular magnification (e.g., 2x, 3x, 4x, 5x, 10x). 10x, or 50x) by counting visible tumors.

Treatment of cancer may result in a reduction 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 greater than or equal to 5% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) of the number before treatment. %, or more). The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules can be measured by counting metastatic nodules visible to the naked eye or at a particular magnification (eg, 2x, 10x, or 50x).

Treatment of cancer may result in inhibition or slowing of metastatic progression of the cancer. For example, the patient may be administered an amount of an agent that reduces the activity or level of BRG1 and/or BRM effective in inhibiting metastasis of the cancer to other parts of the body (e.g., has metastasized (e.g., patients with uveal melanoma that has metastasized to the liver)). The agent can be administered in a pre-operative or post-operative setting (such as before or after surgical resection of cancer) and results in a decreased incidence of cancer metastasis.

Treating cancer can result in an increase in median survival time in a population of subjects treated according to the present invention as compared to a population of untreated subjects. For example, median survival is increased by more than 30 days (60, 90, or 120 days). An increase in average survival time of a population can be measured by any reproducible means. An increase in median survival time of a population can be measured, for example, by calculating for a population the median length of survival after initiation of treatment with a compound described herein. The increase in median survival time of a population also calculates, for example, the median length of survival after completion of the first round of treatment with a pharmaceutically acceptable salt of a compound described herein for a population. can be measured by

Treating cancer can also result in decreased mortality in a population of treated subjects compared to an untreated population. For example, mortality is reduced by more than 2% (eg, more than 5%, 10%, or 25%). A reduction in mortality in a population of treated subjects is measured in any reproducible manner, e.g. It can be measured by calculating the average number of disease-related deaths per year. A reduction in the mortality rate of a population is also e.g. can be measured by calculating

Combination Therapy The methods of the invention can be used alone or in combination with additional therapeutic agents, such as other agents to treat cancer or symptoms associated therewith, or with other types of therapies to treat cancer. Can be used in combination. In combination therapy, the dosage of one or more therapeutic compounds may be reduced from the standard dosages when administered alone. For example, doses can be determined empirically from drug combinations and permutations or estimated by isobologram analysis (eg, Black et al., Neurology 65:S3-S6 (2005)). In this case, the doses of the compounds when combined should provide a therapeutic effect.

In some embodiments, the second therapeutic agent is a chemotherapeutic agent (eg, a cytotoxic agent or other compound useful in treating cancer). These include alkylating agents, antimetabolites, folic acid analogues, pyrimidine analogues, purine analogues and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, Included are platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortican inhibitors, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), ilenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide, alkyl sulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carbocone, methledopa, and uredopa, ethyleneimine and methylamelamine, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine, acetogenins (specifically bratacin and bratacinone), camptothecin ( bryostatin, callistatin, CC-1065 (including its adzelesin, carzelesin, and baizelesin synthetic analogues), cryptophycins (specifically cryptophycin 1 and cryptophycin 8), dolastatin, duocarmycins (including synthetic analogues KW-2189 and CB1-TM1), eruterobin, pancratistatin, sarcodictin, spongistatin, nitrogen mustards such as chlorambucil, chlornafadine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novenbitine, phenesterin, prednimustine, trophosfamide, and uracil mustard, nitrosoureas such as camulustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine, antibiotics, For example, enediyne antibiotics (eg, calicheamicins, specifically calicheamicin gamma III and calicheamicin omega III (see, eg, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)). dynemicin, including dynemicin A; bisphosphonates such as clodronate; esperamicin; ), azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophylline, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® ( mitomycins such as epirubicin, ethorubicin, idarubicin, marceromycin, mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin; Antimetabolites such as potofylomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin, methotrexate and 5-fluorouracil (5-FU); denopterin, methotrexate, pteropterin, trimetrex folic acid analogues such as sart; purine analogues such as fludarabine, 6-mercaptopurine, thiamipurine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxfluridine, enocitabine, floxyuridine; carsterone Androgens such as , dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid replacement fluids such as floric acid; elfomithine; elliptinium acetate; epothilone; etogluside; gallium nitrate; hydroxyurea; lentinan; tansinoids; mitoguazone, mitoxantrone, mopidanmol, nitraeline, pentostatin; fenameth; pirarubicin; losoxantrone; podophyllic acid; schizophyllan; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, a chromophore-free, albumin-engineered nanoparticulate formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® docetaxel (Rhone-PoulencRorer, Antony, France). ;chlorambucil 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; daunomycin; aminopterin; Xeloda; ibandronate; irinotecan (eg, CPT-11); topoisomerase inhibitor RFS 2000; retinoids; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. More than one chemotherapeutic agent can be used in the cocktail administered in combination with the first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and can be found, for example, in 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 that is a biologic, such as a cytokine (eg, interferon or interleukin (eg, IL-2)) used in cancer therapy. In some embodiments, the biologic is an anti-VEGF agent, eg, an anti-angiogenic agent such as bevacizumab (AVASTIN®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody that stimulates a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer (eg, humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof). 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-I-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® (laxibakumab), BENLYSTA® (belimumab), YERVOY® (ipilimumab), ADCETRIS® (brentuximab vedotin), PERJETA® (pertuzumab), KADCYLA® (ado-trastuzumab entansine), and GAZYVA® (obinutuzumab). Antibody-drug conjugates are also included.

In some embodiments, the second agent is dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, CTLA-4 inhibitors (eg, ipilimumab), PD-1 inhibitors (eg, nivolumab or pembrolizumab) , PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or trametinib), and/or protein kinase C (PKC) inhibitors ( For example, sotrastaurine or LXS196).

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

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

The second agent can be a therapeutic agent that is a non-drug therapy. For example, the second therapeutic agent is radiotherapy, hyperthermia, photocoagulation, cryotherapy, hyperthermia surgical resection, and/or stem cell transplantation (eg, allogeneic or hematopoietic stem cell transplantation) of the tumor.

The second agent can be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (eg, a monospecific antibody such as a monoclonal antibody). An antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, eg, an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with the checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein ligand. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion protein such as ipilimumab/YERVOY® or tremelimumab). agent). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody) of PD-1 (e.g., nivolumab/OPDIVO®, pembrolizumab/KEYTRUDA®, pidilizumab/CT-011) or small molecule inhibitors). In some embodiments, the checkpoint inhibitor is an inhibitor (eg, an inhibitory antibody or small molecule inhibitor) of PDL1 (eg, MPDL3280A/RG7446, MEDI4736, MSB0010718C, BMS936559). In some embodiments, the checkpoint inhibitor is an inhibitor (eg, an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (eg, a PDL2/Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is B7-H3 (eg, MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1 , CHK2, A2aR, B-7 family ligands, or combinations thereof (eg, inhibitory antibodies or small molecule inhibitors).

In some embodiments, the anti-cancer therapy is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. T cells can 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, CAR-T cells can be generated by introducing a suitable expression vector encoding CAR into T cells. A source of T cells is obtained from a subject prior to expansion and genetic modification of T cells. T cells can be obtained from several sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymic tissue, tissue from sites of infection, ascites, pleural effusion, splenic tissue, and tumors. Any number of T cell lines available in the art may be used in certain embodiments of the invention. In some embodiments, the T cells are autologous T cells. Whether before or after genetic modification of the T cells to express the desired protein (e.g., CAR), the T cells are generally treated with, for example, U.S. Pat. , 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 No. 6,867,041, and US Patent Application Publication No. 20060121005.

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 can be administered immediately before, immediately after, 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 after the second therapeutic agent. Hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to It can be administered before or after 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30.

Delivery of Anti-BRG1 and/or BRM Agents Various methods are available for delivering anti-BRG1 and/or BRM agents to a subject, including viral and non-viral methods.

Viral Delivery Methods In some embodiments, an agent that reduces BRG1 and/or BRM levels and/or activity is delivered by a viral vector (eg, a viral vector expressing an anti-BRG1 and/or BRM agent). Viral genomes provide a rich source of vectors that can be used for efficient delivery of exogenous genes into mammalian cells. Viral genomes are particularly useful vectors for gene delivery because the polynucleotides contained within such genomes are integrated into the nuclear genome of mammalian cells, typically by general or specialized transduction. These processes occur as part of the natural viral replication cycle and do not require additional proteins or reagents to induce gene integration. Examples of viral vectors include retroviruses (e.g., retroviridae viral vectors), adenoviruses (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvoviruses (e.g., adeno-associated viruses), coronaviruses, Minus-strand RNA viruses (orthomyxoviruses (e.g., influenza virus), rhabdoviruses (e.g., rabies virus and varicella stomatitis virus), paramyxoviruses (e.g., measles virus and Sendai virus)), plus-strand RNA viruses ( picornaviruses and alphaviruses), and double-stranded DNA viruses (adenoviruses, herpesviruses (e.g., herpes simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus, replication-defective herpesvirus), and pox). viruses, including vaccinia virus, modified vaccinia Ankara (MVA), fowlpox virus and canarypox virus. Other viruses include, for example, Norwalk virus, togavirus, flavivirus, reovirus, papovavirus, hepadnavirus, human papillomavirus, human foamy virus, and hepatitis virus. Examples of retroviruses include avian leukemia sarcoma virus, avian C viruses, mammalian C, B and D viruses, oncoretroviruses, HTLV-BLV group viruses, lentiviruses, alpharetroviruses, gammaretroviruses, Spumaviruses (Coffin, JM, Retroviridae: The viruses and their replication, Virology (Third Edition) Lippincott-Raven, Philadelphia, 1996). Other examples include murine leukemia virus, murine sarcoma virus, murine mammary tumor virus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T-cell leukemia virus, baboon endogenous virus, gibbon leukemia virus, Mason • Pfizer simian virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and lentivirus. Other examples of vectors are described, for example, in US Pat. No. 5,801,030, the teachings of which are incorporated herein by reference.

Exemplary viral vectors include lentiviral vectors, AAV vectors, and retroviral vectors. Lentiviral and AAV vectors can integrate into the genome without cell division and both types have been tested in preclinical animal studies. Methods for preparing AAV are described in the art, for example, US 5,677,158, US 6,309,634, and US 6,683,058, each of which is incorporated herein by reference. incorporated into. Methods for lentivirus preparation and in vivo administration are described in US20020037281, incorporated herein by reference. Preferably, the lentiviral vector is a replication-defective lentiviral particle. Such lentiviral particles comprise a 5' lentiviral LTR, a tRNA binding site, a packaging signal, a promoter operably linked to a polynucleotide signal encoding a fusion protein, an initiation point for second strand DNA synthesis, and three 'can be produced from a lentiviral vector containing a lentiviral LTR.

Retroviruses, having 7-8 kb, are most commonly used in human clinical trials and have the ability to infect cells and stably integrate their genetic material into host cells with high efficiency (eg, WO95/ 30761, WO95/24929, each of which is incorporated herein by reference). Preferably, the retroviral vector is replication defective. This prevents further generation of infectious retroviral particles in the target tissue. Thus, the replication-defective virus becomes a "trapped" transgene that is stably integrated into the target cell genome. This is typically accomplished by deleting the gag, env, and pol genes (along with most of the rest of the viral genome). A heterologous nucleic acid is inserted in place of the deleted viral gene. The heterologous gene can be under the control of an endogenous heterologous promoter, another heterologous promoter active in the target cell, or the retroviral 5'LTR (viral LTRs are active in a variety of tissues).

These delivery vectors described herein can be made target specific by, for example, attaching a sugar, glycolipid, or protein (eg, an antibody to a target cell receptor).

A reversible delivery expression system may also be used. Cre-loxP or FLP/FRT systems and other similar systems can be used for reversible delivery expression of one or more of the nucleic acids described above. See WO2005/112620, WO2005/039643, US20050130919, US20030022375, US20020022018, US20030027335, and US20040216178. Specifically, the reversible delivery expression system described in US20100284990 can be used to provide selective or acute blockade.

Non-Viral Methods of Delivery There are several non-viral methods for delivery of anti-BRG1 and/or BRM agents, including polymeric, biodegradable microparticle, or microcapsule delivery devices known in the art. do. For example, colloidal dispersion systems can be used for targeted delivery of anti-BRG1 and/or BRM agents described herein. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, beads, and lipid-based systems such as oil-in-water emulsions, micelles, mixed micelles, and liposomes. Liposomes are artificial membrane vesicles useful as delivery vehicles in vitro and in vivo. It has been shown that large unilamellar vesicles (LUVs), which range in size from 0.2 to 4.0 μm, can encapsulate a significant proportion of aqueous buffers containing large macromolecules.

The composition of liposomes is usually a combination of phospholipids, usually combined with steroids, especially cholesterol. Other phospholipids or other lipids may also be used. The physical characteristics of liposomes depend on pH, ionic strength, and the presence of divalent cations.

Lipids useful in forming liposomes include phosphatidyl compounds such as phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerebrosides, and gangliosides. Exemplary phospholipids include egg phosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine. Targeting of liposomes can be based, for example, on organ-specificity, cell-specificity, and organelle-specificity, and is known in the art. In the case of liposome-targeted delivery systems, lipid groups may be incorporated into the lipid bilayer of the liposome to maintain the targeting ligand in stable association with the liposome bilayer. A variety of linking groups can be used to link the lipid chain to the targeting ligand. Additional methods are known in the art and are described, for example, in US Patent Application Publication No. 20060058255.

Pharmaceutical Compositions 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. be.

The compounds described herein can be used in free base form, in salt, solvate form, and as prodrugs. All forms are within the scope of the methods described herein. As will be appreciated by those skilled in the art, according to the methods of the present invention, the compounds described, or salts, solvates, or prodrugs thereof, can be administered to patients in a variety of forms depending on the route of administration chosen. . The compounds described herein can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration, and the pharmaceutical composition is accordingly Formulated. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

The compounds described herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier, or can be enclosed in hard or soft shell gelatin capsules, or compressed into tablets. or can be incorporated directly with dietary food. For oral therapeutic administration, the compounds described herein may be incorporated with excipients into the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. form may be used. The compounds described herein can also be administered parenterally. Solutions of compounds 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 alcohols, and in oils. These preparations may contain a preservative to prevent microbial growth under normal conditions of storage and use. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and The United States Pharmacopeia: The National Formulary (USP 41 NF36), publication headed in 2018 It is described in. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the form must be sterile and must be fluid to the extent that easy administration via a syringe is possible. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active agent in a physiologically acceptable aqueous or non-aqueous solvent and usually take the form of cartridges or refills for use with a nebulizing device. provided in single or multi-dose form in sterile form in a hermetically sealed container. Alternatively, the closed container may be a single dispensing device such as a single dose nasal inhaler or aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it contains a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. Aerosol dosage forms can also take the form of a pump-atomiser. Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles in which the active ingredient is formulated with carriers such as sugar, acacia, tragacanth, gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. The compounds described herein can be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is direct injection into tumor blood vessels and is specifically contemplated for individual solid, accessible tumors. Local, regional, or systemic administration may also be suitable. The compounds described herein can advantageously be contacted by administering an injection or multiple injections into the tumor, eg, spaced at about 1 cm intervals. In the case of surgical intervention, the present invention can be used pre-operatively, such as to subject an inoperable tumor to resection. Continuous administration may also be applied where appropriate, for example by implanting a catheter into the tumor or tumor vessels.

The compounds described herein can be administered to animals, e.g., humans, alone or in combination with a pharmaceutically acceptable carrier as described herein, the ratio of the compound being Determined by solubility and chemical properties, chosen route of administration, and standard pharmaceutical practice.

Dosage The dosage of a compound described herein, and/or a composition comprising a compound described herein, may vary depending on the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; The frequency and type of concomitant treatment, if any, of treatment; and the clearance rate of the compound in the treated animal can vary depending on many factors. Appropriate dosages can be determined by one of ordinary skill in the art based on the above factors. The compounds described herein can be administered initially at a suitable dosage that can be adjusted as necessary, depending on clinical response. In general, satisfactory results can be obtained when the compounds described herein are administered to humans in daily doses of, for example, 0.05 mg to 3000 mg (measured as solid form).

Alternatively, the patient's weight can be used to calculate dosage. For example, the dose of compound or pharmaceutical composition thereof administered to a patient can range from 0.1 to 50 mg/kg.

Kits The present invention also provides (a) a pharmaceutical composition comprising an agent that reduces the level and/or activity of BRG1 and/or BRM in a cell or subject, as described herein, and (b) A kit comprising a package insert with instructions for performing any of the methods described in . In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent that reduces BRG1 and/or BRM levels and/or activity in a cell or subject as described herein; (b) additional therapeutic agents (eg, anti-cancer agents); and (c) package inserts with instructions for performing any of the methods described herein.

Example 1. compound 17
Synthesis of Compound 17: Compound 17, a BRG1/BRM inhibitor, has the following structure.

Compound 17 was synthesized as shown in Scheme 1 below.

Step 1: Preparation of 2-bromo-1-(3-bromophenyl)ethene (Intermediate B)

To a solution of 1-(3-bromophenyl)ethanone (132.45 mL, 1.00 mol) in CHCl ₃ (250 mL) was added Br ₂ (77.70 mL, 1.51 mol) at 20° C. under N ₂ (g). was added dropwise. The reaction mixture was then stirred at 80°C. After 1 hour, the mixture was cooled to room temperature and concentrated to give Intermediate B (279.27 g) as a yellow oil, which was used directly in the next step.

Step 2: Preparation of 4-(3-bromophenyl)thiazol-2-amine (Intermediate C)

Intermediate B (279 g, 1.00 mol) was added to a solution of thiourea (229.23 g, 3.01 mol) in EtOH (1.5 L). The reaction mixture was stirred at 85°C. After 2 hours, the mixture was cooled to room temperature and concentrated in vacuo to give an oil. The oil was carefully poured into a saturated aqueous solution of NaHCO ₃ (2 L). The resulting basic (pH ~8) solution was extracted with ethyl acetate (3 x 2 L). The combined organic layers _were washed with brine (4 L), dried over _Na2SO4 , filtered and concentrated to give an oil. The oil was purified by column chromatography (SiO ₂ .PE:EA=5:1) to give Intermediate C (130.00 g, 494.40 mmol, 49.25% yield) as a yellow solid. LCMS (ESI) m/z: [M+H] ⁺ = 257.0. ¹ H NMR (400 MHz, DMSO-d6) δ 7.98 (m, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.44 - 7.42 (m, 1H), 7 .33 - 7.29 (m, 1H), 7.14 (s, 1H), 7.09 (s, 2H).

Step 3: Preparation of 4-[3-(4-pyridyl)phenyl]thiazol-2-amine (Intermediate E)

Intermediate C (20.00 g, 78.40 mmol), 4-pyridylboronic acid (28.9 g, 239.18 mmol), dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II) ) (2.56 g, 3.92 mmol) and K ₃ PO ₄ (66.56 g, 313.56 mmol) were diluted in 1,4-dioxane (240 mL) and water (24 mL). The mixture was purged with N ₂ (g) three times and then stirred at 80°C. After 7 hours, the reaction mixture was cooled to room temperature and water (800 mL) was added. The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layers _were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The resulting oil was stirred over a mixture of dichloromethane (30 mL) and MTBE (100 mL). After stirring for 5 min, the precipitate was filtered and washed with MTBE (10 mL) to give Intermediate E (16.20 g, 61.17 mmol, 78.03% yield) as a yellow solid. LCMS (ESI) m/z: [M+H] ⁺ = 254.0.

Step 4: Preparation (S)-4-(methylthio)-1-oxo-1-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)butan-2-aminium chloride (intermediate G)

Intermediate E (12.60 g, 49.74 mmol) and (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoic acid (18.60 g, 74.61 mmol) in dichloromethane (900 mL). EEDQ (24.60 g, 99.48 mmol) was added to the mixture. After stirring for 2 hours at room temperature, the reaction mixture was concentrated in vacuo. The residue was triturated with dichloromethane (100 mL) followed by MeOH (200 mL) to give Intermediate G (11.70 g, 23.73 mmol, 47.71% yield, ee%=99.44%) as a white Obtained as a solid. LCMS (ESI) m/z: [M+H] ⁺ = 485.1. ¹ H NMR (400 MHz, DMSO) δ 12.39 (s, 1H), 8.68-8.66 (m, 2H), 8.30 (s, 1H), 8.02-7.99 (m , 1H), 7.83 (s, 1H), 7.76-7.74 (m, 3H), 7.61-7.57 (m, 1H), 7.28 (d, J=7.6 Hz, 1H), 4.31-4.30 (m, 1H), 2.65-2.44 (m, 2H), 2.06 (s, 3H) 2.01-1.85 (m, 2H), 1.38 (s, 9H).

Step 5: (S)-4-(methylthio)-1-oxo-1-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)butan-2-aminium chloride Preparation of (Intermediate H)

To a mixture of Intermediate G (11.50 g, 23.73 mmol) in MeOH (50 mL) was added a solution of 4M HCl in 1,4-dioxane (100 mL). After stirring for 1 hour at room temperature, the mixture was poured into MTBE (1000 mL). The resulting precipitate was filtered to give Intermediate H (9.99 g, 23.73 mmol, 100.00% yield, HCl salt) as a yellow solid. LCMS (ESI) m/z: [M+H] ⁺ = 385.0

Step 6: 4-Amino-N-[(1S)-3-methylsulfanyl-1-[[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]carbamoyl]propyl]benzamide (compound 17) preparation of

To a mixture of intermediate H (4.00 g, 9.50 mmol) and 4-aminobenzoic acid (1.30 g, 9.50 mmol) in DMF (40 mL) was added N,N-diisopropylethylamine (6.62 mL, 38.5 mL). 01 mmol), EDCI (2.73 g, 14.25 mmol) and HOBt (1.93 g, 14.25 mmol) were added sequentially. The solution was stirred at 25° C. for 14 hours and then poured into water (200 mL). The resulting precipitate was collected by filtration. The solid was triturated in MeOH (200 mL) and filtered. The solid was further purified by column chromatography (SiO ₂ , DCM:MeOH=80:1 to 20:1) to give compound 17 (2.13 g, 4.19 mmol, 44.11% yield, ee%=99. 28%) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 504.0. ¹ H NMR (400 MHz, DMSO) δ 12.40 (s, 1H), 8.68-8.66 (m, 2H), 8.31-8.30 (m, 1H), 8.22 (d , J = 7.2 Hz, 1H), 8.02-7.99 (m, 1H), 7.82 (s, 1H), 7.76-7.74 (m, 3H), 7.67- 7.63 (m, 2H), 7.61-7.57 (m, 1H), 6.58-6.54 (m, 2H), 5.67 (s, 2H), 4.72-4. 67 (m, 1 H), 2.65-2.54 (m, 2 H), 2.12-2.06 (m, 5 H).

ATPase activity of compound 17 ATPase catalytic activity of BRM or BRG-1 in the presence of compound 17 was measured by an in vitro biochemical assay using ADP-Glo™ (Promega, V9102). Once the reaction is complete, the ADP-Glo™ Kinase Assay is performed in two steps. The first step is to deplete the ATP not consumed during the reaction. The second step is the conversion of the reaction product, ADP, to ATP, which is utilized by luciferase to generate luminescence and is detected by a luminescence reader such as Envision.

The assay reaction mixture (10 μL) contained 20 mM Tris (pH 8), 20 mM MgCl ₂ , 50 mM NaCl, 0.1% Tween-20, and 1 mM fresh DTT (Pierce™ DTT (dithiothreitol)). 30 nM BRM or BRG1, 20 nM salmon sperm DNA (from Invitrogen, UltraPure™ Salmon Sperm DNA Solution, catalog number 15632011), and 400 μM Contains ATP. The reaction was initiated by adding 2.5 μL of ATPase solution to 2.5 μL of ATP/DNA solution on a small white Proxiplate-384 Plus plate (Perkin Elmer, Catalog #6008280) and incubated for 1 hour at room temperature. incubate. Reactions are then incubated at room temperature for 40 minutes after adding 5 μL of ADP-Glo™ reagent provided in the kit. 10 μL of the kinase detection reagent provided in the kit is then added to convert ADP to ATP and the reaction is incubated at room temperature for 60 minutes. Finally, luminescence measurements are collected on a plate-reading luminometer such as the Envision.

BRM and BRG1 were synthesized from the top five insect cell lines with greater than 90% purity. Compound 17 was found to have an IP ₅₀ of 10.4 nM against BRM and 19.3 nM against BRG1 in the assay.

Example 2. Effect of Inhibition of BRG1/BRM ATPases on Cancer Cell Line Proliferation and an immortalized embryonic kidney line (HEK293T) were seeded in 96-well plates containing growth medium (see Table 1). Compound 17, a BRG1/BRM ATPase inhibitor, was dissolved in DMSO and added to cells in a 0-10 μM gradient at the time of plating. Cells were incubated at 37°C for 3 days. After 3 days of treatment, media was removed from the cells and 30 μL of TrypLE (Gibco) was added to the cells for 10 minutes. Cells were detached from the plate and resuspended by adding 170 μL growth medium. Cells were counted from two DMSO-treated control wells and the initial cell numbers plated at the start of the experiment were replated onto plates containing fresh compound for an additional 4 days at 37°C. On day 7, cells were harvested as described above.

On days 3 and 7, relative cell proliferation was measured by adding Cell-titer glo (Promega) and luminescence was measured with an Envision plate reader (Perkin Elmer). The concentration of compound 17 at which the growth of each cell line is inhibited by 50% ( _GI50 ) was calculated using Graphpad Prism and plotted in FIG.

Multiple myeloma cell lines (OPM2, MM1S, LP1), ALL cell lines (TALL1, JURKAT, RS411), DLBCL cell lines (SUDHL6, SUDHL4, DB, WSUDLCL2, PFEIFFER), AML cell lines (OCIAML5), MDS cell lines (SKM1), ovarian cancer cell lines (OV7, TYKNU), esophageal cancer cell lines (KYSE150), rhabdoid tumor lines (RD, G402, G401, HS729, A204), liver cancer cell lines (HLF, HLE, PLCRPF5), and For lung cancer cell lines (SW1573, NCIH2444), the above method was performed with the following modifications. Cells were seeded in 96-well plates and the next day the BRG1/BRM ATPase inhibitor Compound 17 was dissolved in DMSO and added to the cells in a gradient of 0-10 μM. At the time of cell splitting on days 3 and 7, cells were split into new 96-well plates and fresh compound was added 4 hours after replating.

Table 1 lists the cell lines tested and the growth media used.

Results: As shown in Figure 1, AML cell lines were more sensitive to BRG1/BRM inhibition than other tested cell lines. Inhibition of AML cell lines was maintained up to 7 days.

Example 3. Synthesis of Compound 18 Compound 18, a BRG1/BRM inhibitor, has the following structure.

Compound 18 was synthesized as shown in Scheme 2 below.

Step 1: (S)-1-(methylsulfonyl)-N-(4-(methylthio)-1-oxo-1-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl) ) Preparation of amino)butan-2-yl)-1H-pyrrole-3-carboxamide (Compound 18)

(S)-4-(methylthio)-1-oxo-1-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)butane-2- in DMF (20 mL) To a mixture of aminium chloride (2.00 g, 4.75 mmol) and 1-methylsulfonylpyrrole-3-carboxylic acid (0.899 g, 4.75 mmol) was added EDCI (1.37 g, 7.13 mmol), HOBt (0 .963 g, 7.13 mmol) and N,N-diisopropylethylamine (3.31 mL, 19.00 mmol) were added. After stirring for 3 hours, the mixture was poured into water (100 mL) and the resulting precipitate was filtered. The solid was triturated in MeOH (20 mL) and the precipitate collected by filtration. The solid was redissolved in DMSO (10 mL) and poured into MeOH (50 mL). The precipitate was filtered and lyophilized to give compound 18 (2.05 g, 3.66 mmol, 77.01% yield) as a white solid. LCMS (ESI) m/z [M+H] ⁺ = 555.9. ¹ H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 8.68-8.66 (m, 2H), 8.46 (d, J = 7.2 Hz, 1H), 8. 31-8.30 (m, 1H), 8.02-8.00 (m, 1H), 7.94-7.96 (m, 1H), 7.83 (s, 1H), 7.73- 7.74 (m, 3H), 7.61-7.57 (m, 1H), 7.31-7.29 (m, 1H), 6.79-6.77 (m, 1H), 4. 74-4.69 (m, 1H), 3.57 (s, 3H), 2.67-2.53 (m, 2H), 2.13-2.01 (m, 5H). SFC: AS-3-MeOH(DEA)-40-3mL-35T. lcm, t = 0.932 min, ee% = 100%.

Example 4. Effect of inhibition of BRG1/BRM ATPase on proliferation of cancer cell lines Procedure: All cell lines described above in Example 2 were also tested with compound 18 as described above. Additionally, the following cell lines were also tested as follows. Briefly, Ewing sarcoma cell lines (CADOES1, RDES, SKES1), retinoblastoma cell lines (WERIRB1), ALL cell lines (REH), AML cell lines (KASUMI1), prostate cancer cell lines (PC3, DU145, 22RV1). , melanoma cell lines (SH4, SKMEL28, WM115, COLO829, SKMEL3, A375), breast cancer cell lines (MDAMB415, CAMA1, MCF7, BT474, HCC1419, DU4475, BT549), B-ALL cell line (SUPB15), CML cell line (K562, MEG01), Burkitt's lymphoma cell line (RAMOS2G64C10, DAUDI), mantle cell lymphoma cell line (JEKO1, REC1), bladder cancer cell line (HT1197), and lung cancer cell line (SBC5). The following modifications were used: Cells were seeded in 96-well plates and the next day the BRG1/BRM ATPase inhibitor Compound 18 was dissolved in DMSO and added to the cells in a 0-10 μM gradient. At the time of cell splitting on days 3 and 7, cells were split into new 96-well plates and fresh compound was added 4 hours after replating.

Table 2 lists the cell lines tested and the growth media used.

Results: As shown in Figure 2, AML cell lines were more sensitive to BRG1/BRM inhibition than other tested cell lines. Inhibition of AML cell lines was maintained up to 7 days.

Example 5. Effect of inhibition of BRG1/BRM ATPase on proliferation of cancer cell lines.
Procedure: As previously described (“High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines”, Yu et al, Nature Biotechnolo gy 34, 419-423, 2016), PRISM (of relative inhibition in mixtures A pooled cell viability assay using simultaneous profiling) was performed with the following modifications. Cell lines were obtained from the Cancer Cell Line Encyclopedia (CCLE) collection, and 10% inactivated fetal bovine serum was used to apply a proprietary infection and pooling protocol to a large panel of such cell lines. They were adapted to phenol red-free RPMI-1640 medium supplemented with (FBS). Using blasticidin as a selectable marker, a lentiviral spin-infection protocol was performed at an estimated multiplicity of infection (MOI) of 1 for all cell lines to label each cell line with a 24-nucleotide barcode. introduced. Over 750 stably barcoded PRISM cancer cell lines were then pooled together into 25 pools according to doubling time. For the screening run, instead of seeding each well with a pool of 25 cell lines as previously described (Yu et al.), pools of all adherent cell lines or all suspension cell lines were They were seeded together using T25 flasks (100,000 cells/flask) or 6-well plates (50,000 cells/well). Cells were treated with either DMSO or compound starting from the highest concentration of 10 μM, with 8 measurement points, 3-fold dose response in triplicate. As a control for assay robustness, cells were treated with the two previous validated compounds, AZ-628, a pan-Raf inhibitor, and Parallel treatments were performed with the proteasome inhibitor bortezomib.

After 3 days of treatment with compounds, cells were lysed, genomic DNA was extracted and barcodes were amplified by PCR and detected by next generation sequencing. Cell viability was determined by comparing cell line-specific barcode counts in treated samples to those in DMSO and day 0 controls. A dose-response curve was fitted for each cell line and the corresponding area under the curve (AUC) was calculated and compared to the median AUC of all cell lines (Fig. 4). Cell lines with AUC below the median were considered the most sensitive.

Example 6. Synthesis of Compound 19 Compound 19, a BRG1/BRM inhibitor, has the following structure.

Compound 19 was synthesized as shown in Scheme 3 below.

Step 1: Preparation of 6-fluoropyridine-2-carbonyl chloride (Intermediate L)

To a cooled (0° C.) solution of 6-fluoropyridine-2-carboxylic acid (50.00 g, 354.36 mmol) in dichloromethane (500 mL) and N,N-dimethylformamide (0.26 mL, 3.54 mmol) was Oxalyl chloride (155.10 mL, 1.77 mol) was added. After complete addition of oxalyl chloride, the reaction mixture was warmed to room temperature and stirred for an additional 0.5 hours. The mixture was then concentrated in vacuo to give Intermediate L (56.50 g) as a white solid, which was used in the next step without further purification.

Step 2: Preparation of 2-chloro-1-(6-fluoro-2-pyridyl)ethene (Intermediate M)

To a cooled (0° C.) mixture of Intermediate L (56.00 g, 351.00 mmol) in 1,4-dioxane (800 mL) was added dropwise a solution of 2M trimethylsilyldiazomethane in hexanes (351 mL). The resulting reaction mixture was stirred at 25° C. for 10 hours. The reaction mixture was then quenched with a solution of 4M HCl in 1,4-dioxane (500 mL). After stirring for 2 hours, the reaction solution was concentrated in vacuo to give an oil. The residue was diluted with saturated aqueous _NaHCO3 (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give Intermediate M (35.50 _g ) as a white solid, Used it directly for the next step. LCMS (ESI) m/z: [M+H] ⁺ = 173.8.

Step 3: Preparation of 4-(6-fluoro-2-pyridyl)thiazol-2-amine (Intermediate O)

NaF (3.56 g, 84.82 mmol) was added. After stirring for 30 minutes, the reaction mixture was partially concentrated in vacuo to remove MeOH. The resulting solution was acidified to pH~3 with 2M aqueous HCl and extracted with EtOAc (3 x 200 mL). The combined organic layers were discarded and the aqueous phase was basified with saturated aqueous NaHCO ₃ (500 mL). After stirring for 30 minutes, the aqueous phase was extracted with EtOAc (3 x 325 mL). The combined organic layers were washed with brine (3 x 225 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The solid was triturated with petroleum ether (300 mL), stirred at 25° C. for 10 minutes and filtered. The solid was dried under vacuum to give Intermediate O (28.00 g, 143.43 mmol, 70.13% yield, 100% purity) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 195.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00-7.96 (m, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.24 (s, 1H ), 7.16 (s, 2H), 7.02 (d, J = 8.0 Hz, 1H).

Step 4: Preparation of tert-butyl N-[2-[[4-(6-fluoro-2-pyridyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (Intermediate P)

A solution of N-Boc-glycine (5.92 g, 33.81 mmol), HATU (12.86 g, 33.81 mmol), and N,N-diisopropylethylamine (21.41 mL, 122.94 mmol) in dichloromethane (100 mL) was added Intermediate O (6.00 g, 30.74 mmol). After stirring for 2 hours, the reaction mixture was concentrated. The resulting oil was diluted with water (100 mL) and then extracted with EtOAc (4 x 60 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a solid _. The solid was triturated with a 1:1 mixture of petroleum ether and MeOH (40 mL). After stirring for 20 min at 25° C., the suspension was filtered and the filter cake was washed with MTBE (20 mL). The solid was dried in vacuo to give Intermediate P (7.70 g, 21.63 mmol, 70.4% yield, 99.0% purity) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 353.1.

Step 5: Preparation of 2-((4-(6-fluoropyridin-2-yl)thiazol-2-yl)amino)-2-oxoethane-1-aminium chloride (Intermediate Q)

A solution of Intermediate P (5.40 g, 15.32 mmol) in 4 M HCl in 1,4-dioxane (35 mL) was stirred at 25° C. for 1.5 hours. The reaction mixture was then concentrated under vacuum to give Intermediate Q (4.42 g) as a white solid, which was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H] ⁺ = 252.9.

Step 6: 1-tert-butyl-N-[2-[[4-(6-fluoro-2-pyridyl)thiazol-2-yl]amino]-2-oxo-ethyl]pyrrole-3-carboxamide (intermediate Preparation of S)

Intermediate Q (3.00 g, 10.39 mmol), 1-tert-butylpyrrole-3-carboxylic acid (1.74 g, 10.39 mmol) and N,N-diisopropylethylamine (9.05 mL) in dichloromethane (40 mL). , 51.95 mmol) was added sequentially with HOBt (1.68 g, 12.47 mmol) and EDCI (2.39 g, 12.47 mmol). After stirring for 4 hours, the mixture was concentrated in vacuo. The residue was diluted with water (250 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The resulting solid was triturated with a 1:1 mixture of MTBE/EtOAc (400 mL) and stirred for 30 minutes before filtering the suspension. The solid was washed with MTBE (3×85 mL) and dried under vacuum to give Intermediate S (3.10 g, 7.64 mmol, 73.6% yield, 99.0% purity) as a white solid. Obtained. LCMS (ESI) m/z: [M+H] ⁺ = 402.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 8.18-8.15 (m, 1H), 8.09-8.08 (m, 1H), 7 .87-7.83 (m, 2H), 7.52 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.97 (m, 1H), 6.47 ( s, 1H), 4.10 (d, J=5.6 Hz, 2H), 1.49 (s, 9H).

Step 7: 1-(tert-butyl)-N-(2-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-2- Preparation of oxoethyl)-1H-pyrrole-3-carboxamide (Compound 19)

To a solution of intermediate S (0.100 g, 0.249 mmol) in DMSO (1 mL) was added N,N-diisopropylethylamine (0.130 mL, 0.747 mmol) and cis-2,6-dimethylmorpholine (0.057 g). , 0.498 mmol) was added. The resulting reaction mixture was stirred at 120°C. After 12 hours, the solution was cooled to room temperature, diluted with MeOH (3 mL) and then concentrated in vacuo. The resulting oil was purified by preparative HPLC (0.1% TFA, column: Luna C18 150*25 5u, mobile phase: [water (0.075% TFA)-ACN], B%: 30 %-60%, 2 min). Appropriate fractions were collected and lyophilized to give compound 19 (0.079 g, 0.129 mmol, 51.94% yield, 100% purity) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ = 497.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.27 (s, 1H), 8.17 - 8.14 (m, 1H), 7.75 (s, 1H), 7.63 - 7 .59 (m, 1H), 7.51 (s, 1H), 7.25 (d, J = 7.2 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J = 8.8 Hz, 1 H), 6.47 (s, 1 H), 4.24 (d, J = 12.4 Hz, 2 H), 4.08 (d, J = 5.6 Hz, 2 H), 3 .64 - 3.61 (m, 2H), 2.44 - 2.38 (m, 2H), 1.49 (s, 9H), 1.18 (d, J = 5.6 Hz, 6H).

Example 7. BRM/BRG1 inhibition causes slowing and steady cell growth in MV4;11 and EOL-1 human AML tumors in vivo.
Methods: BALB/c nude mice (Beijing Anikeeper Biotech, Beijing) were injected with single cells of EOL-1 or MV4;11 human AML tumor cells (1×10 ⁷ ) in 100 μL IDMD in 10% fetal bovine serum (FBS) The suspension was inoculated subcutaneously in the right thigh. When the size reached approximately 100 mm3, the mice were randomized to vehicle group [20% HP-B-CD] or treatment group: Compound 19 (50 mg/kg/day po for 21 days). All dose volumes were adjusted by weight to mg/kg.

Results: As shown in Figure 4, treatment with 50 mg/kg of Compound 19 led to cellular stasis in MV4;11. As shown in Figure 5, treatment with 50 mg/kg Compound 19 retarded the growth of EOL-1 tumors. All treatments were well tolerated based on the observed % body weight change.

Example 8: Synthesis of Compound 20 N-((S)-1-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3 -Methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 20) was synthesized as shown in Scheme 4 below.
Scheme 4

Step 1: Preparation of 6-fluoropyridine-2-carbonyl chloride (Intermediate B)

To a cooled (0° C.) solution of 6-fluoropyridine-2-carboxylic acid (50.0 g, 354 mmol) in dichloromethane (500 mL) and N,N-dimethylformamide (0.26 mL, 3.54 mmol) was added oxalyl chloride. (155 mL, 1.77 mol) was added. After complete addition of oxalyl chloride, the reaction mixture was allowed to warm to room temperature. After 0.5 h, the mixture was concentrated under vacuum to give Intermediate B (56.50 g) as a white solid, which was used in the next step without further purification.

Step 2: 2-chloro-1-(6-fluoro-2-pyridyl)ethenone (Intermediate C)

To a cooled (0° C.) mixture of Intermediate B (56.0 g, 351 mmol) in 1,4-dioxane (800 mL) was added dropwise a 2M solution of trimethylsilyldiazomethane in hexanes (351 mL, 702 mmol). The resulting reaction mixture was stirred at 25° C. for 10 hours. The reaction mixture was sequentially quenched with a solution of 4M HCl in 1,4 dioxane (500 mL, 2.0 mol). After stirring for 2 hours, the reaction solution was concentrated under vacuum to give an oil. The residue was diluted with saturated aqueous NaHCO ₃ and extracted with ethyl acetate three times. The combined organic layers were washed twice with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give Intermediate C (35.5 g) as a white solid, used directly in the next step.
LCMS (ESI) m/z: [M+H] ⁺ = 173.8.

Step 3: Preparation of 4-(6-fluoro-2-pyridyl)thiazol-2-amine (Intermediate E)

To a solution of Intermediate C (35.5 g, 205 mmol) and thiourea (14.0 g, 184 mmol) in a mixture of methanol (250 mL) and water (250 mL) at room temperature was added NaF (3.56 g, 84.8 mmol). added. After stirring for 0.5 h, the reaction mixture was partially concentrated under vacuum to remove MeOH and the resulting solution was acidified to pH ~3 with 2M aqueous HCl. After 15 minutes, the solution was extracted three times with ethyl acetate. The organic layer was discarded and the aqueous phase was alkalinized with saturated aqueous _NaHCO3 , stirred for 30 minutes and extracted three times with ethyl acetate. The combined organic layers were washed with brine three _times , dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether, stirred for 10 minutes at 25°C and filtered. The resulting solid was dried under vacuum to give Intermediate E (28.0 g, 143 mmol, 70.1% yield, 100% purity) as a white solid.
LCMS (ESI) m/z: [M+H] ⁺ = 195.8.
¹ H NMR (400 MHz, DMSO- _d6 ) δ 8.00 - 7.96 (m, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 2H), 7.02 (d, J = 8.0 Hz, 1H).

Step 4: Preparation of 4-[6-[cis-2,6-dimethylmorpholin-4-yl]-2-pyridyl]thiazol-2-amine (Intermediate G)

Intermediate E (2.00 g, 10.3 mmol), cis-2,6-dimethylmorpholine (3.54 g, 30.7 mmol), and DIPEA (5.35 mL, 30.7 mmol) in dimethylsulfoxide (10 mL). The mixture in 10 portions was stirred in parallel at 120° C. under N ₂ atmosphere. After 36 hours, the reaction mixtures were combined and added dropwise to water. The resulting suspension was filtered, washed with filter cake water three times and petroleum ether once, then dried under reduced pressure to give Intermediate G (25.5 g, 87.8 mmol, 95.2% yield) was obtained as a yellow solid.
LCMS (ESI) m/z: [M+H] ⁺ = 291.2.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56 - 7.54 (m, 1H), 7.17 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H) , 7.01 (s, 2H), 6.72 (d, J = 8.8 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.67 - 3.55 (m, 2H ), 2.38 - 2.34 (m, 2H), 1.17 (d, J = 6.4 Hz, 6H).

Step 5: tert-butyl N-[(1S)-2-[[4-[6-[cis-2,6-dimethylmorpholin-4-yl]-2-pyridyl]thiazol-2-yl]amino]- Preparation of 1-(methoxymethyl)-2-oxo-ethyl]carbamate (Intermediate I)

To a solution of intermediate G (12.0 g, 41.3 mmol) and (2S)-2-(tertbutoxycarbonylamino)-3-methoxy-propanoic acid (10.9 g, 49.6 mmol) in dichloromethane (60 mL), EEDQ (12.3 g, 49.6 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1-3:2) to give Intermediate I (20.0 g, 40.7 mmol, 98.5% yield) as a yellow gum. .
LCMS (ESI) m/z: [M+H] ⁺ = 492.2.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.37 (s, 1H), 7.78 (s, 1H), 7.64 - 7.60 (m, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.50 - 4.48 (m , 1H), 4.25 (d, J = 11.6 Hz, 2H), 3.70 - 3.51 (m, 4H), 3.26 (s, 3H), 2.44 - 2.40 ( m, 2H), 1.39 (s, 9H), 1.18 (d, J = 6.4 Hz, 6H).

Step 6: (S)-4-(4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-methoxy-3-oxobutane-2-aminium Preparation of Chloride (Intermediate J)

A solution of 4M HCl in 1,4-dioxane (200 mL, 800 mmol) was added to a solution of Intermediate I (20.0 g, 40.7 mmol) in dichloromethane (50 mL). After stirring for 2 hours at room temperature, the mixture is diluted with methyl tert-butyl ether to give a suspension. The solid was collected by filtration, washed twice with methyl tert-butyl ether and dried under vacuum to give Intermediate J (19.0 g) as a yellow solid which was used in the next step without further purification. did.
LCMS (ESI) m/z: [M+H] ⁺ = 392.3.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.44 - 12.30 (m, 1H), 8.65 (d, J = 4.4 Hz, 3H), 7.87 (s, 1H) , 7.66 - 7.64 (m, 1H), 7.25 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.25 (d, J = 11.6 Hz, 2H), 3.94 - 3.86 (m, 1H), 3.85 - 3.77 (m, 1H) , 3.69 - 3.57 (m, 2H), 3.31 (s, 3H), 2.43 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H).

Preparation of 1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (Intermediate K) 1-(Methylsulfonyl)-1H-pyrrole-3-carboxylic acid was synthesized as shown in Scheme 5 below.

Step A: Preparation of tert-butyl 1H-pyrrole-3-carboxylate (Intermediate N)

A mixture of tert-butyl-prop-2-enoate (78.6 mL, 542 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (106 g, 542 mmol) in THF (1300 mL) was treated with 60% NaH in mineral oil ( 25.97 g, 649 mmol) was added slowly over 1 hour at 30°C and then heated to 70°C. After 2 hours, the reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted three times with ethyl acetate. The combined organic phase was washed twice with brine, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced _pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1-3:1) to give Intermediate N (41.5 g, 236 mmol, 43% yield) as a yellow solid.
LCMS (ESI) m/z [M+Na] ⁺ = 180.4.
¹ H NMR (400 MHz, CDCl ₃ ) δ8.36 (br s, 1H), 7.35 - 7.25 (m, 1H), 6.71 - 6.62 (m, 1H), 6.59 - 6.49 (m, 1H), 1.48 (s, 9H).

Step B: Preparation of tert-butyl 1-methylsulfonylpyrrole-3-carboxylate (Intermediate O)

To a cooled (0° C.) solution of intermediate N (40.5, 242 mmol) in THF (1500 mL) was added 1M NaHMDS (484 mL, 484 mmol). After stirring for 30 minutes at 0°C, methanesulfonyl chloride (28.1 mL, 363 mmol) was added slowly and the mixture was warmed to 30°C. After 16 hours, the reaction mixture was slowly poured into saturated aqueous NH ₄ Cl and extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced _pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1) to give a yellow solid. The yellow solid was triturated with methyl tert-butyl ether at room temperature, stirred for 20 min, filtered and dried under vacuum to give Intermediate O (25.7 g, 105 mmol, 43% yield) as a white solid. .
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66-7.64 (m, 1H), 7.10-7.08 (m, 1H), 6.73-6.71 (m, 1H), 3.21 (s, 3H), 1.56 (s, 9H).

Step C: Preparation of 1-methylsulfonylpyrrole-3-carboxylic acid (Intermediate K)

To a mixture of intermediate O (25.7 g, 105 mmol) in 1,4-dioxane (100 mL) was added a solution of 4M HCl in 1,4-dioxane (400 mL, 1.6 mol) at 15°C. After stirring for 14 hours at 15° C., the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with methyl tert-butyl ether at 15° C. for 16 hours, the mixture was filtered and dried under vacuum to give Intermediate K (18.7 g, 98.8 mmol, 94% yield) as a white solid. .
LCMS (ESI) m/z [M+H] ⁺ = 189.8.
¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.78 - 7.77 (m, 1H), 7.25 - 7.23 (m, 1H), 6.72 - 6.70 (m, 1H) , 3.37 (s, 3H).

Step 7: N-((S)-1-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino-3-methoxy-1-oxo Preparation of propan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide

1-methylsulfonylpyrrole-3-carboxylic acid (Intermediate K) (2.43 g, 12.9 mmol), EDCl (2.69 g, 14.0 mmol), HOBt (1.89 g, 14.0 mmol), and DIPEA ( 10.2 mL, 58.4 mmol) in dichloromethane (50 mL) was added Intermediate J (5.00 g, 11.7 mmol). After stirring for 4 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed 3 times with saturated aqueous NH ₄ Cl, 1 time with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1-1:2). The residue was triturated with methyl tert-butyl ether. After 0.5 hours, the suspension was filtered and the filter cake was washed with methyl tert-butyl ether and dried under vacuum. The solid was dissolved in dimethylsulfoxide (12 mL) and added dropwise to water (800 mL). The suspension was filtered to obtain a filter cake. The filter cake was suspended in water and stirred at room temperature. After 1 hour, the solids were collected by filtration, washed with water three times, dried under vacuum and given to N-((S)-1-((4-(6-(cis-2,6-dimethylmorpholino ) pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (3.9 g, 6 .93 mmol, 59.3% yield) as a white solid.
LCMS (ESI) m/z: [M+H] ⁺ = 563.1.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.49 (br s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 7.98 - 7.97 (m, 1H ), 7.78 (s, 1H), 7.67 - 7.57 (m, 1H), 7.29 - 7.27 (m, 1H), 7.26 (d, J = 7.2 Hz, 1H), 6.88 - 6.74 (m, 2H), 4.94 - 4.91 (m, 1H), 4.25 (d, J = 11.6 Hz, 2H), 3.77 - 3 .67 (m, 2H), 3.63 - 3.62 (m, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 2.44 - 2.38 (m, 2H ), 1.18 (d, J = 6.0 Hz, 6H).

Example 9. BRM/BRG1 Inhibition Causes Tumor Growth Delay in OCI-AML2 Tumors Carrying DNMT3A Mutations Methods: SCID mice (Charles River, Wilmington) were injected with 100 μL of OCI-AML2 human AML tumor cells (1×10 cells) in RPMI-1640 medium. ⁷ ) were inoculated subcutaneously in the right thigh with single cell suspensions. When tumor size reached approximately 100 mm ³ , mice were neutered into either the vehicle group (20% HP-B-CD) or the treatment group (compound 20 at 1.5 mg/kg/day by oral route for 21 days). artificialized. All dose volumes were weight adjusted to mg/kg.
Results: As shown in Figure 6, treatment with 1.5 mg/kg Compound 20 inhibited the growth of OCI-AML2 tumors. All observed % body weight changes were well tolerated.

OTHER EMBODIMENTS All publications, patents and patent applications mentioned in this specification are expressly and individually indicated that each individual publication, patent or patent application is incorporated by reference in its entirety. to the same extent that they are incorporated herein by reference in their entireties. Where a term in this application is found to be defined differently in documents incorporated herein by reference, the definitions provided herein shall serve as the definition for that term.

While this invention has been described in relation to specific embodiments thereof, the invention is capable of further modifications and this application is generally consistent with the principles of the invention and is intended to be used in the art to which this invention pertains. The essential It will be understood that it can be applied to any feature as long as it is within the scope of the claims.

Other embodiments are within the claims.

Claims (35)

A method of treating acute myeloid leukemia in a subject in need thereof, comprising administering to said subject an effective amount of an agent that reduces the level and/or activity of BRG1 and/or BRM , said method. A method of reducing tumor growth of acute myeloid leukemia in a subject in need thereof, comprising administering to said subject an effective amount of an agent that reduces the level and/or activity of BRG1 and/or BRM in said tumor The above method, comprising administering to A method of inhibiting metastatic progression of acute myeloid leukemia in a subject, comprising administering an effective amount of an agent that reduces the level and/or activity of BRG1 and/or BRM. A method of inhibiting metastatic colonization of acute myeloid leukemia in a subject, said method comprising administering an effective amount of an agent that reduces the level and/or activity of BRG1 and/or BRM. A method of reducing BRG1 and/or BRM levels and/or activity in acute myelogenous leukemia, wherein said cells are treated with an effective amount of an agent that reduces BRG1 and/or BRM levels and/or activity in said cells. The above method, comprising contacting. 6. The method of claim 5, wherein said cell is within a subject. The method of any one of claims 1-6, wherein the acute myeloid leukemia is metastatic. said AML is acute promyelocytic leukemia, preexisting myelodysplastic syndrome or myeloproliferative disease, therapy-related AML, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related bone marrow tumor, myelosarcoma, Down syndrome-associated myeloproliferation, blast plasmacytoid dendritic cell tumor, minimally differentiated AML, AML without maturation, AML with granulocytic maturation, myeloid monomyeloma with myeloid eosinophil 8. The method of any one of claims 1-7, resulting from karyocytic, acute monoblastic leukemia, acute erythrocytic leukemia, acute megakaryoblastic leukemia, or acute basophilic leukemia. 9. The AML of any one of claims 1-8, wherein the AML has a DNMT3A mutation, FLT3-ITD mutation, NPM1 mutation, CEBPA mutation, c-KIT mutation, RUNX1 mutation, ASXL1 mutation, IDH1 mutation, or IDH2 mutation. Method. 10. The method of any one of claims 1-9, wherein the method further comprises administering induction chemotherapy. 11. The method of claim 10, wherein said induction chemotherapy comprises cytarabine, anthracyclines such as daunorubicin, arsenic trioxide, all-trans-retinoic acid, or combinations thereof. The method of any one of claims 1-11, wherein the method further comprises administering a consolidation therapy. 13. The method of claim 12, wherein said consolidation therapy comprises xenogeneic stem cell transplantation and/or immunotherapy. 14. The method of any one of claims 1-13, wherein the method further comprises administering hematopoietic stem cell transplantation, gemtuzumab ozogamicin, or a combination thereof. 15. The method of any one of claims 1-14, wherein the subject or cancer has and/or has been identified as having a loss-of-function mutation of BRG1. 16. The method of any one of claims 1-15, wherein the subject or cancer has and/or has been identified as having a loss-of-function mutation of a BRM. 17. The method of any one of claims 1-16, wherein the acute myeloid leukemia has failed to respond to or has progressed following administration of one or more chemotherapeutic or cytotoxic agents. 18. The method of any one of claims 1-17, wherein the acute myeloid leukemia is or is predicted to be resistant to one or more chemotherapeutic agents. The one or more chemotherapeutic or cytotoxic agents is cytarabine, anthracyclines such as daunorubicin, arsenic trioxide, all-trans-retinoid acid, histamine dihydrochloride, interleukin-2, and/or gemtuzumab ozo 19. The method of claim 17 or 18, which is gamycin. 20. The method of any one of claims 1-19, wherein the effective amount of the agent reduces the level and/or activity of BRG1 and/or BRM by at least 5% compared to baseline. 21. The method of any one of claims 1-20, wherein the agent that reduces the level and/or activity of BRG1 and/or BRM in cells is a small molecule compound, an antibody, an enzyme, and/or a polynucleotide. 22. The method of claim 21, wherein said agent that reduces the level and/or activity of BRG1 and/or BRM in cells is an enzyme. The enzymes are clustered regularly interspaced short palindromic repeats (CRISPR)-related proteins, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases. , TALEN) , or a meganuclease. 24. The method of claim 23, wherein the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9) or CRISPR-associated protein 12a (Casl2a). 22. The method of claim 21, wherein the agent that reduces BRG1 and/or BRM levels and/or activity in cells is a polynucleotide. 26. The method of claim 25, wherein the polynucleotide is an antisense nucleic acid, small interfering RNA, small hairpin RNA, microRNA, CRISPR/Cas9 nucleotide, or ribozyme. 22. The method of claim 21, wherein said agent that reduces BRG1 and/or BRM levels and/or activity in cells is a small molecule compound. 28. The method of claim 27, wherein said small molecule compound is a small molecule BRG1 inhibitor and/or a small molecule BRM inhibitor. 29. The method of claim 28, wherein said small molecule BRG1 inhibitor and/or small molecule BRM inhibitor is a compound of Formula I. 29. The method of claim 28, wherein said small molecule BRG1 inhibitor and/or small molecule BRM inhibitor is a compound of Formula II. 29. The method of claim 28, wherein said small molecule BRG1 inhibitor and/or small molecule BRM inhibitor is a compound of formula III. 29. The method of claim 28, wherein said small molecule BRG1 and/or BRM inhibitor is a compound of Formula IV. 29. The method of claim 28, wherein said small molecule BRG1 and/or BRM inhibitor is a compound of Formula V. 29. The method of claim 28, wherein said small molecule BRG inhibitor and/or small molecule BRM inhibitor has the structure of any one of compounds 1-20. 29. The method of claim 28, wherein said small molecule compound is a degrader of Formula VI.