EP4188447A1 - Composés et leurs utilisations - Google Patents

Composés et leurs utilisations

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Publication number
EP4188447A1
EP4188447A1 EP20947059.0A EP20947059A EP4188447A1 EP 4188447 A1 EP4188447 A1 EP 4188447A1 EP 20947059 A EP20947059 A EP 20947059A EP 4188447 A1 EP4188447 A1 EP 4188447A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
compound
cancer
formula
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20947059.0A
Other languages
German (de)
English (en)
Inventor
Sabine K. RUPPEL
Zhaoxia Yang
Jason T. LOWE
Johannes H. Voigt
Matthew Netherton
Francois BRUCELLE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Foghorn Therapeutics Inc
Original Assignee
Foghorn Therapeutics Inc
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Filing date
Publication date
Application filed by Foghorn Therapeutics Inc filed Critical Foghorn Therapeutics Inc
Publication of EP4188447A1 publication Critical patent/EP4188447A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • BRD9 is a component of the BAF complex.
  • the present invention relates to useful compositions and methods for the treatment of BAF complex-related disorders, such as cancer and infection.
  • Summary Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9 gene on chromosome 5.
  • BRD9 is a component of the BAF (BRG1- or BRM-associated factors) complex, a SWI/SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomain- containing proteins. BRD9 is present in several SWI/SNF ATPase chromatin remodeling complexes and is upregulated in multiple cancer cell lines. Accordingly, agents that reduce the levels and/or activity of BRD9 may provide new methods for the treatment of disease and disorders, such as cancer and infection. The inventors have found that depleting BRD9 in cells results in the depletion of the SS18-SSX fusion protein in those cells.
  • the SS18-SSX fusion protein has been detected in more than 95% of synovial sarcoma tumors and is often the only cytogenetic abnormality in synovial sarcoma. Additionally, evidence suggests that the BAF complex is involved in cellular antiviral activities.
  • agents that degrade BRD9 e.g., compounds
  • the present disclosure features compounds and methods useful for treating BAF-related disorders (e.g., cancer or infection).
  • the disclosure features a compound having the structure of Formula I: A-L-B Formula I, where L has the structure of Formula II: A 1 –E 1 –F–E 2 –A 2 , Formula II A 1 is a bond between the linker and A; A 2 is a bond between B and the linker; each of E 1 and E 2 is, independently, absent, CH 2 , O, or NCH 3 ; and F is optionally substituted C 3 -C 10 carbocyclylene or optionally substituted C 2–10 heterocyclylene; B is a degradation moiety; and A has the structure of Formula III: Formula III, where R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 carbocyclyl; Z 1 is CR 2 or N; R 2 is H, halogen, optionally substituted C 1 -C 6 alkyl
  • R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 carbocyclyl. In some embodiments, R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 3 -C 10 carbocyclyl. In some embodiments, R 1 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 10 carbocyclyl. In some embodiments, R 1 is H. In some embodiments, R 1 is optionally substituted C 1 -C 6 alkyl.
  • R 1 is optionally substituted C 2 -C 6 alkenyl. In some embodiments, R 1 is optionally substituted C 3 -C 10 carbocyclyl. In some embodiments, optionally substituted C 1 -C 6 alkyl is C 1 -C 6 perfluoroalkyl. In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is . In some embodiments, R 1 is H, or In some emb 1 odiments, R is , or In some embodiments, R 1 is H, or In some embodiments, R 1 is H, , or . In some embodiments, R 1 is H, In some embodiments, R 1 is H or . In some embodiments, R 1 is H. In some embodiments, R 1 is H.
  • R 1 is . In some embodiments, Z 1 is CR 2 . In some embodiments, Z 1 is N. In some embodiments, R 2 is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 carbocyclyl, or optionally substituted C 6 -C 10 aryl. In some embodiments, R 2 is H, halogen, or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 2 is H, F, or . In some embodiments, R 2 is H. In some embodiments, R 2 is F. In some embodiments, R 2 is .
  • R 7 ⁇ is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms.
  • R 7 ⁇ is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms.
  • R 7 ⁇ is optionally substituted C 1 -C 6 alkoxy or optionally substituted amino.
  • R 7 ⁇ is optionally substituted sulfone or optionally substituted sulfonamide. In some embodiments, R 7 ⁇ is optionally substituted C 1 -C 6 alkyl or optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is optionally substituted C 1 -C 6 heteroalkyl or optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 7 ⁇ is optionally substituted C 1 -C 6 alkyl.
  • R 7 ⁇ is optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 7 ⁇ is optionally substituted C 1 -C 6 alkoxy. In some embodiments, R 7 ⁇ is optionally substituted amino. In some embodiments, R 7 ⁇ is optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is optionally substituted sulfone. In some embodiments, R 7 ⁇ is optionally substituted sulfonamide. In some embodiments, R 7 ⁇ is optionally substituted C 1 -C 3 alkyl.
  • R 7 ⁇ is optionally substituted C 1 -C 3 heteroalkyl. In some embodiments, R 7 ⁇ is , , , or . In some embodiments, R 7 ⁇ is –NR 3 R 4 or –OR 4 , where R 3 is H or optionally substituted C 1 -C 6 alkyl, and R 4 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 7 ⁇ is –NR 3 R 4 . In some embodiments, R 7 ⁇ is –OR 4 . In some embodiments, R 3 is H. In some embodiments, R 3 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 3 is H and R 4 is methyl.
  • R 3 is methyl and R 4 is methyl.
  • R 7 ⁇ is .
  • R 7 ⁇ is In some embodiments, R 7 ⁇ is optionally substituted carbocyclyl having 3 to 6 atoms or optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is optionally substituted heterocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is carbocyclyl having 3 to 6 atoms or heterocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is carbocyclyl having 3 to 6 atoms.
  • R 7 ⁇ is heterocyclyl having 3 to 6 atoms. In some embodiments, R 7 ⁇ is , , , , , , or In some embodiments, R 7 ⁇ is , , , , , , , o In some embodiments, R 7 ⁇ is or . In some embodiments, R 7 ⁇ is , In some embodiments, R 7 ⁇ is , , , , In some embodiments, R 7 ⁇ is . In some embodiments, R 7 ⁇ is , , , , , , , , . In some embodiments, R 7 ⁇ is In some embodiments, R 7 ⁇ is , In some embodiments, R 7 ⁇ is , In some embodiments, R 7 ⁇ is , In some embodiments, R 7 ⁇ is , In some embodiments, X 1 is N and X 2 is C-R 7 ⁇ .
  • X 1 is CH and X 2 is C-R 7 ⁇ . In some embodiments, X 1 is C-R 7 ⁇ and X 2 is N. In some embodiments, X 1 is C-R 7 ⁇ and X 2 is CH. In some embodiments, X 1 is N or CH, and X 2 is C-NR 3 R 4 , C-OR 4 , , , or ; or X 1 is C-NR 3 R 4 , C-OR 4 , 2 , and X is N or CH.
  • X 1 is N or CH
  • X 2 is C-NR 3 R 4 , , or ; or X 1 is C-NR 3 R 4 , , , or , and X 2 is N or CH.
  • X 1 is N or CH
  • X 2 is C-NR 3 R 4 or ; or X 1 is C-NR 3 R 4 or , and X 2 is N or CH.
  • X 1 is N or CH
  • X 2 is C-NR 3 R 4 or ; or X 1 is C-NR 3 R 4 or , and X 2 is N or CH.
  • X 1 is N or CH
  • X 2 is C- NR 3 R 4 or ; or X 1 is C-NR 3 R 4 or , and X 2 is N or CH.
  • R 7 ⁇ is -NR 3 R 4 , -OR 4 , or optionally substituted heterocyclyl having 3 to 6 atoms.
  • X 1 is N and X 2 is C-NR 3 R 4 .
  • X 1 is C-NR 3 R 4 and X 2 is N.
  • R 3 is H.
  • R 3 is optionally substituted C 1 -C 6 alkyl.
  • R 3 is , , , , , , In some embodiments, R 3 is . In some embodiments, R 3 is , or . In some embodiments, R 3 is methyl, ethyl, In some embodiments, R 4 is In some embodiments, R 4 is or . In some embodiments, R 4 is , , or . In some embodiments, R 4 is methyl, ethyl, , , o In some embodiments, X 3 is N. In some embodiments, X 3 is CH. In some embodiments, X 4 is N. In some embodiments, X 4 is CH. In some embodiments, X 3 is N and X 4 is N.
  • X 3 is N and X 4 is CH. In some embodiments, X 3 is CH and X 4 is N. In some embodiments, X 3 is CH and X 4 is CH. In some embodiments, G ⁇ is In some embodiments, G ⁇ is optionally substituted C 3 -C 10 carbocyclylene or optionally substituted C 2 -C 9 heterocyclylene. In some embodiments, G ⁇ is optionally substituted C 6 -C 10 arylene or optionally substituted C 2 -C 9 heteroarylene. In some embodiments, G ⁇ is optionally substituted C 3 -C 10 carbocyclylene. In some embodiments, G ⁇ is optionally substituted C 6 -C 10 arylene.
  • G ⁇ is optionally substituted C 2 -C 9 heterocyclylene. In some embodiments, G ⁇ is optionally substituted C 2 -C 9 heteroarylene. In some embodiments, G ⁇ is , where each of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is, independently, H, A 1 , 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl
  • each of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is, independently, H, A 1 , 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thiol, or optional
  • each of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is, independently, H, A 1 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl; or R G1 ⁇ and R G2 ⁇ , R G2 ⁇ and R G3 ⁇ , R G3 ⁇ and R G4 ⁇ , and/or R G4 ⁇ and R G5 ⁇ , together with the carbon atoms to which each is attached, combine to form is optionally substituted C 2 -C 9 heteroaryl or optionally substituted C 2 -C 9 heterocyclyl, any of which is optionally substituted with A 1 , where one of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ ,
  • each of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is, independently, H, A 1 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl.
  • each of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is, independently, H, A 1 , F, Cl
  • each of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is, independently, H, A 1 , F, ,
  • each of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is, independently, H, A 1 , F, Cl, , , , , , ,
  • R G3 ⁇ is A 1 .
  • R G1 ⁇ is H; R G2 ⁇ is ; R G3 ⁇ is A 1 ; R G4 ⁇ is ; and R G5 ⁇ is H.
  • R G1 ⁇ is H; R G2 ⁇ is ; R G3 ⁇ is A 1 ; R G4 ⁇ is H; and R G5 ⁇ is .
  • R G1 ⁇ is H; R G2 ⁇ is ; R G3 ⁇ is A 1 ; R G4 ⁇ is Cl or F; and R G5 ⁇ is H.
  • R G1 ⁇ is H; R G2 ⁇ is ; R G3 ⁇ is A 1 ; R G4 ⁇ is H; and R G5 ⁇ is H.
  • R G1 ⁇ is H; R G2 ⁇ is ; R G3 ⁇ is A 1 ; R G4 ⁇ is ; and R G5 ⁇ is H.
  • R G1 ⁇ and R G2 ⁇ , R G2 ⁇ and R G3 ⁇ , R G3 ⁇ and R G4 ⁇ , and/or R G4 ⁇ and R G5 ⁇ together with the carbon atoms to which each is attached, combine to form ; and is optionally substituted C 2 -C 9 heterocyclyl, which is optionally substituted with A 1 , where one of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is A 1 , or is substituted with A 1 .
  • R G1 ⁇ and R G2 ⁇ , R G2 ⁇ and R G3 ⁇ , R G3 ⁇ and R G4 ⁇ , and/or R G4 ⁇ and R G5 ⁇ , together with the carbon atoms to which each is attached, combine to form is optionally substituted C 2 -C 9 heteroaryl, which is optionally substituted with A 1 , where one of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is A 1 , or is substituted with A 1 .
  • G ⁇ is , where G6 1 R ⁇ is H, A , or optionally substituted C 1 -C 6 alkyl.
  • G ⁇ is , where R G6 ⁇ is H, A 1 , or optionally substituted C 1 -C 6 alkyl.
  • R G1 ⁇ and R G2 ⁇ , R G2 ⁇ and R G3 ⁇ , R G3 ⁇ and R G4 ⁇ , and/or R G4 ⁇ and R G5 ⁇ together with the carbon atoms to which each is attached, combine to form is optionally substituted C 2 -C 9 heterocyclyl or optionally substituted C 2 -C 9 heteroaryl, any of which is optionally substituted with A 1 , where one of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is A 1 , or is substituted with A 1 .
  • G ⁇ is , where R G6 ⁇ is H, A 1 , or optionally substituted C 1 -C 6 alkyl. In some embodiments, R G6 ⁇ is H, A 1 , , , In some embodiments, R G6 ⁇ is H, A 1 , or . In some embodiments, R G6 ⁇ is H or A 1 . In some embodiments, R G6 ⁇ is H. In some embodiments, R G6 ⁇ is A 1 . In some embodiments, R G1 ⁇ is H, A 1 , F, , , , , , , , , ,
  • R G2 ⁇ is H, A 1 , F, In some embodiments, R G2 ⁇ is H. In some embodiments, R G3 ⁇ is H, A 1 , F, , , , , , , , , , , , , , o . In some embodiments, R G3 ⁇ is H. In some embodiments, R G4 ⁇ is H, A 1 , F, , , , , , , , , , , , , , , , , o . In some embodiments, R G4 ⁇ is H.
  • R G5 ⁇ is H, A 1 , F, , , , , , , , , , , , , , .
  • R G5 ⁇ is H.
  • one or more of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is H.
  • two or more of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is H.
  • three or more of R G1 ⁇ , R G2 ⁇ , R G3 ⁇ , R G4 ⁇ , and R G5 ⁇ is H.
  • R G1 ⁇ is A 1 . In some embodiments, R G2 ⁇ is A 1 . In some embodiments, R G3 ⁇ is A 1 . In some embodiments, R G4 ⁇ is A 1 . In some embodiments, R G5 ⁇ is A 1 . In some embodiments, is substituted with A 1 .
  • G ⁇ is where each of R G7 ⁇ , R G8 ⁇ , R G9 ⁇ , R G10 ⁇ , and R G11 ⁇ is, independently, H, A 1 , 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thio
  • each of R G7 ⁇ , R G8 ⁇ , R G9 ⁇ , R G10 ⁇ , and R G11 ⁇ is, independently, H, A 1 , 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thiol, or optional
  • each of R G7 ⁇ , R G8 ⁇ , R G9 ⁇ , R G10 ⁇ , and R G11 ⁇ is, independently, H, A 1 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl; or R G7 ⁇ and R G8 ⁇ , R G8 ⁇ and R G9 ⁇ , R G9 ⁇ and R G10 ⁇ , and/or R G10 ⁇ and R G11 ⁇ , together with the carbon atoms to which each is attached, combine to form is optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heteroaryl, or C 2 -C 9 heterocyclyl, any of which is optionally substituted
  • each of R G7 ⁇ , R G8 ⁇ , R G9 ⁇ , R G10 ⁇ , and R G11 ⁇ is, independently, H, A 1 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl.
  • each of R G7 ⁇ , R G8 ⁇ , R G9 ⁇ , R G10 ⁇ , and R G11 ⁇ is, independently, H, A 1 , F, Cl, , , , , , , , , , , , , , , , R G8 ⁇ is . In some embodiments, G ⁇ is . In some embodiments, R G7 ⁇ is H; R G8 ⁇ is ; R G9 ⁇ is A 1 ; and R G11 ⁇ is H.
  • G ⁇ is where each of R G12 ⁇ , R G13 ⁇ , and R G14 ⁇ is, independently, H, A 1 , 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R G
  • each of R G12 ⁇ , R G13 ⁇ , and R G14 ⁇ is, independently, H, A 1 , 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R G12 ⁇ and R
  • R 7 ⁇ is . In some embodiments, R 7 ⁇ is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 10 carbocycylyl. In some embodiments, R 7 ⁇ is H or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 7 ⁇ is H, , , , , , In some embodiments, R 7 ⁇ is H or . In some embodiments, R 7 ⁇ is H. In some embodiments, R 7 ⁇ is . In some embodiments, G ⁇ is optionally substituted C 3 -C 10 carbocyclyl or optionally substituted C 2 - C 9 heterocyclyl.
  • G ⁇ is optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 9 heteroaryl. In some embodiments, G ⁇ is optionally substituted C 3 -C 10 carbocyclyl. In some embodiments, G is optionally substituted C 6 -C 10 aryl. In some embodiments, G is optionally substituted C 2 -C 9 heterocyclyl. In some embodiments, G ⁇ is optionally substituted C 2 -C 9 heteroaryl.
  • G ⁇ is , where each of R G1 , R G2 , R G3 , R G4 , and R G5 is, independently, H, 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thiol, or optionally substituted
  • each of R G1 , R G2 , R G3 , R G4 , and R G5 is, independently, H, 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R G1
  • each of R G1 , R G2 , R G3 , R G4 , and R G5 is, independently, H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl; or R G1 and R G2 , R G2 and R G3 , R G3 and R G4 , and/or R G4 and R G5 , together with the carbon atoms to which each is attached, combine to form optionally substituted C 2 -C 9 heteroaryl or optionally substituted C 2 -C 9 heterocyclyl.
  • each of R G1 , R G2 , R G3 , R G4 , and R G5 is, independently, H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl.
  • each of R G1 , R G2 , R G3 , R G4 , and R G5 is, independently, H, F, Cl, , , , , , , , , In some embodiments, each of R G1 , R G2 , R G3 , R G4 , and R G5 is, independently, H, F, , . In some embodiments, each of R G1 , R G2 , R G3 , R G4 , and R G5 is, independently, H, F, Cl, , , , , , , , In some embodiments, R G1 is H; R G2 is ; and R G5 is H.
  • R G1 is H; R G2 is R G3 is ; R G4 is H; and R G5 is .
  • R G1 is H; R G2 is ; R G3 is ; R G4 is Cl or F; and R G5 is H.
  • R G1 is H; R G2 is ; R G3 is ; R G4 is H; and R G5 is H.
  • R G1 is H; R G2 is G3 G4 ; R is ; R is ; and R G5 is H.
  • R G1 and R G2 , R G2 and R G3 , R G3 and R G4 , and/or R G4 and R G5 together with the carbon atoms to which each is attached, combine to form optionally substituted C 2 -C 9 heteroaryl or optionally substituted C 2 -C 9 heterocyclyl.
  • R G1 and R G2 , R G2 and R G3 , R G3 and R G4 , and/or R G4 and R G5 together with the carbon atoms to which each is attached, combine to form optionally substituted C 2 -C 9 heterocyclyl.
  • R G1 and R G2 , R G2 and R G3 , R G3 and R G4 , and/or R G4 and R G5 together with the carbon atoms to which each is attached, combine to form optionally substituted C 2 -C 9 heteroaryl.
  • R G1 and R G2 , R G2 and R G3 , R G3 and R G4 , and/or R G4 and R G5 together with the carbon atoms to which each is attached, combine to form optionally substituted C 2 -C 9 heterocyclyl.
  • R G1 and R G2 , R G2 and R G3 , R G3 and R G4 , and/or R G4 and R G5 together with the carbon atoms to which each is attached, combine to form optionally substituted C 2 -C 9 heteroaryl.
  • G ⁇ is , , , where R G6 is H or optionally substituted C 1 -C 6 alkyl. In some embodiments, G ⁇ is , where R G6 is H or optionally substituted C 1 -C 6 alkyl.
  • G ⁇ is , , , , , , , where R G6 is H or optionally substituted C 1 -C 6 alkyl.
  • R G6 is H, , , o In some embodiments, R G6 is H or .
  • R G6 is H.
  • R G1 is H, F, , , , o .
  • R G1 is H.
  • R G2 is H, F , , , , , , In some embodiments, R G2 is H.
  • R G3 is H, F, , , , , , , , , , , .
  • R G3 is H.
  • R G4 is H, F, , , , , , , , , , , or .
  • R G4 is H.
  • R G5 is H, F, , , , , , , , or .
  • R G5 is H.
  • one or more of R G1 , R G2 , R G3 , R G4 , and R G5 is H.
  • two or more of R G1 , R G2 , R G3 , R G4 , and R G5 is H.
  • R G1 , R G2 , R G3 , R G4 , and R G5 is H. In some embodiments, each of R G1 , R G2 , R G3 , R G4 , and R G5 is H.
  • G ⁇ is , , where each of R G7 , R G8 , R G9 , R G10 , and R G11 is, independently, H, 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl, hydroxyl, thiol, or
  • each of R G7 , R G8 , R G9 , R G10 , and R G11 is, independently, H, 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, hydroxyl, thiol, or optionally substituted amino; or R G7 and R G8 , R G8 and R G9 , R G9 and R G10 , and/or R G10 and R G11 , together with the carbon atoms to which each is attached, combine to form optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C
  • each of R G7 , R G8 , R G9 , R G10 , and R G11 is, independently, H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl; or R G7 and R G8 , R G8 and R G9 , R G9 and R G10 , and/or R G10 and R G11 , together with the carbon atoms to which each is attached, combine to form optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 - C 9 heteroaryl, or C 2 -C 9 heterocyclyl.
  • each of R G7 , R G8 , R G9 , R G10 , and R G11 is, independently, H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, or optionally substituted -C 1 -C 3 alkyl-C 2 -C 5 heterocyclyl.
  • each of R G7 , R G8 , R G9 , R G10 , and R G11 is, independently, H, F, Cl, , , , , , , , , , .
  • R G8 is .
  • G ⁇ is .
  • G ⁇ is where each of R G12 , R G13 , and R G14 is, independently, H, 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, optionally substituted -O-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -C 6 carbocyclyl, optionally substituted -C 1 -C 3 alkyl-C 3 -
  • each of R G12 , R G13 , and R G14 is, independently, H, 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, hydroxyl, thiol, or optionally substituted amino; or R G12 and R G14 , together with the carbon atoms to which each is attached, combine to form optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heteroaryl, or optionally substituted C 2 -C 9 heterocyclyl.
  • A has the structure of Formula IIIa: Formula IIIa, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIb: Formula IIIb, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIc: Formula IIIc, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIId: Formula IIId, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIe: Formula IIIe, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIf: Formula IIIf, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIg: Formula IIIg, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIh: Formula IIIh, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIi: Formula IIIi, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIj: Formula IIIj, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIk: Formula IIIk, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIm: Formula IIIm, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIn: Formula IIIn, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIo: Formula IIIo, or a pharmaceutically acceptable salt thereof.
  • A has the structure of Formula IIIp: Formula IIIp, or a pharmaceutically acceptable salt thereof. In some embodiments, A has the structure of Formula IIIq: Formula IIIq, or a pharmaceutically acceptable salt thereof. In some embodiments, A has the structure of Formula IIIr: Formula IIIr, or a pharmaceutically acceptable salt thereof. In some embodiments, A has the structure of Formula IIIs: Formula IIIs, or a pharmaceutically acceptable salt thereof. In some embodiments, A has the structure of Formula IIIt: Formula IIIt, or a pharmaceutically acceptable salt thereof. In some embodiments, A has the structure of Formula IIIu: Formula IIIu, or a pharmaceutically acceptable salt thereof. In some embodiments, A has the structure of Formula IIIv: Formula IIIv, or a pharmaceutically acceptable salt thereof.
  • the degradation moiety is a ubiquitin ligase binding moiety.
  • the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof.
  • the degradation moiety is a ubiquitin ligase binding moiety.
  • the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof.
  • the degradation moiety has the structure of Formula A: Formula A where Y 1 is R A5 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl; R A6 is H or optionally substituted C 1 -C 6 alkyl; and R A7 is H or optionally substituted C 1 -C 6 alkyl; or R A6 and R A7 , together with the carbon atom to which each is bound, combine to form optionally substituted C 3 -C 6 carbocyclyl or optionally substituted C 2 -C 5 heterocyclyl; or R A6 and R A7 , together with the carbon atom to which each is bound, combine to form optionally substituted C 3 -C 6 carbocyclyl or optionally substituted C 2 -C 5 heterocyclyl; R A8 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl; each of R A1 ,
  • each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , 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, hydroxyl, thiol, or optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , and/or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form is optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 carbocyclyl, optionally
  • each of R A1 , R A2 , R A3 , and R A4 is, H, A 2 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted -O-C 3 -C 6 carbocyclyl, hydroxyl, optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form is optionally substituted C 2 -C 9 heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4 is A 2 , is substituted with A 2 .
  • each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , F, ; or R A1 and R A2 , R A2 and R A3 , or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form ; is optionally substituted C 2 - C 9 heterocyclyl, which is optionally substituted with A 2 , where one of R A1 , R A2 , R A3 , and R A4 is A 2 , or is substituted with A 2 .
  • R A1 is A 2 .
  • R A2 is A 2 .
  • R A3 is A 2 .
  • R A4 is A 2 .
  • R A5 is A 2 .
  • R A5 is H or optionally substituted C 1 -C 6 alkyl.
  • R A5 is H or In some embodiments, R A5 is H.
  • R A5 is In some embodiments, Y 1 is . In some embodiments, Y 1 is . In some embodiments, Y 1 is In some embodiments, each of R A6 and R A7 is, independently, H, F, , or ; or R A6 and R A7 , together with the carbon atom to which each is bound, combine to form .
  • R A6 is H and R A7 is H.
  • Y 1 is , , , , , , , or . In some embodiments, Y 1 is . In some embodiments, Y 1 is .
  • the structure of Formula A has the structure of Formula A1: , Formula A1 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A2: , Formula A2 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A3: , Formula A3 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A4: , Formula A4 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A5: Formula A5 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A6: , Formula A6 or a pharmaceutically acceptable salt thereof.
  • the structure of Formula A has the structure of Formula A7: , Formula A7 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A8: , Formula A8 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A9: , Formula A9 or a pharmaceutically acceptable salt thereof. In some embodiments, the structure of Formula A has the structure of Formula A10: , Formula A10 or a pharmaceutically acceptable salt thereof. In some embodiments, wherein the structure of Formula A is , , or derivative or analog thereof. In some embodiments, the structure of Formula A is In some embodiments, the structure of Formula A is , or derivative or analog thereof.
  • the linker has the structure of Formula II: A 1 –E 1 –F–E 2 –A 2 , Formula II A 1 is a bond between the linker and A; A 2 is a bond between B and the linker; each of E 1 and E 2 is, independently, absent, CH 2 , O, or NCH 3 ; and F has the structure: In some embodiments, E 1 is absent. In some embodiments, E 1 is CH 2 . In some embodiments, E 1 is O. In some embodiments, E 1 is NCH 3 . In some embodiments, E 2 is absent. In some embodiments, E 2 is CH 2 . In some embodiments, E 2 is O. In some embodiments, E 2 is NCH 3 . In some embodiments, the linker comprises the structure: In some embodiments, the compound has the structure of any one of compounds D1-D66 in Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Compounds D1-D184 of the Disclosure
  • the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
  • the disclosure features a method of inhibiting the level and/or activity of BRD9 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the disclosure features a method of reducing the level and/or activity of BRD9 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the cell is a cancer cell.
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer.
  • the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), lung cancer (e.g., non-small cell lung cancer (e.g., squamous or adenocarcinoma)), stomach cancer, or breast cancer.
  • the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma.
  • the disclosure features a method of treating a BAF complex-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the BAF complex-related disorder is cancer. In some embodiments, the BAF complex-related disorder is infection.
  • the disclosure features a method of treating an SS18-SSX fusion protein- related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the SS18-SSX fusion protein-related disorder is cancer.
  • the SS18-SSX fusion protein-related disorder is infection.
  • the SS18-SSX fusion protein is a SS18-SSX1 fusion protein, a SS18-SSX2 fusion protein, or a SS18-SSX4 fusion protein.
  • the disclosure features a method of treating a BRD9-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
  • the BRD9-related disorder is cancer.
  • the BRD9- related disorder is infection.
  • the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblast
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer.
  • the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer.
  • the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma).
  • the sarcoma is synovial sarcoma.
  • the infection is viral infection (e.g., an infection with a virus of the Retroviridae family such as the lentiviruses (e.g. Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g.
  • hepatitis B virus HBV
  • Flaviviridae family e.g. hepatitis C virus (HCV)
  • Adenoviridae family e.g. Human Adenovirus
  • Herpesviridae family e.g. Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvitus K*, CMV, varicella-zoster virus
  • Papillomaviridae family e.g. Human Papillomavirus (HPV, HPV E1)
  • Parvoviridae family e.g.
  • Parvovirus B19 Parvovirus B19); Polyomaviridae family (e.g. JC virus and BK virus); Paramyxoviridae family (e.g. Measles virus); or Togaviridae family (e.g. Rubella virus)).
  • the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or Multiple Meningioma.
  • the disclosure features a method of treating a cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.
  • the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblast
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve
  • the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer.
  • the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer.
  • the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma).
  • the sarcoma is synovial sarcoma.
  • the disclosure features a method for treating a viral infection in a subject in need thereof. This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions.
  • the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g.
  • HAV Human immunodeficiency virus
  • deltaretroviruses e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitis B virus (HBV)), Flaviviridae family (e.g. hepatitis C virus (HCV)), Adenoviridae family (e.g. Human Adenovirus), Herpesviridae family (e.g.
  • HCMV Human cytomegalovirus
  • HMV-1 herpes simplex virus 1
  • HSV-2 herpes simplex virus 2
  • HHV-6 human herpesvirus 6
  • Herpesvitus K* Herpesvitus K*, CMV, varicella-zoster virus
  • Papillomaviridae family e.g. Human Papillomavirus (HPV, HPV E1)
  • Parvoviridae family e.g. Parvovirus B19
  • Polyomaviridae family e.g. JC virus and BK virus
  • Paramyxoviridae family e.g. Measles virus
  • Togaviridae family e.g. Rubella virus.
  • the method further includes administering to the subject an additional anticancer therapy (e.g., chemotherapeutic or cytotoxic agent or radiotherapy).
  • the additional anticancer therapy is: a chemotherapeutic or cytotoxic agent (e.g., doxorubicin or ifosfamide), a differentiation-inducing agent (e.g., retinoic acid, vitamin D, cytokines), a hormonal agent, an immunological agent, or an anti-angiogenic agent.
  • a chemotherapeutic or cytotoxic agent e.g., doxorubicin or ifosfamide
  • a differentiation-inducing agent e.g., retinoic acid, vitamin D, cytokines
  • a hormonal agent e.g., an immunological agent, or an anti-angiogenic agent.
  • Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum).
  • alkylating agents include, but are not limited to, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum).
  • paclitaxel paclitaxel
  • taxol docetaxel
  • taxotere cis-platinum
  • the compound of the invention and the additional anticancer therapy and any of the foregoing compounds or pharmaceutical compositions are administered within 28 days of each other (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) each in an amount that together are effective to treat the subject.
  • Chemical Terms The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety.
  • an unsubstituted C 2 alkyl group has the formula –CH 2 CH 3 .
  • a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups.
  • a reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.
  • optionally substituted X e.g., optionally substituted alkyl
  • X optionally substituted
  • alkyl wherein said alkyl is optionally substituted
  • the feature “X” (e.g., alkyl) per se is optional.
  • certain compounds of interest may contain one or more “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • aliphatic refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In one embodiment, “aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl.
  • Unsaturated aliphatic groups can be in a cis or trans configuration.
  • the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms.
  • the aliphatic group contains from 1 to about 8 carbon atoms.
  • the aliphatic group is C 1 -C 2 , C 1 -C 3 , C 1 - C 4 , C 1 -C 5 , or C 1 -C 6 .
  • the specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species.
  • C 1 -C 6 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 1 - C 4 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety.
  • heteroaliphatic refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties.
  • heteroaliphatic is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety.
  • Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, —O-alkyl-O-alkyl, and alkyl- O-haloalkyl.
  • acyl represents a hydrogen or an alkyl group that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl.
  • exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1 to 21 carbons.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).
  • An “alkylene” is a divalent alkyl group.
  • alkenyl as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • alkenylene is a divalent alkenyl group.
  • alkynyl refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • alkynylene is a divalent alkynyl group.
  • amino represents –N(R N1 ) 2 , wherein each R N1 is, independently, H, OH, NO 2 , N(R N2 ) 2 , SO 2 OR N2 , SO 2 R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited R N1 groups can be optionally substituted; or two R N1 combine to form an alkylene or heteroalkylene, and wherein each R N2 is, independently, H, alkyl, or aryl.
  • the amino groups of the compounds described herein can be an unsubstituted amino (i.e., –NH 2 ) or a substituted amino (i.e., –N(R N1 ) 2 ).
  • aryl refers to an aromatic mono- or polycarbocyclic radical of, e.g., 6 to 12, carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.
  • arylalkyl represents an alkyl group substituted with an aryl group.
  • exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C 6 alkyl C 6 -C 10 aryl, C 1 -C 10 alkyl C 6 -C 10 aryl, or C 1 -C 20 alkyl C 6 -C 10 aryl), such as, benzyl and phenethyl.
  • the alkyl and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • bridged cyclyl refers to a bridged polycyclic group of 5 to 20 atoms, containing from 1 to 3 bridges. Bridged cyclyl includes bridged carbocyclyl (e.g., norbornyl) and bridged heterocyclyl (e.g., 1,4-diazabicyclo[2.2.2]octane).
  • cyano represents a –CN group.
  • Carbocyclyl refers to a non-aromatic C 3 -C 1 2, monocyclic or polycyclic (e.g., bicyclic or tricyclic) structure in which the rings are formed by carbon atoms.
  • Carbocyclyl structures include cycloalkyl groups (e.g., cyclohexyl) and unsaturated carbocyclyl radicals (e.g., cyclohexenyl).
  • Polycyclic carbocyclyl includes spirocyclic carbocyclyl, bridged carbocyclyl, and fused carbocyclyl.
  • a “carbocyclylene” is a divalent carbocyclyl group.
  • cycloalkyl refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.
  • halo or halogen,” as used herein, mean a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers to alkyl–O– (e.g., methoxy and ethoxy), and an “alkylamino” which, as used herein, refers to –N(alkyl)R Na , where R Na is H or alkyl (e.g., methylamino).
  • heteroalkylene is a divalent heteroalkyl group.
  • heteroalkenyl refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups.
  • heteroalkenyl groups are an “alkenoxy” which, as used herein, refers to alkenyl–O–.
  • a “heteroalkenylene” is a divalent heteroalkenyl group.
  • heteroalkynyl refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups.
  • Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers to alkynyl–O–.
  • a “heteroalkynylene” is a divalent heteroalkynyl group.
  • heteroaryl refers to an aromatic monocyclic or polycyclic structure of 5 to 12 atoms having at least one aromatic ring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
  • a “heteroarylene” is a divalent heteroaryl group.
  • heteroarylalkyl represents an alkyl group substituted with a heteroaryl group.
  • exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C 6 alkyl C 2 -C 9 heteroaryl, C 1 -C 10 alkyl C 2 -C 9 heteroaryl, or C 1 -C 20 alkyl C 2 -C 9 heteroaryl).
  • the alkyl and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • heterocyclyl refers a monocyclic or polycyclic radical (e.g., bicyclic or tricyclic) having 3 to 12 atoms having at least one non-aromatic ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and no aromatic ring containing any N, O, or S atoms.
  • Polycyclic heterocyclyl includes spirocyclic heterocyclyl, bridged heterocyclyl, and fused heterocyclyl.
  • heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl.
  • a “heterocyclylene” is a divalent heterocyclyl group.
  • the term “heterocyclylalkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group.
  • Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -C 6 alkyl C 2 -C 9 heterocyclyl, C 1 -C 10 alkyl C 2 -C 9 heterocyclyl, or C 1 -C 20 alkyl C 2 -C 9 heterocyclyl).
  • the alkyl and the heterocyclyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • the term “hydroxyalkyl,” as used herein, represents alkyl group substituted with an –OH group.
  • hydroxyl represents an –OH group.
  • N-protecting group 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, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L, or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyl
  • N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t- butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • nitro represents an —NO 2 group.
  • thiol represents an —SH group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified.
  • Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH 2 or mono- or dialkyl amino), azido, cyano, nitro, oxo, sulfonyl, or thiol.
  • alkyl e.g., unsubstituted and substituted, where the substituents include any group described herein,
  • Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).
  • Compounds described herein e.g., compounds of the invention
  • optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable.
  • Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms.
  • Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art.
  • Racemate or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds described herein e.g., the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure.
  • Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure.
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
  • percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
  • Isotopically-labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art.
  • isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate).
  • compounds of the present invention may be utilized in any such form, including in any solid form.
  • compounds described or depicted herein may be provided or utilized in hydrate or solvate form.
  • the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.
  • the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.
  • administration refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.
  • bronchial including by bronchial instillation
  • adult soft tissue sarcoma refers to a sarcoma that develops in the soft tissues of the body, typically in adolescent and adult subjects (e.g., subjects who are at least 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, 18 years old, or 19 years old).
  • Non-limiting examples of adult soft tissue sarcoma include, but are not limited to, synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, leiomyosarcoma, hemangiosarcoma, Kaposi’s sarcoma, lymphangiosarcoma, malignant peripheral nerve sheath tumor/neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, and extraskeletal mesenchymal.
  • antisense refers to a nucleic acid comprising a polynucleotide that is sufficiently complementary to all or a portion of a gene, primary transcript, or processed mRNA, so as to interfere with expression of the endogenous gene (e.g., BRD9).
  • endogenous gene e.g., BRD9
  • complementary polynucleotides are those that are capable of base pairing according to the standard Watson-Crick complementarity rules.
  • purines will base pair with pyrimidines to form a combination of guanine paired with cytosine (G:C) and adenine paired with either thymine (A:T) in the case of DNA, or adenine paired with uracil (A:U) in the case of RNA.
  • G:C guanine paired with cytosine
  • A:T thymine
  • A:U uracil
  • two polynucleotides may hybridize to each other even if they are not completely complementary to each other, provided that each has at least one region that is substantially complementary to the other.
  • antisense nucleic acid includes single-stranded RNA as well as double-stranded DNA expression cassettes that can be transcribed to produce an antisense RNA.
  • “Active” antisense nucleic acids are antisense RNA molecules that are capable of selectively hybridizing with a primary transcript or mRNA encoding a polypeptide having at least 80% sequence identity (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) with the targeted polypeptide sequence (e.g., a BRD9 polypeptide sequence).
  • the antisense nucleic acid can be complementary to an entire coding strand, or to only a portion thereof.
  • an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence.
  • the term “coding region” refers to the region of the nucleotide sequence comprising codons that are translated into amino acid residues.
  • the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence.
  • noncoding region refers to 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).
  • the antisense nucleic acid molecule can be complementary to the entire coding region of mRNA, or can be antisense to only a portion of the coding or noncoding region of an mRNA.
  • the antisense oligonucleotide can be complementary to the region surrounding the translation start site.
  • An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length.
  • the term “BAF complex” refers to the BRG1- or HRBM-associated factors complex in a human cell.
  • BAF complex-related disorder refers to a disorder that is caused or affected by the level and/or activity of a BAF complex.
  • GBAF complex and “GBAF” refer to a SWI/SNF ATPase chromatin remodeling complex in a human cell.
  • GBAF complex subunits may include, but are not limited to, ACTB, ACTL6A, ACTL6B, BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC 1 , SMARCD1, SMARCD2, SMARCD3, and SS18.
  • cancer refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
  • BRD9 refers to bromodomain-containing protein 9, a component of the BAF (BRG1- or BRM-associated factors) complex, a SWI/SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomain-containing proteins.
  • BRD9 is encoded by the BRD9 gene, the nucleic acid sequence corresponding to positions 863735-892803 in RefSeq sequence NC_000005.10 of GRCh38.p13 (RefSeq assembly accession No. GCF_000001405.39).
  • BRD9 also refers to natural variants of the wild-type BRD9 protein, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) to the amino acid sequence of wild-type BRD9, which is set forth in SEQ ID NO: 1.
  • BRD9-related disorder refers to a disorder that is caused or affected by the level and/or activity of BRD9.
  • cancer refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
  • a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated.
  • the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen.
  • administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic).
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • 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.
  • a “compound of the present invention” and similar terms as used herein, whether explicitly noted or not, refers to compounds useful for treating BAF-related disorders (e.g., cancer or infection) described herein, including, e.g., compounds of Formula I (e.g., a compound of Table 1), as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.
  • tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form.
  • moieties with prototropic tautomeric forms are ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • tautomeric forms result from acetal interconversion.
  • the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., BRD9) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject.
  • a protein e.g., BRD9
  • degradation moiety refers to a moiety whose binding results in degradation of a protein, e.g., BRD9. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., BRD9.
  • determining the level of a protein is meant the detection of a protein, or an mRNA encoding the protein, by methods known in the art either directly or indirectly.
  • Directly determining means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
  • Indirectly determining refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value).
  • Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners.
  • ELISA enzyme-linked immunosorbent assay
  • RIA radioimmunoassay
  • immunoprecipitation immunofluorescence
  • surface plasmon resonance chemiluminescence
  • fluorescent polarization fluorescent polarization
  • the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and/or activity of BRD9 (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and/or activity of BRD9 sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and/or activity of BRD9.
  • a given agent that reduces the level and/or activity of BRD9 described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and/or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art.
  • a “therapeutically effective amount” of an agent that reduces the level and/or activity of BRD9 of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control.
  • a therapeutically effective amount of an agent that reduces the level and/or activity of BRD9 of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.
  • the term “inhibitor” refers to any agent which reduces the level and/or activity of a protein (e.g., BRD9). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA).
  • the term “inhibitory RNA agent” refers to an RNA, or analog thereof, having sufficient sequence complementarity to a target RNA to direct RNA interference.
  • RNA interference refers to a sequence-specific or selective process by which a target molecule (e.g., a target gene, protein, or RNA) is down-regulated.
  • a target molecule e.g., a target gene, protein, or RNA
  • an interfering RNA (“iRNA”) is a double-stranded short-interfering RNA (siRNA), short hairpin RNA (shRNA), or single- stranded micro-RNA (miRNA) that results in catalytic degradation of specific mRNAs, and also can be used to lower or inhibit gene expression.
  • level is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein.
  • a “decreased level” or an “increased level” of a protein is meant a decrease or increase in protein level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1.2-fold, about 1.4-fold, about 1.5-fold
  • a level of a protein may be expressed in mass/vol (e.g., g/dL, mg/mL, ⁇ g/mL, ng/mL) or percentage relative to total protein or mRNA in a sample.
  • miRNA and “microRNA” refer to an RNA agent, preferably a single-stranded agent, of about 10-50 nucleotides in length, preferably between about 15-25 nucleotides in length, which is capable of directing or mediating RNA interference.
  • Naturally-occurring miRNAs are generated from stem-loop precursor RNAs (i.e., pre-miRNAs) by Dicer.
  • Dicer includes Dicer as well as any Dicer ortholog or homolog capable of processing dsRNA structures into siRNAs, miRNAs, siRNA-like or miRNA-like molecules.
  • microRNA miRNA
  • stRNA small temporal RNA
  • modulating the activity of a BAF complex is meant altering the level of an activity related to a BAF complex (e.g., GBAF), or a related downstream effect.
  • the activity level of a BAF complex may be measured using any method known in the art, e.g., the methods described in Kadoch et al, Cell 153:71- 85 (2013), the methods of which are herein incorporated by reference.
  • Percent (%) sequence identity with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity.
  • Alignment for purposes of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign 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 may be generated using the sequence comparison computer program BLAST.
  • the percent sequence identity of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, is calculated as follows: 100 multiplied by (the fraction X/Y) where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program’s alignment of A and B, and where Y is the total number of nucleic acids in B.
  • a “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C,
  • pharmaceutically acceptable salt means any pharmaceutically acceptable salt of the compound of any of the compounds described herein.
  • pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.
  • the compounds described herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds described herein, be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • pharmaceutical composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
  • reducing the activity of BRD9 is meant decreasing the level of an activity related to an BRD9, or a related downstream effect.
  • a non-limiting example of inhibition of an activity of BRD9 is decreasing the level of a BAF complex (e.g., GBAF) in a cell.
  • a BAF complex e.g., GBAF
  • the activity level of BRD9 may be measured using any method known in the art.
  • an agent which reduces the activity of BRD9 is a small molecule BRD9 inhibitor.
  • an agent which reduces the activity of BRD9 is a small molecule BRD9 degrader.
  • reducing the level of BRD9 is meant decreasing the level of BRD9 in a cell or subject.
  • the level of BRD9 may be measured using any method known in the art.
  • a “reference” is meant any useful reference used to compare protein or mRNA levels.
  • the reference can be any sample, standard, standard curve, or level that is used for comparison purposes.
  • the reference can be a normal reference sample or a reference standard or level.
  • a “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any described herein) at a known normal concentration.
  • reference standard or level is meant a value or number derived from a reference sample.
  • a “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker.
  • a normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound described herein.
  • the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health.
  • a standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference.
  • short interfering RNA and “siRNA” refer to an RNA agent, preferably a double-stranded agent, of about 10-50 nucleotides in length, the strands optionally having overhanging ends comprising, for example 1, 2 or 3 overhanging nucleotides (or nucleotide analogs), which is capable of directing or mediating RNA interference.
  • Naturally-occurring siRNAs are generated from longer dsRNA molecules (e.g., >25 nucleotides in length) by a cell's RNAi machinery (e.g., Dicer or a homolog thereof).
  • RNA agent refers to an RNA agent having a stem-loop structure, comprising a first and second region of complementary sequence, the degree of complementarity and orientation of the regions being sufficient such that base pairing occurs between the regions, the first and second regions being joined by a loop region, the loop resulting from a lack of base pairing between nucleotides (or nucleotide analogs) within the loop region.
  • subject refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).
  • a subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • SS18-SSX fusion protein-related disorder refers to a disorder that is caused or affected by the level and/or activity of SS18-SSX fusion protein.
  • the terms "treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • FIG.1 is a series of graphs illustrating the effect of specific guide RNA (sgRNA) targeting of the BRD9 BAF complex subunit on synovial sarcoma cell growth.
  • sgRNA specific guide RNA
  • the Y-axis indicated the dropout ratio.
  • the X-axis indicates the nucleotide position of the BRD9 gene.
  • the grey box indicates the range of the negative control sgRNAs in the screen.
  • the SYO1 cell line carries SS18-SSX2 fusion protein.
  • the breakpoint joining the N-terminal region of SS18 to the C-terminal region of SSX2 are indicated by the black lines in their respective panel.
  • the linear protein sequence is show with BRD9 PFAM domains annotated from the PFAM database.
  • FIG.2 is an image illustrating dose dependent depletion of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrader.
  • FIG.3 is an image illustrating sustained suppression of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrader over 72 hours.
  • FIG.4 is an image illustrating sustained suppression of BRD9 levels in two cell lines (293T and SYO1) in the presence of a BRD9 degrader over 5 days.
  • FIG.5 is an image illustrating sustained suppression of BRD9 levels in synovial sarcoma cell lines (SYO1 and Yamato) in the presence of a BRD9 degrader over 7 days compared to the levels in cells treated with CRISPR reagents.
  • FIG.6 is an image illustrating the effect on cell growth of six cell lines (SYO1, Yamato, A549, HS- SY-II, ASKA, and 293T) in the presence of a BRD9 degrader and a BRD9 inhibitor.
  • FIG.7 is an image illustrating the effect on cell growth of two cell lines (SYO1 and G401) in the presence of a BRD9 degrader.
  • FIG.8 is an image illustrating the effect on cell growth of three synovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) in the presence of a BRD9 degrader, BRD9 binder and E3 ligase binder.
  • FIG.9 is an image illustrating the effect on cell growth of three non-synovial sarcoma cell lines (RD, HCT116, and Calu6) in the presence of a BRD9 degrader, BRD9 binder and E3 ligase binder.
  • FIG.10 is a graph illustrating the percentage of SYO1 in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, or Compound 1 at 1 ⁇ M for 8 or 13 days.
  • FIG.11 is a series of contour plots illustrating the percentage of SYO1 cells in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 ⁇ M, or lenalidomide at 200nM for 8 days.
  • FIG.12 is a series of contour plots illustrating the percentage of SYO1 cells in various cell cycle phases following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 ⁇ M, or lenalidomide at 200nM for 13 days. Numerical values corresponding to each contour plot are found in the table below.
  • FIG.13 is a series of contour plots illustrating the percentage of early- and late-apoptotic SYO1 cells following treatment with DMSO, Compound 1 at 200 nM, Compound 1 at 1 ⁇ M, or lenalidomide at 200nM for 8 days. Numerical values corresponding to each contour plot are found in the table below.
  • FIG.14 is a graph illustrating the proteins present in BAF complexes including the SS18-SSX fusion protein.
  • the present disclosure features compositions and methods useful for the treatment of BAF- related disorders (e.g., cancer and infection).
  • the disclosure further features compositions and methods useful for inhibition of the level and/or activity of BRD9, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof.
  • Compounds Compounds described herein reduce the level of an activity related to BRD9, or a related downstream effect, or reduce the level of BRD9 in a cell or subject.
  • Exemplary compounds described herein have the structure according to Formula I.
  • Formula I is: A-L-B Formula I, where L has the structure of Formula II: A 1 –E 1 –F–E 2 –A 2 , Formula II A 1 is a bond between the linker and A; A 2 is a bond between B and the linker; each of E 1 and E 2 is, independently, absent, CH 2 , O, or NCH 3 ; and F is optionally substituted C 3 -C 10 carbocyclylene or optionally substituted C 2–10 heterocyclylene; B is a degradation moiety; and A has the structure of Formula III: Formula III, where R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 carbocyclyl; Z 1 is CR 2 or N; R 2 is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 hetero
  • the compound has the structure of any one of compounds D1-D66 in Table 1, or a pharmaceutically acceptable salt thereof.
  • Other embodiments, as well as exemplary methods for the synthesis of production of these compounds, are described herein.
  • Pharmaceutical Uses The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and/or activity of a BAF complex, e.g., by inhibiting the activity or level of the BRD9 protein in a cell within the BAF complex in a mammal.
  • An aspect of the present invention relates to methods of treating disorders related to BRD9 such as cancer in a subject in need thereof.
  • the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject. Treating cancer can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer may further result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x). Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement.
  • the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).
  • Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein. Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.
  • the methods of the inventions include an oral administration of a compound of the invention to a subject in need thereof.
  • methods of the invention are particularly preferred for subjects suffering from a sarcoma (e.g., synovial sarcoma).
  • methods of the invention are particularly preferred for subjects suffering from a breast cancer.
  • methods of the invention are particularly preferred for subjects suffering from a lung cancer (e.g., non-small cell lung cancer).
  • methods of the invention are particularly preferred for subjects suffering from an ovarian cancer. In some embodiments, methods of the invention are particularly preferred for subjects suffering from acute myeloid leukemia (AML).
  • a method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of therapies to treat cancer.
  • the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).
  • the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer).
  • chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
  • 5-fluorouracil 5-FU
  • leucovorin LV
  • irenotecan oxaliplatin
  • capecitabine paclitaxel
  • doxetaxel Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, 6-diazo- 5-oxo-L-norle
  • chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).
  • the second therapeutic agent is a DNA damaging agent (e.g., a platinum- based antineoplastic agent, topoisomerase inhibitors, PARP inhibitors, alkylating antineoplastic agents, and ionizing radiation).
  • platinum-based antineoplastic agent examples include cisplatin, carboplatin, oxaliplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, triplatin tetranitrate, phenanthrilplatin, picoplatin, and satraplatin.
  • the second therapeutic agent is cisplatin and the treated cancer is a testicular cancer, ovarian cancer, or a bladder cancer (e.g., advanced bladder cancer).
  • the second therapeutic agent is carboplatin and the treated cancer is an ovarian cancer, lung cancer, head and neck cancer, brain cancer, or neuroblastoma.
  • the second therapeutic agent is oxaliplatin and the treated cancer is a colorectal cancer.
  • the second therapeutic agent is dicycloplatin and the treated cancer is a non-small cell ung cancer or prostate cancer.
  • the second therapeutic agent is eptaplatin and the treated cancer is a gastric cancer.
  • the second therapeutic agent is lobaplatin and the treated cancer is a breast cancer.
  • the second therapeutic agent is miriplatin and the treated cancer is a hepatocellular carcinoma.
  • the second therapeutic agent is nedaplatin and the treated cancer is a nasopharyngeal carcinoma, esophageal cancer, squamous cell carcinoma, or cervical cancer.
  • the second therapeutic agent is triplatin tetranitrate and the treated cancer is a lung cancer (e.g., small cell lung cancer) or pancreatic cancer.
  • the second therapeutic agent is picoplatin and the treated cancer is a lung cancer (e.g., small cell lung cancer), prostate cancer, bladder cancer, or colorectal cancer.
  • the second therapeutic agent is satrapltin and the treated cancer is a prostate cancer, breast cancer, or lung cancer.
  • topoisomerase inhibitors examples include etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, irinotecan, topotecan, camptothecin, and diflomotecan.
  • the second therapeutic agent is etoposide and the treated cancer is a lung cancer (e.g., small cell lung cancer) or testicular cancer.
  • the second therapeutic agent is teniposide and the treated cancer is an acute lymphoblastic leukemia (e.g., childhood acute lymphoblastic leukemia).
  • the second therapeutic agent is doxorubicin and the treated cancer is an acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, breast cancer, Wilm’s tumor, neuroblastoma, soft tissue sarcoma, bone sarcomas, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, or bronchogenic carcinoma.
  • the second therapeutic agent is daunorubicin and the treated cancer is an acute lymphoblastic leukemia or acute myeloid leukemia.
  • the second therapeutic agent is mitoxantrone and the treated cancer is a prostate cancer or acute nonlymphocytic leukemia.
  • the second therapeutic agent is amsacrine and the treated cancer is a leukemia (e.g., acute adult leukemia).
  • the second therapeutic agent is irinotecan and the treated cancer is a colorectal cancer.
  • the second therapeutic agent is topotecan and the treated cancer is a lung cancer (e.g., small cell lung cancer).
  • the second therapeutic agent is diflomotecan and the treated cancer is a lung cancer (e.g., small cell lung cancer).
  • alkylating antineoplastic agents that may be used as a second therapeutic agent in the compositions and methods of the invention are cyclophosphamide, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, chlorozotocin, fotemustine, nimustine, ranimustine, busulfan, improsulfan, piposulfan, chlornaphazine, cholophosphamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, novembichin, phenesterine, prednimustine, trofosfamide, procarbazine, altretamine, dacarbazine, mitozolomide, and temozolomide.
  • the second therapeutic agent is cyclophosphamide and the treated cancer is a Non- Hodgking lymphoma.
  • the second therapeutic agent is melphalan and the treated cancer is a multiple myeloma, ovarian cancer, or melanoma.
  • the second therapeutic agent is chlorambucil and the treated cancer is a chronic lymphatic leukemia, malignant lymphoma (e.g., lymphosarcoma, giant follicular lymphoma, or Hodgkin’s lymphoma).
  • the second therapeutic agent is ifosfamide and the treated cancer is a testicular cancer.
  • the second therapeutic agent is bendamustine and the treated cancer is a chronic lymphocytic leukemia or non-Hodgkin lymphoma.
  • the second therapeutic agent is carmustine and the treated cancer is a brain cancer (e.g., glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, or a metastatic brain tumor), multiple myeloma, Hodgkin’s disease, or Non-Hodgkin’s lymphoma.
  • the second therapeutic agent is lomustine and the treated cancer is a brain cancer or Hodgkin’s lymphoma.
  • the second therapeutic agent is fotemustine and the treated cancer is a melanoma.
  • the second therapeutic agent is nimustine and the treated cancer is a brain cancer.
  • the second therapeutic agent is ranimustine and the treated cancer is a chronic myelogenous leukemia or polycythemia vera.
  • the second therapeutic agent is busulfan and the treated cancer is a chronic myelogenous leukemia.
  • the second therapeutic agent is improsulfan and the treated cancer is a sarcoma.
  • the second therapeutic agent is estramustine and the treated cancer is a prostate cancer (e.g., prostate carcinoma).
  • the second therapeutic agent is mechlomethamine and the treated cancer is a cutaneous T-cell lymphoma.
  • the second therapeutic agent is trofosfamide and the treated cancer is a sarcoma (e.g., soft tissue sarcoma).
  • the second therapeutic agent is procarbazine and the treated cancer is a Hodgkin’s disease.
  • the second therapeutic agent is altretamine and the treated cancer is an ovarian cancer.
  • the second therapeutic agent is dacarbazine and the treated cancer is a melanoma, Hodgkin’s lymphoma, or sarcoma.
  • the second therapeutic agent is temozolomide and the treated cancer is a brain cancer (e.g., astrocytoma or glioblastoma) or lung cancer (e.g., small cell lung cancer).
  • a brain cancer e.g., astrocytoma or glioblastoma
  • lung cancer e.g., small cell lung cancer.
  • PARP inhibitors that may be used as a second therapeutic agent in the compositions and methods of the invention are niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib, CK-102, or E7016.
  • the compounds of the invention and a DNA damaging agent may act synergistically to treat cancer.
  • the second therapeutic agent is niraparib and the treated cancer is an ovarian cancer (e.g., BRCA mutated ovarian cancer), fallopian tube cancer (e.g., BRCA mutated fallopian tube cancer), or primary peritoneal cancer (e.g., BRCA mutated primary peritoneal cancer).
  • ovarian cancer e.g., BRCA mutated ovarian cancer
  • fallopian tube cancer e.g., BRCA mutated fallopian tube cancer
  • primary peritoneal cancer e.g., BRCA mutated primary peritoneal cancer
  • the second therapeutic agent is olaparib and the treated cancer is a lung cancer (e.g., small cell lung cancer), ovarian cancer (e.g., BRCA mutated ovarian cancer), breast cancer (e.g., BRCA mutated breast cancer), fallopian tube cancer (e.g., BRCA mutated fallopian tube cancer), primary peritoneal cancer (e.g., BRCA mutated primary peritoneal cancer), prostate cancer (e.g., castration-resistant prostate cancer), or pancreatic cancer (e.g., pancreatic adenocarcinoma).
  • lung cancer e.g., small cell lung cancer
  • ovarian cancer e.g., BRCA mutated ovarian cancer
  • breast cancer e.g., BRCA mutated breast cancer
  • fallopian tube cancer e.g., BRCA mutated fallopian tube cancer
  • primary peritoneal cancer e.g., BRCA mutated primary peritoneal cancer
  • prostate cancer
  • the second therapeutic agent is rucaparib and the treated cancer is an ovarian cancer (e.g., BRCA mutated ovarian cancer), fallopian tube cancer (e.g., BRCA mutated fallopian tube cancer), or primary peritoneal cancer (e.g., BRCA mutated primary peritoneal cancer).
  • the second therapeutic agent is talazoparib and the treated cancer is a breast cancer (e.g., BRCA mutated breast cancer).
  • the second therapeutic agent is veliparib and the treated cancer is a lung cancer (e.g., non-small cell lung cancer), malenoma, breast cancer, ovarian cancer, prostate cancer, or brain cancer.
  • the second therapeutic agent is pamiparib and the treated cancer is an ovarian cancer.
  • the second therapeutic agent is CK-102 and the treated cancer is a lung cancer (e.g., non-small cell lung cancer).
  • the second therapeutic agent is E7016 and the treated cancer is a melanoma.
  • the synergy between the compounds of the invention and DNA damaging agents may be attributed to the necessity of BRD9 for DNA repair; inhibition of BRD9 may sensitize cancer (e.g., cancer cell or cancer tissue) to DNA damaging agents.
  • the second therapeutic agent is a JAK inhibitor (e.g., JAK1 inhibitor).
  • JAK inhibitors that may be used as a second therapeutic agent in the compositions and methods of the invention include tofacitinib, ruxolitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, cerdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, abrocitinib, solcitinib, itacitinib, or SHR0302.
  • the synergy between the compounds of the invention and JAK inhibitors may be inhibitor of SAGA complex to their combined effect of downregulating Foxp3+ Treg cells.
  • the second therapeutic agent is ruxolitinib and the treated cancer is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis), ovarian cancer, breast cancer, pancreatic cancer.
  • the second therapeutic agent is fedratinib and the treated cancer is a myeloproliferative neoplasm (e.g., myelofibrosis).
  • the second therapeutic agent is cerdulatinib and the treated cancer is a lymphoma (e.g., peripheral T-cell lymphoma).
  • the second therapeutic agent is gandotinib and the treated cancer is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis).
  • the second therapeutic agent is lestaurtinib and the treated cancer is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis), leukemia (e.g., acute myelogenous leukemia), pancreatic cancer, prostate cancer, or neuroblastoma.
  • the second therapeutic agent is momelotinib and the treated cancer is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis) or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).
  • the second therapeutic agent is momelotinib and the treated cancer is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis).
  • the second therapeutic agent is momelotinib and the treated cancer is a myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis) or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).
  • the second therapeutic agent is an inhibitor of SAGA complex or a component thereof.
  • a SAGA complex inhibitor may be, e.g., an inhibitory antibody or small molecule inhibitor, of CCDC 1 01, Tada2B, Tada3, Usp22, Tada1, Taf6l, Supt5, Supt20, or a combination thereof.
  • the synergy between the compounds of the invention and inhibitors of SAGA complex may be attributed to their combined effect of downregulating Foxp3+ Treg cells.
  • the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment.
  • the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®).
  • the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer.
  • a monoclonal antibody e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof
  • agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer.
  • Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-I- 131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panit
  • the second agent may be a therapeutic agent which is a non-drug treatment.
  • the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.
  • the second agent may be a checkpoint inhibitor.
  • the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody).
  • the antibody may be, e.g., humanized or fully human.
  • the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein.
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab/YERVOY® or tremelimumab).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; pidilizumab/CT-011).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/Ig fusion protein such as AMP 224).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof.
  • the second therapeutic agent is ipilimumab and the treated cancer is a melanoma, kidney cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), or prostate cancer.
  • the second therapeutic agent is tremelimumab and the treated cancer is a melanoma, mesothelioma, or lung cancer (e.g., non-small cell lung cancer).
  • the second therapeutic agent is nivolumab and the treated cancer is a melanoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, Hodgkin lymphoma, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), urothelial carcinoma, hepatocellular carcinoma, or colorectal cancer.
  • the second therapeutic agent is pembrolizumab and the treated cancer is a melanoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), Hodgkin lymphoma, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), primary mediastinal large B-cell lymphoma, urothelial carcinoma, hepatocellular carcinoma, microsatellite instability-high cancer, gastric cancer, esophageal cancer, cervical cancer, Merkel cell carcinoma, kidney carcinoma, or endometrial carcinoma.
  • lung cancer e.g., non-small cell lung cancer or small cell lung cancer
  • Hodgkin lymphoma e.g., non-small cell lung cancer or small cell lung cancer
  • head and neck cancer e.g., squamous cell carcinoma of the head and neck
  • primary mediastinal large B-cell lymphoma urothelial carcinoma
  • hepatocellular carcinoma hepatocellular carcinoma
  • the second therapeutic agent is MPDL3280A and the treated cancer is a lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), urothelial carcinoma, hepatocellular carcinoma, or breast cancer.
  • the second therapeutic agent is MEDI4736 and the treated cancer is a lung cancer (e.g., non-small cell lung cancer or small cell lung cancer) or urothelial carcinoma.
  • the second therapeutic agent is MSB0010718C and the treated cancer is a urothelial carcinoma.
  • the second therapeutic agent is MSB0010718C and the treated cancer is a melanoma, lung cancer (e.g., non-small cell lung cancer), colorectal cancer, kidney cancer, ovarian cancer, pancreatic cancer, gastric cancer, and breast cancer.
  • the compounds of the invention and a checkpoint inhibitor may act synergistically to treat cancer. Without wishing to be bound by theory, the synergy between the compounds of the invention and checkpoint inhibitors may be attributed to the checkpoint inhibitor efficacy enhancement associated with the BRD9 inhibition-induced downregulation of Foxp3+ Treg cells.
  • the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy.
  • the T cell is an activated T cell.
  • the T cell may be modified to express a chimeric antigen receptor (CAR).
  • CAR modified T (CAR-T) cells can be generated by any method known in the art.
  • the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell.
  • a source of T cells Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject.
  • T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
  • the T cell is an autologous T cell.
  • a desirable protein e.g., a CAR
  • the T cells can be activated and expanded generally using methods as described, for example, in U.S.
  • the first and second therapeutic agents are administered simultaneously or sequentially, in either order.
  • the first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.
  • 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.
  • the compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein.
  • the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • a compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
  • a compound described herein may also be administered parenterally.
  • Solutions of a compound described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders.
  • Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.
  • a compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate.
  • a compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals.
  • the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection.
  • Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.
  • the compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
  • the dosage of the compounds described herein, and/or compositions including a compound described herein can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form).
  • kits including (a) a pharmaceutical composition including an agent that reduces the level and/or activity of BRD9 in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein.
  • the kit includes (a) a pharmaceutical composition including an agent that reduces the level and/or activity of BRD9 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.
  • a pharmaceutical composition including an agent that reduces the level and/or activity of BRD9 in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.
  • Protein domains were obtained from PFAM regions defined for the UNIPROT identifier: Q9H8M2. Results: As shown in FIG.1, targeted inhibition of the GBAF complex component BRD9 by sgRNA resulted in growth inhibition of the SYO1 synovial sarcoma cell line. sgRNAs against other components of the BAF complexes resulted in increased proliferation of cells, inhibition of cell growth, or had no effect on SYO1 cells. These data show that targeting various subunits of the GBAF complex represents a therapeutic strategy for the treatment of synovial sarcoma. Table 2: BRD9 sgRNA Library Table 3: Control sgRNA Library
  • Example 2 – BRD9 degrader depletes BRD9 protein The following example demonstrates the depletion of the BRD9 protein in synovial sarcoma cells treated with a BRD9 degrader.
  • Whole cell extracts were fractionated by SDS-PAGE and transferred to a polyvinylidene difluoride membrane using a transfer apparatus according to the manufacturer’s protocols (Bio-Rad).
  • Example 3 Inhibition of growth of synovial cell lines by BRD9 inhibitors and BRD9 degraders The following example demonstrates that BRD9 degraders and inhibitors selectively inhibit growth of synovial sarcoma cells.
  • Procedures Cells were treated with DMSO or the BRD9 degrader, Compound A, at indicated concentrations, and proliferation was monitored from day 7 to day 14 by measuring confluency over time using an IncuCyte live cell analysis system (FIG.5). Growth medium and compounds were refreshed every 3-4 days.
  • FOG.5 IncuCyte live cell analysis system
  • Cells were seeded into 12-well plates and treated with DMSO, 1 ⁇ M BRD9 inhibitor, Compound B (also known as BI-7273, see Martin et al, J Med Chem.59(10):4462-4475 (2016); see structure of Compound B below), or 1 ⁇ M BRD9 degrader, Compound A.
  • the number of cells was optimized for each cell line. Growth medium and compounds were refreshed every 3-5 days. SYO1, Yamato, A549, 293T and HS-SY-II cells were fixed and stained at day 11. ASKA cells were fixed and stained at day 23.
  • SYO1 cells were treated for 8 or 13 days with DMSO, a BRD9 degrader (Compound A) at 200nM or 1 ⁇ M, or an E3 ligase binder (lenalidomide) at 200nM. Compounds were refreshed every 5 days.
  • Cell cycle analysis was performed using the Click-iTTM Plus EdU Flow Cytometry Assay (Invitrogen).
  • the apoptosis assay was performed using the Annexin V-FITC Apoptosis Detection Kit (Sigma A9210). Assays were performed according to the manufacturer’s protocol.
  • Example 6 Composition for SS18-SSX1-BAF The following example shows the identification of BRD9 as a component of SS18-SSX containing BAF complexes. Procedure: A stable 293T cell line expressing HA-SS18SSX1 was generated using lentiviral integration.
  • BAF complexes including the SS18-SSX fusion protein also included BRD9.
  • ARID1A More than 5 unique peptides were identified for ARID1A (95 peptides), ARID1B (77 peptides), SMARCC 1 (69 peptides), SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32 peptides), SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 (22 peptides), DPF1 Isoform 2 (18 peptides), DPF3 (13 peptides), and ACTL6B (6 peptides).
  • Step 3 Preparation of 3,3,3-trifluoropropanoic acid; 6-([2-[2-(2-aminoethoxy)ethoxy]ethyl](methyl)amino)- 4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one (i4)
  • tert-butyl N-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]- 7-methyl-8-oxo-2,7-naphthyridin-3-yl)(methyl)amino]ethoxy]ethoxy)ethyl]carbamate (75.00mg, 0.122 mmol, 1.00 equiv) in dichloromethane (3 mL) was added TFA (1 mL) dropwise at room temperature.
  • Step 4 Preparation of 4-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7- naphthyridin-3-yl)-4,7-dioxa-1,10-diazaundecan-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound C) To a stirred solution of 6-([2-[2-(2-aminoethoxy)ethoxy]ethyl](methyl)amino)-4-[4-[(dimethylamino) methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one (68.00 mg, 0.132 mmol, 1.00 equiv) in DMF (1 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-
  • Example 9 Preparation of 4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4- yl)-2,6-dimethoxybenzaldehyde
  • Step 1 Preparation of 6-chloro-4-methylpyridine-3-carboxamide To a stirred mixture of 6-chloro-4-methylpyridine-3-carboxylic acid (20.00 g, 116.564 mmol, 1.00 equivalent) and NH4Cl (62.35 g, 1.17 mol, 10.00 equivalent) in DCM (400 mL) was added DIEA (22.60 g, 174.846 mmol, 3.00 equivalent).
  • Step 2 Preparation of 6-chloro-N-[(1E)-(dimethylamino)methylidene]-4-methylpyridine-3-carboxamide
  • 6-chloro-4-methylpyridine-3-carboxamide 18.30 g, 107.268 mmol, 1.00 equivalent
  • 2-methyltetrahydrofuran 100 mL
  • DMF-DMA (19.17 g, 160.903 mmol, 1.50 equivalent
  • Step 3 Preparation of 6-chloro-2H-2,7-naphthyridin-1-one To a stirred mixture of 6-chloro-N-[(1E)-(dimethylamino)methylidene]-4-methylpyridine-3- carboxamide (26.30 g) in THF (170.00 mL) was added t-BuOK (174.00 mL,1mol/L in THF), the resulting solution was stirred at 60 °C under nitrogen atmosphere for 30 min.
  • Step 4 Preparation of 6-chloro-2-methyl-2,7-naphthyridin-1-one
  • 6-chloro-2H-2, 7-naphthyridin-1-one 14.10 g, 78.077 mmol, 1.00 equivalent
  • anhydrous THF 280.00 mL
  • NaH 9.37 g, 234.232 mmol, 3.00 equivalent, 60%
  • MeI 33.25 g, 234.232 mmol, 3.00 equivalent
  • Step 5 Preparation of 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one
  • DMF 160.00 mL
  • NBS 8.78 g, 49.327 mmol, 1.20 equivalent
  • the reaction mixture was cooled and diluted with DCM (150mL), and washed with water (3x100 mL), the organic layers were dried and concentrated.
  • Step 6 Preparation of 4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one
  • Step 7 Preparation of (4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxy benzaldehyde
  • 4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one (5.70 g, 20.203 mmol, 1.00 equivalent)
  • 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (8.26 g, 28.284 mmol, 1.40 equivalent) in dioxane (100.00 mL) and H 2 O (10.00 mL) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (1.65 g, 2.020 mmol, 0.10 equivalent) and Cs 2 CO 3 (13.16 g, 40.405 mmol, 2.00 equivalent
  • Example 10 Preparation of 3-(6-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7- naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione formic acid; and 3-(5-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)- 2,6-dimethoxybenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione formic acid; Step 1: Preparation of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione.
  • Step 2 Preparation of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro-2H- pyridine-1-carboxylate
  • 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (3.00 g, 8.899 mmol, 1.00 equivalent)
  • tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- 1-carboxylate (3.30 g, 10.672 mmol, 1.20 equivalent)
  • K3PO4 (5.67 g, 26.712 mmol, 3.00 equivalent) in dioxane (20.00 mL) and H 2 O (4.00 mL) was added Pd(PPh 3 )
  • Step 3 Preparation of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1- carboxylate
  • tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro- 2H-pyridine-1-carboxylate (0.80 g) in THF (20.00 mL) was added 10% Pd/C (500.0 mg) under nitrogen atmosphere in a 100 mL round-bottom flask.
  • Step 4 Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxoisoindolin-5-yl)piperidine-1- carboxylate; tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxoisoindolin-5-yl)piperidine-1- carboxylate
  • tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1- carboxylate (0.73 g, 16.55 mmol, 1.00 equivalent) and Zn (1.08 g, 1.65 mmol, 10.00 equivalent) in AcOH (10.00 mL) at room temperature.
  • Step 6 Preparation of 3-(6-(1-(4-(6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)- 2,6-dimethoxybenzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione formic acid; and 3-(5-(1-(4- (6-(dimethylamino)-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzyl)piperidin-4-yl)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione formic acid To a stirred solution of 3-[1-oxo-6-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6
  • the resulting mixture was stirred for 16 h at room temperature.
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH 3 CN in water (0.05% FA), 0% to 50% gradient in 30 min; detector, UV 254 nm.
  • the crude product was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD Column, 10 ⁇ m, 19*250 mm; mobile phase, water (0.05% FA) and CH 3 CN (15% to 22% CH 3 CN in 15 min); Detector, UV 254 nm.
  • Step 2 Preparation of 4-bromo-6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one
  • DMF dimethyl-2,7-naphthyridin-1-one
  • NBS 106.66 mg, 0.599 mmol, 1.20 equivalent
  • the resulting mixture was stirred for 2h at 90 °C.
  • the resulting mixture was diluted with water (12 mL), extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 .
  • Step 3 Preparation of 4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde
  • 4-bromo-6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one 420.00 mg, 1.505 mmol, 1.00 equivalent
  • 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (527.48 mg, 1.806 mmol, 1.2 equivalent) in dioxane (10.00mL) and water (2.00 mL) was added Pd(dppf)Cl 2 (110.09 mg, 0.150 mmol, 0.10 equivalent) and K 2 CO 3 (415.90 mg, 3.009 mmol, 2.00 equivalent) at room temperature under nitrogen atmosphere.
  • Example 12 Preparation of 3-[6-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6- dimethoxyphenyl]methyl]129zetidine-3-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione
  • Step 1 Preparation of tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (25).
  • Step 2 Preparation of tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy] azetidine-1- carboxylate
  • a solution of tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1- carboxylate (4.40 g, 13.439 mmol, 1.00 equivalent) and KI (0.22 g, 1.344 mmol, 0.10 equivalent) in DMF was added KHCO3 (4.04 g, 40.318 mmol, 3.00 equivalent) in portions at 100 °C under air atmosphere.
  • Step 3 Preparation of tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol -5- yl]oxy]azetidine-1-carboxylate,and tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1- oxo-3H-isoindol- 5-yl]oxy]azetidine-1-carboxylate
  • the resulting mixture was concentrated under reduced pressure.
  • the crude product (mg) was purified by Prep-HPLC with the following conditions (Column: Xcelect CSH F-pheny OBD Column, 19*250mm,5 ⁇ m; Mobile Phase A:Water (0.05% TFA ), Mobile Phase B: can; Flow rate: 30 mL/min; Gradient:5 B to 21 B in 10 min; 254/220 nm; RT1: 7.20/8.67 min) to afford 3-[6- (azetidin-3-yloxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (165 mg, 8.27%) as an off-white solid.
  • the crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250mm, 5 ⁇ m; Mobile Phase A:Water (0.05% TFA ), Mobile Phase B:ACN; Flow rate: 25 mL/min; Gradient:15 B to 23 B in 12 min; 254/220 nm; RT1: 10.38 min) to afford 3-[6-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl] methyl]azetidin-3-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (18.9 mg, 11.69%) as an off-white solid.
  • Example 13 Preparation of 4-(6-cyclopropyl-2-(methyl-d3)-1-oxo-1,2-dihydro-2,7-naphthyridin-4- yl)-2,6-dimethoxybenzaldehyde
  • Step 1 Preparation of 6-chloro-2-(2H3)methyl-2,7-naphthyridin-1-one
  • a solution of 6-chloro-2H-2,7-naphthyridin-1-one (500.00 mg, 2.769 mmol, 1.00 equivalent) in THF (5.00 mL) was treated with NaH (132.89 mg, 5.537 mmol, 2.00 equivalent) for 5min at 0 °C followed by the addition of CD3I (802.69 mg, 5.537 mmol, 2.00 equivalent) in portions at 0 °C.
  • Step 2 Preparation of 6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one
  • cyclopropylboronic acid 260.78 mg, 3.036 mmol, 1.50 equivalent
  • K 3 PO 4 (1288.81 mg, 6.072 mmol, 3.00 equivalent
  • PCy3 113.51 mg, 0.405 mmol, 0.20 equivalent
  • Pd(AcO) 2 45.44 mg, 0.202 mmol, 0.10 equivalent
  • Step 4 Preparation of 4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6- dimethoxybenzaldehyde
  • Step 2 Preparation of 4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6- dimethoxybenzaldehyde
  • 6-(azetidin-1-yl)-4-bromo-2-methyl-2,7-naphthyridin-1-one (1.42 g, 4.827 mmol, 1.00 equivalent)
  • 4-formyl-3,5-dimethoxyphenylboronic acid (1.52 g, 7.241 mmol, 1.5 equivalent) in dioxane (16.00 mL) and H 2 O (4.00 mL) were added Pd(dppf)Cl 2 (353.2 mg, 0.483 mmol, 0.1 equivalent) and Cs2CO3 (3.15 g, 9.655 mmol, 2 equivalent), and the resulting solution was stirred at 70 °C for 2 hours.
  • Step 2 Preparation of 3-(5-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione
  • tert-butyl 2-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]- 2,7-diazaspiro[3.5]nonane-7-carboxylate 250.0 mg, 0.516 mmol, 1.00 equivalent
  • DCM 2.00 mL
  • TFA 0.50 mL
  • Et 3 SiH 0.20 mL
  • Step 3 Preparation of 3-[5-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyph enyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione; formic acid To a stirred solution of 3-(5-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (400.0 mg, 1.086 mmol, 1.00 equivalent) and 4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4- yl]-2,6-dimethoxybenz
  • Step 2 Preparation of 3-[3-hydroxy-1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione and 3-[1- hydroxy-3-oxo-5-(piperidin-4-yl)-1H-isoindol-2-yl]piperidine-2,6-dione
  • 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindole-1,3-dione 300.0 mg, 0.879 mmol, 1.00 equivalent) in AcOH (5.00 mL) was added Zn (574.9 mg, 8.788 mmol, 10 equivalent), and the resulting solution was stirred at 25 °C for 2 hours.
  • Step 2 Preparation of 2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridin -4- yl]benzaldehyde
  • 4-bromo-2-methyl-6-(morpholin-4-yl)-2,7-naphthyridin-1-one 540.00 mg, 1.666 mmol, 1.00 equivalent
  • 4-formyl-3,5-dimethoxyphenylboronic acid (454.73 mg, 2.165 mmol, 1.30 equivalent)
  • Cs2CO3 (1628.20 mg, 4.997 mmol, 3.00 equivalent) in H 2 O (1.00 mL) and dioxane (5.00 mL) was added Pd(dppf)Cl 2 CH 2 Cl 2 (136.03 mg, 0.167 mmol, 0.10 equivalent) under nitrogen.
  • Step 3 Preparation of 3-(5-[[1-([2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7- naphthyridin-4- yl]phenyl]methyl)azetidin-3-yl]oxy]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione
  • 3-[5-(azetidin-3-yloxy)-1-oxo-3H-isoindol-2-yl]piperidine -2,6-dione (100.00 mg, 0.317 mmol, 1.00 equivalent) and 2,6-dimethoxy-4 -[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7- naphthyridin-4-yl]benzaldehyde (129.85 mg, 0.317 mmol, 1.00 equivalent) in DMF was added NaBH(OAc)3 (
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 45 min; detector, UV 254 nm.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: Xcelect CSH F-pheny OBD Column, 19*250mm, 5 ⁇ m; Mobile Phase A: Water(0.05%FA); Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 13 B to 33 B in 14 min; 254/220 nm; RT1: 12.85 min) to afford 3-(5-[[1-([2,6-dimethoxy-4-[2-methy l-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridin-4- yl]phenyl]methyl)azetidin-3-yl]oxy]-1-oxo-3H-isoindol-2-yl)piper
  • %Inhibition 100 x (LumHC – LumSample) / (LumHC –LumLC).
  • DMSO treated cells are employed as High Control (HC) and 1 ⁇ M of a known BRD9 degrader standard treated cells are employed as Low Control (LC).

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Abstract

La présente invention concerne des procédés et des compositions pour le traitement de troubles liés à BAF tels que des cancers et des infections virales.
EP20947059.0A 2020-07-29 2020-07-29 Composés et leurs utilisations Withdrawn EP4188447A1 (fr)

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MA40943A (fr) * 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc Pyrrolopyridines substituées utilisées en tant qu'inhibiteurs de bromodomaines
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WO2017007612A1 (fr) * 2015-07-07 2017-01-12 Dana-Farber Cancer Institute, Inc. Procédés pour induire la dégradation ciblée de protéines par des molécules bifonctionnelles
CA3025806C (fr) * 2016-06-23 2023-04-04 Dana-Farber Cancer Institute, Inc. Degradation de la proteine contenant un bromodomaine 9 (brd9) par conjugaison d'inhibiteurs de brd9 avec un ligand de la ligase e3 et procedes d'utilisation

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