JP2023536139A - Compounds and uses thereof - Google Patents

Abstract

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

Description

SEQUENCE LISTING This application contains a Sequence Listing which has been electronically compiled in ASCII format and is hereby incorporated by reference in its entirety. The name of this ASCII copy, created on July 29, 2020, is 51121-053WO1_Sequence_Listing_07_29_20_ST25 and is 99,298 bytes in size.

BACKGROUND OF THE INVENTION Disorders can be affected by the BAF complex. BRD9 is a component of the BAF complex. The present invention relates to useful compositions and methods for the treatment of BAF complex-associated disorders such as cancer and infectious diseases.

Bromodomain-containing protein 9 (BRD9) is the protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of the BAF (BRG1-associated or BRM-associated factor) complex, the SWI/SNF ATPase chromatin remodeling complex, and belongs to family IV of bromodomain-containing proteins. BRD9 is present in several SWI/SNF ATPase chromatin remodeling complexes and is upregulated in multiple cancer cell lines. Agents that reduce the level and/or activity of BRD9 may therefore provide new methods for the treatment of diseases and disorders such as cancer and infectious diseases. We found that depletion of BRD9 in cells resulted in depletion of SS18-SSX fusion protein in those cells. The SS18-SSX fusion protein has been detected in over 95% of synovial sarcoma tumors and is often the only cytogenetic abnormality in synovial sarcoma. Furthermore, evidence suggests that the BAF complex is involved in cellular antiviral activity. Agents (eg, compounds) that degrade BRD9 are therefore useful in treating disorders (eg, cancer or infectious diseases) associated with BAF, BRD9, and/or SS18-SSX.

This disclosure features compounds and methods useful for treating BAF-related disorders (eg, cancer or infectious diseases).
In one aspect, the disclosure provides a compound having the structure of Formula I,
ALB
Formula I
During the ceremony,
L has the structure of formula II,
A ¹ -E ¹ -FE ² -A ²
Formula II
A ¹ is the bond between the linker and A;
^A2 is the bond between B and the linker,
each of E ¹ and E ² is independently absent CH ₂ , O, or NCH ₃ ;
F is optionally substituted C ₃ -C ₁₀ carbocyclylene or optionally substituted C _2-10 heterocyclylene;
B is the decomposition part,
A has the structure of formula III,

During the ceremony,
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 - _Cio 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 heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted C ₂ -C ₉ heteroaryl;
X ¹ is N or CH and X ² is C—R ″, or X ¹ is C— ^{R 7 ″} and X ² is N or CH;
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 amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;
R ⁷ ′ is H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, or optionally substituted C ₃ -C ₁₀ carbocyclyl;
X ³ is N or CH,
X ⁴ is N or CH,
G” is

, optionally substituted C ₃ -C ₁₀ carbocyclyl, C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted C ₂ -C ₉ heteroaryl;
G′ is optionally substituted C ₃ -C ₁₀ carbocyclylene, C ₂ -C ₉ heterocyclylene, optionally substituted C ₆ -C ₁₀ arylene, or optionally substituted C ₂ -C ₉ is heteroarylene,
A ¹ is the bond between A and the linker,
G” is

or R ⁷ ″ is

or a pharmaceutically acceptable salt thereof.
In some embodiments, 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 is. 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 be. 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. In some embodiments, 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

is.
In some embodiments, R ¹ is

is.
In some embodiments, R ¹ is

is.
In some embodiments, R ¹ is H,

is. In some embodiments, R ¹ is

is. In some embodiments, R ¹ is H,

is.
In some embodiments, R ¹ is H,

is.
In some embodiments, R ¹ is H,

is.
In some embodiments, R ¹ is H or

is.
In some embodiments, R ¹ is H. In some embodiments, R ¹ is

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 is 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

is.
In some embodiments, ^R2 is H. In some embodiments, ^R2 is F. In some embodiments, R ² is

is.
In some embodiments, R ⁷ ″ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted C ₁ -C ₆ alkoxy, 3 optionally substituted carbocyclyl having ˜6 atoms, or optionally substituted heterocyclyl having 3-6 atoms. In some embodiments, R ⁷ ″ is optionally substituted C ₁ - _C6 alkyl, optionally substituted _C1 - _C6 heteroalkyl, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms be. In some embodiments, R ⁷ ″ is optionally substituted C ₁ -C ₆ alkoxy or optionally substituted amino. In some embodiments, R ⁷ ″ is optionally substituted sulfones or optionally substituted sulfonamides.

In some embodiments, R ⁷ ″ is optionally substituted C ₁ -C ₆ alkyl or optionally substituted carbocyclyl having 3-6 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. In some embodiments, R ⁷ ″ is optionally substituted C ₁ -C ₆ heteroalkyl. is. 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 3-6 atoms. In some embodiments, R ⁷ ″ is optionally substituted carbocyclyl having 3-6 atoms. is heterocyclyl substituted with In some embodiments, R ⁷ ″ is an optionally substituted sulfone. In some embodiments, R ⁷ ″ is an optionally substituted sulfonamide.

In some embodiments, R ⁷ ″ is optionally substituted C ₁ -C ₃ alkyl. In some embodiments, R ⁷ ″ is optionally substituted C ₁ -C ₃ heteroalkyl. is.
In some embodiments, R ⁷ ″ is

is.
In some embodiments, R ⁷ ″ is —NR ³ R ⁴ or —OR ⁴ , wherein R ³ is H or optionally substituted C ₁ -C ₆ alkyl and R ⁴ is , 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, ^R3 is H. In some embodiments, R ³ is optionally substituted C ₁ -C ₆ alkyl.

In some embodiments, ^R3 is H and ^R4 is methyl. In some embodiments, ^R3 is methyl and ^R4 is methyl.
In some embodiments, R ⁷ ″ is

is. In some embodiments, R ⁷ ″ is

is.
In some embodiments, R ⁷ ″ is optionally substituted carbocyclyl having 3-6 atoms or optionally substituted heterocyclyl having 3-6 atoms. , R ⁷ ″ is optionally substituted carbocyclyl having 3 to 6 atoms. In some embodiments, R ⁷ ″ is optionally substituted heterocyclyl having 3-6 atoms.

In some embodiments, R ⁷ ″ is carbocyclyl ^having 3-6 atoms or heterocyclyl having 3-6 atoms. is a carbocyclyl having an atom of In some embodiments, R ⁷ ″ is heterocyclyl having 3-6 atoms.

In some embodiments, R ⁷ ″ is

is.
In some embodiments, R ⁷ ″ is

is.
In some embodiments, R ⁷ ″ is

is.
In some embodiments, R ⁷ ″ is

is.
In some embodiments, R ⁷ ″ is

is. In some embodiments, R ⁷ ″ is

is. In some embodiments, R ⁷ ″ is

is. In some embodiments, R ⁷ ″ is

is. In some embodiments, R ⁷ ″ is

is.
In some embodiments, X ¹ is N and X ² is C—R ⁷ ″. In some embodiments, 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 It is CH.

In some embodiments, X ¹ is N or CH and X ² is C-NR ³ R ⁴ , C-OR ⁴ ,

or X ¹ is C—NR ³ R ⁴ , C—OR ⁴ ,

and X ² is N or CH. In some embodiments, X ¹ is N or CH, X ² is C—NR ³ R ⁴ ,

or X ¹ is C—NR ³ R ⁴ ,

and X ² is N or CH. In some embodiments, X ¹ is N or CH and 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. In some embodiments, X ¹ is N or CH and 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. In some embodiments, X ¹ is N or CH and 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.
In some embodiments, R ⁷ ″ is —NR ³ R ⁴ , —OR ⁴ , or optionally substituted heterocyclyl having 3-6 atoms.

In some embodiments, X ¹ is N and X ² is C-NR ³ R ⁴ . In some embodiments, X ¹ is C—NR ³ R ⁴ and X ² is N.
In some embodiments, ^R3 is H. In some embodiments, R ³ is optionally substituted C ₁ -C ₆ alkyl.

In some embodiments, R ³ is

is. In some embodiments, R ³ is

is. In some embodiments, R ³ is

is. In some embodiments, R ³ is methyl, ethyl,

is.
In some embodiments, R ⁴ is

is. In some embodiments, R ⁴ is

is. In some embodiments, R ⁴ is

is. In some embodiments, R ⁴ is methyl, ethyl,

is.
In some embodiments, ^X3 is N. In some embodiments, ^X3 is CH.

In some embodiments, ^X4 is N. In some embodiments, X ⁴ is CH.
In some embodiments, ^X3 is N and ^X4 is N.

In some embodiments, X ³ is N and X ⁴ is CH.
In some embodiments, ^X3 is CH and ^X4 is N.
In some embodiments, ^X3 is CH and ^X4 is CH.

In some embodiments, G″ is

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 an optionally substituted _C6 - _C10 arylene. In some embodiments, 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

and
During the ceremony,
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 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 —C ₁ -C ₃ alkyl-C ₃ -C ₆ carbocyclyl substituted with , optionally substituted —C ₁ -C ₃ alkyl-C ₂ -C ₅ heterocyclyl, hydroxyl, thiol, or optionally substituted amino or R ^{G1 ′} and R ^{G2 ′} , R ^{G2 ′} and R ^{G3 ′} , R ^{G3 ′} and R ^G4 ′, and/or R ^{G4 ′} and R ^{G5 ′} are each bonded to the carbon atom combined together,

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 optionally substituted C ₂ -C ₉ heterocyclyl any of which is optionally substituted with A ¹ , wherein one of R ^G1 ′, R ^{G2 ′} , R ^G3 ′, R ^G4 ′, and R ^G5 ′ is , A ¹ , or

is replaced by ^A1 .
In some embodiments, 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 - _C6 carbocyclyl, optionally substituted _-C1 - _C3 alkyl- _C3 - _C6 carbocyclyl, optionally substituted _-C1 - _C3 alkyl- _C2 - _C5 heterocyclyl, hydroxyl, thiol, or optionally substituted amino, or R ^G1 ′ and R ^{G2 ′} , R ^{G2 ′} and R ^G3 ′, R ^G3 ′ and R ^G4 ′, and/or R ^G4 ′ and R ^{G5 ′} are each Combined with the bonding carbon atoms,

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 optionally substituted C ₂ -C ₉ heterocyclyl any of which is optionally substituted with A ¹ , wherein one of R ^G1 ′, R ^{G2 ′} , R ^G3 ′, R ^G4 ′, and R ^G5 ′ is , A ¹ , or

is replaced by ^A1 .
In some embodiments, 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 ′ are each attached carbon Combined with atoms,

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 , wherein one of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is A ¹ ; or

is replaced by ^A1 .
In some embodiments, 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.

In some embodiments, each of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is independently H, A ¹ , F, Cl,

is.
In some embodiments, each of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is independently H, A ¹ , F,

is.
In some embodiments, each of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is independently H, A ¹ , F, Cl,

is.
In some embodiments, R ^G3 ' is A ¹ .
In some embodiments, R ^G1 ' is H and R ^G2 ' is

and R ^G3 ' is A ¹ and R ^G4 ' is

and R ^G5 ' is H. In some embodiments, R ^G1 ' is H and R ^G2 ' is

, R ^G3 ' is A ¹ , R ^G4 ' is H, and R ^G5 ' is

is. In some embodiments, R ^G1 ' is H and R ^G2 ' is

, R ^G3 ′ is A ¹ , R ^G4 ′ is Cl or F, and R ^G5 ′ is H. In some embodiments, R ^G1 ' is H and R ^G2 ' is

, R ^G3 ′ is A ¹ , R ^G4 ′ is H, and R ^G5 ′ is H. In some embodiments, R ^G1 ' is H and R ^G2 ' is

and R ^G3 ' is A ¹ and R ^G4 ' is

and R ^G5 ' is H.
In some embodiments, R ^G1 ′ and R ^{G2 ′} , R ^{G2 ′} and R ^{G3 ′} , R ^{G3 ′} and R ^G4 ′, and/or R ^{G4 ′} and R ^G5 ′ are each attached Combined with atoms,

to form

is optionally substituted C ₂ -C ₉ heterocyclyl optionally substituted with A ¹ , wherein R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ' is A ¹ , or

is replaced by ^A1 . In some embodiments, R ^G1 ′ and R ^{G2 ′} , R ^{G2 ′} and R ^{G3 ′} , R ^{G3 ′} and R ^G4 ′, and/or R ^{G4 ′} and R ^G5 ′ are each attached Combined with atoms,

to form

is optionally substituted C ₂ -C ₉ heteroaryl optionally substituted with A ¹ , wherein R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R one of ^G5 ' is ^A1 , or

is replaced by ^A1 .
In some embodiments, G' is

where R ^G6 is H, A ¹ , or optionally substituted C ₁ -C ₆ alkyl. In some embodiments, G' is

where R ^G6 ' is H, A ¹ , or optionally substituted C ₁ -C ₆ alkyl.
In some embodiments, R ^G1 ′ and R ^{G2 ′} , R ^{G2 ′} and R ^{G3 ′} , R ^{G3 ′} and R ^G4 ′, and/or R ^{G4 ′} and R ^G5 ′ are each attached Combined with atoms,

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 , wherein one of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is A ¹ ; or

is replaced by ^A1 .
In some embodiments, 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 ,

is.
In some embodiments, R ^G6 ′ is H, A ¹ , or

is.
In some embodiments, R ^G6 ' is H or A ¹ .
In some embodiments, ^RG6 ' is H. In some embodiments, R ^G6 ' is A ¹ .

In some embodiments, R ^G1 ' is H, A ¹ , F,

is. In some embodiments, R ^G1 ' is H.
In some embodiments, R ^G2 ' is H, A ¹ , F,

is. In some embodiments, R ^G2 ' is H.
In some embodiments, R ^G3 ′ is H, A ¹ , F,

is. In some embodiments, R ^G3 ' is H.
In some embodiments, R ^G4 ′ is H, A ¹ , F,

is. In some embodiments, R ^G4 ' is H.
In some embodiments, R ^G5 ' is H, A ¹ , F,

is. In some embodiments, R ^G5 ' is H.
In some embodiments, one or more of R ^{G1 ′} , R ^{G2 ′} , R ^G3 ′, R ^G4 ′, and R ^G5 ′ is H. In some embodiments, two or more of R ^{G1 ′} , R ^{G2 ′} , R ^G3 ′, R ^G4 ′, and R ^G5 ′ are H. In some embodiments, three or more of R ^{G1 ′} , R ^{G2 ′} , R ^G3 ′, R ^G4 ′, and R ^G5 ′ are H.

In some embodiments, 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 replaced by ^A1 .
In some embodiments, G' is

and
During the ceremony,
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 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 —C ₁ -C ₃ alkyl-C ₃ -C ₆ carbocyclyl substituted with , optionally substituted —C ₁ -C ₃ alkyl-C ₂ -C ₅ heterocyclyl, 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 ′ are each bonded to the carbon atom combined together,

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, is optionally substituted with A ¹ , wherein one of R ^G7 ', R ^G8 ', R ^G9 ', R ^G10 ', and R ^G11 ' is A ¹ or

is replaced by ^A1 .
In some embodiments, 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 - _C6 carbocyclyl, optionally substituted _-C1 - _C3 alkyl- _C3 - _C6 carbocyclyl, optionally substituted _-C1 - _C3 alkyl- _C2 - _C5 heterocyclyl, 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 ′ are each Combined with the bonding carbon atoms,

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, is optionally substituted with A ¹ , wherein one of R ^G7 ', R ^G8 ', R ^G9 ', R ^G10 ', and R ^G11 ' is A ¹ or

is replaced by ^A1 .
In some embodiments, 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 ′ are each attached carbon Combined with atoms,

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, is optionally substituted with A ¹ , wherein one of R ^G7 ', R ^G8 ', R ^G9 ', R ^G10 ', and R ^G11 ' is A ¹ or

is replaced by ^A1 .
In some embodiments, 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.

In some embodiments, each of R ^G7 ′, R ^G8 ′, R ^G9 ′, R ^G10 ′, and R ^G11 ′ is independently H, A ¹ , F, Cl,

is. In some embodiments, R ^G8 ' is

is.
In some embodiments, G' is

is.
In some embodiments, R ^G7 ' is H and R ^G8 ' is

, R ^G9 ′ is A ¹ and R ^G11 ′ is H.
In some embodiments, G' is

and
During the ceremony,
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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 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 — is 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 ^G14 ′ in combination with the carbon atom to which each is attached,

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 optionally substituted C ₂ -C ₉ heterocyclyl, any of which is optionally substituted with A ¹ , wherein one of R ^G12 ′, R ^G13 ′, and R ^G14 ′ is A ¹ , or

is replaced by ^A1 .
In some embodiments, 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 with 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 ^G14 ′ in combination with the carbon atom to which each is attached,

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 optionally substituted C ₂ -C ₉ heterocyclyl, any of which is optionally substituted with A ¹ , wherein one of R ^G12 ′, R ^G13 ′, and R ^G14 ′ is A ¹ , or

is replaced by ^A1 .
In some embodiments, R ⁷ ″ is

is.
In some embodiments, R ⁷ ′ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₃ -C ₁₀ carbocyclyl. In some embodiments, R ⁷ ' is H or optionally substituted C ₁ -C ₆ alkyl.

In some embodiments, R ⁷ ' is H,

is. In some embodiments, R ⁷ ' is H or

is. In some embodiments, R ⁷ ' is H. In some embodiments, R ⁷ ' is

is.
In some embodiments, G″ is optionally substituted C ₃ -C ₁₀ carbocyclyl or optionally substituted C ₂ -C ₉ heterocyclyl. In some embodiments, 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.

In some embodiments, G″ is

and
During the ceremony,
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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 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 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 in combination with the carbon atom to which each is attached, optionally substituted C ₆ -C ₁₀ Form aryl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heteroaryl, or optionally substituted C ₂ -C ₉ heterocyclyl.

In some embodiments, 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 with 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 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 in combination with the carbon atom to which each is attached, optionally substituted 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.

In some embodiments, 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 in combination with the carbon atom to which each is attached, optionally substituted C ₂ — Form C ₉ heteroaryl or optionally substituted C ₂ -C ₉ heterocyclyl.

In some embodiments, 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 is 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.

In some embodiments, each of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 is independently H, F, Cl,

is.
In some embodiments, each of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 is independently H, F,

is.
In some embodiments, each of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 is independently H, F, Cl,

is.
In some embodiments, R ^G1 is H and R ^G2 is

and R ^G3 is

and R ^G4 is

and R ^G5 is H. In some embodiments, R ^G1 is H and R ^G2 is

and R ^G3 is

, ^RG4 is H, and ^RG5 is

is. In some embodiments, R ^G1 is H and R ^G2 is

and R ^G3 is

, R ^G4 is Cl or F, and R ^G5 is H. In some embodiments, R ^G1 is H and R ^G2 is

and R ^G3 is

, ^RG4 is H, and ^RG5 is H. In some embodiments, R ^G1 is H and R ^G2 is

and R ^G3 is

and R ^G4 is

and R ^G5 is H.
In some embodiments, R ^G1 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 are combined together with the carbon atom to which each is attached, Forms optionally substituted C ₂ -C ₉ heteroaryl or optionally substituted C ₂ -C ₉ heterocyclyl.

In some embodiments, R ^G1 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 are combined together with the carbon atom to which each is attached, Forms an optionally substituted C ₂ -C ₉ heterocyclyl. In some embodiments, R ^G1 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 are combined together with the carbon atom to which each is attached, Forms an optionally substituted C ₂ -C ₉ heteroaryl.

In some embodiments, R ^G1 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 are combined together with the carbon atom to which each is attached, Forms an optionally substituted C ₂ -C ₉ heterocyclyl. In some embodiments, R ^G1 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 are combined together with the carbon atom to which each is attached, Forms an optionally substituted C ₂ -C ₉ heteroaryl.

In some embodiments, 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.
In some embodiments, G″ is

where R ^G6 is H or optionally substituted C ₁ -C ₆ alkyl.
In some embodiments, R ^G6 is H,

is.
In some embodiments, R ^G6 is H or

is.
In some embodiments, R ^G6 is H.
In some embodiments, R ^G1 is H, F,

is. In some embodiments, R ^G1 is H.
In some embodiments, R ^G2 is H, F,

is. In some embodiments, R ^G2 is H.
In some embodiments, R ^G3 is H, F,

is. In some embodiments, R ^G3 is H.
In some embodiments, R ^G4 is H, F,

is. In some embodiments, R ^G4 is H.
In some embodiments, R ^G5 is H, F,

is. In some embodiments, R ^G5 is H.
In some embodiments, one or more of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 is H. In some embodiments, two or more of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 are H. In some embodiments, three or more of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 are H. In some embodiments, each of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 is H.

In some embodiments, G″ is

and
During the ceremony,
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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 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 ^G7 and R ^G8 , R ^G8 and R ^G9 , R ^G9 and R ^G10 , and/or R ^G10 and R ^G11 in combination with the carbon atom to which each is attached, optionally substituted C ₆ -C ₁₀ Form aryl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heteroaryl, or optionally substituted C ₂ -C ₉ heterocyclyl.

In some embodiments, 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 is 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 in combination with the carbon atom to which each is attached, optionally substituted C ₆ — Form C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heteroaryl, or C ₂ -C ₉ heterocyclyl.

In some embodiments, 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 in combination with the carbon atom to which each is attached, optionally substituted C ₆ — Form C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heteroaryl, or C ₂ -C ₉ heterocyclyl.

In some embodiments, 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 is 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.

In some embodiments, each of R ^G7 , R ^G8 , R ^G9 , R ^G10 , and R ^G11 is independently H, F, Cl,

is. In some embodiments, R ^G8 is

is.
In some embodiments, G″ is

is.
In some embodiments, R ^G7 is H and R ^G8 is

, ^RG9 is H, and ^RG11 is H.
In some embodiments, G″ is

and
During the ceremony,
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 ₂ -C ₅ heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R ^G12 and R ^G14 are each optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heteroaryl, in combination with the bonding carbon atom, or form an optionally substituted C ₂ -C ₉ heterocyclyl.

In some embodiments, 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 _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 hetero aryl, 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 are optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ hetero, in combination with the carbon atom to which each is attached. Forms aryl, or optionally substituted C ₂ -C ₉ heterocyclyl.

In some embodiments, A has the structure of Formula IIIa,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIb,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIc,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A is the structure of formula IIId

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of formula IIIe,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIf,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of formula IIIg,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of formula IIIh,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIi,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A is the structure of formula IIIj,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of formula IIIk,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIm,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIn,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIo,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of Formula IIIp,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A is the structure of formula IIIq,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A is the structure of formula IIIr,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A is the structure of Formula IIIs

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of formula IIIt,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A has the structure of formula IIIu,

or a pharmaceutically acceptable salt thereof.
In some embodiments, A is the structure of formula IIIv,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety.
In some embodiments, the ubiquitin ligase binding moiety is a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homolog (MDM2), or a von Hippel-Lindau (VHL) ligand, or a derivative thereof. or analogues.

In some embodiments, the degradation moiety is a ubiquitin ligase binding moiety.
In some embodiments, the ubiquitin ligase binding moiety is a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homolog (MDM2), or a von Hippel-Lindau (VHL) ligand, or a derivative thereof. or analogues.

In some embodiments, the resolution moiety is the structure of Formula A,

During the ceremony,
Y ¹ is

and
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 are each together with the carbon atom to which is attached to form an optionally substituted C ₃ -C ₆ carbocyclyl or an optionally substituted C ₂ -C ₅ heterocyclyl, or R ^A6 and R ^A7 are combine together with the carbon atoms to which each is attached to form an optionally substituted C ₃ -C ₆ carbocyclyl or an 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 , 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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 heteroaryl , optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, optionally substituted —O—C ₃ -C ₆ carbocyclyl, hydroxyl, thiol, or optionally substituted or R ^A1 and R ^A2 , R ^A2 and R ^A3 , and/or R ^A3 and R ^A4 in combination with the carbon atom to which each is attached,

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, is optionally substituted with ^A2 , wherein one of R ^A1 , R ^A2 , R ^A3 , and R ^A4 is ^A2 , or

is substituted with ^A2 , or a pharmaceutically acceptable salt thereof.
In some embodiments, 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 is 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 in combination with the carbon atom to which each is attached,

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, is optionally substituted with ^A2 , wherein one of R ^A1 , R ^A2 , R ^A3 , and R ^A4 is ^A2 , or

is substituted with ^A2 or a pharmaceutically acceptable salt thereof.
In some embodiments, 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 - is C ₆ heteroalkyl, optionally substituted —O—C ₃ -C ₆ carbocyclyl, hydroxyl, or optionally substituted amino, or R ^A1 and R ^A2 , R ^A2 and R ^A3 , or R ^A3 and R ^A4 in combination with the carbon atom to which each is attached,

to form

is optionally substituted C ₂ -C ₉ heterocyclyl optionally substituted with A ² , wherein one of R ^A1 , R ^A2 , R ^A3 and R ^A4 is A ² or

is replaced by ^A2 .
In some embodiments, 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 in combination with the carbon atom to which each is attached,

to form

is optionally substituted C ₂ -C ₉ heterocyclyl optionally substituted with A ² , wherein one of R ^A1 , R ^A2 , R ^A3 and R ^A4 is A ² or

is replaced by ^A2 .
In some embodiments, R ^A1 is ^A2 . In some embodiments, R ^A2 is ^A2 . In some embodiments, R ^A3 is ^A2 . In some embodiments, R ^A4 is ^A2 . In some embodiments, R ^A5 is ^A2 .

In some embodiments, R ^A5 is H or optionally substituted C ₁ -C ₆ alkyl.
In some embodiments, R ^A5 is H or

is. In some embodiments, R ^A5 is H. In some embodiments, R ^A5 is

is.
In some embodiments, Y ¹ is

is. In some embodiments, Y ¹ is

is. In some embodiments, Y ¹ is

is.
In some embodiments, each of R ^A6 and R ^A7 is independently H, F,

or R ^A6 and R ^A7 in combination with the carbon atom to which each is attached,

to form In some embodiments, R ^A6 is H and R ^A7 is H.
In some embodiments, Y ¹ is

is. In some embodiments, Y ¹ is

is. In some embodiments, Y ¹ is

is.
In some embodiments, the structure of Formula A is the structure of Formula A1,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A2,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A3,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A4,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A5,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A6,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A7,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A8,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A9,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is the structure of Formula A10,

or a pharmaceutically acceptable salt thereof.
In some embodiments, the structure of Formula A is

, or a derivative or analogue thereof.
In some embodiments, the structure of Formula A is

is.
In some embodiments, the structure of Formula A is

, or a derivative or analogue thereof.
In some embodiments, the linker has the structure of Formula II,
A ¹ -E ¹ -FE ² -A ²
Formula II
A ¹ is the bond between the linker and A;
^A2 is the bond between B and the linker,
each of E ¹ and E ² is independently absent CH ₂ , O, or NCH ₃ ;
F is

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, ^E2 is absent. In some embodiments, ^E2 is _CH2 . In some embodiments, ^E2 is O. In some embodiments, ^E2 is _NCH3 .

In some embodiments, the linker has the structure:

,including.
In some embodiments, the compound has the structure of any one of compounds D1-D66 of Table 1, or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure features a pharmaceutical composition comprising any of the compounds described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In one aspect, the present disclosure provides a method of inhibiting BRD9 levels and/or activity in a cell, comprising treating the cell with an effective amount of any of the foregoing compounds, or a pharmaceutically acceptable salt thereof. or a pharmaceutical composition thereof.

In another aspect, the present disclosure provides a method of reducing the level and/or activity of BRD9 in a cell, comprising treating the cell with an effective amount of any of the foregoing compounds or a pharmaceutically acceptable compound thereof. A method is featured comprising contacting with a salt or a pharmaceutical composition thereof.

In some embodiments, the cells are cancer cells.
In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer Cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelial sarcoma, fibromyxous sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxoid fibrosarcoma, low-grade rhabdomyosarcoma), non Small cell lung cancer (eg, squamous cell or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colon rectal cancer. In some embodiments, the cancer is sarcoma (eg, synovial sarcoma or Ewing's sarcoma), lung cancer (eg, non-small cell lung cancer (eg, squamous cell or adenocarcinoma)), gastric cancer, or breast cancer. In some embodiments, the cancer is sarcoma (eg, synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

In one aspect, the disclosure provides a method of treating a BAF complex-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of any of the aforementioned compounds or A method is featured comprising administering a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the BAF complex-associated disorder is cancer. In some embodiments, the BAF complex-associated disorder is an infectious disease.

In another aspect, the present disclosure provides a method of treating an SS18-SSX fusion protein-associated disorder in a subject in need of treatment for an SS18-SSX fusion protein-associated disorder, comprising: or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the SS18-SSX fusion protein associated disorder is cancer. In some embodiments, the SS18-SSX fusion protein-associated disorder is an infectious disease. In some embodiments of any of the preceding methods, the SS18-SSX fusion protein is an SS18-SSX1 fusion protein, an SS18-SSX2 fusion protein, or an SS18-SSX4 fusion protein.

In yet another aspect, the present disclosure provides a method of treating a BRD9-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of any of the aforementioned compounds or a pharmaceutical agent thereof. or a pharmaceutical composition thereof. In some embodiments, the BRD9-related disorder is cancer. In some embodiments, the BRD9-related disorder is an infectious disease.

In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver , lung, neck, ovarian, pancreatic, prostate, and stomach cancer; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, Sarcoma, including ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer , ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms tumor, and teratocarcinoma. Additional cancers that 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, adenocarcinoma, sarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, 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 cancer, metastatic breast cancer, luminal A breast cancer, Luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL) ), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, Ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube carcinoma, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stroma tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal carcinoma, invasive ductal carcinoma (IDC) ), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic cholangiocarcinoma, invasive/invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, renal cancer, laryngeal cancer, smooth muscle tumor, leptomeningeal metastasis, leukemia, lip carcinoma, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma , meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monodermal monodermal teratoma, mouth cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma cell tumor, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, intraocular melanoma, oligodendroglioma, oral cancer, oral cancer, Oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal tumor, pineoblastoma, pituitary gland Cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic carcinoma, rhabdomyosarcoma, salivary gland carcinoma, soft tissue sarcoma, bone sarcoma, sarcoma, sinus carcinoma , skin cancer, small cell lung cancer (SCLC), small bowel cancer, spine cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, Vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre- B-lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (AML) subtypes), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal enlargement Cellular B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; unclassifiable splenic lymphoma/leukemia, diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, Plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary follicular cutaneous lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in patients; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL leg type, ALK + large B-cell lymphoma, plasmablastic lymphoma; HHV8-associated multicentric Large B-cell lymphoma arising in Castleman disease; unclassifiable B-cell lymphoma with features intermediate to diffuse large B-cell lymphoma, or intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma unclassifiable B-cell lymphomas with typical features.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer Cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelial sarcoma, fibromyxous sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxoid fibrosarcoma, low-grade rhabdomyosarcoma), non Small cell lung cancer (eg, squamous cell or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colon rectal cancer. In some embodiments, the cancer is sarcoma (eg, synovial sarcoma or Ewing's sarcoma), non-small cell lung cancer (eg, squamous cell or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is sarcoma (eg, synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

In some embodiments, the infection is a viral infection (e.g., lentiviruses (e.g., human immunodeficiency virus (HIV)) and deltaretroviruses (e.g., human T-cell leukemia virus type I (HTLV-I), human T cell leukemia virus type II (HTLV-II)), family Hepadnaviridae (e.g. hepatitis B virus (HBV)), family Flaviviridae (e.g. hepatitis C virus (HCV)), family Adenoviridae (e.g. human adenovirus) , Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpes virus type 6 (HHV-6) , herpesvirus K*, CMV, varicella-zoster virus), Papilomaviridae family (e.g. human papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g. parvovirus B19), Polyomaviridae family (e.g. JC virus and BK virus) , Paramyxoviridae (e.g., measles virus), or Togaviridae (e.g., rubella virus).In some embodiments, the disorder is Coffin Siris, neurofibromatosis. (eg, NF-1, NF-2, or schwannomatosis), or multiple meningioma In one aspect, the present disclosure treats cancer in a subject in need thereof. A method comprising administering to a subject an effective amount of any of the aforementioned compounds or pharmaceutically acceptable salts thereof or any of the aforementioned pharmaceutical compositions. and

In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver , lung, neck, ovarian, pancreatic, prostate, and stomach cancer; leukemia; benign and malignant lymphomas, especially Burkitt's and non-Hodgkin's lymphomas; benign and malignant melanoma; myeloproliferative disorders; sarcoma, liposarcoma, sarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, nerve sarcomas, including arthroglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, Ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms tumor, and teratocarcinoma. Additional cancers that may be treated using the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma. , adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, intestine 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 cancer, metastatic breast cancer, luminal A breast cancer, ductal Cavity B breast cancer, HER2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependyma tumor, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube carcinoma, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal carcinoma, invasive ductal carcinoma (IDC) , invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic cholangiocarcinoma, invasive/invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, renal cancer, laryngeal carcinoma, leiomyosarcoma , leptomeningeal metastasis, leukemia, lip carcinoma, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, Meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monodermal malformation monodermal teratoma, mouth cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma tumor, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, intraocular melanoma, oligodendroglioma, mouth cancer, oral cancer, oral cavity Pharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian primary peritoneal cancer, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus carcinoma , parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal tumor, pineoblastoma, pituitary cancer , primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic carcinoma, rhabdomyosarcoma, salivary gland carcinoma, soft tissue sarcoma, bone sarcoma, sarcoma, sinus carcinoma, Skin cancer, small cell lung cancer (SCLC), small intestine cancer, spine cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma/thymic carcinoma, thyroid cancer , tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulva cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B Lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML) type), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large cell Type B-cell lymphoma, nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell Prolymphocytic leukemia; unclassifiable splenic lymphoma/leukemia, diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, phenotype Cellular myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary follicular cutaneous lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL leg type, ALK + large B-cell lymphoma, plasmablastic lymphoma; HHV8-associated multicentric castle Large B-cell lymphoma arising in Mann's disease; unclassifiable B-cell lymphoma with features intermediate to diffuse large B-cell lymphoma or intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma A non-classifiable B-cell lymphoma with common features.

In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer Cancer, sarcoma (e.g., soft tissue sarcoma, synovial sarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelial sarcoma, fibromyxous sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxoid fibrosarcoma, low-grade rhabdomyosarcoma), non Small cell lung cancer (eg, squamous cell or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colon rectal cancer. In some embodiments, the cancer is sarcoma (eg, synovial sarcoma or Ewing's sarcoma), non-small cell lung cancer (eg, squamous cell or adenocarcinoma), gastric cancer, or breast cancer. In some embodiments, the cancer is sarcoma (eg, synovial sarcoma or Ewing's sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

In another aspect, the disclosure features a method for treating a viral infection in a subject in need thereof. The method comprises administering to the subject an effective amount of any of the aforementioned compounds or pharmaceutically acceptable salts thereof or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is lentiviruses (eg, human immunodeficiency virus (HIV) and deltaretroviruses (eg, human T-cell leukemia virus type I (HTLV-I), human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae (e.g., hepatitis B virus (HBV)), Flaviviridae (e.g., hepatitis C virus (HCV)), Adenoviridae (e.g., human adenovirus), Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), human herpes virus type 6 (HHV-6), herpesvirus K*, CMV, varicella-zoster virus), Papilomaviridae family (e.g., human papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), It is an infectious disease caused by viruses of the families Paramyxoviridae (eg measles virus), Togaviridae (eg rubella virus).

In another embodiment of any of the foregoing methods, the method further comprises administering to the subject an additional anti-cancer therapy (eg, a chemotherapeutic or cytotoxic agent or radiation therapy).

In certain embodiments, the additional anti-cancer therapy is chemotherapeutic or cytotoxic agents (e.g. doxorubicin or ifosfamide), differentiation-inducing agents (e.g. retinoic acid, vitamin D, cytokines), hormonal agents, immunological agents therapeutic agents, or anti-angiogenic agents. Chemotherapeutic and cytotoxic agents include alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposide, and other agents such as paclitaxel, taxol, docetaxel, taxotere, cisplatin. but not limited to these. A list of additional compounds with anticancer activity can be found in L.L. Brunton, B.; Chabner andB. Knollman (eds). Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Twelfth Edition, 2011, McGraw Hill Companies, New York, NY.

In certain embodiments, the compound of the invention and the additional anti-cancer therapy and any of the foregoing compounds or pharmaceutical compositions are administered within 28 days of each other (e.g., 21, 14, 10, 7, within 5, 4, 3, 2, or 1 day), or within 24 hours (e.g., 12, 6, 3, 2, or 1 hour, or simultaneously), each together to treat a subject. Administered in an effective amount.

Chemical Terminology The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

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

As used herein, phrases of the form "optionally substituted X" (e.g., optionally substituted alkyl) are referred to as "X (wherein X is optionally substituted)" (e.g., "alkyl (wherein said alkyl is optionally substituted)"). It is not intended to imply that the feature "X" (eg, alkyl) per se is optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the specified moiety are a suitable substituent, e.g. It means substituted with any of the substituents or groups described in the specification. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and more than one position within any given structure may be specified When it can be substituted with two or more substituents selected from the groups of, the substituents may be the same or different at all positions. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to their production, detection and, in certain embodiments, their production for one or more of the purposes disclosed herein. Refers to a compound that is substantially unchanged when subjected to conditions that permit its recovery, purification, and use.

As used herein, the term "aliphatic" refers to saturated or unsaturated, straight chain, branched, or cyclic hydrocarbons. "Aliphatic," as used herein, is intended 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. Aliphatic chains can be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups may be in cis or trans configuration. In one embodiment, aliphatic groups contain 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In one embodiment, an aliphatic group contains 1 to about 8 carbon atoms. In certain embodiments, aliphatic groups are C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , or C ₁ -C ₆ . As used herein, specific ranges refer to aliphatic groups with each member of the range recited as an independent species. For example, as used herein, the term C ₁ -C ₆ aliphatic includes a straight or branched chain alkyl, alkenyl, having 1, 2, 3, 4, 5 or 6 carbon atoms. or alkynyl groups, each of which is intended to be described as an independent species. For example, as used herein, the term C ₁ -C ₄ aliphatic refers to straight or branched chain alkyl, alkenyl, or alkynyl groups having 1, 2, 3, or 4 carbon atoms. are intended to mean that each of these is described as an independent species. In one embodiment, aliphatic groups are substituted with one or more functional groups that result in the formation of stable moieties.

As used herein, the term "heteroaliphatic" means at least one heteroatom in the chain, e.g., amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen in place of a carbon atom. , refers to an aliphatic moiety containing a phosphorus, silicon, or boron atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. "Heteroaliphatic," as used herein, is intended to include, but not be limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. In one embodiment, heteroaliphatic groups are optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic moieties include polyethylene glycols, polyalkylene glycols, amides, polyamides, polylactides, polyglycolides, thioethers, ethers, alkyl-heterocycle-alkyls, -O-alkyl-O-alkyls, and alkyl —O-haloalkyl.

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

As used herein, the term "alkyl" refers to 1 to 20 carbon atoms, such as 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. , or 1 to 3 carbon atoms) branched or straight chain monovalent saturated aliphatic hydrocarbon radicals. An "alkylene" is a divalent alkyl group.

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

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

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

As used herein, the term "aryl" refers to an aromatic mono- or polycarbocyclic radical of, for example, 6-12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

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

As used herein, the term "azido" represents a _-N3 group.
As used herein, the term "bridged cyclyl" refers to a bridged polycyclic group of 5-20 atoms containing 1-3 bridges. Bridged cyclyls include bridged carbocyclyls (eg norbornyl) and bridged heterocyclyls (eg 1,4-diazabicyclo[2.2.2]octane).

As used herein, the term "cyano" represents a -CN group.
As used herein, the term “carbocyclyl” refers to a non-aromatic C ₃ -C ₁₂ monocyclic or polycyclic (eg, bicyclic or tricyclic) ring in which the ring is formed by carbon atoms. refers to structure. Carbocyclyl structures include cycloalkyl groups (eg, cyclohexyl) and unsaturated carbocyclyl radicals (eg, cyclohexenyl). Polycyclic carbocyclyls include spirocyclic carbocyclyls, bridged carbocyclyls, and fused carbocyclyls. A "carbocyclylene" is a divalent carbocyclyl group.

As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monovalent monocarbocyclic or polycarbocyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. . This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

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

As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced with nitrogen, oxygen, or sulfur. point to In some embodiments, heteroalkyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are "alkoxy", which as used herein refers to alkyl-O- (eg, methoxy and ethoxy), and "alkylamino", which refers to the As used herein, it refers to -N(alkyl)R ^Na , where R ^Na is H or alkyl (eg, methylamino). A "heteroalkylene" is a divalent heteroalkyl group.

As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms are replaced with nitrogen, oxygen, or sulfur. point to In some embodiments, heteroalkenyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkenyl groups. An example of a heteroalkenyl group is "alkenoxy," which as used herein refers to alkenyl-O-. A "heteroalkenylene" is a divalent heteroalkenyl group.

As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms are replaced with nitrogen, oxygen, or sulfur. point to In some embodiments, heteroalkynyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkynyl groups. An example of a heteroalkynyl group is "alkynoxy," which as used herein refers to alkynyl-O-. A "heteroalkynylene" is a divalent heteroalkynyl group.

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

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

As used herein, the term "heterocyclyl" has at least one non-aromatic ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S Refers to a monocyclic or polycyclic radical (eg, bicyclic or tricyclic) having 3-12 atoms, the aromatic ring not containing any N, O, or S atoms. Polycyclic heterocyclyls include spirocyclic heterocyclyls, bridged heterocyclyls, and fused heterocyclyls. Examples of 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.

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

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

As used herein, the term "imine" represents the =NR ^N group, where R ^N is, for example, H or alkyl.
As used herein, the term "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 formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-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; or carbamyl groups; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- carbamate-forming groups such as methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and silyl groups such as trimethylsilyl. but not limited to these. Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein, the term "nitro" represents a _-NO2 group.
As used herein, the term "oxo" represents a =O group.
As used herein, the term "thiol" represents a -SH group.

Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (eg, cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. When substituted, there are generally 1-4 substituents present unless otherwise specified. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, where 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., _NH2 or mono- or dialkylamino), azide, cyano, nitro, oxo, sulfonyl, or thiol. Aryl, carbocyclyl (eg, cycloalkyl), heteroaryl, and heterocyclyl groups can also be substituted with alkyl (unsubstituted and substituted, such as arylalkyl (eg, substituted and unsubstituted benzyl)).

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

Compounds of the present disclosure also include all isotopes of atoms occurring in the intermediate or final compounds. "Isotope" refers to atoms having the same atomic number but different mass numbers that arise from different numbers of neutrons in the nucleus. 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 invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, ^2H , ^3H , ^11C , ^13C . , 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 (eg, those labeled with ³ H and ¹⁴ C) may be useful in compound or substrate tissue distribution assays. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes can be useful for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., ² H), confers certain therapeutic benefits (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. obtain. In some embodiments, 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 in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically-labeled compounds are generally prepared by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent, following procedures similar to those disclosed for the compounds of the invention described herein. can be prepared by

As is known in the art, many chemical entities can adopt a variety of different solid forms, e.g., amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). . In some embodiments, the compounds of the present invention may be utilized in any such form, including any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present disclosure are described herein. Other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

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

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

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

As used herein, the term "adult soft tissue sarcoma" typically refers to adolescent and adult subjects (e.g., at least 10, 11, 12, 13, 14, 15 years old). refers to sarcomas that develop in the soft tissues of the body in subjects who are 16, 17, 18, or 19 years old. Non-limiting examples of adult soft tissue sarcomas include, but are not limited to, synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, leiomyosarcoma, angiosarcoma, Kaposi's sarcoma, Lymphangiosarcoma, malignant peripheral nerve sheath tumor/neurofibrosarcoma, extraosseous chondrosarcoma, extraosseous osteosarcoma, extraosseous myxoid chondrosarcoma, and extraosseous mesenchyme.

As used herein, the term "antisense" refers to all or part of a gene, primary transcript, or mRNA processed so as to interfere with the expression of an endogenous gene (eg, BRD9). Refers to a nucleic acid comprising a sufficiently complementary polynucleotide. "Complementary" polynucleotides are those that are capable of base pairing according to the standard Watson-Crick complementarity rules. Specifically, purines base-pair with pyrimidines, guanine paired with cytosine (G:C) for DNA, adenine paired with either thymine (A:T), or for RNA Forms adenine (A:U) combinations paired with uracil. It is understood that two polynucleotides can hybridize to each other, provided that they each have at least one region that is substantially complementary to each other, even if they are not completely complementary to each other.

The term "antisense nucleic acid" includes single-stranded RNA as well as double-stranded DNA expression cassettes that can be transcribed to produce antisense RNA. An "active" antisense nucleic acid is at least 80% (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%) a targeting polypeptide sequence (e.g., BRD9 polypeptide sequence) %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) It is an antisense RNA molecule that can selectively hybridize to a substance or mRNA. An antisense nucleic acid can be complementary to an entire coding strand, or only a portion thereof. In another embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence. The term "coding region" refers to a region of a nucleotide sequence that contains codons translated into amino acid residues. In another embodiment, an antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleic acid sequence. The term "noncoding region" refers to the 5' and 3' sequences that flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions). An antisense nucleic acid molecule can be complementary to an entire coding region of an mRNA or can be antisense to only a portion of the coding or noncoding region of an mRNA. For example, an antisense oligonucleotide can be complementary to the region surrounding the translation initiation site. Antisense oligonucleotides can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length.

As used herein, the term "BAF complex" refers to the BRG1 or HRBM-associated factor complex in human cells.
As used herein, the term "BAF complex-associated disorder" refers to a disorder caused or influenced by the level and/or activity of the BAF complex.

The terms "GBAF complex" and "GBAF" as used herein refer to the SWI/SNF ATPase chromatin remodeling complex in human cells. GBAF complex subunits include, but are not limited to, ACTB, ACTL6A, ACTL6B, BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2, SMARCD3, and SS18. The term "cancer" refers to conditions caused by the growth of malignant neoplastic cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

As used herein, the term "BRD9" refers to the BAF (BRG1 or BRM-associated factor) complex, bromodomain-containing protein 9, a component of the SWI/SNF ATPase chromatin remodeling complex; It belongs to family IV of domain-containing proteins. BRD9 is encoded by the BRD9 gene, whose nucleic acid sequence is GRCh38. Corresponds to positions 863735-892803 in RefSeq sequence NC_000005.10 of p13 (RefSeq Assembly Accession No. GCF_000001405.39). The term "BRD9" also includes at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%) to the wild-type BRD9 amino acid sequence shown in SEQ ID NO: 1 , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more)). Point.

As used herein, the term "BRD9-associated disorder" refers to a disorder caused or influenced by the levels and/or activity of BRD9. The term "cancer" refers to conditions caused by the growth of malignant neoplastic cells such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

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

As used herein, "compounds of the invention" and similar terms, whether explicitly stated or not, refer to the BAF-related disorders described herein (e.g., cancer or Infectious diseases), e.g., compounds of Formula I (e.g., compounds of Table 1), as well as salts thereof (e.g., pharmaceutically acceptable salts), solvates, hydrates isomers, stereoisomers (including atropisomers), and tautomers. One of ordinary skill in the art will recognize that certain compounds described herein can have one or more different isomers (e.g., stereoisomers, geometric isomers, atropisomers, and tautomers) or isotopes (e.g., It will be understood that one or more atoms can exist in different isotope-substituted forms of the atom, such as hydrogen substituted with deuterium. Unless otherwise indicated, or clear from context, depicted structures may be understood to represent any such isomeric or isotopic forms individually or in combination. Compounds described herein may be asymmetric (eg, possess one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in this disclosure. be. Cis and trans geometric isomers of the compounds of this disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, one or more compounds presented herein may exist in different tautomeric forms. As is clear from the context, references to such compounds include all such tautomeric forms, unless expressly excluded. In some embodiments, tautomeric forms result from exchange of single bonds with adjacent double bonds and concomitant proton transfers. In certain embodiments, a tautomeric form can be a prototropic tautomer, which is an isomeric protonated state with the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomeric forms are the ketone-enol pair, the amide-imidic acid pair, the lactam-lactim pair, the amide-imidic acid pair, the enamine-imine pair, and the protons are 1H and 3H-imidazole, 1H- , 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. . In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversions.

As used herein, the term "degrading agent" refers to a small molecule compound comprising a degrading moiety, wherein the compound results in the degradation of a protein, e.g., binding of the compound causes e.g. interacts with proteins (eg, BRD9) in a manner that results in at least a 5% reduction in the level of

As used herein, the term "degradation moiety" refers to a moiety whose binding results in degradation of a protein, eg, BRD9. In one example, the moiety binds to a protease or ubiquitin ligase that metabolizes a protein, eg, BRD9.

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

As used herein, an "effective amount," "therapeutically effective amount," and "sufficient amount" of an agent that reduces the level and/or activity of BRD9 (e.g., in a cell or subject) as described herein. The term "effective amount" refers to an amount sufficient to produce beneficial or desired results, including clinical results, when administered to a subject, including humans; depends on the context in which it is used. For example, in the context of treating cancer, it is important to consider levels of BRD9 and / or the amount of drug that reduces activity. Amounts of a given agent that reduce the level and/or activity of BRD9 as described herein that would correspond to such amount would correspond to a given agent, pharmaceutical formulation, route of administration, disease or Varies depending on a variety of factors, such as the type of disorder, the identity of the subject (e.g., age, sex, and/or weight), or the host being treated, but is nevertheless routinely determined by those skilled in the art. obtain. Also, as used herein, a "therapeutically effective amount" of an agent that reduces the level and/or activity of BRD9 of the present disclosure is an amount that produces beneficial or desirable results in a subject as compared to a control. be. A therapeutically effective amount of an agent that reduces the level and/or activity of BRD9 of the present disclosure, as defined herein, can be readily determined by a person skilled in the art by routine methods known in the art. . Dosage regimens may be adjusted to provide the optimum therapeutic response.

As used herein, the term "inhibitor" refers to any agent that reduces the level and/or activity of a protein (eg, BRD9). Non-limiting examples of inhibitors include small molecule inhibitors, degradants, antibodies, enzymes, or polynucleotides (eg, siRNA).

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

By "level" is meant the level of a protein, or mRNA encoding a protein, compared to a reference material. A reference material, as defined herein, can be any useful reference material. A "decreased level" or "increased level" of a protein means a decrease or increase in protein level when compared to a reference material (e.g., about 5%, about 10%, about 15%, about 20% , about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more decrease or increase, about greater than 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200% decrease or increase, about 0.01-fold, about 0.02-fold, about 0.1-fold , about 0.3-fold, about 0.5-fold, less than about 0.8-fold, or less, or about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1. 8 times, about 2.0 times, about 3.0 times, about 3.5 times, about 4.5 times, about 5.0 times, about 10 times, about 15 times, about 20 times, about 30 times, about 40-fold, about 50-fold, about 100-fold, about 1000-fold or greater). Protein levels can be expressed as mass/volume (eg, g/dL, mg/mL, μg/mL, ng/mL) or as a percentage of total protein or mRNA in the sample.

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

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

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

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

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

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

As used herein, the term "pharmaceutical composition" is formulated with pharmaceutically acceptable excipients and used as part of a therapeutic regimen for the treatment of disease in a mammal. Represents a composition containing a compound described herein manufactured or marketed with the approval of a governmental regulatory agency. Pharmaceutical compositions are for oral administration, eg, in unit dosage form (eg, tablets, capsules, caplets, gelcaps, or syrups), for topical administration (eg, as creams, gels, lotions, or ointments). , for intravenous administration (e.g., as a sterile solution free of particulate embolic agents and in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation. .

By "reducing the activity of BRD9" is meant reducing the level of an activity or associated downstream effect associated with BRD9. A non-limiting example of inhibition of BRD9 activity is decreasing levels of BAF complexes (eg, GBAF) in cells. The activity level of BRD9 can be measured using any method known in the art. In some embodiments, the agent that reduces BRD9 activity is a small molecule BRD9 inhibitor. In some embodiments, the agent that reduces the activity of BRD9 is a small molecule BRD9 degrading agent.

"Reducing the level of BRD9" means reducing the level of BRD9 in a cell or subject. Levels of BRD9 can be measured using any method known in the art.

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

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

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

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

As used herein, the term "SS18-SSX fusion protein-associated disorder" refers to a disorder caused or influenced by the level and/or activity of the SS18-SSX fusion protein.

As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to To prevent or slow (reduce) a physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, whether detectable or undetectable; reduction in the extent of a condition, disorder, or disease; stabilizing (i.e., not worsening) the disease state; delaying or slowing the onset of a condition, disorder, or disease progression; of a condition, disorder, or disease state amelioration or remission (partial or complete); improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of a condition, disorder, or disease including. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

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

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

FIG. 4 is a series of graphs showing the effect of specific guide RNA (sgRNA) targeting of BRD9 BAF complex subunits on synovial sarcoma cell growth. The Y-axis showed the dropout rate. The X-axis indicates the nucleotide positions of the BRD9 gene. Gray squares indicate the extent of the negative control sgRNA in the screen. The SYO1 cell line carries the SS18-SSX2 fusion protein. Breakpoints joining the N-terminal region of SS18 to the C-terminal region of SSX2 are indicated by black lines in their respective panels. The linear protein sequence is shown with the BRD9 PFAM domain annotated from the PFAM database. Images showing dose-dependent depletion of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of BRD9-degrading agents. Images showing sustained suppression of BRD9 levels in a synovial sarcoma cell line (SYO1) in the presence of a BRD9 degrading agent for 72 hours. Images showing sustained suppression of BRD9 levels in two cell lines (293T and SYO1) in the presence of a BRD9-degrading agent for 5 days. FIG. 11 is an image showing sustained suppression of BRD9 levels in synovial sarcoma cell lines (SYO1 and Yamato) in the presence of BRD9 degrading agents over 7 days compared to levels in cells treated with CRISPR reagent. FIG. 4 is an image showing the effect on cell growth of six cell lines (SYO1, Yamato, A549, HS-SY-II, ASKA, and 293T) in the presence of BRD9 degrading agents and BRD9 inhibitors. FIG. 4 is an image showing the effect on cell growth of two cell lines (SYO1 and G401) in the presence of BRD9 degrading agents. Figure 10 is an image showing the effect on cell growth of three synovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) in the presence of a BRD9 degrading agent, a BRD9 binding agent, and an E3 ligase binding agent. FIG. 4 is an image showing the effect on cell growth of three non-synovial sarcoma cell lines (RD, HCT116 and Calu6) in the presence of a BRD9 degrading agent, a BRD9 binding agent and an E3 ligase binding agent. Graph showing the percentage of SYO1 at various cell cycle stages after 8 or 13 days of treatment with DMSO, 200 nM Compound 1, or 1 μM Compound 1. FIG. FIG. 4 is a series of contour plots showing the percentage of SYO1 cells at various cell cycle stages after 8 days of treatment with DMSO, 200 nM Compound 1, 1 μM Compound 1, or 200 nM Lenalidomide. The numerical values corresponding to each contour plot are found in the table below. FIG. 4 is a series of contour plots showing the percentage of SYO1 cells at various cell cycle stages after 13 days of treatment with DMSO, 200 nM Compound 1, 1 μM Compound 1, or 200 nM Lenalidomide. The numerical values corresponding to each contour plot are found in the table below. FIG. 4 is a series of contour plots showing the percentage of early and late apoptotic SYO1 cells after 8 days of treatment with DMSO, 200 nM Compound 1, 1 μM Compound 1, or 200 nM Lenalidomide. The numerical values corresponding to each contour plot are found in the table below. Graph showing proteins present in the BAF complex containing the SS18-SSX fusion protein.

The present disclosure features compositions and methods useful for treating BAF-related disorders (eg, cancer and infectious diseases). The present disclosure provides guidance on the level and/or activity of BRD9 for the treatment of disorders such as cancer (e.g. sarcoma) and infectious diseases (e.g. viral infections), e.g. Compositions and methods useful for inhibition are further featured.

Compounds Compounds described herein reduce the level of activities associated with BRD9, or associated downstream effects, or reduce levels of BRD9 in a cell or subject. Exemplary compounds described herein have structures according to Formula I.

Formula I is
ALB
Formula I
During the ceremony,
L has the structure of formula II,
A ¹ -E ¹ -FE ² -A ²
Formula II
A ¹ is the bond between the linker and A;
^A2 is the bond between B and the linker,
each of E ¹ and E ² is independently absent CH ₂ , O, or NCH ₃ ;
F is optionally substituted C ₃ -C ₁₀ carbocyclylene or optionally substituted C _2-10 heterocyclylene;
B is the decomposition part,
A is the structure of Formula III,

During the ceremony,
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 - _Cio 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 heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted C ₂ -C ₉ heteroaryl;
X ¹ is N or CH and X ² is C—R ″, or X ¹ is C— ^{R 7 ″} and X ² is N or CH;
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 amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;
R ⁷ ′ is H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, or optionally substituted C ₃ -C ₁₀ carbocyclyl;
X ³ is N or CH,
X ⁴ is N or CH,
G” is

, optionally substituted C ₃ -C ₁₀ carbocyclyl, C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted C ₂ -C ₉ heteroaryl;
G′ is optionally substituted C ₃ -C ₁₀ carbocyclylene, C ₂ -C ₉ heterocyclylene, optionally substituted C ₆ -C ₁₀ arylene, or optionally substituted C ₂ -C ₉ is heteroarylene,
A ¹ is the bond between A and the linker,
G” is

or R ⁷ ″ is

or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound has the structure of any one of compounds D1-D66 of Table 1, or a pharmaceutically acceptable salt thereof.

Other embodiments, as well as exemplary methods for the synthesis of the production of these compounds, are described herein.
Pharmaceutical Uses The compounds described herein are useful in the methods of the present invention, and without being bound by theory, through their ability to modulate the level, status, and/or activity of the BAF complex, e.g. It is believed to exert their desired effects by inhibiting the activity or level of intracellular BRD9 protein within the BAF complex in mammals.

One aspect of the invention relates to a method of treating a BRD9-related disorder, such as cancer, in a subject in need of such treatment. In some embodiments, the compound is capable of (a) reducing tumor size, (b) reducing tumor growth rate, (c) increasing tumor cell death, (d) reducing tumor progression, (e) reducing the number of metastases. (f) reduced metastasis rate; (g) reduced tumor recurrence; (h) increased survival in a subject; and (i) increased progression-free survival in a subject (or more; for example, 2 or more, 3 or more, 4 or more).

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

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

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

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

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

Preferably, the methods of the invention comprise oral administration of a compound of the invention to a subject in need thereof. In some embodiments, the methods of the invention are particularly preferred for subjects suffering from sarcoma (eg, synovial sarcoma). In some embodiments, the methods of the invention are particularly preferred for subjects suffering from breast cancer. In some embodiments, the methods of the invention are particularly preferred for subjects with lung cancer (eg, non-small cell lung cancer). In some embodiments, the methods of the invention are particularly preferred for subjects suffering from ovarian cancer. In some embodiments, the methods of the invention are particularly preferred for subjects suffering from acute myeloid leukemia (AML).

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

In some embodiments, the second therapeutic agent is a chemotherapeutic agent (eg, a cytotoxic agent or other compound useful in treating cancer). These include alkylating agents, antimetabolites, folic acid analogues, pyrimidine analogues, purine analogues and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, Included are platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortican inhibitors, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), ilenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide, alkyl sulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carbocone, methledopa, and uredopa, ethyleneimine and methylamelamine, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine, acetogenins (specifically bratacin and bratacinone), camptothecin ( bryostatin, callistatin, CC-1065 (including its adzelesin, carzelesin, and baizelesin synthetic analogues), cryptophycins (specifically cryptophycin 1 and cryptophycin 8), dolastatin, duocarmycins (including synthetic analogues KW-2189 and CB1-TM1), eruterobin, pancratistatin, sarcodictin, spongistatin, nitrogen mustards such as chlorambucil, chlornafadine, colophosphamide, estramustine, Ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novenvitin, phenesterin, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as camrustin, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine, antibiotics such as enzyne antibiotics substances such as calicheamicins, specifically calicheamicin gamma II and calicheamicin omega II (see, eg, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; bleomycin, cactinomycin, carabicin, caminomycin, cardinophylline, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN™ (morpholino-doxorubicin, cyano mitomycins such as doxorubicin, epirubicin, ethorubicin, idarubicin, marceromycin, mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potofilomycin, puro antimetabolites such as mycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin, methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate purine analogues such as fludarabine, 6-mercaptopurine, thiamipurine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxfluridine, enocitabine, floxyuridine; carsterone, dromostanolone propionate, Androgens, such as epithiostanol, mepithiostane, testolactone; anti-adrenal agents, such as aminoglutethimide, mitotane, trilostane; folic acid replacement fluids, such as floric acid; acegratone; aldophosphamide glycosides; elfomithine; elliptinium acetate; epothilone; etogluside; gallium nitrate; hydroxyurea; mitoxantrone, mopidanmol, nitraeline, pentostatin; fenameth; pirarubicin; losoxantrone; podophyllic acid; 2,2′,2″-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ®, a chromophore-free, albumin-engineered nanoparticulate formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); Mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. More than one chemotherapeutic agent can be used in the cocktail administered in combination with the first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and can be found, for example, in Saltz et al. , Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al. , Lancet 355 (9209): 1041-1047 (2000).

In some embodiments, the second therapeutic agent is a DNA damaging agent (eg, platinum-based antineoplastic agents, topoisomerase inhibitors, PARP inhibitors, alkylating antineoplastic agents, and ionizing radiation).

Examples of platinum-based antineoplastic agents that may be used as second therapeutic agents in the compositions and methods of the present invention include cisplatin, carboplatin, oxaliplatin, dicycloplatin, eptaplatin, donkeyplatin, miriplatin, nedaplatin, triplatin tetranitrate. , phenanthrylplatin, picoplatin, and satraplatin. In some embodiments, the second therapeutic agent is cisplatin and the cancer treated is testicular, ovarian, or bladder cancer (eg, advanced bladder cancer). In some embodiments, the second therapeutic agent is carboplatin and the cancer treated is ovarian cancer, lung cancer, head and neck cancer, brain cancer, or neuroblastoma. In some embodiments, the second therapeutic agent is oxaliplatin and the cancer treated is colorectal cancer. In some embodiments, the second therapeutic agent is dicycloplatin and the cancer treated is non-small cell lung (ung) cancer or prostate cancer. In some embodiments, the second therapeutic agent is eptaplatin and the cancer treated is gastric cancer. In some embodiments, the second therapeutic agent is donkeyplatin and the cancer treated is breast cancer. In some embodiments, the second therapeutic agent is miriplatin and the cancer treated is hepatocellular carcinoma. In some embodiments, the second therapeutic agent is nedaplatin and the cancer treated is nasopharyngeal carcinoma, esophageal cancer, squamous cell carcinoma, or cervical cancer. In some embodiments, the second therapeutic agent is triplatin tetranitrate and the cancer treated is lung cancer (eg, small cell lung cancer) or pancreatic cancer. In some embodiments, the second therapeutic agent is picoplatin and the cancer treated is lung cancer (eg, small cell lung cancer), prostate cancer, bladder cancer, or colorectal cancer. In some embodiments, the second therapeutic agent is satraptin and the cancer treated is prostate cancer, breast cancer, or lung cancer.

Examples of topoisomerase inhibitors that may be used as second therapeutic agents in the compositions and methods of this invention are etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, irinotecan, topotecan, camptothecin, and diflomotecan. . In some embodiments, the second therapeutic agent is etoposide and the cancer treated is lung cancer (eg, small cell lung cancer) or testicular cancer. In some embodiments, the second therapeutic agent is teniposide and the cancer treated is acute lymphoblastic leukemia (eg, childhood acute lymphoblastic leukemia). In some embodiments, the second therapeutic agent is doxorubicin and the cancer treated is acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast cancer, Wilm's tumor , neuroblastoma, soft tissue sarcoma, osteosarcoma, ovarian cancer, transitional cell bladder cancer, thyroid cancer, gastric cancer, or bronchogenic cancer. In some embodiments, the second therapeutic agent is daunorubicin and the cancer treated is acute lymphoblastic leukemia or acute myeloid leukemia. In some embodiments, the second therapeutic agent is mitoxantrone and the cancer treated is prostate cancer or acute nonlymphocytic leukemia. In some embodiments, the second therapeutic agent is amsacrine and the cancer treated is leukemia (eg, acute adult leukemia). In some embodiments, the second therapeutic agent is irinotecan and the cancer treated is colorectal cancer. In some embodiments, the second therapeutic agent is topotecan and the cancer treated is lung cancer (eg, small cell lung cancer). In some embodiments, the second therapeutic agent is diflomotecan and the cancer treated is lung cancer (eg, small cell lung cancer).

Examples of alkylating antineoplastic agents that may be used as second therapeutic agents in the compositions and methods of this invention include cyclophosphamide, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, chlorozotocin, fotemustine, Nimustine, ranimustine, busulfan, improsulfan, piposulfan, chlornafadine, colophosfamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, novenbitine, phenesterine, prednimustine, trophosphamide, procarbazine, altretamine, dacarbazine, mitozolomide, and temozolomide is. In some embodiments, the second therapeutic agent is cyclophosphamide and the cancer treated is non-Hodgkin's lymphoma. In some embodiments, the second therapeutic agent is melphalan and the cancer treated is multiple myeloma, ovarian cancer, or melanoma. In some embodiments, the second therapeutic agent is chlorambucil and the cancer being treated is chronic lymphocytic leukemia, malignant lymphoma (eg, lymphosarcoma, giant follicular lymphoma, or Hodgkin's lymphoma). In some embodiments, the second therapeutic agent is ifosfamide and the cancer treated is testicular cancer. In some embodiments, the second therapeutic agent is bendamustine and the cancer treated is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. In some embodiments, the second therapeutic agent is carmustine and the cancer to be treated is brain cancer (e.g., glioblastoma, brain stem glioma, medulloblastoma, astrocytoma, ependymoma, or metastasis). brain tumor), multiple myeloma, Hodgkin disease, or non-Hodgkin lymphoma. In some embodiments, the second therapeutic agent is lomustine and the cancer treated is brain cancer or Hodgkin's lymphoma. In some embodiments, the second therapeutic agent is fotemustine and the cancer treated is melanoma. In some embodiments, the second therapeutic agent is nimustine and the cancer treated is brain cancer. In some embodiments, the second therapeutic agent is ranimustine and the cancer treated is chronic myelogenous leukemia or polycythemia vera. In some embodiments, the second therapeutic agent is busulfan and the cancer treated is chronic myelogenous leukemia. In some embodiments, the second therapeutic agent is improsulfan and the cancer treated is sarcoma. In some embodiments, the second therapeutic agent is estramustine and the cancer treated is prostate cancer (eg, prostate carcinoma). In some embodiments, the second therapeutic agent is mechlorethamine and the cancer treated is cutaneous T-cell lymphoma. In some embodiments, the second therapeutic agent is trophosphamide and the cancer treated is sarcoma (eg, soft tissue sarcoma). In some embodiments, the second therapeutic agent is procarbazine and the cancer treated is Hodgkin's disease. In some embodiments, the second therapeutic agent is altretamine and the cancer treated is ovarian cancer. In some embodiments, the second therapeutic agent is dacarbazine and the cancer treated is melanoma, Hodgkin's lymphoma, or sarcoma. In some embodiments, the second therapeutic agent is temozolomide and the cancer being treated is brain cancer (eg, astrocytoma or glioblastoma) or lung cancer (eg, small cell lung cancer).

Examples of PARP inhibitors that may be used as second therapeutic agents in the compositions and methods of the invention are niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib, CK-102, or E7016. Advantageously, a compound of the invention and a DNA damaging agent may act synergistically to treat cancer. In some embodiments, the second therapeutic agent is niraparib and the cancer treated is ovarian cancer (e.g., BRCA-mutated ovarian cancer), fallopian tube cancer (e.g., BRCA-mutated fallopian tube cancer), or Primary peritoneal cancer (eg, BRCA-mutated primary peritoneal cancer). In some embodiments, the second therapeutic agent is olaparib and the cancer treated is 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). In some embodiments, the second therapeutic agent is rucaparib and the cancer treated is ovarian cancer (e.g., BRCA-mutated ovarian cancer), fallopian tube cancer (e.g., BRCA-mutated fallopian tube cancer), or Primary peritoneal cancer (eg, BRCA-mutated primary peritoneal cancer). In some embodiments, the second therapeutic agent is talazoparib and the cancer treated is breast cancer (eg, BRCA-mutated breast cancer). In some embodiments, the second therapeutic agent is veliparib and the cancer treated is lung cancer (e.g., non-small cell lung cancer), maleoma, breast cancer, ovarian cancer, prostate cancer, or Brain cancer. In some embodiments, the second therapeutic agent is pamiparib and the cancer treated is ovarian cancer. In some embodiments, the second therapeutic agent is CK-102 and the cancer treated is lung cancer (eg, non-small cell lung cancer). In some embodiments, the second therapeutic agent is E7016 and the cancer treated is melanoma.

While not wishing to be bound by theory, the synergy between the compounds of the invention and DNA damaging agents may be due to the requirement of BRD9 for DNA repair, and inhibition of BRD9 may be associated with DNA damaging agents. It can sensitize cancer (eg, cancer cells or cancer tissue).

In some embodiments, the second therapeutic agent is a JAK inhibitor (eg, JAK1 inhibitor). Non-limiting examples of JAK inhibitors that can be used as second therapeutic agents in the compositions and methods of this invention include tofacitinib, ruxolitinib, ocracitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, serduratinib, gandotinib, lestaurtinib , momelotinib, pacritinib, abrocitinib, sorcitinib, itacitinib, or SHR0302. While not wishing to be bound by theory, synergy between compounds of the invention and JAK inhibitors may be inhibitors of the SAGA complex to their combined effect of downregulating Foxp3+ Treg cells. In some embodiments, the second therapeutic agent is ruxolitinib and the cancer treated is myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis), ovarian cancer, breast cancer, pancreatic cancer . In some embodiments, the second therapeutic agent is fedratinib and the cancer treated is a myeloproliferative neoplasm (eg, myelofibrosis). In some embodiments, the second therapeutic agent is selduratinib and the cancer treated is lymphoma (eg, peripheral T-cell lymphoma). In some embodiments, the second therapeutic agent is gandotinib and the cancer treated is a myeloproliferative neoplasm (eg, polycythemia or myelofibrosis). In some embodiments, the second therapeutic agent is lestaurtinib and the cancer treated is myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis), leukemia (e.g., acute myeloid leukemia) , pancreatic cancer, prostate cancer, or neuroblastoma. In some embodiments, the second therapeutic agent is momerotinib and the cancer treated is myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis) or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma) is. In some embodiments, the second therapeutic agent is momerotinib and the cancer treated is a myeloproliferative neoplasm (eg, polycythemia or myelofibrosis). In some embodiments, the second therapeutic agent is momerotinib and the cancer treated is myeloproliferative neoplasm (e.g., polycythemia or myelofibrosis) or pancreatic cancer (e.g., pancreatic ductal adenocarcinoma) is.

In some embodiments, the second therapeutic agent is an inhibitor of the SAGA complex or a component thereof. A SAGA complex inhibitor can be, for example, an inhibitory antibody or small molecule inhibitor of CCDC101, Tada2B, Tada3, Usp22, Tada1, Taf61, Supt5, Supt20, or combinations thereof. While not wishing to be bound by theory, the synergy between the compounds of the invention and inhibitors of the SAGA complex may be due to their combined effect of down-regulating Foxp3+ Treg cells.

In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine (eg, interferon or interleukin (eg, IL-2)) used in cancer therapy. In some embodiments, the biologic is an anti-VEGF agent, eg, an anti-angiogenic agent such as bevacizumab (AVASTIN®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody that stimulates a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer (eg, humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof). Such agents include RITUXAN® (rituximab), ZENAPAX® (daclizumab), SIMULECT® (basiliximab), SYNAGIS® (palivizumab), REMICADE® (infliximab) ), HERCEPTIN® (trastuzumab), MYLOTARG® (gemtuzumab ozogamicin), CAMPATH® (alemtuzumab), ZEVALIN® (ibritumomab tiuxetan), HUMIRA ( (adalimumab), XOLAIR® (omalizumab), BEXXAR™ (tositumomab-I-131), RAPTIVA™ (efalizumab), ERBITUX® (cetuximab), AVASTIN® (bevacizumab), TYSABRI® (natalizumab), ACTEMRA® (tocilizumab), VECTIBIX® (panitumumab), LUCENTIS® (ranibizumab), SOLIRIS® (eculizumab), CIMZIA ® (certolizumab pegol), SIMPONI® (golimumab), ILARIS® (canakinumab), STELARA® (ustekinumab), ARZERRA® (ofatumumab), PROLIA ( (denosumab), NUMAX® (motavizumab), ABTHRAX™ (laxivacumab), BENLYSTA® (belimumab), YERVOY® (ipilimumab), ADCETRIS® (brentuximab) buvedotin), PERJETA® (pertuzumab), KADCYLA® (ado-trastuzumab emtansine), and GAZYVA® (obinutuzumab). Antibody-drug conjugates are also included.

The second agent can be a therapeutic agent that is a non-drug therapy. For example, the second therapeutic agent is radiotherapy, cryotherapy, hyperthermia, and/or surgical resection of tumor tissue.
The second agent can be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (eg, a monospecific antibody such as a monoclonal antibody). An antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, eg, an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with the checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein ligand. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion protein such as ipilimumab/YERVOY® or tremelimumab). agent). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody) of PD-1 (e.g., nivolumab/OPDIVO®, pembrolizumab/KEYTRUDA®, pidilizumab/CT-011) or small molecule inhibitors). In some embodiments, the checkpoint inhibitor is an inhibitor (eg, an inhibitory antibody or small molecule inhibitor) of PDL1 (eg, MPDL3280A/RG7446, MEDI4736, MSB0010718C, BMS 936559). In some embodiments, the checkpoint inhibitor is an inhibitor (eg, an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (eg, a PDL2/Ig fusion protein such as AMP 224). In some embodiments, the checkpoint inhibitor is B7-H3 (eg, MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1 , CHK2, A2aR, B-7 family ligands, or combinations thereof (eg, inhibitory antibodies or small molecule inhibitors). In some embodiments, the second therapeutic agent is ipilimumab and the cancer treated is melanoma, renal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), or prostate cancer . In some embodiments, the second therapeutic agent is tremelimumab and the cancer treated is melanoma, mesothelioma, or lung cancer (eg, non-small cell lung cancer). In some embodiments, the second therapeutic agent is nivolumab and the cancer treated is melanoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), renal cancer, Hodgkin's lymphoma, head and neck Cancer (eg, squamous cell carcinoma of the head and neck), urothelial carcinoma, hepatocellular carcinoma, or colorectal cancer. In some embodiments, the second therapeutic agent is pembrolizumab and the cancer treated is melanoma, lung cancer (e.g., non-small cell or small cell lung cancer), Hodgkin's 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 unstable carcinoma, gastric cancer, esophageal cancer, cervical cancer, Merkel cell carcinoma, renal cancer , or endometrial cancer. In some embodiments, the second therapeutic agent is MPDL3280A and the cancer treated is lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), urothelial cancer, hepatocellular carcinoma, or breast cancer is. In some embodiments, the second therapeutic agent is MEDI4736 and the cancer treated is lung cancer (eg, non-small cell lung cancer or small cell lung cancer) or urothelial cancer. In some embodiments, the second therapeutic agent is MSB0010718C and the cancer treated is urothelial carcinoma. In some embodiments, the second therapeutic agent is MSB0010718C and the cancer treated is melanoma, lung cancer (e.g., non-small cell lung cancer), colorectal cancer, renal cancer, ovarian cancer, pancreatic cancer , gastric cancer, and breast cancer.

Advantageously, compounds of the invention and checkpoint inhibitors may act synergistically to treat cancer. While not wishing to be bound by theory, the synergy between the compounds of the invention and checkpoint inhibitors is attributed to increased efficacy of checkpoint inhibitors in relation to BRD9 inhibition-induced downregulation of Foxp3+ Treg cells. can.

In some embodiments, the anti-cancer therapy is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding CAR into T cells. Prior to T cell expansion and genetic modification, a T cell source is obtained from a subject. T cells can be obtained from several sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymic tissue, tissue from sites of infection, ascites, pleural effusion, splenic tissue, and tumors. Any number of T cell lines available in the art may be used in certain embodiments of the invention. In some embodiments, the T cells are autologous T cells. Whether before or after genetic modification of the T cells to express the desired protein (e.g., CAR), T cells are generally treated according to, for example, US Pat. 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, 7,144, 575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 5,883,223, 6,905,874, 6,797,514, 6,867,041, and US Patent Application Publication No. 20060121005.

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

Pharmaceutical Compositions The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. be.

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

The compounds described herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier, or can be enclosed in hard or soft shell gelatin capsules, or compressed into tablets. or can be incorporated directly with dietary food. For oral therapeutic administration, the compounds described herein can be incorporated with excipients and made into ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. form may be used. The compounds described herein can also be administered parenterally. Solutions of compounds described herein can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof, with or without alcohols, and in oils. These preparations may contain a preservative to prevent microbial growth under normal conditions of storage and use. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and The United States Pharmacopeia: The National Formulary, published in 2018 (USP 41 NF3 6 )It is described in. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the form must be sterile and must be fluid to the extent that easy administration via a syringe is possible. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active agent in a physiologically acceptable aqueous or non-aqueous solvent and usually take the form of cartridges or refills for use with a nebulizing device. provided in single or multi-dose form in sterile form in a hermetically sealed container. Alternatively, the sealed container may be a single dispensing device such as a single dose nasal inhaler or aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it contains a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. Aerosol dosage forms can also take the form of a pump-atomiser. Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles in which the active ingredient is formulated with carriers such as sugar, acacia, tragacanth, gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. The compounds described herein can be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is direct injection into tumor blood vessels and is specifically contemplated for individual solid, accessible tumors. Local, regional, or systemic administration may also be suitable. The compounds described herein can advantageously be contacted by administering an injection or multiple injections into the tumor, eg, spaced approximately 1 cm apart. In the case of surgical intervention, the present invention can be used pre-operatively, such as to subject an inoperable tumor to resection. Continuous administration may also be applied where appropriate, for example by implanting a catheter into the tumor or tumor vessels.

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

Dosage The dosage of a compound described herein, and/or a composition comprising a compound described herein, may vary depending on the pharmacodynamic properties of the compound; the mode of administration; the age, health and well-being of the recipient; nature and extent of symptoms; frequency of treatment, and type of concomitant treatment, if any; and clearance rate of the compound in the treated animal. Appropriate dosages can be determined by one of ordinary skill in the art based on the above factors. The compounds described herein can be administered initially at a suitable dosage that can be adjusted as necessary, depending on clinical response. In general, satisfactory results can be obtained when the compounds described herein are administered to humans in daily doses of, for example, 0.05 mg to 3000 mg (measured as solid form). Dosage ranges include, for example, 10-1000 mg.

Alternatively, the patient's weight can be used to calculate dosage. For example, the dose of compound or pharmaceutical composition thereof administered to a patient can range from 0.1 to 100 mg/kg.

Kits The present invention also provides (a) a pharmaceutical composition comprising an agent that reduces the level and/or activity of BRD9 in a cell or subject as described herein, and (b) a Kits are featured that include package inserts containing instructions for carrying out any of the methods. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent that reduces BRD9 levels and/or activity in a cell or subject as described herein, (b) an additional therapeutic agent (eg, an anti-cancer agent); and (c) package inserts containing instructions for practicing any of the methods described herein.

Example 1 - High Density Tiling sgRNA Screen Against Human BAF Complex Subunits of Synovial Sarcoma Cell Line SYO1 The following example demonstrates that BRD9 sgRNA inhibits cell growth in synovial sarcoma cells.

Procedure: To perform high-density sgRNA tiling screens, sgRNA libraries against BAF complex subunits were custom synthesized in Cellecta (Mountain View, Calif.). The sequences of DNA encoding the BRD9 target sgRNAs used in this screen are shown in Table 2. Negative and positive control sgRNAs were included in the library. Negative controls consisted of 200 sgRNAs that do not target the human genome. Positive controls are sgRNAs targeting essential genes (CDC16, GTF2B, HSPA5, HSPA9, PAFAH1B1, PCNA, POLR2L, RPL9, and SF3A3). DNA sequences encoding all positive and negative control sgRNAs are shown in Table 3. Procedures for virus generation, cell infection, and performing sgRNA screens were previously described (Tsherniak et al, Cell 170:564-576 (2017), Munoz et al, Cancer Discovery 6:900-913 (2016). )). For each sgRNA, 50 counts were added to the sequencing counts and at each time point the resulting counts were normalized to the total number of counts. The log2 of the ratio of counts (defined as dropout rate) at 24 days and 1 day post-infection was calculated. For negative control sgRNAs, the 2.5 and 97.5 percentiles of log2 dropout rates for all non-targeting sgRNAs were calculated and considered as background (gray squares in graphs). The protein domain was obtained from the PFAM region defined for UNIPROT identifier: Q9H8M2.

Results: As shown in Figure 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 complex resulted in increased cell proliferation, inhibition of cell growth, or had no effect on SYO1 cells. These data indicate that targeting different subunits of the GBAF complex represents a therapeutic strategy for the treatment of synovial sarcoma.

Example 2 - BRD9 Degrading Agents Deplete BRD9 Protein The following example demonstrates depletion of BRD9 protein in synovial sarcoma cells treated with BRD9 degrading agents.

Procedure: Cells were treated with DMSO or the BRD9 degrading agent Compound A (also known as dBRD9, Remillard et al, Angew. Chem. Int. Ed. Engl. 56(21):5738-5743) at the indicated doses and time points. (2017); see structure of compound 1 below).

Whole cell extracts were fractionated by SDS-PAGE and transferred to polyvinylidene fluoride membranes using a transfer device according to the manufacturer's protocol (Bio-Rad). After incubation with 5% non-fat milk in TBST (10 mM Tris, pH 8.0, 150 mM NaCl, 0.5% Tween 20) for 60 minutes, membranes were incubated overnight at 4°C with BRD9 (1:1,000, Bethyl laboratory A303-781A), GAPDH (1:5,000, Cell Signaling Technology), and/or MBP (1:1,000, BioRad). Membranes were washed three times for 10 min and treated with anti-mouse or anti-mouse conjugated with either horseradish peroxidase (HRP, Figures 2-3) or IRDye (Figure 4, 1:20,000, LI-COR). Incubated with rabbit antibody for at least 1 hour. Blots were washed three times with TBST and developed on the ECL system according to the manufacturer's protocol (Figures 2-3) or scanned on the Odyssey CLx imaging system (Figure 4).

Results: Treatment of SYO1 synovial sarcoma cells with the BRD9 degrading agent Compound A results in a dose-dependent (Figure 2) and time-dependent (Figure 3) depletion of BRD9 in the cells. Furthermore, as shown in Figure 4, depletion of BRD9 by Compound 1 can be replicated in a non-synovial sarcoma cell line (293T) and persisted for at least 5 days.

Example 3 Inhibition of Growth of Synovial Cell Lines by BRD9 Inhibitors and BRD9 Degradants The following example demonstrates that BRD9 degradants and inhibitors selectively inhibit the growth of synovial sarcoma cells.

procedure:
Cells were treated with DMSO or the BRD9 degrading agent, Compound A, at the indicated concentrations and measured from day 7 to day 14 by measuring confluency over time using the IncuCyte live cell assay system. Proliferation was monitored (Fig. 5). Growth medium and compounds were refreshed every 3-4 days.

Cells were seeded in 12-well plates and treated with DMSO, 1 μM BRD9 inhibitor Compound B (also known as BI-7273, see Martin et al, J Med Chem. 59(10):4462-4475 (2016)). see the structure of Compound B below), or treated with 1 μM of the BRD9 degrading agent, Compound A.

Cell numbers were 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 on day 11. ASKA cells were fixed and stained on day 23. Staining was incubated with crystal violet solution (0.5 g crystal violet, 27 ml 37% formaldehyde, 100 mL 10x PBS, 10 mL methanol, 863 dH20-1 L) for 30 min, followed by 3 washes with water and incubation for at least 24 h at room temperature. This was done by drying the plates. The plate was then scanned with the Odyssey CLx imaging system (Fig. 6).

Cells were seeded in 200 μL of complete medium in 96-well ultra-low cluster plates (Costar, #7007) and treated on day 2 with DMSO, staurosporine, or BRD9 degrading agent Compound 1 at the indicated doses. (Fig. 7). Media and compounds were changed every 5 days and cell colonies were imaged on day 14.

Results: As shown in Figures 5, 6, and 7, synovial sarcoma cell lines (SYO1, Yamato, HS-SY-II, and ASKA ) resulted in inhibition of growth of cells, but not of non-synovial control cancer cell lines (293T, A549, G401).

Example 4 Selective Inhibition of Growth of Synovial Cell Lines by BRD9 Degrading Agents and BRD9 Binding Agents The following example demonstrates that BRD9 degrading agents and binding agents selectively inhibit the growth of synovial sarcoma cells. show.

Procedure: Cells were seeded in 6-well or 12-well plates and treated with a BRD9 degrading agent (compound 1), bromodomain BRD9 binder (compound 2), E3 ligase binder (lenalidomide), DMSO, or DMSO at the concentrations indicated. Treated daily with staurosporine (positive control for cell killing). Cell numbers were optimized for each cell line. Growth medium was refreshed every 5 days. By day 14, the medium was removed and the cells were washed with PBS using 500 μL of 0.005 (w/v) % crystal violet solution in 25 (v/v) % methanol for at least 1 hour at room temperature. dyed. Plates were then scanned with an Odyssey CLx imaging system.

Results: As shown in Figures 8 and 9, treatment of synovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) with Compound A or Compound B resulted in inhibition of cell growth, but no It did not result in inhibition of growth of synovial control cancer cell lines (RD, HCT116, and Calu6). Overall, Compound A showed the most significant growth inhibition in all synovial cell lines.

Example 5 Inhibition of Cell Growth in Synovial Sarcoma Cells The following example demonstrates that BRD9 degrading agents inhibit cell growth and induce apoptosis in synovial sarcoma cells.

Procedure: SYO1 cells were treated with DMSO, 200 nM or 1 μM BRD9 degrading agent (compound A), or 200 nM E3 ligase binder (lenalidomide) for 8 or 13 days. Compounds were refreshed every 5 days. Cell cycle analysis was performed using the Click-iT™ Plus EdU flow cytometry assay (Invitrogen). Apoptosis assays were performed using the Annexin V-FITC Apoptosis Detection Kit (Sigma A9210). Assays were performed according to the manufacturer's protocol.

Results: As shown in Figures 10-13, treatment with Compound A for 8 or 13 days resulted in a reduction in the number of cells in the S phase of the cell cycle compared to DMSO and lenalidomide. Eight days of treatment with Compound A also resulted in increased numbers of early and late apoptotic cells compared to the DMSO control.

Example 6 Composition of SS18-SSX1-BAF The following example demonstrates the identification of BRD9 as a component of the SS18-SSX containing BAF complex.

Procedure: A stable 293T cell line expressing HA-SS18SSX1 was generated using lentiviral integration. SS18-SSX1 containing BAF complexes were subjected to affinity purification followed by mass spectrometric analysis revealing SS18-SSX1 interacting proteins.

Results: As shown in Figure 14, the BAF complex containing the SS18-SSX fusion protein also contained BRD9. ARID1A (95 peptides), ARID1B (77 peptides), SMARCC1 (69 peptides), SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32 peptides), SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 ( More than 5 unique peptides were identified for DPF1 isoform 2 (18 peptides), DPF3 (13 peptides), and ACTL6B (6 peptides).

Example 7-4-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)- Preparation of 4,7-dioxa-1,10-diazaundecane-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound C)

Step 1: tert-butyl N-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2, Preparation of 7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]carbamate (i2)

6-chloro-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-2,7-naphthyridin-1-one (335.0 mg, 0 .864 mmol, 1.00 eq) and tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (643.4 mg, 2.591 mmol, 3.00 eq), _K2CO3 (238.7 _mg , 1.727 mmol, 2.00 eq) was added at room temperature. The resulting mixture was stirred overnight at 130°C. The mixture was allowed to cool to room temperature. The _resulting mixture was filtered and the filter cake was washed with _CH2Cl2 (2 x 3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase A: water/0.05% TFA, mobile phase B: ACN; flow rate: 50 mL/min; gradient: 0% B to 40% over 15 minutes). B; detector, 254 nm) to give tert-butyl N-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7 -methyl-8-oxo-2,7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]carbamate (380 mg, 73.36%) as a yellow oil. LCMS (ESI) m/z: [M+H] ⁺ =600.
Step 2: tert-Butyl N-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2, Preparation of 7-naphthyridin-3-yl)(methyl)amino]ethoxy]ethoxy)ethyl]carbamate (i3)

tert-butyl N-[2-(2-[2-[(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo in acetone (3 mL) -2,7-naphthyridin-3-yl)amino]ethoxy]ethoxy)ethyl]carbamate (190.0 mg, 0.317 mmol, 1.00 eq) and K ₂ CO ₃ (87.6 mg, 0.634 mmol, 2 eq) ) at room temperature was added dimethyl sulfide (44.0 mg, 0.348 mmol, 1.10 eq). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The aqueous layer was extracted with _CH2Cl2 / _isopropanol (3 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give 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 (95.00 mg, 48.86%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H] ⁺ =614.
Step 3: 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 in dichloromethane (3 mL) -2,7-naphthyridin-3-yl)(methyl)amino]ethoxy]ethoxy)ethyl]carbamate (75.00 mg, 0.122 mmol, 1.00 eq) was added dropwise with TFA (1 mL) at room temperature. added. The resulting mixture was concentrated under vacuum to yield 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 (103 mg, crude) was obtained as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H] ⁺ =514.
Step 4: 4-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-2,7-naphthyridin-3-yl)-4 Preparation of ,7-dioxa-1,10-diazaundecane-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (Compound C)

6-([2-[2-(2-aminoethoxy)ethoxy]ethyl](methyl)amino)-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl in DMF (1 mL) ]-2-methyl-2,7-naphthyridin-1-one (68.00 mg, 0.132 mmol, 1.00 eq) was added with 2-(2,6-dioxopiperidin-3-yl)- 4-fluoroisoindole-1,3-dione (34.6 mg, 0.125 mmol, 0.95 eq) and DIEA (85.6 mg, 0.662 mmol, 5.00 eq) were added at room temperature. The resulting mixture was stirred at 80° C. overnight. The crude product was subjected to preparative HPLC (conditions: Xselect CSH F-phenyl OBD column 19*150 mm 5 um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: 12 9B to 19B in min; 254 nm; R _t : 12.63 min) to give 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 ) gave isoindole-1,3-dione (3.2 mg, 3.14%) as a yellow solid. ¹ H NMR (400 MHz, methanol-d4) δ 8.96 (s, 1H), 7.54-7.46 (m, 2H), 6.99 (dd, J = 15.8, 7.7Hz, 2H) , 6.84 (s, 2H), 6.74 (s, 1H), 4.96-4.94 (m, 1H), 4.57 (s, 2H), 3.97 (s, 6H), 3.77-3.69 (m, 8H), 3.59-3.53 (m, 5H), 3.41 (t, J=5.2Hz, 2H), 3.17-3.11 (m , 9H), 2.83-2.53 (m, 3H), 2.04-1.95 (m, 1H). LCMS (ESI) m/z: [M+H] ⁺ =770.50.
Example 8 Preparation of Compounds D32-D184 Analogously to the procedures described for compound C in the examples above, compounds D1-D59 were prepared using the appropriate starting materials.

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

6-chloro-4-methylpyridine-3-carboxylic acid (20.00 g, 116.564 mmol, 1.00 eq) and NH ₄ Cl (62.35 g, 1.17 mol, 10.00 eq) in DCM (400 mL) ) was added DIEA (22.60 g, 174.846 mmol, 3.00 eq). After stirring for 5 minutes, HATU (66.48 g, 174.846 mmol, 1.50 eq) was added in portions. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluted with 1/1 to 3/2 PE/EtOAc to give 6-chloro-4-methylpyridine-3-carboxamide. (18.30 g, 61.3%) was obtained as a yellow solid. LCMS (ESI) m/z: [M+H] ⁺ =171.
Step 2: Preparation of 6-chloro-N-[(1E)-(dimethylamino)methylidene]-4-methylpyridine-3-carboxamide

To a stirred mixture of 6-chloro-4-methylpyridine-3-carboxamide (18.30 g, 107.268 mmol, 1.00 eq) and 2-methyltetrahydrofuran (100 mL) was added DMF-DMA (19.17 g, 160.903 mmol). , 1.50 equivalents) was added at 80° C. under a nitrogen atmosphere and stirred for an additional hour. The mixture was then cooled and concentrated to give 6-chloro-N-[(1E)-(dimethylamino)methylidene]-4-methylpyridine-3-carboxamide (26.3 g, 91.3%) as a yellow liquid. Obtained as a crude solid and used it directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =226.
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, 1 mol/L in THF) was added and the resulting solution was stirred at 60° C. for 30 minutes under a nitrogen atmosphere. The mixture was then cooled, concentrated under reduced pressure and the crude solid was washed with saturated NaHCO ₃ solution (100 mL) and collected to give 6-chloro-2H-2,7-naphthyridin-1-one (14.1 g). , 67.0%) was obtained as a pink solid, which was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =181.
Step 4: Preparation of 6-chloro-2-methyl-2,7-naphthyridin-1-one

NaH (9.37 g, 234 .232mmol, 3.00eq, 60%) was added in portions at 0°C. After 10 minutes, MeI (33.25 g, 234.232 mmol, 3.00 eq) was added to the above mixture at 0° C. and the mixture was stirred at 0° C. for 10 minutes. The mixture was then stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The crude solid was slurried with water (100 mL), filtered and collected to give 6-chloro-2-methyl-2,7-naphthyridin-1-one (14.6 g, 94.1%) as a yellow solid. which was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =195.
Step 5: Preparation of 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one

NBS (8.78 g, 49.327 mmol, 1.20 eq.) was added and the resulting mixture was stirred at 90° C. for 2 hours. The reaction mixture was cooled, diluted with DCM (150 mL), washed with water (3 x 100 mL), the organic layer dried and concentrated. The residue was then slurried with EtOAc (20 mL), the slurry was filtered, and the filter cake was washed with EtOAc (20 mL) to give 4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one. (6.32 g, 55.7%) was obtained as a white solid, which was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =273.
Step 6: Preparation of 4-bromo-6-(dimethylamino)-2-methyl-2,7-naphthyridin-1-one

4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (6.00 g, 21.937 mmol, 1.00 eq), dimethylamine hydrochloride (5 .37 _g , 65.811 mmol, 3.00 eq) and _K2CO3 (15.16 g, 109.685 mmol, 5.00 eq) was heated at 130° C. under a nitrogen atmosphere. After 3 hours, the resulting mixture was cooled, diluted with water (100 mL), then extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with saturated NaCl solution (3×50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 4-bromo-6-(dimethylamino)-2-methyl-2 ,7-naphthyridin-1-one (5.91 g, 93.6%) was obtained as a yellow solid, which was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =282.
Step 7: Preparation of (4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde

4-bromo-6-( _{dimethylamino} )-2-methyl-2,7-naphthyridin-1-one (5.70 g, 20.203 mmol, 1.00 eq.) and 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (8.26 g, 28.284 mmol, 1.00 eq). 40 equivalents) of Pd(dppf)Cl _{2. CH2Cl2} (1.65 g, 2.020 mmol, 0.10 eq) and _Cs2CO3 (13.16 g, 40.405 mmol, 2.00 eq) were added and _{the mixture} was then evacuated under a nitrogen atmosphere to Stir at 70° C. for 4 hours. The resulting mixture was cooled, concentrated under reduced pressure, the residue slurried with water (100 mL), filtered and the filter cake collected. This solid was further slurried with MeOH (100 mL), filtered, and the solid collected to give the product, 4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridine -4-yl]-2,6-dimethoxybenzaldehyde (6.10 g, 77.6%) was obtained as a brown solid. LCMS (ESI) m/z: [M+H] ⁺ =368.
Example 10-3-(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-dioneformic 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) Preparation of piperidine-2,6-dioneformate

Step 1: Preparation of 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

5-bromo-2-benzofuran-1,3-dione (10.00 g, 44.050 mmol, 1.00 eq), NaOAc (7.23 mg, 88.134 mmol, 2.00 eq) in AcOH (80.00 mL) ) and 3-aminopiperidine-2,6-dione (11.29 g, 88.113 mmol, 2.00 eq) at room temperature. The resulting mixture was stirred at 115° C. for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether/EtOAc (10:1) to give 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3 -dione (13.6 g, 91.6%) was obtained as a dark brown solid. LCMS (ESI) m/z: [M+H] ⁺ =337.
Step 2: tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,6-dihydro-2H-pyridine-1 - Preparation of carboxylates

5 _- bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (3.00 g, 8 .899 mmol, 1.00 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 - To a stirred solution of carboxylate ( _3.30 g, 10.672 mmol, 1.20 eq), _K3PO4 (5.67 g, 26.712 mmol, 3.00 eq) was added Pd( _PPh3 ) _{2Cl2 (} 0.62 g, 0.883 mmol, 0.10 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (8/1) to give tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.8 g, 20.5%) was obtained as a colorless oil. LCMS (ESI) m/z: [M+H] ⁺ =440.
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- in THF (20.00 mL) To a stirred solution of 2H-pyridine-1-carboxylate (0.80 g) was added 10% Pd/C (500.0 mg) in a 100 mL round bottom flask under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature for 12 hours, filtered through a celite pad and concentrated under reduced pressure. This gave tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1-carboxylate (0.73 g, crude ) was obtained as a white solid, which was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H] ⁺ =442.
Step 4: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxoisoindolin-5-yl)piperidine-1-carboxylate; tert-butyl 4 Preparation of -(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 eq) and Zn (1.08 g, 1.65 mmol, 10.00 eq) at room temperature. The resulting mixture was stirred at 60° C. for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (2:1) to give 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-oxoisoindoline-5 -yl)piperidine-1-carboxylate (0.546 g, 74.8%, mixture of two regioisomers) was obtained as a colorless solid. LCMS (ESI) m/z: [M+H] ⁺ =444.
Step 5: 3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(piperidin-4-yl) Preparation of isoindolin-2-yl)piperidine-2,6-dione.

tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxoisoindolin-5-yl)piperidine-1-carboxylate in DCM (9.00 mL) tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (two regioisomeric To a stirred solution of the mixture (573.00 mg, 1.00 eq) and TFA (3.00 mL) was added TES (450.7 mg, 3.876 mmol, 3.00 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and used directly without further purification to give 3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (200 mg 36.6% mixture of two regioisomers). Obtained as an off-white oil. LCMS (ESI) m/z: [M+H] ⁺ =328.
Step 6: 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-dioneformic 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- Preparation of 2,6-dioneformic acid

3-[1-oxo-6-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione (165.0 mg, 0.504 mmol, 1.00 equivalents) and 3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(piperidine-4 -yl)isoindolin-2-yl)piperidine-2,6-dione (mixture of two regioisomers, 222.2 mg, 0.605 mmol, 1.20 eq) was added to a stirred solution of NaBH(OAc) ₃ ( 427.3 mg, 2.016 mmol, 4.00 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH ₃ CN (0.05% FA) in water, gradient 0% to 50% over 30 min; detector, UV 254 nm. did. The crude product was subjected to the following conditions: column, Sunfire Prep C18 OBD column, 10 μm, 19*250 mm; mobile phase, water (0.05% FA) and CH ₃ CN (15%-22% CH ₃ CN in 15 minutes ); purified by preparative HPLC with detector, UV 254 nm. This gives 3-[6-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl ) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidin-2,6-dione; formic acid (52.5 mg, 26.3%) as a white solid, and 3-[5 -[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl] -1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione; formic acid (68.4 mg, 34.2%) was obtained as a yellow solid.

3-[6-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidine- 4-yl]-1-oxo-3H-isoindol-2-yl]piperidin-2,6-dione; for formic acid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 9.04 (s, 1H), 8.20 (s, 1H, FA), 7.58 (d, J=14.5Hz, 2H), 7.52 (s, 2H), 6.79 (s, 2H), 6.50 (s, 1H), 5.10 (dd, J = 13.4, 5.1Hz, 1H), 4.41 (d, J = 17.1Hz, 1H), 4.28 ( d, J = 17.0 Hz, 1H), 3.84 (s, 6H), 3.68 (s, 2H), 3.49 (s, 3H), 3.08-3.05 (m, 8H) , 2.91-2.89 (m, 1H), 2.66-2.56 (m, 2H), 2.40-2.35 (m, 1H), 2.30 (t, J=11. 3Hz, 2H), 2.03-1.95 (m, 1H), 1.88-1.57 (m, 4H). LCMS (ESI) m/z: [M+H] ⁺ = 679.32.
3-[5-[1-([4-[6-(dimethylamino)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidine- 4-yl]-1-oxo-3H-isoindol-2-yl]piperidin-2,6-dione; for formic acid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 9.05 (s, 1H), 8.15 (s, 1H, FA), 7.69 (d, J=7.8Hz, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.40 (d, J = 7.9Hz, 1H), 6.87 (s, 2H), 6.51 (s, 1H), 5.11 (dd, J = 13.3, 5. 1Hz, 1H), 4.44 (d, J = 17.3Hz, 1H), 4.31 (d, J = 17.3Hz, 1H), 4.05 (s, 2H), 3.90 (s, 6H), 3.49 (s, 3H), 3.31 (d, J = 11.7 Hz, 2H), 3.09 (s, 6H), 2.99-2.71 (m, 4H), 2 .65-2.56 (m, 1H), 2.47-2.33 (m, 1H), 2.04-1.96 (m, 1H), 1.92 (m, 4H). LCMS (ESI) m/z: [M+H] ⁺ = 679.32.
Example 1 Preparation of 1-4-(6-cyclopropyl-2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde

Step 1: Preparation of 6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one.

6-chloro-2-methyl-2,7-naphthyridin-1-one (500.00 mg, 2.569 mmol, 1.00 equiv) and cyclopropylboron in toluene (20.00 mL) and water (1.00 mL) To a stirred solution of acid (441.37 mg, 5.138 mmol, 2 eq) was added tricyclohexylphosphane (144.09 mg, 0.514 mmol, 0.20 eq), Pd(AcO) ₂ (57.68 mg, 0.257 mmol). , 0.10 eq.), and _K3PO4 ( _1636.01 mg, 7.707 mmol, 3.00 eq.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110° C. for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH ₂ Cl ₂ /MeOH (50:1) to give 6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one (340 mg, 59.0 mg). 48%) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 201.
Step 2: Preparation of 4-bromo-6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one

To a stirred solution of 6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one (100.00 mg, 0.499 mmol, 1.00 eq) in DMF (4.00 mL) was added NBS (106.66 mg). , 0.599 mmol, 1.20 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90° C. for 2 hours. The resulting mixture was diluted with water (12 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give 4-bromo-6-cyclopropyl-2-methyl-2,7-naphthyridin-1-one (400 mg, 75.96%) as a brown solid. It was used directly without further purification. LCMS (ESI) m/z: [M+H]+ = 279.
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 equiv.) in dioxane (10.00 mL) and water (2.00 mL) ) and 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (527.48 mg, 1.806 mmol, 1.2 eq). To the stirred solution was added Pd ₍ dppf) _Cl2 (110.09 mg, 0.150 mmol, 0.10 eq) and _K2CO3 (415.90 mg, 3.009 mmol, 2.00 eq) under a nitrogen atmosphere at room temperature. was added with The resulting mixture was stirred at 80° C. overnight. The mixture was concentrated under reduced pressure. The residue is purified by preparative TLC (CH2Cl2/MeOH 50:1) to give 4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6- Dimethoxybenzaldehyde (440 mg, 72.22%) was obtained as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 365.
Example 12-3-[6-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl ]
Preparation of azetidin-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)

To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.50 g, 14.433 mmol, 1.00 eq) and TsCl (4.13 g, 21.650 mmol, 1.50 eq) in DCM , DMAP (264.49 mg, 2.165 mmol, 0.15 eq) and TEA (4.38 g, 43.300 mmol, 3.00 eq) were added in portions at 0° C. under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether/EtOAc (1:1) to give tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (4.4 g , 93.11%) as a brown oil. LCMS (ESI) m/z: [M+H] ⁺ =328.
Step 2: Preparation of tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate

tert-butyl 3-[(4-methylbenzenesulfonyl)oxy]azetidine-1-carboxylate (4.40 g, 13.439 mmol, 1.00 equiv) and KI (0.22 g, 1.344 mmol, 0 .10 equiv), KHCO ₃ (4.04 g, 40.318 mmol, 3.00 equiv) was added in portions at 100° C. under an air atmosphere. The resulting mixture was washed with 3 x 150 mL of EtOAc. The resulting mixture was concentrated under reduced pressure. 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 over 40 minutes; detector, UV 254 nm. This gives tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate (1. 73 g, 29.98%) as an off-white solid. LCMS (ESI) m/z: [M+H] ⁺ =430.
Step 3: tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]azetidine-1-carboxy rate and tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]azetidine-1-carboxylate preparation of

tert-Butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]azetidine-1-carboxylate (1. A solution of 73 g, 4.029 mmol, 1.00 eq.) and Zn (2.64 g, 40.286 mmol, 10.00 eq.) was stirred at 60° C. for 2 hours under an air atmosphere. The resulting mixture was washed with 3 x 100 mL of ethyl acetate. The resulting mixture was concentrated under reduced pressure. The crude product is used directly in the next step without further purification to give 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 (2.73 g, 78.53%) was obtained as an off-white solid. LCMS (ESI) m/z: [M+H] ⁺ =432.
Step 4: 3-[6-(
Preparation of zetidin-3-yloxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-1-hydroxy-3-oxo-1H-isoindol-5-yl]oxy]azetidine-1-carboxy in DCM rate and tert-butyl 3-[[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]oxy]azetidine-1-carboxylate (2.73 g, 3.164 mmol, 1.00 eq) and TFA (1.50 mL, 20.195 mmol, 6.38 eq) was added _Et3SiH (3.68 g, 31.638 mmol, 10.00 eq). ) was added in portions at room temperature under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (mg) was subjected to the following conditions (column: Xselect CSH F-pheny OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: can; flow rate: 30 mL /min; Gradient: 5B to 21B in 10 min; 254/220 nm; RT1: 7.20/8.67 min) to give 3-[6-(azetidin-3-yloxy)-1 -oxo-3H-isoindol-2-yl]piperidine-2,6-dione (165 mg, 8.27%) was obtained as an off-white solid. LCMS (ESI) m/z: [M+H] ⁺ =316.
Step 5: 3-[6-[(1-[[4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl] Preparation of azetidin-3-yl)oxy]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione

3-[6-(azetidin-3-yloxy)-1-oxo-3H-isoindol-2-ylpiperidine-2,6-dione (75.00 mg, 0.238 mmol, 1.00 eq) in DMF and A stirred solution of 4-(6-cyclopropyl-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxybenzaldehyde (86.67 mg, 0.238 mmol, 1.00 eq) To was added NaBH(OAc) ₃ (100.82 mg, 0.476 mmol, 2.00 eq) dropwise at room temperature for 2 hours under air atmosphere. The crude product (mg) was subjected to the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/ 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%) was obtained as an off-white solid. ¹ H NMR (400 MHz, methanol-d4) δ 9.39 (d, J=0.8 Hz, 1 H), 7.80 (d, J=4.5 Hz, 1 H), 7.60 (t, J=7. 2 Hz, 1 H), 7.42 (d, J = 5.4 Hz, 1 H), 7.32-7.24 (m, 1 H), 7.22 (d, J = 3.2 Hz, 1 H), 6. 89 (s, 2H), 5.35-5.19 (m, 1H), 5.16 (dd, J=13.3, 5.2Hz, 1H), 4.84-4.69 (m, 2H) ), 4.65 (s, 2H), 4.48 (d, J = 10.6Hz, 2H), 4.42 (s, 2H), 3.98 (d, J = 22.6Hz, 6H), 3.69 (s, 3H), 2.93 (ddd, J = 17.6, 13.5, 5.4 Hz, 1H), 2.80 (ddd, J = 17.6, 4.7, 2. 4 Hz, 1 H), 2.52 (qd, J = 13.2, 4.7 Hz, 1 H), 2.21 (dddd, J = 14.5, 10.7, 6.9, 3.9 Hz, 2 H) , 1.23-1.12 (m, 2H), 1.09 (d, J=4.4 Hz, 2H). LCMS (ESI) m/z: [M+H] ⁺ =664.
Example 1 Preparation of 3-4-(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 eq) in THF (5.00 mL) was treated with NaH (132.89 mg, 5.537 mmol). , 2.00 equiv) for 5 min at 0<0>C followed by the portionwise addition of _CD3I (802.69 mg, 5.537 mmol, 2.00 equiv) at 0<0>C. After stirring for 1 hour at 0° C., the reaction mixture was poured into ice water (50 mL) and the precipitated solid was collected by filtration and washed with water (3×50 mL) before drying the solid under vacuum to give 6 -Chloro-2-(2H3)methyl-2,7-naphthyridin-1-one (500 mg, 91.37%) was obtained as a pale yellow solid, which was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =198.
Step 2: 6-Cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one

6-chloro-2-(2H3)methyl-2,7-naphthyridin-1-one (400.00 mg, 2.024 mmol, 1.00 equiv.) in toluene (20.00 mL) and H ₂ O (1.00 mL) ) _, cyclopropylboronic acid (260.78 mg, 3.036 mmol, 1.50 eq), _K3PO4 (1288.81 mg, 6.072 mmol, 3.00 eq), _PCy3 (113.51 mg, 0.405 mmol). , 0.20 eq.) and Pd(AcO) ₂ (45.44 mg, 0.202 mmol, 0.10 eq.) was stirred at 110° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH ₂ Cl ₂ /MeOH (10:1) to give 6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one (350 mg, 85.08%) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ =204
Step 3: Preparation of 4-bromo-6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one

6-Cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one (300.00 mg, 1.476 mmol, 1.00 equiv) and NBS (315.23 mg, 1.771 mmol, 1.20 equiv) was stirred at 90° C. for 2 hours. The resulting mixture was diluted with 1 x 50 mL of water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to give 4-bromo-6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one (350 mg, 84.04%) as a yellow solid. , which was used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =282.
Step 4: Preparation of 4-[6-cyclopropyl-2-(2H3)methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde

4-bromo-6-cyclopropyl-2-(2H3)methyl-2,7-naphthyridin-1-one (350.00 mg, 1.240 mmol) in dioxane (3.00 mL) and H ₂ O (1.00 mL) , 1.00 equivalents), 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (434.86 mg, 1.489 mmol, 1 .20 eq.), _Cs2CO3 ( _808.33 mg, 2.481 mmol, 2.00 eq.), and Pd(dppf) _Cl2 (90.76 mg, 0.124 mmol, 0.10 eq.) under nitrogen. The mixture was stirred at 90° C. for 3 hours under atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH ₂ Cl ₂ /MeOH (10:1) to give 4-[6-cyclopropyl-2(2H3)methyl-1-oxo-2,7-naphthyridine -4-yl]-2,6-dimethoxybenzaldehyde (200 mg, 43.88%) was obtained as an orange solid. LCMS (ESI) m/z: [M+H] ⁺ =368.
Example 14-3-[5-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6- Preparation of dimethoxyphenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid

Step 1: Preparation of 6-(azetidin-1-yl)-4-bromo-2-methyl-2,7-naphthyridin-1-one

4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (5.00 g, 18.281 mmol, 1.00 equiv) and azetidine hydrochloride (3 .2 _g , 54.843 mmol, 3 eq) was added _K2CO3 (12.6 g, 91.404 mmol, 5 eq). The resulting solution was stirred at 130° C. for 2 hours. The resulting mixture was cooled, diluted with water (100 mL), then extracted with EtOAc (3 x 100 mL). The combined organic layers are washed with saturated NaCl solution (3×50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 6-(azetidin-1-yl)-4-bromo-2- Methyl-2,7-naphthyridin-1-one (3.7 g, 68.8%) was obtained as a gray solid and used directly without further purification. LCMS (ESI) m/z: [M+H] ⁺ =294.
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 eq) and 4-formyl-3,5-dimethoxyphenylboronic acid (1.52 g, 7.241 mmol, 1.5 eq) was added Pd(dppf)Cl ₂ (353.2 mg, 0.483 mmol, 0.1 eq) and Cs ₂ CO ₃ (3.15 g, 9.655 mmol, 2 eq) were added and the resulting solution was stirred at 70° C. for 2 h. The resulting mixture was cooled and concentrated under reduced pressure. The residue was slurried with water (30 mL), filtered, and the filter cake collected. This solid was further slurried with MeOH (30 mL) and filtered. Collect the solid to give the product, 4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde (1.42 g, 77.5%) was obtained as a gray solid. LCMS (ESI) m/z: [M+H] ⁺ =380.
Example 15-3-[5-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6- Preparation of dimethoxyphenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid

Step 1: tert-butyl 2-[2-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1-oxo-3H-isoindol-5-yl]-2,7-diazaspiro[3 .5] Preparation of nonane-7-carboxylate

tert-Butyl 2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro [ in AcOH (4.00 mL) Zn (677.7 mg, 10.362 mmol, 10.00 eq) was added to a stirred solution of 3.5]nonane-7-carboxylate (500.0 mg, 1.036 mmol, 1.00 eq). The resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was filtered and the filtrate was evaporated to give the crude product. The crude product was purified by reverse phase column (elution gradient 0-30% MeCN in water containing 0.1% formic acid). Pure fractions are evaporated to dryness to give 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 (277.3 mg, 55.2%) was obtained as a yellow solid. LCMS (ESI) m/z: [M+H] ⁺ =485.
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, in DCM (2.00 mL) To a stirred solution of 7-diazaspiro[3.5]nonane-7-carboxylate (250.0 mg, 0.516 mmol, 1.00 equiv) was added TFA (0.50 mL) and Et ₃ SiH (0.20 mL). did. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This gives 3-(5-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (267.5 mg , crude) was obtained as a yellow gum. The crude product was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H] ⁺ =369.
Step 3: 3-[5-[7-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxy Phenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione; preparation of formic acid

3-(5-[2,7-diazaspiro[3.5]nonan-2-yl]-1-oxo-3H-isoindol-2-yl)piperidine-2,6- in DMF (3.00 mL) dione (400.0 mg, 1.086 mmol, 1.00 eq) and 4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2, To a stirred solution of 6-dimethoxybenzaldehyde (494.3 mg, 1.303 mmol, 1.20 eq) was added NaBH(OAc) ₃ (920.4 mg, 4.343 mmol, 4.00 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The crude reaction solution was subjected to the following conditions (column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; : 14B to 22B in 15 min; )-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)-2,7-diazaspiro[3.5]nonan-2-yl]-1- Oxo-3H-isoindol-2-yl]piperidine-2,6-dione; formic acid (99.2 mg, 12.5%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.02 (s, 1H), 8.15 (s, 1H, FA), 7.61 (s, 1H), 7.48 (d, J=8.2 Hz, 1H), 6.75 (s, 2H), 6.53-6.44 (m, 2H), 6.21 (s, 1H), 5.04 (dd, J = 13.3, 5.2 Hz, 1H), 4.30 (d, J = 17.0 Hz, 1H), 4.17 (d, J = 16.9 Hz, 1H), 4 .01 (t, J=7.4 Hz, 4H), 3.83 (s, 6H), 3.61 (d, J=13.2 Hz, 6H), 3.48 (s, 3H), 2 .96-2.84 (m, 1H), 2.63-2.54 (m, 3H), 2.51-2.45 (m, 2H), 2.35 (q, J = 6.6 Hz , 3H), 1.95 (d, J=12.9 Hz, 1H), 1.75 (s, 4H). LCMS (ESI) m/z: [M+H] ⁺ =732.45.
Example 16-3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6- dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid and 3-[6-[1-([4-[6-( Azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindole Preparation of 2-yl]piperidine-2,6-dioneformic acid

Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindole-1,3-dione

tert-Butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-1-carboxylate (1. 00 g, 2.265 mmol, 1.00 eq) was added TFA (2.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. This gave 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindole-1,3-dione (1.23 g, crude) as a white solid. , which was used directly in the next step without further purification. LCMS (ESI) m/z: [M+H] ⁺ =342.
Step 2: 3-[3-Hydroxy-1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione and 3-[1-hydroxy-3- Preparation of 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 eq.) was added Zn (574.9 mg, 8.788 mmol, 10 eq.) and the resulting solution was stirred at 25° C. for 2 h. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by flash C18 chromatography (elution gradient 0-11% ACN in H ₂ O) to give 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 (280 mg, mixture of two regioisomers, 92.8%) was obtained as a white solid. LCMS (ESI) m/z: [M+H] ⁺ =344.
Step 3: 3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxy Phenyl]methyl)piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione and 3-[5-[1-([4-[6 -(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-hydroxy-3- Preparation of oxo-1H-isoindol-2-yl]piperidine-2,6-dione

3-[3-Hydroxy-1-oxo-5-(piperidin-4-yl)-3H-isoindol-2-yl]piperidine-2,6-dione and 3-[1-hydroxy in DMF (3 mL) -3-oxo-5-(piperidin-4-yl)-1H-isoindol-2-yl]piperidine-2,6-dione (mixture of two regioisomers, 260.0 mg, 0.757 mmol, 1. 00 equivalents), 4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxybenzaldehyde (287.3 mg, 0.757 mmol , 1 eq) was added NaBH(OAc) ₃ (321.0 mg, 1.514 mmol, 2 eq) and the resulting solution was stirred at 25° C. for 4 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 10:1) to give 3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl -1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]piperidine -2,6-dione and 3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2 ,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-hydroxy-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (208 mg, mixture of two regioisomers, 38.9%) as a white solid. LCMS (ESI) m/z: [M+H] ⁺ =707.
Step 4: 3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxy Phenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dioneformic acid and 3-[6-[1-([4-[6-( Azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindole Preparation of 2-yl]piperidine-2,6-dioneformic acid

3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]- in DCM (3.00 mL) 2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-3-hydroxy-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione and 3-[5-[1-( [4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1 -hydroxy-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (mixture of two regioisomers, 200.0 mg, 0.141 mmol, 1.00 equiv.), TFA (2.00 mL, 26.926 mmol, 95.16 eq) and triethylsilane (1.00 mL, 6.192 mmol, 21.88 eq) were added and the resulting solution was stirred at 25° C. for 1 hour. The crude product was subjected to preparative HPLC (column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL/min; 3B to 26B in 14 min; 254 nm; RT1: 13.32 min) to give 3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1- oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione ( 39.5 mg, 39.1%) and 3-[6-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl ]-2,6-dimethoxyphenyl]methyl)piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione; formic acid (24.8 mg, 22.7%) were obtained as white solids.

3-[5-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl ) for piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidin-2,6-dione, ¹ H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.02 (s, 1H), 8.16 (s, 1H, FA), 7.68-7.60 (m, 2H), 7.49 (s, 1H), 7.39 (dd, J = 7.8, 1.4 Hz, 1 H), 6.76 (s, 2 H), 6.22 (s, 1 H), 5.10 (dd, J = 13.3, 5.1 Hz, 1 H), 4. 42 (d, J = 17.3Hz, 1H), 4.28 (d, J = 17.3Hz, 1H), 4.01 (t, J = 7.4Hz, 4H), 3.84 (s, 6H ), 3.69 (s, 2H), 3.49 (s, 3H), 3.05 (d, J = 11.2 Hz, 2H), 2.92 (ddd, J = 17.3, 13.6 , 5.4 Hz, 1H), 2.66-2.60 (m, 1H), 2.60-2.55 (m, 1H), 2.46-2.38 (m, 1H), 2.37 -2.28 (m, 4H), 2.04-1.95 (m, 1H), 1.78-1.65 (m, 4H). LCMS (ESI) m/z: [M+H] ⁺ =691.35.
3-[6-[1-([4-[6-(azetidin-1-yl)-2-methyl-1-oxo-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl ) piperidin-4-yl]-1-oxo-3H-isoindol-2-yl]piperidin-2,6-dione; for formic acid, ¹ H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H ), 9.02 (s, 1H), 8.18 (s, FA), 7.62 (s, 1H), 7.58-7.48 (m, 3H), 6.75 (s, 2H) , 6.22(s, 1H), 5.10(dd, J=13.3, 5.1Hz, 1H), 4.41(d, J=17.1Hz, 1H), 4.27(d, J = 17.1Hz, 1H), 4.01 (t, J = 7.4Hz, 4H), 3.84 (s, 6H), 3.63 (s, 2H), 3.48 (s, 3H) , 3.00 (d, J = 11.0 Hz, 2H), 2.97-2.85 (m, 1H), 2.65-2.60 (m, 1H), 2.60-2.56 ( m, 1H), 2.45-2.37 (m, 1H), 2.37-2.30 (m, 1H), 2.24 (t, J = 11.3Hz, 2H), 2.03- 1.96 (m, 1H), 1.80-1.73 (m, 2H), 1.73-1.62 (m, 2H). LCMS (ESI) m/z: [M+H] ⁺ =691.55.
Example 17-3-(5-[[1-([2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7-naphthyridine-4- Preparation of yl]phenyl]methyl)azetidin-3-yl]oxy]-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione

Step 1: Preparation of 4-bromo-2-methyl-6-(morpholin-4-yl)-2,7-naphthyridin-1-one

4-bromo-6-chloro-2-methyl-2,7-naphthyridin-1-one (547.00 mg, 2.000 mmol, 1.00 equiv) and morpholine (522.71 mg, _6.000 mmol, 3.00 eq) was added _K2CO3 (1382.00 mg, 10.000 mmol, 5.00 eq). The resulting mixture was stirred at 130° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with EA (100 mL). The resulting mixture was washed with 3 x 100 mL water and 1 x 100 mL saturated brine. The organic layer was dried over _Na2SO4 , filtered and evaporated to give _crude product. The residue was purified by silica gel column chromatography (elution gradient 0-10% MeOH in DCM). Pure fractions were evaporated to dryness to afford 4-bromo-2-methyl-6-(morpholin-4-yl)-2,7-naphthyridin-1-one (541 mg, 83.44%) as a pale yellow solid. obtained as LCMS (ESI) m/z: [M+H] ⁺ =324.
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 eq) and 4-formyl-3,5-dimethoxyphenylboronic acid (454.73 mg, 2.165 mmol, 1.30 eq), Cs ₂ CO ₃ (1628.20 mg, 4.997 mmol, 3 .00 eq) was added Pd( _dppf ) _Cl2CH2Cl2 (136.03 mg, 0.167 mmol, 0.10 eq) under _nitrogen . After stirring for 1 hour at 90° C. under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution gradient 0-10% MeOH in DCM). Pure fractions were evaporated to dryness to give 2,6-dimethoxy-4-[2-methyl-6-(morpholin-4-yl)-1-oxo-2,7 naphthyridin-4-yl]benzaldehyde (356 mg , 52.20%) as a yellow solid. LCMS (ESI) m/z: [M+H] ⁺ =410.
Step 3: 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 equiv) in DMF 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 eq.), NaBH(OAc) ₃ (134.43 mg, 0.634 mmol, 2.00 eq.) was added dropwise for 2 hours at room temperature under an air atmosphere. 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 over 45 minutes; detector, UV 254 nm. The crude product was subjected to the following conditions (column: Xselect CSH F-pheny OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA); mobile phase B: ACN; flow rate: 30 mL/min; 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-isoindole-2 -yl)piperidine-2,6-dione (100 mg, 44.15%) was obtained as a yellow solid. ¹ H NMR (400 MHz, methanol-d4) δ 9.18 (s, 1H), 7.80 (t, J = 6.7 Hz, 1H), 7.49 (s, 1H), 7.09 (t, J = 7.3 Hz, 2H), 6.88 (s, 2H), 6.63 (d, J = 4.9 Hz, 1H), 5.40-5.20 (m, 1H), 5.15 (dd , J=13.3, 5.2 Hz, 1H), 4.77 (ddd, J=24.3, 12.5, 6.8 Hz, 2H), 4.65 (d, J=22.0 Hz, 2H ), 4.48 (d, J = 6.3 Hz, 2H), 4.44-4.28 (m, 2H), 3.96 (d, J = 23.6 Hz, 6H), 3.78 (t , J=4.8 Hz, 4H), 3.61 (s, 3H), 3.56 (d, J=4.7 Hz, 4H), 2.93 (ddd, J=18.5, 13.5, 5.3 Hz, 1 H), 2.80 (ddd, J = 17.5, 4.6, 2.3 Hz, 1 H), 2.49 (qd, J = 13.2, 4.7 Hz, 1 H), 2 .23-2.14 (m, 1H). LCMS (ESI) m/z: [M+H] ^{+ =} 709.
Example 18 - SYO1 BRD9 NanoLuc Degradation Assay This example demonstrates the ability of compounds of the present disclosure to degrade nanoluciferase-BRD9 fusion proteins in a cell-based degradation assay.

Procedure: A stable SYO-1 cell line expressing 3xFLAG-NLuc-BRD9 was generated. On day 0, cells were seeded with 30 μL of medium into each well of a 384-well cell culture plate. The seeding density was 8000 cells/well. On day 1, cells were treated with 30 nL of DMSO or 30 nL of 3-fold serially diluted DMSO compounds (1 μM as final top dose, 10 points in duplicate). Plates were then incubated for 6 hours in a standard tissue culture incubator and allowed to equilibrate for 15 minutes at room temperature. Nanoluciferase activity was measured by adding 15 μL of freshly prepared Nano-Glo Luciferase Assay Reagent (Promega N1130), shaking the plate for 10 minutes and reading bioluminescence using an EnVision reader.

Results: % inhibition was calculated using the following formula; % inhibition=100×(Lum _HC -Lum _sample )/(Lum _HC -Lum _LC ). Cells treated with DMSO are used as a high control (HC) and cells normally treated with 1 μM of a known BRD9 degrading agent are used as a low control (LC). Data were fitted with a 4-parameter non-linear curve fit to calculate IC ₅₀ (μM) values, as shown in Table 4. As shown by the results in Table 4, several compounds of the present disclosure exhibited IC ₅₀ values of <1 μM against degradation of BRD9, demonstrating their efficacy as compounds for reducing BRD9 levels and/or activity. and their potential to treat BRD9-related disorders.

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

While this invention has been described in relation to specific embodiments thereof, and while the invention is capable of further modifications, this application generally conforms to the principles of the invention and is within the skill of the art to which this invention pertains. It is intended to cover any variations, uses, or adaptations of the invention including such departures from this disclosure that come within known or customary practice and which do not conform to essential features described above. It will be understood that as may be applied and is within the scope of the claims.

Other embodiments are within the claims.

Claims (180)

A compound having the structure of Formula I,
ALB
Formula I
During the ceremony,
L has the structure of formula II,
A ¹ -E ¹ -FE ² -A ²
Formula II
A ¹ is the bond between the linker and A;
A ² is the bond between B and said linker;
each of E ¹ and E ² is independently absent CH ₂ , O, or NCH ₃ ;
F is optionally substituted C ₃ -C ₁₀ carbocyclylene or optionally substituted C _2-10 heterocyclylene;
B is the decomposition part,
A has the structure of formula III,

During the ceremony,
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 - _Cio 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 heteroalkyl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted C ₂ -C ₉ heteroaryl;
X ¹ is N or CH and X ² is C—R ″, or X ¹ is C— ^{R 7 ″} and X ² is N or CH;
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 amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;
R ⁷ ′ is H, optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, or optionally substituted C ₃ -C ₁₀ carbocyclyl;
X ³ is N or CH,
X ⁴ is N or CH,
G” is

, optionally substituted C ₃ -C ₁₀ carbocyclyl, C ₂ -C ₉ heterocyclyl, optionally substituted C ₆ -C ₁₀ aryl, or optionally substituted C ₂ -C ₉ heteroaryl;
G′ is optionally substituted C ₃ -C ₁₀ carbocyclylene, C ₂ -C ₉ heterocyclylene, optionally substituted C ₆ -C ₁₀ arylene, or optionally substituted C ₂ -C ₉ is heteroarylene,
A ¹ is the bond between A and said linker;
In the formula, G” is

or R ⁷ ″ is

The compound, which is
or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein 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. Compound. 3. The compound of claim 2, wherein ^R1 is H. 3. The compound of claim 2, wherein R ¹ is optionally substituted C ₁ -C ₆ alkyl. R ¹ is

5. The compound of claim 4, which is 6. The compound of claim 5, wherein R ¹ is optionally substituted _C2 - _C6 alkenyl. R ¹ is

7. The compound of claim 6, which is 8. The compound of claim 7, wherein R ¹ is optionally substituted C ₃ -C ₁₀ carbocyclyl. R ¹ is

9. The compound of claim 8, which is R ¹ is H or

2. The compound of claim 1, which is ^11. The compound of claim 10, wherein R1 is H. R ¹ is

11. The compound of claim 10, which is A compound according to any one of claims 1 to 12, wherein Z ¹ is N. A compound according to any one of claims 1 to 12, wherein Z ¹ is CR ² . Claim 14, wherein 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. The compound described in . 16. The compound of claim 15, wherein R ² is H, halogen, or optionally substituted C ₁ -C ₆ alkyl. R ² is H, F, or

17. The compound of claim 16, which is A compound according to any one of claims 1 to 17, wherein X ¹ is N and X ² is CR ⁷ ″. A compound according to any one of claims 1 to 17, wherein X ¹ is CH and X ² is C—R ⁷ ″. A compound according to any one of claims 1 to 17, wherein X ¹ is CR ⁷ ″ and X ² is N. A compound according to any one of claims 1 to 17, wherein X ¹ is CR ⁷ ″ and X ² is CH. R ⁷ ″ is optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ heteroalkyl, optionally substituted carbocyclyl having 3-6 atoms, or 3-6 A compound according to any one of claims 1 to 21, which is an optionally substituted heterocyclyl having atoms of 23. The compound of claim 22, wherein R ⁷ ″ is optionally substituted C ₁ -C ₆ alkyl. R ⁷ ″ is

24. The compound of claim 23, which is 23. The compound of claim 22, wherein R ⁷ ″ is optionally substituted C ₁ -C ₆ heteroalkyl. 23. The compound of claim 22, wherein R ⁷ ″ is optionally substituted C ₁ -C ₆ alkoxy or optionally substituted amino. 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 27. A compound according to claim 25 or 26, which is ₁ - _C6 alky. 28. A compound according to claim 27, wherein R ⁷ ″ is —NR ³ R ⁴ . 29. The compound of claim 28, wherein X ¹ is N and X ² is C-NR ³ R ⁴ . 29. The compound of claim 28, wherein X ¹ is C-NR ³ R ⁴ and X ² is N. 28. The compound of claim 27, wherein ^R7 is ^-OR4 . 32. The compound of claim 31, wherein X ¹ is N and X ² is C-OR ⁴ . 32. The compound of claim 31, wherein X ¹ is C-OR ⁴ and X ² is N. 34. The compound of any one of claims 27-33, wherein R ³ is H. ^R3 is

The compound of any one of claims 27-34, which is ^R4 is

The compound of any one of claims 27-35, which is 23. The compound of claim 22, wherein R ⁷ ″ is optionally substituted carbocyclyl having 3-6 atoms. R ⁷ ″ is

38. The compound of claim 37, which is 23. The compound of claim 22, wherein R ⁷ ″ is optionally substituted heterocyclyl having 3-6 atoms. R ⁷ ″ is

40. The compound of claim 39, which is 23. The compound of claim 22, wherein R7 ^' ' is optionally substituted sulfone or optionally substituted sulfonamide. R ⁷ ″ is

42. The compound of claim 41, which is R ⁷ ″ is

The compound of any one of claims 1-42, which is R ⁷ ″ is

44. The compound of claim 43, which is R ⁷ ″ is

45. The compound of claim 44, which is G” is

46. The compound of any one of claims 1-45, which is 47. The compound of claim 46, wherein G' is optionally substituted _C6 - _C10 arylene or optionally substituted _C2 - _C9 heteroarylene. 48. The compound of claim 47, wherein G' is optionally substituted _C6 - _C10 arylene. G' is

and
During the ceremony,
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 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 —C ₁ -C ₃ alkyl-C ₃ -C ₆ carbocyclyl substituted with , optionally substituted —C ₁ -C ₃ alkyl-C ₂ -C ₅ heterocyclyl, hydroxyl, thiol, or optionally substituted amino or R ^{G1 ′} and R ^{G2 ′} , R ^{G2 ′} and R ^{G3 ′} , R ^{G3 ′} and R ^G4 ′, and/or R ^{G4 ′} and R ^{G5 ′} are each bonded to the carbon atom combined together,

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 optionally substituted C ₂ -C ₉ heterocyclyl, any of which is optionally substituted with A ¹ ;
wherein one of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is A ¹ , or

49. The compound of claim 48, wherein is substituted with ^A1 . 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 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 ′ in combination with the carbon atom to which each is attached ,

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 ;
wherein one of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is A ¹ , or

50. The compound of claim 49, wherein is substituted with ^A1 . 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 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 50. The compound according to 50. Each of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is independently H, A ¹ , F, Cl,

52. The compound of claim 51, which is Each of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is independently H, A ¹ , F,

53. The compound of claim 52, which is Each of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is independently H, A ¹ , F, Cl,

54. The compound of claim 53, which is 55. The compound of claim 54, wherein R ^G3 ' is ^A1 . R ^G1 ' is H, and R ^G2 ' is

and R ^G3 ' is A ¹ and R ^G4 ' is

and ^RG5 ' is H. R ^G1 ' is H, and R ^G2 ' is

, R ^G3 ' is A ¹ , R ^G4 ' is H, and R ^G5 ' is

55. The compound of claim 54, which is R ^G1 ' is H, and R ^G2 ' is

55. The compound of claim 54, wherein ^RG3 ' is ^A1 , ^RG4 ' is Cl or F, and ^RG5 ' is H. R ^G1 ' is H, and R ^G2 ' is

55. The compound of claim 54, wherein ^RG3 ' is ^A1 , ^RG4 ' is H, and ^RG5 ' is H. R ^G1 ' is H, and R ^G2 ' is

and R ^G3 ' is A ¹ and R ^G4 ' is

and ^RG5 ' is H. R ^G1 ′ and R ^{G2 ′} , R ^{G2 ′} and R ^{G3 ′} , R ^{G3 ′} and R ^G4 ′, and/or R ^{G4 ′} and R ^G5 ′ in combination with the carbon atom to which each is attached ,

to form

is optionally substituted C ₂ -C ₉ heterocyclyl optionally substituted with A ¹ ;
wherein 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 ′ in combination with the carbon atom to which each is attached ,

to form

is optionally substituted C ₂ -C ₉ heteroaryl optionally substituted with A ¹ ;
wherein one of R ^G1 ′, R ^G2 ′, R ^G3 ′, R ^G4 ′, and R ^G5 ′ is A ¹ , or

is substituted with A ¹ . G' is

62. The compound of claim 61, wherein R ^G6 ' is H, A ¹ , or optionally substituted C ₁ -C ₆ alkyl. G' is

63. The compound of claim 62, wherein R ^G6 ' is H, A ¹ , or optionally substituted C ₁ -C ₆ alkyl. R ^G6 ' is H, A ¹ , or

65. The compound of claim 63 or 64, which is 66. The compound of claim 65, wherein ^RG6 ' is H. 48. The compound of claim 47, wherein G' is optionally substituted _C2 - _C9 heteroarylene. G' is

and
During the ceremony,
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 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 —C ₁ -C ₃ alkyl-C ₃ -C ₆ carbocyclyl substituted with , optionally substituted —C ₁ -C ₃ alkyl-C ₂ -C ₅ heterocyclyl, 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 ′ are each bonded to the carbon atom combined together,

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, is optionally substituted with A ¹ ;
wherein one of R ^G7 ′, R ^G8 ′, R ^G9 ′, R ^G10 ′, and R ^G11 ′ is A ¹ , or

is substituted with A ¹ . 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 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 68. A compound according to 68. G' is

70. The compound of claim 68 or 69, which is R ^G7 ' is H, and R ^G8 ' is

71. The compound of any one of claims 68-70, wherein R ^G9 ' is A ¹ and R ^G11 ' is H. G' is

and
During the ceremony,
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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 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 — is 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 ^G14 ′ in combination with the carbon atom to which each is attached,

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 optionally substituted C ₂ -C ₉ heterocyclyl, any of which is optionally substituted with A ¹ ;
wherein one of R ^G12 ′, R ^G13 ′, and R ^G14 ′ is A ¹ , or

is substituted with A ¹ . R ⁷ ″ is

A compound according to any one of claims 1 to 21, which is 74. The compound of claim 73, wherein G" is optionally substituted _C6 - _C10 aryl or optionally substituted _C2 - _C9 heteroaryl. 75. The compound of claim 74, wherein G" is optionally substituted _C6 - _C10 aryl. G” is

and
During the ceremony,
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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 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 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 in combination with the carbon atom to which each is attached, optionally substituted C ₆ -C ₁₀ 76. The compound of claim 75, which forms aryl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heteroaryl, or optionally substituted _C2 - _C9 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 hetero alkyl, 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 in combination with the carbon atom to which each is attached, optionally substituted C ₂ -C ₉ heteroaryl or optionally 77. The compound of claim 76, which forms a substituted _C2 - _C9 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 hetero 78. The compound of claim 77, which is alkyl, optionally substituted -O- _C3 - _C6 carbocyclyl, or optionally substituted _-C1 - _C3 alkyl- _C2 - _C5 heterocyclyl. Each of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 is independently H, F, Cl,

79. The compound of claim 78, which is Each of R ^G1 , R ^G2 , R ^G3 , R ^G4 and R ^G5 independently represents H, F,

80. The compound of claim 79, which is Each of R ^G1 , R ^G2 , R ^G3 , R ^G4 , and R ^G5 is independently H, F, Cl,

81. The compound of claim 80, which is 82. The compound of claim 81, wherein two or more of ^RG1 , ^RG2 , ^RG3 , ^RG4 , and ^RG5 are H. ^RG1 is H, and ^RG2 is

and R ^G3 is

and R ^G4 is

and R ^G5 is H. ^RG1 is H, and ^RG2 is

and R ^G3 is

, ^RG4 is H, and ^RG5 is

83. The compound of claim 82, which is ^RG1 is H, and ^RG2 is

and R ^G3 is

83. The compound of claim 82, wherein ^RG4 is Cl or F, and ^RG5 is H. ^RG1 is H, and ^RG2 is

and R ^G3 is

83. The compound of claim 82, wherein ^RG4 is H and ^RG5 is H. ^RG1 is H, and ^RG2 is

and R ^G3 is

and 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 in combination with the carbon atom to which each is attached, optionally substituted C ₂ 78. A compound according to claim 77, which forms a _{-C9heterocyclyl} . R ^G1 and R ^G2 , R ^G2 and R ^G3 , R ^G3 and R ^G4 , and/or R ^G4 and R ^G5 in combination with the carbon atom to which each is attached, optionally substituted C ₂ 78. The compound of claim 77, which forms a _{-C9heteroaryl} . G” is

and
89. The compound of claim 88, wherein R ^G6 is H or optionally substituted C ₁ -C ₆ alkyl. G” is

and
90. The compound of claim 89, wherein R ^G6 is H or optionally substituted C ₁ -C ₆ alkyl. ^RG6 is H or

92. The compound of claim 90 or 91, which is 93. The compound of claim 92, wherein ^RG6 is H. 75. The compound of claim 74, wherein G" is optionally substituted _C2 - _C9 heteroaryl. G” is

and
During the ceremony,
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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 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 ^G7 and R ^G8 , R ^G8 and R ^G9 , R ^G9 and R ^G10 , and/or R ^G10 and R ^G11 in combination with the carbon atom to which each is attached, optionally substituted C ₆ -C ₁₀ 95. The compound of claim 94, which forms aryl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heteroaryl, or optionally substituted _C2 - _C9 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 hetero 96. The compound of claim 95, which is alkyl, optionally substituted -O- _C3 - _C6 carbocyclyl, or optionally substituted _-C1 - _C3 alkyl- _C2 - _C5 heterocyclyl. G” is

97. The compound of claim 95 or 96, which is ^RG7 is H, and ^RG8 is

98. The compound of claim 97, wherein R ^G9 is H and R ^G11 is H. G” is

and
During the ceremony,
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 ₂ -C ₅ heterocyclyl, hydroxyl, thiol, or optionally substituted amino; or R ^G12 and R ^G14 are each optionally substituted C ₆ -C ₁₀ aryl, optionally substituted C ₃ -C ₁₀ carbocyclyl, optionally substituted C ₂ -C ₉ heteroaryl, in combination with the bonding carbon atom, or a compound of claim 88 which forms an optionally substituted _C2 - _C9 heterocyclyl. 99. Any one of claims 73-99, wherein R ⁷ ′ is H, optionally substituted C ₁ -C ₆ alkyl, or optionally substituted C ₃ -C ₁₀ carbocyclyl. Compound. 101. The compound of claim 100, wherein ^R7 ' is H or optionally substituted _C1 - _C6 alkyl. R ⁷ ' is H,

102. The compound of claim 101, which is R ⁷ ' is H or

103. The compound of claim 102, which is 104. The compound of claim 103, wherein ^R7 ' is H. R ⁷ ' is

104. The compound of claim 103, which is 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIa,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIc,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIe,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIf,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIg,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIh,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIj,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIn,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIo,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIs,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIu,

or a pharmaceutically acceptable salt thereof. 106. The compound of any one of claims 1-105, wherein A has the structure of formula IIIv,

or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1-117, wherein said degradation moiety is a ubiquitin ligase binding moiety. said ubiquitin ligase binding moiety comprises a cereblon ligand, an IAP (inhibitor of apoptosis) ligand, a mouse double minute 2 homologue (MDM2), or a von Hippel-Lindau (VHL) ligand, or a derivative or analogue thereof; 119. A compound of claim 118. The structure of Formula AA has the structure of Formula A,

During the ceremony,
Y ¹ is

and
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 are each together with the carbon atom to which is attached to form an optionally substituted C ₃ -C ₆ carbocyclyl or an optionally substituted C ₂ -C ₅ heterocyclyl, or R ^A6 and R ^A7 are combine together with the carbon atoms to which each is attached to form an optionally substituted C ₃ -C ₆ carbocyclyl or an 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 , 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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 heteroaryl , optionally substituted C ₂ -C ₆ alkenyl, optionally substituted C ₂ -C ₆ heteroalkenyl, optionally substituted —O—C ₃ -C ₆ carbocyclyl, hydroxyl, thiol, or optionally substituted or R ^A1 and R ^A2 , R ^A2 and R ^A3 , and/or R ^A3 and R ^A4 in combination with the carbon atom to which each is attached,

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 optionally substituted C ₂ -C ₉ heterocyclyl, any of which are optionally substituted with ^A2 ;
wherein one of R ^A1 , R ^A2 , R ^A3 , and R ^A4 is ^A2 , or

120. The compound of claim 119, or a pharmaceutically acceptable salt thereof, wherein is substituted with ^A2 . 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 hetero alkyl, optionally substituted _C3 - _C10 carbocyclyl, optionally substituted _C2 - _C9 heterocyclyl, optionally substituted _C6 - _C10 aryl, optionally substituted _C2 - _C9 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 in combination with the carbon atom to which each is attached,

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 optionally substituted C ₂ -C ₉ heterocyclyl, any of which are optionally substituted with ^A2 ;
wherein one of R ^A1 , R ^A2 , R ^A3 , and R ^A4 is ^A2 , or

121. The compound of claim 120, or a pharmaceutically acceptable salt thereof, wherein is substituted with ^A2 . 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 are each linked combined with the carbon atoms in the

to form

is optionally substituted C ₂ -C ₉ heterocyclyl optionally substituted with A ² ;
wherein one of R ^A1 , R ^A2 , R ^A3 , and R ^A4 is ^A2 , or

is substituted with ^A2 . 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 in combination with the carbon atom to which each is attached,

to form

is optionally substituted C ₂ -C ₉ heterocyclyl optionally substituted with A ² ;
wherein one of R ^A1 , R ^A2 , R ^A3 , and R ^A4 is ^A2 , or

is substituted with ^A2 . Y ¹ is

The compound of any one of claims 120-123, which is Y ¹ is

125. The compound of claim 124, which is Y ¹ is

125. The compound of claim 124, which is Y ¹ is

127. The compound of claim 126, which is Y ¹ is

128. The compound of claim 127, which is The compound of any one of claims 120-128, wherein the structure of formula A has the structure of formula A1,

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of formula A has the structure of formula A2,

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of Formula A has the structure of Formula A3;

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of Formula A has the structure of Formula A4;

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of Formula A has the structure of Formula A5;

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of formula A has the structure of formula A6;

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of Formula A has the structure of Formula A7;

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of formula A has the structure of formula A8;

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of Formula A has the structure of Formula A9;

or a pharmaceutically acceptable salt thereof. The compound of any one of claims 120-128, wherein the structure of formula A has the structure of formula A10,

or a pharmaceutically acceptable salt thereof. The structure of Formula A above is

, or a derivative or analogue thereof. The structure of Formula A above is

140. The compound of claim 139, which is The structure of Formula A above is

141. The compound of claim 140, which is , or a derivative or analogue thereof. the linker has the structure of formula II,
A ¹ -E ¹ -FE ² -A ²
Formula II
A ¹ is the bond between the linker and A;
A ² is the bond between B and said linker;
each of E ¹ and E ² is independently absent CH ₂ , O, or NCH ₃ ;
F is

142. The compound of any one of claims 1-141, having the structure of 143. The compound of any one of claims 1-142, wherein E ¹ is absent. 143. The compound of any one of claims 1-142, wherein E ¹ is CH ₂ . 143. The compound of any one of claims 1-142, wherein E ¹ is O. 143. The compound of any one of claims 1-142, wherein E ¹ is NCH ₃ . 147. The compound of any one of claims 1-146, wherein ^E2 is absent. 147. The compound of any one of claims 1-146, wherein E ² is CH ₂ . 147. The compound of any one of claims 1-146, wherein ^E2 is O. 147. The compound of any one of claims 1-146, wherein E ² is NCH ₃ . The linker has the structure:

151. The compound of any one of claims 1-150, comprising 152. The compound of any one of claims 1-151, or a pharmaceutically acceptable salt thereof, wherein said compound has the structure of any one of compounds D1-D66 of Table 1. A pharmaceutical composition comprising a compound according to any one of claims 1-152 and a pharmaceutically acceptable excipient. A method of inhibiting the level of BRD9 in a cell, wherein said cell is treated with an effective amount of a compound of any one of claims 1-152, or a pharmaceutically acceptable salt thereof, or claim 153. The method comprising contacting with the pharmaceutical composition according to 153. A method of inhibiting the activity of BRD9 in a cell, wherein said cell is treated with an effective amount of a compound of any one of claims 1-152, or a pharmaceutically acceptable salt thereof, or claim 153. The method comprising contacting with the pharmaceutical composition according to 153. 156. The method of claim 154 or 155, wherein said cells are cancer cells. The cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell cancer, melanoma, colorectal cancer, sarcoma, lung cancer, 157. The method of claim 156, which is gastric cancer, breast cancer, or acute myelogenous leukemia (AML). 158. The method of claim 157, wherein said cancer is sarcoma. The sarcoma is soft tissue sarcoma, synovial sarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma , fibromyxous sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxofibrosarcoma, or low-grade rhabdomyosarcoma 159. The method of Paragraph 158. 160. The method of claim 159, wherein said sarcoma is synovial sarcoma. A method of treating a BAF complex-related disorder in a subject in need thereof, comprising administering to said subject an effective amount of a compound of any one of claims 1-152, or 154. The method comprising administering a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 153. 153. A method of treating an SS18-SSX fusion protein-associated disorder in a subject in need thereof, comprising administering to said subject an effective amount of any one of claims 1-152 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 153. 153. A method of treating a BRD9-related disorder in a subject in need thereof, comprising administering to said subject an effective amount of a compound of any one of claims 1-152, or a pharmaceutically 154. The method comprising administering an acceptable salt or the pharmaceutical composition of claim 153. 164. The method of any one of claims 161-163, wherein the disorder is cancer. 153. A method of treating cancer in a subject in need of cancer treatment, comprising administering to said subject an effective amount of a compound of any one of claims 1-152, or a pharmaceutically acceptable or the pharmaceutical composition of claim 153. The cancer is malignant rhabdoid tumor, CD8+ T-cell lymphoma, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell cancer, melanoma, colorectal cancer, sarcoma, lung cancer, 166. The method of claim 164 or 165, which is gastric cancer, breast cancer, or AML. 167. The method of claim 166, wherein said cancer is sarcoma. 167. The method of claim 156 or 166, wherein said cancer is breast cancer. 167. The method of claim 156 or 166, wherein said cancer is lung cancer. 170. The method of claim 169, wherein said lung cancer is non-small cell lung cancer. 167. The method of claim 156 or 166, wherein said cancer is ovarian cancer. 167. The method of claim 156 or 166, wherein said cancer is AML. The sarcoma is soft tissue sarcoma, synovial sarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft tissue sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma , fibromyxous sarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, myxofibrosarcoma, or low-grade rhabdomyosarcoma 168. The method of Paragraph 167. 174. The method of claim 173, wherein said sarcoma is synovial sarcoma. 164. The method of any one of claims 161-163, wherein the disorder is an infectious disease. 153. A method of treating an infection in a subject in need thereof, comprising administering to said subject an effective amount of a compound of any one of claims 1-152, or a pharmaceutically acceptable or the pharmaceutical composition of claim 153. 177. The method of claim 175 or 176, wherein said infection is a viral infection. The viral infection includes the family Retroviridae, the family Hepadnaviridae, the family Flaviviridae, the family Adenoviridae, the family Herpesviridae, the family Papilomaviridae, the family Parvoviridae, the family Polyomaviridae, and the family Paramyxoviridae , or an infection caused by a virus of the Togaviridae family, according to claim 177 Method. 179. The method of claim 177 or 178, wherein the viral infection is Coffin Siris, neurofibromatosis, or multiple meningioma. 179. The method of any one of claims 154-179, wherein said compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered orally.