Brm degrading compounds and associated methods of use

Patent metadata

Field	Value
Publication number	US-2025059198-A1
Application number	US-202218710130-A
Country	US
Kind code	A1
Filing date	Nov 23, 2022
Priority date	Nov 24, 2021
Publication date	Feb 20, 2025
Grant date	—

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

First claim

What is claimed is:

1 . A bifunctional compound having the chemical structure:
PTM-L-ULM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,
wherein:
(a) the L is a chemical linking moiety connecting the ULM and the PTM, and has a chemical structural unit represented by the formula
-(A L ) q -,
wherein:
(A L ) q is a group which is connected to at least one of ULM, PTM, or both;
q is an integer greater than or equal to 1;
each A L is independently selected from the group consisting of CR L1 R L2 , O, SO 2 , NR L3 , CONR L3 , CO, CR L1 ═CR L2 , C≡C, C 3-11 cycloalkyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 3-11 heteocyclyl optionally substituted with 1-6 R L1 and/or R L2 groups, aryl optionally substituted with 1-6 R L1 and/or R L2 groups, and heteroaryl optionally substituted with 1-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 1-4 R L5 groups; and
R L1 , R L2 , R L3 , R L and R L5 are, each independently, halogen, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, CN, CF 3 , CHF 2 , CH 2 F, NO 2 CONHC 1-8 alkyl, or CON(C 1-8 alkyl) 2 ; and

(b) the ULM is an E3 ubiquitin ligase binding moiety that binds a Von Hippel-Lindau E3 ubiquitin ligase and has a chemical structure represented by:

wherein:
W 3 is selected from the group of an optionally substituted aryl, optionally substituted heteroaryl, or

R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9 , R 10 , and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
R 11 is selected from the group of an optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R 12 is selected from the group of H or optionally substituted alkyl;
R 13 is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
R 14a , R 14b , are each independently selected from the group of H, amine, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyl alkyl, optionally substituted alkylamine, optionally substituted amide, optionally substituted alkyl-amide, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphate, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 , alkyl-COR 26 , CONR 27a R 27b , NHCOR 26 , or NHCH 3 COR 26 , and the other of R 14a and R 14b is H; or R 14a , R 14b , together with the carbon atom to which they are attached, form an optionally substituted 3 to 5 membered cycloalkyl, heterocycloalkyl, spirocycloalkyl or spiroheterocyclyl, wherein the spiroheterocyclyl is not epoxide or aziridine;
W 5 is optionally substituted phenyl, optionally substituted napthyl, or an optionally substituted 5-10 membered heteroaryl;
R 15 is selected from the group of H, halogen, CN, C≡CH, OH, NO 2 , NR 27a R 27b , OR 27a , CONR 27a R 27b , NR 27a COR 27b , SO 2 NR 27a R 27b , NR 27a SO 2 R 27b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted heterocyclyl;
each R 16 is independently selected from the group of halogen, CN, optionally substituted alkyl, optionally substituted alkylamine, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
R 18 is independently selected from the group of H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;
each R 26 is independently selected from H, OH, optionally substituted alkyl or NR 27a R 27b ;
each R 27a and R 27b is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or R 27a and R 27b together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;
p is 0, 1, 2, 3, or 4, and
the of the ULM indicates the site of attachment of a chemical linking moiety the PTM to the ULM; and

(c) the PTM is a small molecule SMARCA2 protein targeting moiety having a chemical structure selected from:

wherein is the attachment point to the chemical linking moiety (e.g., the chemical linking moiety is attached to a carbon of the indicated ring or a non-aryl nitrogen of the indicated ring).

2 . The compound according to claim 1 , wherein the PTM is selected from the group consisting of:

wherein is the attachment point to the chemical linking moiety (e.g., the chemical linking moiety is attached to a carbon of the indicated ring or a non-aryl nitrogen of the indicated ring).

3 . The compound according to claim 1 or 2 , wherein the compound has a structure selected from:

or a pharmaceutically acceptable salt thereof,
wherein:
X is CH or N;
R 30 is H, F or Cl; and
R 1 is a C 1-6 alkyl.

4

Assignees

• Arvinas Operations Inc
• Genentech Inc

Inventors

• Berlin Michael
• Broccatelli Fabio
• Chen Huifen
• Dragovich Peter Scott
• Wang Jing

Classifications

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/5386

  spiro-condensed or forming part of bridged ring systems · CPC title