Modulators of BCL6 proteolysis and associated methods of use

Patent metadata

Field	Value
Publication number	US-12310975-B2
Application number	US-202017073135-A
Country	US
Kind code	B2
Filing date	Oct 16, 2020
Priority date	Oct 17, 2019
Publication date	May 27, 2025
Grant date	May 27, 2025

Abstract

Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that binds to the respective 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 bifunctional compounds of the present disclosure exhibit 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 compound having the chemical structure:
ULM-L-PTM,
or a pharmaceutically acceptable salt thereof,
wherein:
(a) the ULM is:

wherein:
W 3 is selected from optionally substituted aryl, optionally substituted heteroaryl, and

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 and R 10 , together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl;
R 11 is selected from optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R 12 is H or optionally substituted alkyl;
R 13 is 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 and R 14b , are each independently selected from H, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxyl alkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CONR 27a R 27b , CH 2 NHCOR 26 , and (CH 2 )N(CH 3 )COR 26 ; or R 14a and R 14b , together with the carbon atom to which they are attached, form an optionally substituted 3 to 6 membered cycloalkyl, heterocycloalkyl, spirocycloalkyl or spiroheterocyclyl, wherein the spiroheterocyclyl is not epoxide or aziridine;
W 5 is phenyl or 5-10 membered heteroaryl optionally substituted with one or more halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy;
R 15 is H; halogen; CN; OH; NO 2 ; NR 14a R 14b ; OR 14a ; CONR 14a R 14b ; NR 14a COR 14b ; SO 2 NR 14a R 14b ; NR 14a SO 2 R 14b ; optionally substituted alkyl; optionally substituted haloalkyl; optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; or optionally substituted cycloheteroalkyl;
each R 26 is independently selected from H, optionally substituted alkyl or NR 27a R 27b ;
each R 27a and R 27b is independently H, optionally substituted alkyl, or R 27a and R 27b together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;
each R 16 is independently selected from CN, halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, and optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
R 18 is H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy;
p is 0, 1, 2, 3, or 4; and
wherein the dashed line indicates the site of attachment of the chemical linker moiety coupling the PTM to the ULM;
(b) the PTM is:

wherein:
Q 6 , Q 7 , Q 8 , Q 9 , Q 12 , Q 13 , Q 14 , and Q 15 are each independently N, O, or C, each optionally substituted with one R PTMI ;
Q 16 is CH;
each R PTMI is independently H, halogen, CN, OH, NO 2 , NH 2 , C 1-6 alkyl, or

t 1 is 1, 2, 3, 4, or 5;
t 2 is 0, 1, 2, 3, 4, or 5;
R PTM1a and R PTM2a are independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and CH 2 OCH 3 ; or R PTM1a and R PTM2a are joined together to form a 3-10 membered ring;
X is O, S, or CH 2 ;
is a single bond or a double bond;
n is an integer from 0 to 10; and
of the PTM indicates the point of attachment with a chemical linker group; and
(c) the L is:
-(A L ) q -, wherein:
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, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, C 3-11 cycloalkyl substituted with 0-6 R L1 groups, C 5-13 spirocycloalkyl substituted with 0-9 R L1 groups, C 3-11 heterocyclyl substituted with 0-6 R L1 groups, C 5-13 spiroheterocyclyl substituted with 0-8 R L1 groups, aryl substituted with 0-6 R L1 groups, and heteroaryl substituted with 0-6 R L1 groups; and
R L1 , R L2 , R L3 , and R L4 are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OH, NH 2 , SH, SO 2 C 1-8 alkyl, 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, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, or CON(C 1-8 alkyl) 2 .

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is:

wherein:
W L1 and W L2 are each independently absent or a 4-8 membered ring with 0-4 heteroatoms, wherein the 4-8 membered ring is optionally substituted with RQ;
each RQ is independently a H, halo, OH, CN, CF 3 , unsubstituted or substituted linear or branched C1-C6, unsubstituted or substituted linear or branched C1-C6 alkoxy, or 2 RQ groups taken together with the atom they are attached to form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 is each independently a bond, unsubstituted or substituted linear or branched C1-C6 alkyl optionally having one or more C atoms are replaced with O; or unsubstituted or substituted linear or branched C 1 -C 6 alkoxy;
n is 0-10; and
indicates the attachment point to the PTM or the ULM.

3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

4. A compound selected from

Ex. #

49

50

51

Assignees

• Arvinas Operations Inc

Inventors

• Berlin Michael
• Dong Hanqing
• Sherman Dan
• Snyder Lawrence
• Wang Jing
• Zhang Wei

Classifications

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title