Benzimidazolone derived inhibitors of BCL6

Patent metadata

Field	Value
Publication number	US-12110286-B2
Application number	US-201816616901-A
Country	US
Kind code	B2
Filing date	May 25, 2018
Priority date	May 26, 2017
Publication date	Oct 8, 2024
Grant date	Oct 8, 2024

Abstract

The present invention relates to compounds of Formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity: wherein X1, X2, R1, R2 and R3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.

First claim

The invention claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as shown below:

wherein:
X 1 is selected from N or CR a , wherein R a is selected from hydrogen, (1-2C)alkyl, halogen, hydroxy, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (2-4C)alkenyl, (2-4C)alkynyl, nitro, cyano or NR b R c , wherein R b and R c are independently selected from hydrogen or (1-2C)alkyl;
X2 is selected from N or CR d , wherein R d is selected from hydrogen, (1-2C)alkyl, fluoro, chloro, bromo, hydroxy, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;
R 1 is a group of the formula:
-L-Z

wherein:
L is absent or (1-2C)alkylene; and
Z is (1-6C)alkyl, (3-6C)cycloalkyl or 4 to 7 membered heterocyclyl; wherein Z is optionally further substituted by one or more substituent groups independently selected from oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, amino, (1-2C)aminoalkyl, cyano, hydroxy, NR g R h or OR g ; wherein R g and R h are each independently selected from hydrogen or (1-2C)alkyl;

R 2 is selected from:
(i) a group of the formula:

wherein:

 denotes the point of attachment;
W 1 is selected from CR 4 R 5 or C(O), wherein R 4 and R 5 are independently selected from hydrogen, (1-2C)alkyl, fluoro, hydroxy, cyano, nitro, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or NR j R k , wherein R j and R k are independently selected from hydrogen or (1-2C)alkyl; or
R 4 and R 5 can be linked such that, together with the carbon atom to which they are attached, they form a 3-6-membered carbocyclic ring or a 3-6-membered heterocyclic ring, which is optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, amino, cyano or hydroxy;

W 2 is selected from cyano, a 5- or 6-membered heteroaryl, phenyl, C(O)R 1 , SO 2 R 1 , C(O)OCH 3 , C(O)N(H)CH 3 , CR 6 R 7 R 8 or NR l R m , wherein R l and R m are independently selected from hydrogen or (1-4C)alkyl, and wherein:
R 6 is selected from hydroxy, amino, or (1-2C)alkoxy;
R 7 is selected from hydrogen, (1-2C)alkyl, fluoro, chloro, bromo, hydroxy, cyano, nitro, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or a group of the formula:
—Y 2 -L 2 -Z 2

wherein:
 Y 2 is absent or selected from O, N(R n ), S, SO, SO 2 , C(O), C(O)O, OC(O), C(O)N(R n ), N(R n )C(O), S(O) 2 N(R n ), or N(R n )SO 2 , wherein R n is selected from hydrogen or (1-2C)alkyl;
 L 2 is absent or (1-2C)alkylene; and
 Z 2 is hydrogen, (1-6C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, phenyl, (3-6C)cycloalkyl, 5-6 membered heteroaryl or a 4-6-membered heterocyclyl; wherein Z 2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, amino, cyano, nitro, hydroxy, C(O)R o , C(O)OR o , OC(O)R o , C(O)N(R o )R p , or NR o C(O)R p , wherein R o and R p are independently selected from hydrogen or (1-4C)alkyl; and
R 8 is selected from (1-2C)alkyl, —C(O)OR q , OR q , or a 5-membered heteroaryl, wherein R q is selected from hydrogen or (1-2C)alkyl;
or R 6 and R 7 can be linked such that, together with the carbon atom to which they are attached, they form a 3-6-membered carbocyclic ring or a 3-6-membered heterocyclic ring, which is optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, amino, cyano or hydroxyl; or

(ii) a group of the formula:

wherein:

 denotes the point or attachment;
ring A is a 4 to 6 membered cycloalkyl or heterocyclyl ring, optionally substituted with one or more substituent groups selected from (1-2C)alkyl, halo, hydroxy, cyano or (1-2C)alkoxy;
W 3 is selected from NR 100 or CR 101 R 102 , wherein R 100 is selected from hydrogen, (1-2C)alkyl, (1-4C)haloalkyl, (1-4C)hydroxyalkyl, —C(O)—CH 3 or —C(O)OR ab , wherein R ab is (1-4C)alkyl, R 101 and R 102 are each independently selected from hydrogen, (1-2C)alkyl, cyclopropyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, —C(O)OR ac , —NR ac R ad , phenyl or a 5-membered heteroaryl, wherein R ac and R ad are independently selected from hydrogen or (1-2C)alkyl; and

R 3 is selected from:
i) a group of Formula A shown below:

wherein:

 denotes the point of attachment,
X a and X b are independently selected from N or CR x1 , wherein R x1 is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, nitro, acetylenyl, CH 2 F, CF 2 H or CF 3 ;
R 9 is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, nitro, acetylenyl, CH 2 F, CF 2 H or CF 3 ;
R 10 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, (2-4C)alkenyl, (2-4C)alkynyl or a group of the formula:
-Y 3 -Z 3

wherein:
 Y 3 is absent or O, N(R s )(CR s R t ) q1 (where q 1 is 0, 1 or 2), S, SO, SO 2 , C(O), C(O)O, OC(O), C(O)N(R s ), N(R s )C(O), N(R s )C(O)N(R t ), N(R s )C(O)O, OC(O)N(R s ), S(O) 2 N(R s ), or N(R s )SO 2 , wherein R s and R t are each independently selected from hydrogen or (1-4C)alkyl; and
 Z 3 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkenyl, heteroaryl or 4 to 11-membered heterocyclyl; wherein Z 3 is optionally further substituted by one or more substituent groups independently selected from oxo, (1-4C)alkyl, (3-6C)cycloalkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)hydroxyalkyl, amino, cyano, hydroxy, amido, carboxy, carbamoyl, sulphamoyl, mercapto, C(O)NR u R v , NR u R v or OR u , wherein R u and R v are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; and/or Z 3 is optionally further substituted by a group of the formula:
-L Z -W Z

 wherein:
 L Z is absent or a (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; and
 W Z is aryl, heteroaryl, 4- to 7-membered heterocyclyl, 3- to 6-membered carbocyclyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, C(O)R xa , COOR xa , C(O)NR xa R xb or NR xa R xb , wherein R xa and R xb are each independently selected from hydrogen or (1-4C)alkyl; and wherein each aryl, heteroaryl, 4- to 7-membered heterocyclyl or 3- to 6-membered carbocyclyl is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, amino, cyano or hydroxy;

ii) a group of Formula B shown below:

wherein:

Assignees

• Cancer Research Tech Ltd
• The Institute Of Cancer Res Royal Cancer Hospital
• The Institute Of Cancer Res

Inventors

• Bellenie Benjamin Richard
• Carter Michael K
• Cheung Kwai Ming Jack
• Davis Owen Alexander
• Hoelder Swen
• Lloyd Matthew Garth
• Varela Rodriguez Ana
• Woodward Hannah
• Innocenti Paolo

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D235/26

  Oxygen atoms · CPC title