BCL6 inhibitors

Patent metadata

Field	Value
Publication number	US-11512095-B2
Application number	US-201917046650-A
Country	US
Kind code	B2
Filing date	Apr 12, 2019
Priority date	Apr 13, 2018
Publication date	Nov 29, 2022
Grant date	Nov 29, 2022

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, R30, R31 and Ring A 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, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano or NR b R c , wherein R b and R c are each independently selected from hydrogen or (1-2C)alkyl;
X 2 is selected from N, CH, CF, CCl or C—CH 3 ;
R 1 is selected from hydrogen or a group of the formula:
-L-Y—Z

wherein:
L is absent or (1-3C)alkylene;
Y is absent or O, C(O), C(O)O or C(O)N(R e ), wherein R e is selected from hydrogen or (1-4C)alkyl; and
Z is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, 5 or 6 membered heteroaryl 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, (1-2C)aminoalkyl, cyano, NR g R h or OR g ; wherein R g and R h are each independently selected from hydrogen or (1-4C)alkyl;
R 2 is selected from a group of Formula A shown below:

wherein:

 denotes the point of attachment;
X a is selected from N, CH or CF;
X b is selected from N or CR x1 , wherein R x1 is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, acetylenyl, CH 2 F, CF 2 H or CF 3 ;
R 6 is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, acetylenyl, CH 2 F, CF 2 H or CF 3 ;
R 7 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, S, SO, SO 2 , N(R j )(CR j R k ) q1 (where q 1 is 0, 1 or 2), C(O), C(O)O, OC(O), C(O)N(R j ), N(R j )C(O), N(R j )C(O)N(R k ), N(R j )C(O)O, OC(O)N(R j ), S(O) 2 N(R j ) or N(R j )SO 2 , wherein R j and R k 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 12-membered heterocyclyl; wherein Z 3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, (3-6C)cycloalkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, CO 2 H, SO 2 NH 2 , C(O)NR l R m , NR l R m , OR 1 or SR 1 wherein R l and R m are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or
Z 3 is optionally further substituted by a group of the formula:
-L Z -W Z

wherein:
L Z is a (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; and
W Z is 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;
R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and/or (3-6C)cycloalkyl substituent is optionally further substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, wherein R u and R y are independently selected from hydrogen or (1-2C)alkyl;
R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl or a group of the formula:
Y 5 -L 5 -Z 5

wherein:
Y 5 is absent or selected from C(O)O or C(O)N(R w ), wherein R w is selected from hydrogen or (1-2C)alkyl;
L 5 is absent or (1-2C)alkylene; and
Z 5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered heteroaryl or 4 to 6-membered heterocyclyl; wherein Z 5 is optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH 2 , cyano, nitro or hydroxy; or
R 30 and R 31 are linked such that, together with the carbon atom to which they are attached, they form a 4-6 membered carbocyclic ring or a heterocyclic ring; and
Ring A is a 6- or 7-membered heterocyclic ring, which, in addition to the substituent groups R 30 and R 31 , is optionally further substituted by one or more substituent groups selected from oxo, (1-2C)alkyl, cyclopropyl, spiro-cyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH 2 , cyano or hydroxy.

2. A compound, or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 , wherein X 2 is CH.

3. A compound, or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 , wherein X 1 is selected from N or CH.

4. A compound, or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 , wherein R 2 is a group of Formula A shown below:

wherein:

 denotes the point of attachment;

X a is selected from N, CH or CF;
X b is selected from N or CR x1 , wherein R x1 is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, acetylenyl, CH 2 F, CF 2 H or CF 3 ;
R 6 is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, cyano, acetylenyl, CH 2 F, CF 2 H or CF 3 ;
R 7 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano or a group of the formula:
—Y 3 —Z 3

wherein:
Y 3 is absent or O, C(O), C(O)O, OC(O), C(O)N(R j ) or N(R j )C(O), wherein R j is selected from hydrogen or (1-4C)alkyl; and
Z 3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 4 to 12-membered heterocyclyl; wherein Z 3 is optionally further substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NR l R m , NR l R m or OR l , wherein R l and R m are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl.

5. A compound, or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 , wherein the compound has the structural formula Ic shown below:

wherein each of R 1 , R 6 , R 7 , X a , X b , R 30 , R 31 and Ring A are as defined in claim 1 .

6. A compound according to claim 5 , wherein X b is selected from CH, CCl, CF, CBr or CCH 3 .

7. A compound according to claim 5 , wherein R 6 is selected from chloro, fluoro, bromo, methyl or cyano.

8. A compound according to claim 5 , wherein R 7 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano or a group of the formula:
—Y 3 —Z 3

wherein:
Y 3 is absent or O, C(O), C(O)O or C(O)N(R j ), wherein R j is selected from hydrogen or (1-4C)alkyl; and
Z 3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl or 4 to 11-membered heterocyclyl; wherein Z 3 is

Assignees

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

Inventors

• Bellenie Benjamin Richard
• Cheung Kwai Ming Jack
• Davis Owen Alexander
• Hoelder Swen
• Huckvale Rosemary
• Collie Gavin
• Meniconi Mirco
• Brennan Alfie
• Lloyd Matthew Garth

Classifications

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D498/20

  Spiro-condensed systems · CPC title

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title