BCL6 inhibitors

Patent metadata

Field	Value
Publication number	US-12486285-B2
Application number	US-202217968159-A
Country	US
Kind code	B2
Filing date	Oct 18, 2022
Priority date	Apr 13, 2018
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

The present invention relates to compounds of formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity:

wherein X 1 , X 2 , R 1 , R 2 , R 30 , R 31 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 (II):

or a salt, hydrate or solvate thereof, 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 (1-4° C.) 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 v 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 . The compound of claim 1 , wherein R 1 is selected from hydrogen or a group of the formula:
-L-Z wherein:
L is absent or (1-3C) alkylene; and
Z is (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6 membered heteroaryl or 5 or 6 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 (1-2C) alkyl.

3 . The compound of claim 1 , wherein 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, cyclopropyl, hydroxy, (1-2C) alkoxy or halo.

4 . The compound of claim 1 , wherein Ring A is a 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, fluoro, (1-2C) fluorooalkyl, (1-2C) alkoxy, or cyano.

5 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
(S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; (R)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; 10-amino-2-ethyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; (S)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinoline-6 (7H)-one; (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinoline-6 (7H)-one; 10-amino-2,3,3,7-tetramethyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinoline-6 (7H)-one; 10′-amino-2′,7′-dimethyl-1′,2′-dihydro-4′H-spiro [cyclopropane-1,3′-[1,4]oxazepino [2,3-c]quinolin]-6′ (7′H)-one; (2S,4S)-10-amino-2,4,7-trimethyl-1,2,3,4-tetrahydro-[1,4]-oxazepino [2,3-c]quinoline-6 (7H)-one; 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinoline-6 (7H)-one; (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; 10-amino-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; 10′-amino-7′-methyl-3′,4,4′,5-tetrahydro-1′H,2H-spiro [furan-3,2′-[1,4]oxazepino [2,3-c]quinolin]-6′ (7′H)-one; 10-amino-2-(difluoromethyl)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro [1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl) methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; (R)-10-amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one; and (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c][1,8]naphthyridin-6 (7H)-one, or a salt, hydrate or solvate thereof.

6 . The compound of claim 1 , wherein the compound is(S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino [2,3-c]quinolin-6 (7H)-one.

7 . A compound of Formula (III):

or a salt, hydrate or solvate thereof, wherein:
W is NO 2 , halogen, or OTf;
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 c ), wherein R c 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 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 v 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:

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

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D498/20

  Spiro-condensed systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title