US 12,486,285 B2Granted

BCL6 inhibitors

AssigneesCancer Research Technology Limited, The Institute of Cancer Research: Royal Cancer Hospital

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

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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.

Claims22

Dependent claims

A compound of Formula (II):

or a salt, hydrate or solvate thereof, wherein:
X1 is selected from N or CRa, wherein Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NRbRc, wherein Rb and Rc are each independently selected from hydrogen or (1-2C) alkyl;
X2 is selected from N, CH, CF, CCl or C—CH3;
R1 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(Re), wherein Re 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, NRgRh or ORg;
wherein Rg and Rh are each independently selected from hydrogen or (1-4° C.) alkyl;
R30 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, NRuRv, (1-2C) aminoalkyl or halo, wherein Ru and Rv are independently selected from hydrogen or (1-2C) alkyl;
R31 is selected from hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl or a group of the formula:
Y5-L5-Z5
wherein:
Y5 is absent or selected from C(O)O or C(O)N(Rw), wherein Rw is selected from hydrogen or (1-2C) alkyl;
L5 is absent or (1-2C) alkylene;
and
Z5 is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6 membered heteroaryl or 4 to 6-membered heterocyclyl;
wherein Z5 is optionally substituted by one or more substituents selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, NH2, cyano, nitro or hydroxy;
or
R30 and R31 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 R30 and R31, 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, NH2, cyano or hydroxy.

22 more elements

A compound of Formula (III):

or a salt, hydrate or solvate thereof, wherein:
W is NO2, halogen, or OTf;
X1 is selected from N or CRa, wherein Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NRbRc, wherein Rb and Rc are each independently selected from hydrogen or (1-2C) alkyl;
X2 is selected from N, CH, CF, CCl or C—CH3;
R1 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(Rc), wherein Rc 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, NRgRh or ORg;
wherein Rg and Rh are each independently selected from hydrogen or (1-4C) alkyl;
R30 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, NRuRv, (1-2C) aminoalkyl or halo, wherein Ru and Rv are independently selected from hydrogen or (1-2C) alkyl;
R31 is selected from hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl or a group of the formula:
Y5-L5-Z5
wherein:
Y5 is absent or selected from C(O)O or C(O)N(Rw), wherein Rw is selected from hydrogen or (1-2C) alkyl;
L5 is absent or (1-2C) alkylene;
and
Z5 is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6 membered heteroaryl or 4 to 6-membered heterocyclyl;
wherein Z5 is optionally substituted by one or more substituents selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, NH2, cyano, nitro or hydroxy;
or
R30 and R31 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 R30 and R31, 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, NH2, cyano or hydroxy.

23 more elements

A process of synthesising a compound of Formula (II) from a compound of Formula (III):

the process comprising reducing the W group of Formula (III) to provide the compound of Formula (II), wherein:
W is NO2;
X1 is selected from N or CRa, wherein Ra is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NRbRc, wherein Rb and Rc are each independently selected from hydrogen or (1-2C) alkyl;
X2 is selected from N, CH, CF, CCl or C—CH3;
R1 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(Rc), wherein Rc 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, NRgRh or ORg;
wherein Rg and Rh are each independently selected from hydrogen or (1-4° C.) alkyl;
R30 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, NRuRv, (1-2C) aminoalkyl or halo, wherein Ru and Rv are independently selected from hydrogen or (1-2C) alkyl;
R31 is selected from hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl or a group of the formula:
Y5-L5-Z5
wherein:
Y5 is absent or selected from C(O)O or C(O)N(Rw), wherein Rw is selected from hydrogen or (1-2C) alkyl;
L5 is absent or (1-2C) alkylene;
and
Z5 is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6 membered heteroaryl or 4 to 6-membered heterocyclyl;
wherein Z5 is optionally substituted by one or more substituents selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, NH2, cyano, nitro or hydroxy;
or
R30 and R31 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 R30 and R31, 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, NH2, cyano or hydroxy.

23 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/968,159Filed 18 Oct 2022 · continuation
Priority: GB 1806132.513 Apr 2018
Published: US 2023/0287003 A114 Sep 2023
Granted: 2 Dec 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 498/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 35/00
Antineoplastic agents
C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
C07D 498/08
In which the condensed system contains two hetero rings: bridged systems

Family

PCT/GB2019/051058Parent of this continuation · filed 12 Apr 2019
US 2023/0287003 A1Pre-grant publication · published 14 Sep 2023
Application17/046,650Parent of this continuation
US 11,512,095 B2Parent of this continuation
US 2021/0163497 A1Published application
US 12,486,285 B2This patent

From the US filing history. Foreign family members aren’t listed.