Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor I

Patent metadata

Field	Value
Publication number	US-11124501-B2
Application number	US-201816212455-A
Country	US
Kind code	B2
Filing date	Dec 6, 2018
Priority date	Oct 4, 2013
Publication date	Sep 21, 2021
Grant date	Sep 21, 2021

Abstract

The present invention relates to compounds of formula I as defined herein. The compounds of the present invention are inhibitors of heat shock factor 1 (HSF1). In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

First claim

The invention claimed is:

1. A method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein:
A 1 is selected from N or CR 1 , A 2 is selected from N or CR 2 , with the proviso that only one of A 1 or A 2 can be N;
R 1 and R 2 are each independently selected from hydrogen, fluoro, chloro, cyano, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy;
R 4 is selected from hydrogen, fluoro, chloro, bromo, iodo, CF 3 , OCF 3 , cyano, NO 2 , (1-4C)alkyl, (1-4C)alkoxy, or a group of the formula:
W—X—Y—Z

wherein
W is absent or (1-3C)alkylene;
X is —O— or —N(R a )—, wherein R a is selected from hydrogen or (1-2C)alkyl;
Y is absent or a (1-3C)alkylene;
Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;
and wherein any alkylene, alkyl or cycloalkyl group present in a R 4 substituent group is optionally further substituted by one or more substituent groups independently selected from halo, hydroxy, NR b R c , (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy, and
wherein R b and R c are each independently selected from hydrogen or (1-3C)alkyl;
Q is a group of formula III:

wherein
A 5 is selected from N or CR 5 , where R 5 is selected from hydrogen, halo, cyano, nitro, hydroxy, NR q R u , (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered heterocyclyl; wherein R q and R u are each independently selected from hydrogen or (1-3C)alkyl, and wherein any (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered heterocyclyl group present in a R 5 substituent group is optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, NR v R w , or (1-3C)alkoxy, wherein R v and R w are each independently selected from hydrogen or (1-3C)alkyl;
Ring A is:
a fused phenyl ring;
a fused 5 or 6 membered carbocyclic ring;
a fused 5 or 6 membered heteroaryl ring comprising one or two heteroatoms independently selected from N, S and O; or
a fused 5, 6 or 7-membered heterocyclic ring comprising one or two heteroatoms independently selected from N, S and O;
A 6 is selected from N, O, S, S(O), S(O) 2 , CR 6 , C(R 6 ) 2 , NR 60 , where R 6 is selected from hydrogen, oxo, fluoro, chloro, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or (1-2C)haloalkyl and R 60 is hydrogen, O − , (1-6C)alkyl, —C(O)—R 61 , —C(O)O—R 61 , or —C(O)N(R 62 )R 61 , wherein R 61 is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heteroaryl or heterocyclyl and R 62 is selected from hydrogen or (1-3C)alkyl;
A 7 is selected from N, O, CR, S, S(O), S(O) 2 , C(R) 2 , NR 70 , where R 70 is hydrogen, O − , (1-6C)alkyl, —C(O)—R 71 , —C(O)O-R 71 , or —C(O)N(R 72 )R 71 , wherein R 71 is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heteroaryl or heterocyclyl and R 72 is selected from hydrogen or (1-3C)alkyl;
m is 0, 1 or 2;
R 7 and R 11 are each independently halo, cyano, oxo, or a group
W 2 —X 2 —Y 2 —X 3 —Z 2

wherein
W 2 is absent or a linker group of the formula —[CR x R y ] r — in which r is an integer selected from 1, 2, 3 or 4, and R x and R y are each independently selected from hydrogen or (1-2C)alkyl;
X 2 is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR z )—, —N(R z ), —N(R z )—C(O)—, —N(R z )—C(O)O—, —C(O)—N(R z )—, —N(R z )C(O)N(R z )—, —SO—, —SO 2 —, —S(O) 2 N(R z )—, or —N(R z )SO 2 , wherein R is selected from hydrogen or methyl;
Y 2 is absent or a linker group of the formula —[CR aa R bb ] s — in which s is an integer selected from 1, 2, 3 or 4, and R aa and R bb are each independently selected from hydrogen or (1-2C)alkyl;
X 3 is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —CH(OR cc )—, —N(R cc )—, —N(R cc )—C(O)—, —N(R cc )—C(O)O—, —C(O)—N(R cc )—, —N(R cc )C(O)N(R cc )—, —S—, —SO—, —SO 2 —, —S(O) 2 N(R cc )—, or —N(R cc )SO 2 , wherein R cc is selected from hydrogen or methyl; and
Z 2 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, heteroaryl, or heterocyclyl,
and wherein Z 2 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, carboxy, NR dd R ee , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-4C)alkanoyl, (1-4C)alkylsulphonyl, aryl, aryloxy, heterocyclyl, heterocyclyloxy, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryloxy, heteroaryl-(1-2C)alkyl, C(O)NR dd R ee , NR dd C(O)R ee , NR dd SO 2 R ee and SO 2 NR dd R ee ; wherein R dd and R ee are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R dd and R ee can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring;
and wherein any alkyl, aryl, heterocyclyl or heteroaryl group present in a substituent group on Z 2 is optionally further substituted by halo, cyano, nitro, hydroxy, carboxy, NR ff R gg , (1-2C)alkoxy, or (1-2C)alkyl; wherein R ff and R gg are selected from hydrogen or (1-2C)alkyl;
with the proviso that when R 7 is hydrogen (i.e., when W 2 , X 2 , Y 2 , and X 3 are absent and Z 2 is hydrogen) then ring A is not a fused dioxane ring.

2. A method according to claim 1 , wherein A 1 is CR 1 , A 2 is CR 2 and R 1 and R 2 are both hydrogen or one of R 1 and R 2 is fluoro and the other is hydrogen.

3. A method according to claim 2 , wherein R 1 and R 2 are both hydrogen.

4. A method according to claim 1 , wherein R 4 is selected from fluoro, chloro, bromo, iodo, CF 3 , OCF 3 , cyano, NO 2 , (1-4C)alkyl, (1-4C)alkoxy, or a group of the formula:
W—X—Y—Z

wherein
W is absent or (1-3C)alkylene;
X is —O— or —N(R a )—, wherein R a is selected from hydrogen or (1-2C)alkyl;
Y is absent or a (1-3C)alkylene;
Z is hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl;

and wherein any alkylene, alkyl or cycloalkyl group present in a R 4 substituent group is optionally further substituted by one or more substituent groups independently selected from halo, hydroxy, NR b R c , (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy, and wherein R b and R c are each independently selected from hydrogen or methyl.

5. A method according claim 1 , wherein R 4 is selected from fluoro, chloro or (1-2C)alkyl.

6. A method according to claim 1 , wherein
Q is a group of formula III:

wherein
A 5 is selected from N or CR 5 , where R 5 is selected from hydrogen, halo, cyano, hydroxy, NR q R u , (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered heterocyclyl; wherein R q and R u are each independently selected from hydrogen or (1-3C)alkyl;
and wherein any (1-3C)alkyl, (1-3C)alkoxy, 5 or 6-membered heteroaryl, or 5 or 6 membered heterocyclyl group present in a R 5 substituent group is optionally substituted by one or more substitutents selected from halo, cyano, nitro, hydroxy, NR v R w , or (1-3C)alkoxy, wherein R v and R w are each independently selected from hydrogen or (1-3C)alkyl;
Ring A is:
a fused phenyl ring;
a fused 5 or 6 membered carbocy

Assignees

• Cancer Research Tech Ltd

Inventors

• Jones Keith
• Rye Carl
• Chessum Nicola
• Cheeseman Matthew
• Pasqua Adele E
• Pike Kurt G
• Faulder Paul F

Classifications

• C07D491/056 Primary

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title