Quinoline derivatives as inhibitors of heat shock factor 1 pathway activity

Patent metadata

Field	Value
Publication number	US-10647678-B2
Application number	US-201615563501-A
Country	US
Kind code	B2
Filing date	Apr 1, 2016
Priority date	Apr 1, 2015
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The present invention relates to compounds of formula I

wherein R, R 4 and Q are each as defined herein. The compounds of the present invention are inhibitors of heat shock factor 1 pathway (HSF1 pathway). 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 compound of formula Ia shown below, or a pharmaceutically acceptable salt thereof:

wherein:
C 1 is CR a1 ;
C 2 is CR a2 ;
R a1 and R a2 are each independently selected from hydrogen, fluoro, chloro, cyano, (1-2C)alkyl, (1-2C)alkoxy or (1-2C)haloalkyl;
C 3 is O or CH;
C 4 is O or CH;
a is 0, 1 or 2;
R b is fluoro or (1-2C)alkyl;
subject to the proviso that:
(i) one or two of C 3 or C 4 are oxygen; and
(i) when C 3 and C 4 are both oxygen then a is 1 or 2;

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 40 )—, wherein R 40 is selected from hydrogen or (1-2C)alkyl;
Y is absent or a (1-3C)alkylene;
Z is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or a 4 to 10-membered monocyclic or bicyclic heterocyclic ring;
or Y and Z are linked with R 40 such that, together with the nitrogen atom to which they are attached, they form 4 to 10-membered monocyclic or bicyclic heterocyclic ring;
and wherein any alkylene, alkyl, cycloalkyl or heterocyclyl group present in a R 4 substituent group is optionally further substituted by one or more substituent groups independently selected from oxo, halo, nitro, hydroxy, cyano, carboxy, -M-NR 41 R 42 , -M-S(O) d R 41 , -M-C(O)NR 41 R 42 , -M-NR 41 C(O)R 42 , -M-NR 41 S(O) 2 R 42 , -M-S(O) 2 NR 41 R 42 , (1-5C)alkyl, (1-5C)alkoxy, (1-5C)haloalkyl, (1-5C)haloalkoxy or (1-5C)alkanoyl, and wherein M is absent or (1-4C)alkylene, and R 41 and R 42 are each independently selected from hydrogen or (1-5C)alkyl; or R 41 and R 42 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring;

Q is a group of formula:

wherein R 7 is a group of the formula:
W 2 —X 2 —Y 2 —X 3 —Z 2

wherein
W 2 is a linker group of the formula —[CR x R y ] r — in which r is 1, R x is hydrogen and R y is hydrogen or methyl;
X 2 is absent;
Y 2 is absent;
X 3 is absent; and
Z 2 is a 4, 5, 6 or 7-membered nitrogen-linked heterocyclyl optionally comprising one further nitrogen atom; and
wherein Z 2 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, hydroxy, carboxy, NR dd R ee , (1-4C)alkoxy, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (2C)alkanoyl, (1-2C)alkylsulphonyl, 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.

2. A compound according to claim 1 , wherein said compound is of formula Ia1, Ia2, Ia3, or Ia4:

3. A compound according to claim 1 , wherein:
C 1 is CR a1 , wherein R a1 is selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy, —CF 3 or —OCF 3 ;
C 2 is CR a2 wherein Rae is selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy, —CF 3 or —OCF 3 ;
a is 0 or 1; and
R b is methyl.

4. A compound according to claim 1 , wherein R 4 is selected from hydrogen, fluoro, chloro, bromo, iodo, CF 3 , OCF 3 , cyano, (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 40 )—, wherein R 40 is selected from hydrogen or (1-2C)alkyl;
Y is absent or a (1-3C)alkylene;
Z is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or a 4 to 10-membered monocyclic or bicyclic heterocyclic ring;
or Y and Z are linked with R 40 such that, together with the nitrogen atom to which they are attached, they form 4 to 10-membered monocyclic or bicyclic heterocyclic ring optionally comprising one or two further heteroatoms selected from N, O or S;
and wherein any alkylene, alkyl, cycloalkyl or heterocyclyl group present in a R 4 substituent group is optionally further substituted by one or more substituent groups independently selected from halo, hydroxy, cyano, -M-NR 41 R 42 , -M-S(O) d R 41 , (1-5C)alkyl, (1-5C)alkoxy, (1-5C)haloalkyl or (1-5C)haloalkoxy, and wherein M is absent or (1-4C)alkylene, and R 41 and R 42 are each independently selected from hydrogen or (1-5C)alkyl.

5. A compound according to claim 1 , wherein said compound is selected from formula Ia5, Ia6, Ia7, or Ia8:

wherein a is 0 or 1.

6. A compound according to claim 5 , wherein R 4 is methyl or fluoro.

7. A compound according to claim 6 , wherein R 7 is methyl.

8. A compound according to claim 7 , wherein m is 0.

9. A compound according to claim 1 , which is selected from any one of the following:
N-(5-(chroman-7-carboxamido)-2-methylphenyl)-2-methylquinoline-6-carboxamide;
N-(5-(chroman-7-carboxamido)-2-fluorophenyl)-2-methylquinoline-6-carboxamide;
N-(5-(chroman-7-carboxamido)-2-fluorophenyl)-2-(4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide;
N-(2-chloro-5-(chroman-7-carboxamido)phenyl)-2-methylquinoline-6-carboxamide;
2-(azetidin-1-ylmethyl)-N-(2-chloro-5-(chroman-7-carboxamido)phenyl)quinoline-6-carboxamide;
rac-2-methyl-N-(2-methyl-5-(3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;
rac-N-(2-fluoro-5-(3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-methylquinoline-6-carboxamide;
2-((4-ethylpiperazin-1-yl)methyl)-N-(2-fluoro-5-(3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;
N-(2-chloro-5-(3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)-2-((4-ethylpiperazin-1-yl)methyl)quinoline-6-carboxamide
2-(azetidin-1-ylmethyl)-N-(2-chloro-5-(3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;
2-(azetidin-1-ylmethyl)-N-(2-fluoro-5-(3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)phenyl)quinoline-6-carboxamide;
2-methyl-N-(5-(3-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(3-(pyrrolidin-1-yl)propyl)phenyl)quinoline-6-carboxamide; and
N-(5-(chroman-7-carboxamido)-2-(3-(pyrrolidin-1-yl)propyl)phenyl)-2-methylquinoline-6-carboxamide;
or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

11. A compound of formula Ib shown below, or a pharmaceutically acceptable salt thereof:

wherein
C 5 is CR a5 ;
C 6 is CR a6 ;
R a5 and R a6 are each independently selected from hydrogen, fluoro, chloro, cyano, (1-2C)alkyl, (1-2C)alkoxy or (1-2C)haloalkyl;
C 7 is O or CH;
C 8 is O or CH;
b is 0, 1 or 2;
R c is selected from fluoro or (1-2C)alkyl;
subject to the proviso that:
(i) one or both of C 7 or C 8 is O;
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

wherei

Assignees

• Cancer Research Tech Ltd

Inventors

• Jones Keith
• Cheeseman Matthew
• Chessum Nicola
• Pasqua Elisa
• Evans Lindsay
• Tucker Michael
• Wilding Birgit
• Mok Ngai Yi

Classifications

• C07D215/48 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D405/12

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

• A61P35/00

  Antineoplastic agents · CPC title