Pyrrolopyrrolone derivatives and their use as BET inhibitors

Patent metadata

Field	Value
Publication number	US-9550796-B2
Application number	US-201415037116-A
Country	US
Kind code	B2
Filing date	Nov 20, 2014
Priority date	Nov 21, 2013
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:
A is selected from

or A is

R 26 is methyl;
R 27 is methyl;
R 30 is methyl or CF 2 ;
R 31 is methyl;
R 33 is methyl;
R 34 is methyl;
R 8 is (C 1 -C 4 )alkyl;
R 1 is selected from H, chloro and methyl;
B is selected from

R 2 is selected from halo, methoxy, cyano, methyl and H;
R 5 is H;
R 7 is selected from H and halo;
R 3 is selected from H, methyl, ethyl, methoxyethyl, hydroxymethyl, methoxymethyl, hydroxyethyl, —C(O)O—(C 1 -C 2 )alkyl, —C(O)NR 9 R 10 , cyclopropyl, isopropyl,

or R 3 is selected from —CH 2 C(O)NR 9 R 10 , —(C 1 -C 2 )alkyl-NR 9 R 10 and

R x is selected from H, methyl, —C(O)O—(C 1 -C 2 )alkyl, ethyl, isopropyl and —C(O)—(C 1 -C 2 )alkyl; wherein said —C(O)—(C 1 -C 2 )alkyl being optionally substituted by methoxy; or
R x is selected from

R 9 is selected from H and methyl;
R 10 is selected from H and methyl;
R 4a is selected from H, methyl, cyclopropyl,

or R 4a is

R 4b is selected from H, cyclopropyl, methyl, —C(O)NR 9 R 10 , —C(O)OH, —NHC(O)—O—(C 1 -C 4 alkyl), —NHC(O)—(C 1 -C 4 alkyl) and NR 9 R 10 ; or R 4b is selected from —NHC(O)NR 9 R 10 , —C(O)NH(C 1 -C 2 alkyl)-NR 9 R 10 , —NHC(O)—(C 1 -C 2 alkyl)-NR 9 R 10 and

R 15 is selected from methoxy and H;
R 16 is selected from methoxy and hydroxy;
R 17 is methyl;
R 18 is selected from methoxy and —NR 9 R 10 ;
R 19 is selected from methoxy and CF 3 ;
R 20 is methyl;
R 21 is methyl;
R 22 is methyl;
R 23 is selected from —NR 9 R 10 and methoxy;
R 24 is selected from —NR 9 R 10 , H and methoxy;
R x1 is selected from H, methyl and —C(O)—(C 1 -C 2 )alkyl;
and
* indicates the point of attachment to the remainder of the molecule;
with the proviso that
when A is:

and R 3 is selected from ethyl, cyclopropyl and isopropyl;
then R 4a is selected from

or R 4a is

and the remaining substituents are as defined herein.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 ,
wherein:
A is selected from

R 26 is methyl;
R 27 is methyl;
R 30 is methyl or CF 2 ;
R 31 is methyl;
R 33 is methyl;
R 34 is methyl;
R 8 is (C 1 -C 4 )alkyl;
R 1 is selected from H, chloro and methyl;
B is selected from

R 2 is selected from halo, methoxy, cyano, methyl and H;
R 5 is H;
R 7 is selected from H and halo;
R 3 is selected from H, methyl, ethyl, methoxyethyl, hydroxymethyl, methoxymethyl, hydroxyethyl, —C(O)O—(C 1 -C 2 )alkyl, —C(O)NR 9 R 10 , cyclopropyl, isopropyl,

R x is selected from H, methyl, —C(O)O—(C 1 -C 2 )alkyl, ethyl, isopropyl and —C(O)—(C 1 -C 2 )alkyl; wherein said —C(O)—(C 1 -C 2 )alkyl being optionally substituted by methoxy; or
R x is selected from

R 9 is selected from H and methyl;
R 10 is selected from H and methyl;
R 4a is selected from H, methyl, cyclopropyl,

R 4b is selected from H, cyclopropyl, methyl, —C(O)NR 9 R 10 , —C(O)OH, —NHC(O)—O—(C 1 -C 4 alkyl), —NHC(O)—(C 1 -C 4 alkyl) and NR 9 R 10 ;
R 15 is selected from methoxy and H;
R 16 is selected from methoxy and hydroxy;
R 17 is methyl;
R 18 is selected from methoxy and —NR 9 R 10 ;
R 19 is selected from methoxy and CF 3 ;
R 20 is methyl;
R 21 is methyl;
R 22 is methyl;
R 23 is selected from —NR 9 R 10 and methoxy;
R 24 is selected from —NR 9 R 10 , H and methoxy;
and
* indicates the point of attachment to the remainder of the molecule;
with the proviso that
when A is:

and R 3 is selected from ethyl, cyclopropyl and isopropyl;
then R 4a is selected from

and the remaining substituents are as defined herein.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein A is selected from:

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein B is:

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 3 is methyl, —C(O)O—CH 2 CH 3 ,

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R x is selected from methyl, —C(O)—CH 3 and —C(O)O—CH 2 CH 3 .

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 4a is selected from H,

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 4b is selected from —C(O)NR 9 R 10 , cyclopropyl, methyl, H, —NHC(O)—(C 1 -C 4 alkyl), —C(O)NH(C 1 -C 2 alkyl)-NR 9 R 10 and —NHC(O)—(C 1 -C 2 alkyl)-NR 9 R 10 .

Assignees

• Rueger Heinrich
• Blank Jutta
• Bordas Vincent
• Cotesta Simona
• Bold Guido
• Guagnano Vito
• Vaupel Andrea
• Novartis Ag

Inventors

• Rueger Heinrich
• Blank Jutta
• Bordas Vincent
• Cotesta Simona
• Bold Guido
• Guagnano Vito
• Vaupel Andrea

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title