Thienopyrimidine derivatives, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-9670227-B2
Application number	US-201414576683-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 23, 2013
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

Compounds of formula (I):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , X, A and n are as defined in the description.

Medicinal products containing the same which are useful in treating pathologies involving a deficit in apoptosis, such as cancer, auto-immune diseases, and diseases of the immune system.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
A represents linear or branched (C 1 -C 6 )alkyl, linear or branched (C 2 -C 6 )alkenyl, linear or branched (C 2 -C 6 )alkynyl, linear or branched (C 1 -C 6 )alkoxy, —S—(C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )polyhaloalkyl, hydroxy, cyano, —NR 10 R 10 ′, -Cy 6 , or halogen;
R 1 , R 2 , R 3 , R 4 and R 5 independently of one another represent hydrogen, halogen, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 2 -C 6 )alkenyl, linear or branched (C 2 -C 6 )alkynyl, linear or branched (C 1 -C 6 )polyhaloalkyl, hydroxy, linear or branched (C 1 -C 6 )alkoxy, —S—(C 1 -C 6 )alkyl, cyano, nitro, -alkyl(C 0 -C 6 )—NR 8 R 8 ′, —O-Cy 1 , -alkyl(C 0 -C 6 )-Cy 1 , -alkenyl(C 2 -C 6 )-Cy 1 , -alkynyl(C 2 -C 6 )-Cy 1 , —O-alkyl(C 1 -C 6 )—R 9 , —C(O)—OR 8 , —O—C(O)—R 8 , —C(O)—NR 8 R 8 ′, —NR 8 —C(O)—R 8 ′, —NR 8 —C(O)—OR 8 ′, -alkyl(C 1 -C 6 )—NR 8 —C(O)—R 8 ′, —SO 2 —NR 8 R 8 ′, or —SO 2 -alkyl(C 1 -C 6 ),
or the substituents of one of the pairs (R 1 , R 2 ), (R 2 , R 3 ), (R 1 , R 3 ), (R 4 , R 5 ) when grafted onto two adjacent carbon atoms, together with the carbon atoms carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which ring may have from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, and which ring may be optionally substituted by a group selected from linear or branched (C 1 -C 6 )alkyl, —NR 10 R 10 ′, -alkyl(C 0 -C 6 )-Cy 1 , and oxo;
X represents a carbon or a nitrogen atom;
R 6 represents hydrogen, linear or branched (C 1 -C 8 )alkyl, aryl, heteroaryl, arylalkyl(C 1 -C 6 ), heteroarylalkyl(C 1 -C 6 );
R 7 represents linear or branched (C 1 -C 6 )alkyl, linear or branched (C 2 -C 6 )alkenyl, linear or branched (C 2 -C 6 )alkynyl, -Cy 3 , -alkyl(C 1 -C 6 )-Cy 3 , -alkenyl(C 2 -C 6 )-Cy 3 , -alkynyl(C 2 -C 6 )-Cy 3 , -Cy 3 -Cy 4 , -alkynyl(C 2 -C 6 )—O-Cy 3 , -Cy 3 -alkyl(C 0 -C 6 )—O-alkyl(C 0 -C 6 )-Cy 4 , halogen, cyano, —C(O)—R 11 , or —C(O)—NR 11 R 11 ′;
R 8 and R 8 ′ independently of one another represent hydrogen, linear or branched (C 1 -C 6 )alkyl, or -alkyl(C 0 -C 6 )-Cy 1 ,
or (R 8 , R 8 ′), together with the nitrogen atom carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which ring may have, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the nitrogen in question may be substituted by hydrogen, or linear or branched (C 1 -C 6 )alkyl and wherein one or more of the carbon atoms of the possible substituents, may be deuterated;
R 9 represents -Cy 1 , -Cy 1 -alkyl(C 0 -C 6 )-Cy 2 , -Cy 1 -alkyl(C 0 -C 6 )—O-alkyl(C 0 -C 6 )-Cy 2 , -Cy 1 -alkyl(C 0 -C 6 )—NR 8 -alkyl(C 0 -C 6 )-Cy 2 , -Cy 1 -Cy 2 -O-alkyl(C 0 -C 6 )-Cy 5 , —NR 8 R 8 ′, —C(O)—NR 8 R 8 ′, —OR 8 , —NR 8 —C(O)—R 8 ′, —O-alkyl(C 1 -C 6 )—OR 8 , —SO 2 —R 8 , —C(O)—OR 8 , or —NH—C(O)—NH—R 8 ;
R 10 , R 10 ′, R 11 and R 11 ′ independently of one another represent hydrogen or optionally substituted linear or branched (C 1 -C 6 )alkyl;
R 12 represents hydrogen or hydroxy;
Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 and Cy 6 independently of one another, represent cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
n is an integer equal to 0 or 1;

it being understood that:
“aryl” means a phenyl, naphthyl, biphenyl, indanyl, or indenyl;
“heteroaryl” means any mono- or bi-cyclic group having from 5 to 10 ring members, having at least one aromatic moiety and having from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen;
“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
“heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group having from 3 to 10 ring members, and having from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems;

wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may be optionally substituted by from 1 to 4 groups selected from:
linear or branched (C 1 -C 6 )alkyl, optionally substituted by a group selected from:
linear or branched (C 1 -C 6 )alkoxy, optionally substituted by linear or branched (C 1 -C 6 )alkoxy,
linear or branched (C 1 -C 6 )polyhaloalkyl,
hydroxy,
halogen,
oxo,
—NR′R″,
—O—C(O)—R′, and
—CO—NR′R″;

linear or branched (C 2 -C 6 )alkenyl;
linear or branched (C 2 -C 6 )alkynyl, optionally substituted by linear or branched (C 1 -C 6 )alkoxy;
linear or branched (C 1 -C 6 )alkoxy, optionally substituted by a group selected from:
linear or branched (C 1 -C 6 )alkoxy,
linear or branched (C 1 -C 6 )polyhaloalkyl,
linear or branched (C 2 -C 6 )alkynyl,
—NR′R″, and
hydroxy;

(C 1 -C 6 )alkyl-S— optionally substituted by linear or branched (C 1 -C 6 )alkoxy;
hydroxy;
oxo (or N-oxide where appropriate);
nitro;
cyano;
—C(O)—OR′;
—O—C(O)—R′;
—CO—NR′R″;
—NR′R″;
—(C═NR′)—OR″;
linear or branched (C 1 -C 6 )polyhaloalkyl;
trifluoromethoxy; and
halogen;

wherein R′ and R″ independently of one another represent a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group, optionally substituted by linear or branched (C 1 -C 6 )alkoxy; and wherein one or more of the carbon atoms of the preceding possible substituents, may be deuterated,
or an enantiomer, a diastereoisomer, an atropoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base.

2. The compound according to claim 1 , wherein at least one of the groups selected from R 1 , R 2 , and R 3 does not represent hydrogen.

3. The compound according to claim 1 , wherein n is an integer equal to 1.

4. The compound according to claim 1 , wherein A represents linear or branched (C 1 -C 6 )alkyl or halogen.

5. The compound according to claim 1 , wherein X represents a carbon atom.

6. The compound according to claim 1 , wherein R 12 represents hydrogen.

7. The compound according to claim 1 , wherein:

represents

8. The compound according to claim 1 , wherein:

represents

9. The compound according to claim 1 , wherein R 4 represents optionally substituted linear or branched (C 1 -C 6 )alkoxy or —O-alkyl(C 1 -C 6 )—R 9 .

10. The compound according to claim 1 , wherein R 5 represents hydrogen.

11. The compound according to claim 1 , wherein:

represents

12. The compound according to claim 1 , wherein R 6 represents hydrogen, optionally substituted linear or branched (C 1 -C 8 )alkyl, or heteroarylalkyl(C 1 -C 6 ).

13. The compound according to claim 1 , wherein R 7 represents linear or branched (C 1 -C 6 )alkyl, linear or branched (C 2 -C 6 )alkenyl, linear or branched (C 2 -C 6 )alkynyl, aryl, or heteroaryl.

14. The compound according to claim 1 , wherein R 8 and R 8 ′ independently of one

Assignees

• Servier Lab
• Vernalis R&D Ltd
• Vernalis R&D Ltd

Inventors

• Kotschy András
• Szlávik Zoltán
• Csékei Márton
• Paczal Attila
• Szabó Zoltán
• Sipos Szabolcs
• Radics Gábor
• Proszenyák Ágnes
• Bálint Balázs
• Bruno Alain
• Geneste Olivier
• Davidson James Edward Paul
• Murray James Brooke
• Chen I-Jen
• Perron-Sierra Françoise

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title