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

Patent metadata

Field	Value
Publication number	US-10323041-B2
Application number	US-201615738186-A
Country	US
Kind code	B2
Filing date	Jun 22, 2016
Priority date	Jun 23, 2015
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

Medicinal products containing the same which are useful in treating conditions requiring a pro-apoptotic agent.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
A represents the group

in which 1 is linked to the W group and 2 is linked to the phenyl ring, wherein:
the ring system

is selected from the group consisting of:

R 1 represents a halogen atom, a linear or branched (C 1 -C 6 )alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, a linear or branched (C 1 -C 6 )polyhaloalkyl group, a hydroxy group, a hydroxy(C 1 -C 6 )alkyl group, a linear or branched (C 1 -C 6 )alkoxy group, —S—(C 1 -C 6 )alkyl, a cyano group, a nitro group, -alkyl(C 0 -C 6 )—NR 11 R 11 ′, —O-alkyl(C 1 -C 6 )—NR 11 R 11 ′, —O-alkyl(C 1 -C 6 )—R 12 , —C(O)—OR 11 , —O—C(O)—R 11 , —C(O)—NR 11 R 11 ′, —NR 11 —C(O)—R 11 ′, —NR 11 —C(O)—OR 11 ′, -alkyl(C 1 -C 6 )—NR 11 —C(O)—R 11 ′, —SO 2 —NR 11 R 11 ′, —SO 2 -alkyl(C 1 -C 6 ),
R 2 , R 3 , R 4 and R 5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 )alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, a linear or branched (C 1 -C 6 )polyhaloalkyl, a hydroxy group, a hydroxy(C 1 -C 6 )alkyl group, a linear or branched (C 1 -C 6 )alkoxy group, a —S—(C 1 -C 6 )alkyl group, a cyano group, a nitro group, -alkyl(C 0 -C 6 )—NR 11 R 11 ′, —O-alkyl(C 1 -C 6 )—NR 11 R 11 ′, —O-alkyl(C 1 -C 6 )—R 12 , —C(O)—OR 11 , —O—C(O)—R 11 , —C(O)—NR 11 R 11 ′, —NR 11 —C(O)—R 11 ′, —NR 11 —C(O)—OR 11 ′, -alkyl(C 1 -C 6 )—NR 11 —C(O)—R 11 ′, —SO 2 —NR 11 R 11 ′, or —SO 2 -alkyl(C 1 -C 6 ),
or the substituents of the pair (R 1 , R 2 ), together with the carbon atoms carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which ring may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the resulting ring may be substituted by from 1 to 2 groups selected from halogen, linear or branched (C 1 -C 6 )alkyl, -alkyl(C 0 -C 6 )—NR 11 R 11 ′, —NR 13 R 13 ′, -alkyl(C 0 -C 6 )-Cy 1 and oxo,
R 6 and R 7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 )alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, a linear or branched (C 1 -C 6 )polyhaloalkyl, a hydroxy group, a linear or branched (C 1 -C 6 )alkoxy group, a —S—(C 1 -C 6 )alkyl group, a cyano group, a nitro group, -alkyl(C 0 -C 6 )—NR 11 R 11 ′, —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 12 , —C(O)—OR 11 , —O—C(O)—R 11 , —C(O)—NR 11 R 11 ′, —NR 11 —C(O)—R 11 ′, —NR 11 —C(O)—OR 11 ′, -alkyl(C 1 -C 6 )—NR 11 —C(O)—R 11 ′, —SO 2 —NR 11 R 11 ′, —SO 2 -alkyl(C 1 -C 6 ),
or the substituents of the pair (R 6 , R 7 ), when grafted onto two adjacent carbon atoms, together with the carbon atoms carrying them, form an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which ring may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the resulting ring may be substituted by a group selected from a linear or branched (C 1 -C 6 )alkyl group, —NR 13 R 13 ′, -alkyl(C 0 -C 6 )-Cy 1 and oxo,
W represents a —CH 2 — group, a —NH— group or an oxygen atom,
R 8 represents a hydrogen atom, a linear or branched (C 1 -C 8 )alkyl group, a —CHR a R b group, an aryl group, a heteroaryl group, an arylalkyl(C 1 -C 6 ) group, or a heteroarylalkyl(C 1 -C 6 ) group,
R 9 represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, -Cy 2 , -alkyl(C 1 -C 6 )-Cy 2 , -alkenyl(C 2 -C 6 )-Cy 2 , -alkynyl(C 2 -C 6 )-Cy 2 , -Cy 2 -Cy 3 , -alkynyl(C 2 -C 6 )—O-Cy 2 , -Cy 2 -alkyl(C 0 -C 6 )—O-alkyl(C 0 -C 6 )-Cy 3 , a halogen atom, a cyano group, —C(O)—R 15 , or —C(O)—NR 15 R 15 ′,
R 10 represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, a linear or branched (C 2 -C 6 )alkenyl group, a linear or branched (C 2 -C 6 )alkynyl group, an arylalkyl(C 1 -C 6 ) group, a cycloalkylalkyl(C 1 -C 6 ) group, a linear or branched (C 1 -C 6 )polyhaloalkyl, -alkyl(C 1 -C 6 )—O-Cy 4 ,
or the substituents of the pair (R 9 , R 10 ), 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 contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
R 11 and R 11 ′ independently of one another represent a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, or the substituents of the pair (R 11 , R 11 ′), together with the nitrogen atom carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which ring may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the nitrogen may be substituted by a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
R 12 represents -Cy 5 , -Cy 5 -alkyl(C 0 -C 6 )—O-alkyl(C 0 -C 6 )-Cy 6 , -Cy 5 -alkyl(C 0 -C 6 )-Cy 6 , -Cy 5 -alkyl(C 0 -C 6 )—NR 11 -alkyl(C 0 -C 6 )-Cy 6 , -Cy 5 -Cy 6 -O-alkyl(C 0 -C 6 )-Cy 7 , —C(O)—NR 11 R 11 ′, —NR 11 R 11 ′, —OR 11 , —NR 11 —C(O)—R 11 ′, —O-alkyl(C 1 -C 6 )—OR 11 , —SO 2 —R 11 , —C(O)—OR 11 , or —NH—C(O)—NH—R 11 ,
R 13 , R 13 ′, R 15 and R 15 ′, independently of one another, represent a hydrogen atom, or an optionally substituted linear or branched (C 1 -C 6 )alkyl group,
R 14 represents a hydrogen atom, a hydroxy group, or a hydroxy(C 1 -C 6 )alkyl group,
R a represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
R b represents a —O—C(O)—O—R c group, a —O—C(O)—NR c R c ′ group, or a —O—P(O)(OR c ) 2 group,
R c and R c ′, independently of one another, represent a hydrogen atom, a linear or branched (C 1 -C 8 )alkyl group, a cycloalkyl group, a (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl group,
or the substituents of the pair (R c , R c ′), together with the nitrogen atom carrying them, form a non-aromatic ring having from 5 to 7 ring members, which ring may contain, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen and nitrogen, wherein the nitrogen in question may be substituted by a linear or branched (C 1 -C 6 )alkyl group,
Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 , Cy 6 and Cy 7 , independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
n is an integer equal to 0 or 1,

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

wherein the aryl, heteroaryl, cycloalky

Assignees

• Servier Lab
• Vernalis R&D Ltd

Inventors

• Balint Balazs
• Csékei Márton
• Szabó Zoltán
• Szlavik Zoltan
• Kotschy András
• Chanrion Maïa
• Geneste Olivier
• Chen I-Jen
• Davidson James Edward Paul
• Murray James Brooke
• Sipos Szabolcs
• Ondi Levente
• Proszenyák Ágnes

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07D491/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C07D403/12

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