Isoindoline or isoquinoline compounds, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-10689364-B2
Application number	US-201715704330-A
Country	US
Kind code	B2
Filing date	Sep 14, 2017
Priority date	Jul 23, 2013
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

Compounds of formula (I):

wherein Het, R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , T, p, p′, q, and q′ are as defined in the description.

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

First claim

The invention claimed is:

1. A method of treating cancer in a subject in need thereof, wherein the cancer is selected from the group consisting of cancers of the bladder, brain, breast and uterus, cancer of the colon, oesophagus and liver, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, and small-cell lung cancer, comprising administration of a compound of formula (I):

wherein:
Het represents a heteroaryl group;
T represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, an alkyl(C 1 -C 4 )—NR 1 R 2 group or an alkyl(C 1 -C 4 )—OR 6 group;
R 1 and R 2 independently of one another represent a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,
or R 1 and R 2 form with the nitrogen atom carrying them a heterocycloalkyl group;
R 3 represents 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 cycloalkyl group, a (C 3 -C 10 )cycloalkyl-(C 1 -C 6 )alkyl group wherein the alkyl group may be linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated;
R 4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (C 1 -C 6 )alkyl group, wherein one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated;
R 5 represents a hydrogen atom or a halogen atom, a linear or branched (C 1 -C 6 )alkyl group, or a linear or branched (C 1 -C 6 )alkoxy group;
R 6 represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group;
R 7 represents a group selected from R′ 7 , R′ 7 —CO—, R′ 7 —O—CO—, NR′ 7 R″ 7 —CO—, R′ 7 —SO 2 —, and R′ 7 —NR″ 7 —SO 2 — wherein R′ 7 et R″ 7 independently of one another represent 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 5 )alkynyl group, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl;
R 8 and R 9 represent, independently of one another, an oxo group or a halogen atom;
p and p′ are, independently of one another, integers equal to 0, 1, 2, 3 or 4;
q and q′ are, independently of one another, integers equal to 1, 2 or 3;

wherein when the compound of formula (I) contains a hydroxy group, this latter group may be optionally substituted by one of the following groups: —PO(OM)(OM′), —PO(OM)(O − M 1 + ), —PO(O − M 1 + )(O − M 2 + ), —PO(O − )(O − )M 3 2+ , —PO(OM)(O[CH 2 CH 2 O] n CH 3 ), or —PO(O − M 1 + )(O[CH 2 CH 2 O] n CH 3 ), wherein M and M′ independently of one another represent 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, a cycloalkyl or a heterocycloalkyl, both the cycloalkyl and heterocycloalkyl being composed of from 5 to 6 ring members, M 1 + and M 2 + independently of one another represent a pharmaceutically acceptable monovalent cation, M 3 2+ represents a pharmaceutically acceptable divalent cation and n is an integer comprised between 1 to 5,
wherein:
“aryl” means a phenyl, naphthyl, biphenyl 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 having from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen,
“cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group having from 3 to 10 ring members, which may include fused, bridged or spiro ring systems,
“heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group, composed of from 3 to 10 ring members, and having from one to 3 hetero atoms selected from oxygen, sulphur, SO, SO 2 and nitrogen, wherein the bicyclic group may be fused or spiro type,

wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, may be optionally substituted by from 1 to 3 groups selected from the group consisting of: linear or branched (C 1 -C 6 )alkyl group; linear or branched (C 2 -C 6 )alkenyl group; linear or branched (C 2 -C 6 )alkynyl group; (C 3 -C 6 )spiro; linear or branched (C 1 -C 6 )alkoxy; (C 1 -C 6 )alkyl-S—; hydroxyl; oxo; N-oxide; nitro; cyano; —COOR′; —OCOR′; —NR′R″; R′CONR″—; NR′R″CO—; linear or branched (C 1 -C 6 )polyhaloalkyl; trifluoromethoxy; (C 1 -C 6 )alkylsulphonyl; halogen; aryl; heteroaryl; aryloxy; arylthio; cycloalkyl and heterocycloalkyl, wherein R′ and R″ independently of one another represent a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group or an unsubstituted aryl group,
wherein said linear or branched (C 1 -C 6 )alkyl groups, said linear or branched (C 2 -C 6 )alkenyl group, said linear or branched (C 2 -C 6 )alkynyl group, said linear or branched (C 1 -C 6 )alkoxy, said aryl, said heteroaryl, said aryloxy, said arylthio, said cycloalkyl, and said heterocycloalkyl are optionally substituted by from 1 to 3 groups selected from the group consisting of: linear or branched (C 1 -C 6 )alkyl; linear or branched (C 2 -C 6 )alkenyl group; linear or branched (C 2 -C 6 )alkynyl group; (C 3 -C 6 )spiro; linear or branched (C 1 -C 6 )alkoxy; (C 1 -C 6 )alkyl-S—; hydroxyl; oxo; N-oxide; nitro; cyano; —COOR′; —OCOR′; —NR′R″; R′CONR″—; NR′R″CO—; linear or branched (C 1 -C 6 )polyhaloalkyl; trifluoromethoxy; (C 1 -C 6 )alkylsulphonyl; halogen; aryl; heteroaryl; aryloxy; arylthio; cycloalkyl and heterocycloalkyl, wherein R′ and R″ independently of one another represent a hydrogen atom, a linear or branched (C 1 -C 5 )alkyl group or an unsubstituted aryl group,
its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, wherein the compound of formula (I) is administered alone or in combination with one or more pharmaceutically acceptable excipients.

2. The method according to claim 1 , wherein the compound of formula (I) is a compound of formula (IA):

wherein:
W represents a C-A 3 group or a nitrogen atom;
X, Y and Z represent a carbon atom or a nitrogen atom, wherein only one of them represent a nitrogen atom, while the two others represent carbon atoms;
A 1 , A 2 and A 3 independently of one another represent a hydrogen atom or a halogen atom, a linear or branched (C 1 -C 6 )polyhaloalkyl group, a linear or branched (C 1 -C 6 )alkyl group or a cycloalkyl group,
or A 3 represents a hydrogen atom (when W represents a C-A 3 group) and A 1 and A 2 , together with the atoms carrying them, form an optionally substituted aromatic or non-aromatic ring Cy, composed of 5, 6 or 7 ring members, which may have from one to 4 hetero atoms selected independently from oxygen, sulphur and nitrogen, wherein the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group or a —C(O)—O-Alk group wherein Alk is a linear or branched (C 1 -C 6 )alkyl group,
or W represents a nitrogen atom and A 1 and A 2 , together with the atoms carrying them, form an optionally substituted aromatic or non-aromatic ring Cy, composed of 5, 6 or 7 ring members, which may have from one to 4 hetero atoms selected independently from oxygen, sulphur and nitrogen, wherein the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group or a —C(O)—O-Alk group wherein Alk is a linear or branched (C 1 -C 6 )alkyl group;
T rep

Assignees

• Servier Lab
• Vernalis R&D Ltd

Inventors

• Davidson James Edward Paul
• Murray James Brooke
• Chen I-Jen
• Walmsley Claire
• Dodsworth Mark
• Meissner Johannes W G
• Brough Paul
• Fejes Imre
• Tatai János
• Nyerges Miklós
• Kotschy András
• Szlávik Zoltán
• Geneste Olivier
• Le Tiran Arnaud
• Le Diguarher Thierry
• Henlin Jean-Michel
• Starck Jérôme-Benoît
• Guillouzic Anne-Françoise
• De Nanteuil Guillaume

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title