US 9,809,574 B2
Isoindoline or isoquinoline compounds, a process for their preparation and pharmaceutical compositions containing them
James Edward Paul Davidson, Great Shelford (GB); James Brooke Murray, Linton (GB); I-Jen Chen, Cambridge (GB); Claire Walmsley, Ely (GB); Mark Dodsworth, Fulbourn (GB); Johannes W. G. Meissner, Linton (GB); Paul Brough, Haverhill Suffolk (GB); Imre Fejes, Budapest (HU); János Tatai, Budapest (HU); Miklós Nyerges, Leányfalu (HU); András Kotschy, Törökbálint (HU); Zoltán Szlávik, Budapest (HU); Olivier Geneste, Rueil-Malmaison (FR); Arnaud Le Tiran, Croissy sur Seine (FR); Thierry Le Diguarher, Saint Denis de l'Hôtel (FR); Jean-Michel Henlin, Suresnes (FR); Jérôme-Benoît Starck, Rueil Malmaison (FR); Anne-Françoise Guillouzic, Nanterre (FR); and Guillaume De Nanteuil, Suresnes (FR)
Assigned to LES LABORATOIRES SERVIER, Suresnes (FR); and VERNALIS (R&D) LTD, Winnersh (GB)
Appl. No. 14/905,985
Filed by LES LABORATOIRES SERVIER, Suresnes (FR); and VERNALIS (R&D) LTD, Winnersh (GB)
PCT Filed Jul. 22, 2014, PCT No. PCT/EP2014/065764
§ 371(c)(1), (2) Date Jan. 19, 2016,
PCT Pub. No. WO2015/011164, PCT Pub. Date Jan. 29, 2015.
Claims priority of application No. 13 57276 (FR), filed on Jul. 23, 2013.
Prior Publication US 2016/0194304 A1, Jul. 7, 2016
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/4155 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); A61K 31/4725 (2006.01); C07D 409/14 (2006.01); C07D 471/04 (2006.01); A61K 31/496 (2006.01); A61K 31/497 (2006.01); A61K 31/5377 (2006.01); A61K 31/675 (2006.01); A61K 45/06 (2006.01); A61N 5/10 (2006.01); C07D 417/14 (2006.01); C07F 9/6561 (2006.01)
CPC C07D 401/14 (2013.01) [A61K 31/4725 (2013.01); A61K 31/496 (2013.01); A61K 31/497 (2013.01); A61K 31/5377 (2013.01); A61K 31/675 (2013.01); A61K 45/06 (2013.01); A61N 5/10 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07F 9/65616 (2013.01)] 28 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Drawing
wherein:
Het represents a heteroaryl group;
T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an alkyl(C1-C4)—NR1R2 group or an alkyl(C1-C4)—OR6 group;
R1 and R2 independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl group,
or R1 and R2 form with the nitrogen atom carrying them a heterocycloalkyl group;
R3 represents a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl group, a (C3-C10)cycloalkyl-(C1-C6)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;
R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (C1-C6)alkyl group, wherein one or more carbon atoms of the groups defined hereinbefore, or carbon atoms of their possible substituents, may be deuterated;
R5 represents a hydrogen atom or a halogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)alkoxy group;
R6 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group;
R7 represents a group selected from R′7, R′7—CO—, R′7—O—CO—, NR′7R″7—CO—, R′7—SO2—, and R′7—NR″7—SO2— wherein R′7 et R″7 independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl, a heterocycloalkyl, an aryl group, or a heteroaryl;
R8 and R9 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)(OM1+), —PO(OM1+)(OM2+), —PO(O)(O)M32+, —PO(OM)(O[CH2CH2O]nCH3), or —PO(OM1+)(O[CH2CH2O]nCH3), wherein M and M′ independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a cycloalkyl or a heterocycloalkyl, both the cycloalkyl and heterocycloalkyl being composed of from 5 to 6 ring members, M1+ and M2+ independently of one another represent a pharmaceutically acceptable monovalent cation, M32+ 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, SO2 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 (C1-C6)alkyl group; linear or branched (C2-C6)alkenyl group; linear or branched (C2-C6)alkynyl group; (C3-C6)spiro; linear or branched (C1-C6)alkoxy; (C1-C6)alkyl-S—; hydroxyl; oxo; N-oxide; nitro; cyano; —COOR′; —OCOR′; —NR′R″; R′CONR″—; NR′R″CO—; linear or branched (C1-C6)polyhaloalkyl; trifluoromethoxy; (C1-C6)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 (C1-C6)alkyl group or an unsubstituted aryl group,
wherein said linear or branched (C1-C6)alkyl groups, said linear or branched (C2-C6)alkenyl group, said linear or branched (C2-C6)alkynyl group, said linear or branched (C1-C6)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 (C1-C6)alkyl; linear or branched (C2-C6)alkenyl group; linear or branched (C2-C6)alkynyl group; (C3-C6)spiro; linear or branched (C1-C6)alkoxy; (C1-C6)alkyl-S—; hydroxyl; oxo; N-oxide; nitro; cyano; —COOR′; —OCOR′; —NR′R″; R′CONR″—; NR′R″CO—; linear or branched (C1-C6)polyhaloalkyl; trifluoromethoxy; (C1-C6)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 (C1-C6)alkyl group or an unsubstituted aryl group,
its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.