Indolizine compounds, a process for their preparation and pharmaceutical compositions containing them

Patent metadata

Field	Value
Publication number	US-9944620-B2
Application number	US-201414906330-A
Country	US
Kind code	B2
Filing date	Jul 22, 2014
Priority date	Jul 23, 2013
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

Compounds of formula (I) wherein Ra, Rb, Rc, Rd, T, R3, R4, R5, X, Y and Het 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:
X and Y represent a carbon atom or a nitrogen atom, it being understood that they may not simultaneously represent two carbons atoms or two nitrogen atoms;
the group

represents a group selected from 5,6,7,8-tetrahydroindolizine optionally substituted by an amino group; indolizine; 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine optionally substituted by a methyl; and pyrrolo[1,2-a]pyrimidine;
T represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group optionally substituted by from one to three halogen atoms, a (C 2 -C 4 )alkyl-NR 1 R 2 group, or a (C 1 -C 4 )alkyl-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 , together with the nitrogen atom carrying them, form a heterocycloalkyl;
R 3 represents a linear (C 1 -C 6 )alkyl, aryl or heteroaryl group, wherein the latter two groups can be substituted by from one to three groups selected from halogen, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )alkoxy and cyano, wherein one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated;
R 4 represents a 4-hydroxyphenyl group, wherein one or more of the carbon atoms of the preceding group may be deuterated;
R 5 represents a hydrogen or 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 a and R d , each represent a hydrogen atom and (R b , R c ), together with the carbon atoms carrying them, form a 1,3-dioxolane group or a 1,4-dioxane group; or R a , R c and R d each represent a hydrogen atom and R b represents a hydrogen, a halogen, a methyl or a methoxy; or R a , R b and R d each represent a hydrogen atom and R c represents a hydroxy or methoxy group;

wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the groups alkyl, alkenyl, alkynyl and alkoxy may be optionally substituted by from 1 to 3 groups selected from, linear or branched (C 1 -C 6 )alkyl, (C 3 -C 6 )spiro, linear or branched (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-S—, hydroxy, oxo (or N-oxide), nitro, cyano, —COOR′, —OCOR′, NR′R″, linear or branched (C 1 -C 6 )polyhaloalkyl, trifluoromethoxy, (C 1 -C 6 )alkylsulphonyl, halogen, optionally substituted aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, wherein R′ and R″, each independently of the other, represent a hydrogen atom Or an optionally substituted, linear or branched (C 1 -C 6 )alkyl group,
it being understood that:
“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 containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen (including quaternary nitrogens),
“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, condensed or spiro group containing from 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO 2 and nitrogen,

its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. The compound according to claim 1 , wherein T represents hydrogen, methyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, —CH 2 —H, 2-aminoethyl, 2-(3,3-difluoropiperidin-1-yl)ethyl, 2[(2,2-difluoroethyl)amino]ethyl or 2-(3-methoxyazetidin-1-yl)ethyl.

3. The compound according to claim 1 , wherein R 3 represents a heteroaryl group selected front 1H-indole, 2,3-dihydro-1H-indole, 1H-indazole, pyridine, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazole, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, and 1H-pyrazolo[3,4-b]pyridine, all of which may be optionally substituted by a linear or branched (C 1 -C 6 )alkyl group.

4. The compound according to claim 1 , which is selected from:
N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-N-{1-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}-5,6,7,8-tetrahydroindolizine-1-carboxamide,
N-(4-hydroxyphenyl)-3-(6-{[(3S)-3-[2-(morpholin-4-yl)ethyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide,
N-{3-fluoro-4-[2-(morpholin-4-yl)ethoxy]phenyl}-N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)indolizine-1-carboxamide,
N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)indolizine-1-carboxamide,
N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-N-(2-methylpyridin-4-yl)indolizine-1-carboxamide,
N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-indolizine-1-carboxamide,
N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-[3-(morpholin-4-yl)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide,
N-(2,6-dimethylpyridin-4-yl)-N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)indolizine-1-carboxamide,
N-(4-hydroxyphenyl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}-1,3-benzodioxol-5-yl)-N-(pyridin-4-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide,
3-(5-chloro-2-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)indolizine-1-carboxamide,
N-(4-hydroxyphenyl)-N-(2-methoxypyridin-4-yl)-3-(6-{[(3R)-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)indolizine-1-carboxamide, and

their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

5. A pharmaceutical composition comprising the compound according to claim 1 , in combination with one or more pharmaceutically acceptable excipients.

Assignees

• Servier Lab
• Vernalis R&D Ltd

Inventors

• Le Tiran Arnaud
• Le Diguarher Thierry
• Starck Jéròme-Benoît
• Henlin Jean-Michel
• De Nanteuil Guillaume
• Geneste Olivier
• Davidson James Edward Paul
• Murray James Brooke
• Chen I-Jen

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

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