New indole and pyrrole derivatives useful as bcl-2 inhibitors, a process for their preparation and pharmaceutical compositions containing them

• Main Authors: Le Diguarher, Thierry, Geneste, Olivier, Davidson, James Edward Paul, Ray, Stuart, Graham, Christopher John, Chen, I-Jen, Starck, Jérôme-Benoît, Bedford, Simon, Le Tiran, Arnaud, Maddox, Daniel, De Nanteuil, Guillaume, Murray, James Brooke, Walmsley, Claire, Casara, Patrick, Henlin, Jean-Michel
• Format: Patent
• Language: English
• Published: 28.06.2019
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

The present invention relates to indole and pyrrole compounds, to a process for their preparation and to pharmaceutical compositions containing them. The compounds of the present invention are useful in the treatment of Bcl-2 related cancers. More specifically, the present invention provides a compound of formula (I), wherein: W represents a group C-A3, A1, A2 and A3 each independently of the others, represent a hydrogen or halogen atom or a linear or branched (C1-C6)alkyl group, or A1 and A2 form together with the carbon atoms carrying them a cycloalkyl or a benzo ring, these two groups being optionally substituted by a halogen atom, T represents a group selected from methyl, aminomethyl, dimethylaminomethyl, morpholinylmethyl, (4-methyl-1-piperazinyl)methyl, (4-cyclopentyl¬piperazin-1-yl)methyl, (4-cyclobutylpiperazin-1-yl)methyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl and 2-(morpholin-4-yl)ethyl, R3 represents a linear or branched (C1-C6)alkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein one or more carbon atoms of the preceding groups, or carbon atoms of their possible substituents, may be deuterated, R4 represents a 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl or 3-fluoro-4-hydroxyphenyl group, wherein one or more carbon atoms of the preceding groups, or carbon atoms of their possible substituents, may be deuterated, R5 represents a hydrogen or halogen atom, Ra and Rd each represent a hydrogen atom and (Rb,Rc), together with the carbon atoms carrying them, form one of the following groups: 1,3-dioxolane; 1,4-dioxane; cyclopentane; tetrahydrofuran; 2,3-dihydrofuran; or Ra, Rc and Rd each represent a hydrogen atom and Rb represents a hydroxy or methoxy group, a halogen atom; or: one to two of the groups Ra, Rb, Rc, Rd represent a halogen atom, while the others represent a hydrogen; or: Ra and Rd each represent a hydrogen atom, Rb represents a hydrogen, a halogen, a hydroxy or methoxy group, and Rc is selected from one of the following groups: hydroxy, methoxy, 3-phenoxyazetidine, 2-(phenyl¬sulphanyl)¬¬acetamide or 2-(phenoxy)acetamide, 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 containing from 1 to 4 hetero atoms 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 group composed of from 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO2 and nitrogen, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the groups alkyl, alkenyl, alkynyl and alkoxy to be substituted by from 1 to 3 groups selected from linear or branched (C1-C6)alkyl, (C3-C6)spiro, linear or branched (C1-C6)alkoxy, (C1-C6)alkyl-S-, hydroxy, oxo, N-oxide, nitro, cyano, -COOR', -OCOR', NR'R'', linear or branched polyhalo-(C1-C6)alkyl, trifluoromethoxy, (C1-C6)alkylsulphonyl, halogen, 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 a linear or branched (C1-C6)alkyl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.