Combination of a bcl-2 inhibitor and a mcl-1 inhibitor, uses and pharmaceutical compositions thereof

A combination comprising:

• (a) a BCL-2 inhibitor 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,
• A1 and A2, together with the atoms carrying them, form an optionally substituted, aromatic or non-aromatic heterocycle Het having 5, 6 or 7 ring members which may have, in addition to the nitrogen represented by X or by Y, from 1 to 3 hetero atoms selected independently from oxygen, sulphur and nitrogen, wherein the nitrogen in question may be substituted by a a hydrogen atom, a linear or branched (C1-C6)alkyl group or a group —C(O)—O-Alk wherein Alk is a linear or branched (C1-C6)alkyl group,
• or A1 and A2 independently of one another represent a hydrogen atom, a linear or branched (C1-C6)polyhaloalkyl, a linear or branched (C1-C6)alkyl group or a cycloalkyl,
• T represents a hydrogen atom, a linear or branched (C1-C6)alkyl group optionally substituted by from one to three halogen atoms, a group (C1-C4)alkyl-NR1R2, or a group (C1-C4)alkyl-OR6,
• R1 and R2 independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• or R1 and R2, together with the nitrogen atom carrying them, form a heterocycloalkyl,
• 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 moiety is linear or branched, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated,
• R4 represents an aryl group, a heteroaryl group, a cycloalkyl group or a linear or branched (C1-C6)alkyl group, wherein one or more of the carbon atoms of the preceding groups, or of their possible substituents, may be deuterated,
• R5 represents a hydrogen or 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,
• Ra, Rb, Rcand Rd, each independently of the others, represent R7, a halogen atom, a linear or branched (C1-C6)alkoxy group, a hydroxy group, a linear or branched (C1-C6)polyhaloalkyl group, a trifluoromethoxy group, —NR7R7′, nitro, R7—CO—(C0-C6)alkyl-, R7—CO—NH—(C0-C6)alkyl-, NR7R7′—CO—(C0-C6)alkyl-, NR7R7′—CO—(C0-C6)alkyl-O—, R7—SO2—NH—(C0-C6)alkyl-, R7—NH—CO—NH—(C0-C6)alkyl-, R7—O—CO—NH—(C0-C6)alkyl-, a heterocycloalkyl group, or the substituents of one of the pairs (Ra,Rb), (Rb,Rc) or (Rc,Rd), together with the carbon atoms carrying them, form a ring having from 5 to 7 ring members, which may have from 1 to 2 hetero atoms selected from oxygen and sulphur, wherein one or more carbon atoms of the ring defined hereinbefore may be deuterated or substituted by from one to 3 groups selected from halogen and linear or branched (C1-C6)alkyl,
• R7 and R7′ independently of one another represent a hydrogen, a linear or branched (C1-C6)alkyl, a linear or branched (C2-C6)alkenyl, a linear or branched (C2-C6)alkynyl, an aryl or a heteroaryl, or R7 and R7′, together with nitrogen atom carrying them, form a heterocycle composed of from 5 to 7 ring members,
• wherein when the compound of formula (I) contains a hydroxy group, the latter may be optionally converted into one of the following groups:
• —OPO(OM)(OM′), —OPO(OM)(O−M1+), —OPO(O−M1+)(O−M2+), —OPO(O)(O−)M32+, —OPO (OM)(O[CH2CH2O]nCH3), or —OPO(O−M1+)(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 having from 5 to 6 ring members, while 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 from 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 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 composed of 3 to 10 ring members and containing from 1 to 3 hetero atoms selected from oxygen, sulphur, SO, SO2 and nitrogen,
• wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl and alkoxy groups may be substituted by from 1 to 3 groups selected from the group consisting of:
• linear or branched (C1 -C6)alkyl optionally substituted by a hydroxyl, a morpholine, 3,3-difluoropiperidine or a ,3-difluoropyrrolidine;
• (C3-C6)spiro;
• linear or branched (C1-C6)alkoxy optionally substituted by a morpholine;
• (C1-C6)alkyl-S-;
• hydroxyl;
• oxo;
• N-oxide;
• nitro;
• cyano;
• —COOR′;
• —OCOR′;
• NR′R″;
• linear or branched (C1-C6)polyhaloalkyl;
• trifluoromethoxy;
• (C1-C6)alkylsulphonyl;
• halogen;
• aryl optionally substituted by one or more halogens;
• heteroaryl;
• aryloxy;
• arylthio;
• cycloalkyl;
• heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, wherein R′ and R″ independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl group optionally substituted by a methoxy,
• wherein the Het group defined in formula (I) may be substituted by from one to three groups selected from linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, NR1′R1″ and halogen, it being understood that R1′ and R1′ are as defined for the groups R′ and R″ mentioned hereinbefore,
• or its enantiomers, diastereoisomers, or addition salts thereof with a pharmaceutically acceptable acid or base,
• and (b) an MCL1 inhibitor,
• for simultaneous, sequential or separate use.

A combination comprising:

• (a) a BCL-2 inhibitor and
• (b) an MCL1 inhibitor of formula (II):
• wherein:
• A 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 linear or branched (C1-C6)alkoxy group, —S—(C1-C6)alkyl group, a linear or branched (C1-C6)polyhaloalkyl, a hydroxy group, a cyano, —NW10W10′, -Cy6 or a halogen atom,
• W1, W2, W3, W4 and W5 independently of one another represent a hydrogen atom, a halogen 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 linear or branched (C1-C6)polyhaloalkyl, a hydroxy group, a linear or branched (C1-C6)alkoxy group, —S—(C1-C6)alkyl group, a cyano, a nitro group, -alkyl(C0-C6)—NW8W8′, —O-Cy1, -alkyl(C0-C6)-Cy1, -alkenyl(C2-C6)-Cy1, -alkynyl(C2-C6)-Cy1, —O-alkyl(C1-C6)—W9, —C(O)—OW8, —O—C(O)—W8, —C(O)—NW8W8′, —NW8—C(O)—W8′, —NW8—C(O)—OW8′, -alkyl(C1-C6)—NW8—C(O)—W8′, —SO2— NW8W8′, —SO2-alkyl(C1-C6),
• or the substituents of one of the pairs (W1, W2), (W2, W3), (W1, W3), (W4, W5) 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 may have from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the resulting ring may be substituted by a linear or branched (C1-C6)alkyl group, —NW10W10′, -alkyl(C0-C6)-Cy1 or an oxo,
• X′ represents a carbon or a nitrogen atom,
• W6 represents a hydrogen, a linear or branched (C1-C8)alkyl group, an aryl group, a heteroaryl group, an arylalkyl(C1-C6) group, or a heteroarylalkyl(C1-C6) group,
• W7 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, -Cy3, -alkyl(C1-C6)-Cy3, -alkenyl(C2-C6)-Cy3, -alkynyl(C2-C6)-Cy3, -Cy3-Cy4, -alkynyl(C2-C6)—O-Cy3, -Cy3-alkyl(C0-C6)—O-alkyl(Co-C6)-Cy4, an halogen atom, a cyano, —C(O)—W11, or —C(O)—NW11W11′,
• W8 and W8′ independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, or -alkyl(C0-C6)-Cy1,
• or (W8, W8′), together with the nitrogen atom carrying them, form an aromatic or non-aromatic ring having from 5 to 7 ring members, which may have, in addition to the nitrogen atom, from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the nitrogen in question may be substituted by a hydrogen atom, or a linear or branched (C1-C6)alkyl group, wherein one or more of the carbon atoms of the possible substituents, may be deuterated,
• W9 represents -Cy1, -Cy1-alkyl(C0-C6)-Cy2, -Cy1-alkyl(C0-C6)—O-alkyl(C0-C6)-Cy2, -Cy1-alkyl(C0-C6)—NW8-alkyl(C0-C6)-Cy2, -Cy1-Cy2-O-alkyl(C0-C6)-Cy5, —C(O)—NW8W8′, —NW8W8′, —OW8, —NW8—C(O)—W8′, —O-alkyl(C1-C6)—OW8, —SO2—W8, —C(O)—OW8, —NH—C(O)—NH—W8,
• it being possible for the ammonium so defined to exist as a zwitterionic form or to have a monovalent anionic counterion,
• W10, W10′, W11 and W11′ independently of one another represent a hydrogen atom or an optionally substituted linear or branched (C1-C6)alkyl group,
• W12 represents a hydrogen or a hydroxy group,
• W13 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• W14 represents a —O—P(O)(O−)(O−) group, a —O—P(O)(O−)(OW16) group, a —O—P(O)(OW16)(OW16′) group, a —O—SO2—O− group, a —O—SO2—OW16 group, -Cy7, a —O—C(O)—W15 group, a —O—C(O)—OW15 group or a —O—C(O)—NW15W15′ group,
• W15 and W15′ independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group or a linear or branched amino(C1-C6)alkyl group,
• W16 and W16′ independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group or an arylalkyl(C1-C6) group,
• Cy1, Cy2, Cy3, Cy4, Cy5, Cy6 and Cy7 independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl 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 having from 5 to 10 ring members, having at least one aromatic moiety and having from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
• “cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group having from 3 to 10 ring members,
• “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group having from 3 to 10 ring members, and having from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems,
• wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined, and the alkyl, alkenyl, alkynyl, alkoxy groups, may be substituted by from 1 to 4 groups selected from the group consisting of linear or branched (C1-C6)alkyl which may be substituted by a linear or branched (C1-C6)alkoxy which may be substituted by a linear or branched (C1-C6)alkoxy, a linear or branched (C1-C6)polyhaloalkyl, hydroxy, halogen, oxo, —NW′W″, —O—C(O)—W′, or —CO—NW′W″;
• a linear or branched (C2-C6)alkenyl group;
• a linear or branched (C2-C6)alkynyl group which may be substituted by a linear or branched (C1-C6)alkoxy;
• linear or branched (C1-C6)alkoxy which may be substituted by a linear or branched (C1-C6)alkoxy, a linear or branched (C1-C6)polyhaloalkyl, a linear or branched (C2-C6)alkynyl, —NW′W″, or hydroxy;
• (C1-C6)alkyl-S— which may be substituted by a group representing a linear or branched (C1-C6)alkoxy;
• hydroxy;
• oxo;
• N-oxide;
• nitro;
• cyano;
• —C(O)—OW′;
• —O—C(O)—W′;
• —CO—NW′W″;
• —NW′W″;
• —(C═NW′)—OW″;
• linear or branched (C1-C6)polyhaloalkyl;
• trifluoromethoxy;
• or halogen, wherein W′ and W″ independently of one another represent a hydrogen atom or a linear or branched (C1-C6)alkyl group which may be substituted by a linear or branched (C1-C6)alkoxy;
• and wherein one or more of the carbon atoms of the preceding possible substituents, may be deuterated,
• its enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
• for simultaneous, sequential or separate use.