Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof

A combination comprising:

• (a) an MCL-1 inhibitor of formula (I):
• wherein:
• D represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
• E represents a furyl, thienyl or pyrrolyl ring,
• X1, X3, X4 and X5, independently of one another, represent a carbon atom or a nitrogen atom,
• X2 represents a C-R26 group or a nitrogen atom,
• means that the ring is aromatic,
• Y represents a nitrogen atom or a C-R3 group,
• Z represents a nitrogen atom or a C-R4 group,
• R1 represents 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 group, a hydroxy group, a hydroxy(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, —S—(C1-C6)alkyl group, a cyano group, a nitro group, —Cy8, -alkyl(C0-C6)—NR11R11′, —O-alkyl(C1-C6)—NR11R11′, —O-alkyl(C1-C6)-R12, —C(O)—OR11, —O—C(O)-R11, —C(O)—NR11R11′, —NR11—C(O)-R11′, —NR11—C(O)—OR11′, -alkyl(C1-C6)—NR11—C(O)-R11′, —SO2—NR11R11′, or —SO2-alkyl(C1-C6),
• R2, R3, R4 and R5, 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 hydroxy(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a —S—(C1-C6)alkyl group, a cyano group, a nitro group, -alkyl(C0-C6)—NR11R11′, —O—Cy1, -alkyl(C0-C6)—Cy1, -alkenyl(C2-C6)—Cy1, -alkynyl(C2-C6)—Cy1, —O-alkyl(C1-C6)—NR11R11′, —O-alkyl(C1-C6)-R12, —C(O)—OR11, —O—C(O)-R11, —C(O)—NR11R11′, —NR11—C(O)-R11′, —NR11—C(O)—OR11′, -alkyl(C1-C6)—NR11—C(O)-R11!, —SO2—NR11R11′, or —SO2-alkyl(C1-C6),
• or the substituents of the pair (R1, R2), (R2, R3), (R3, R4), (R4, R5), 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, hwherein the resulting ring may be substituted by from 1 to 2 groups selected from halogen, linear or branched (C1-C6)alkyl, -alkyl(C0-C6)—NR11R11′, —NR13R13′, -alkyl(C0-C6)—Cy1 and oxo,
• R6 and R7, 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, a —S—(C1-C6)alkyl group, a cyano group, a nitro group, -alkyl(C0-C6)—NR11R11′, —O-alkyl(C1-C6)—NR11R11—, —O—Cy1, -alkyl(C0-C6)—Cy1, -alkenyl(C2-C6)—Cy1, -alkynyl(C2-C6)—Cy1, —O-alkyl(C1-C6)-R12, —C(O)—OR11, —O—C(O)-R11, —C(O)—NR11R11′, —NR11—C(O)-R11′, —NR11—C(O)—OR11′, -alkyl(C1-C6)—NR11—C(O)-R11′, —SO2—NR11R11′, or —SO2-alkyl(C1-C6),
• or the substituents of the pair (R6, R7), 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, hwherein the resulting ring may be substituted by a group selected from a linear or branched (C1-C6)alkyl group, —NR13R13′, -alkyl(C0-C6)—Cy1 and oxo,
• W represents a —CH2— group, an —NH— group or an oxygen atom,
• R8 represents a hydrogen atom, a linear or branched (C1-C8)alkyl group, a —CHRaRb group, an aryl group, a heteroaryl group, an arylalkyl(C1-C6) group, or a heteroarylalkyl(C1-C6) group,
• R9 represents 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, —Cy2, -alkyl(C1-C6)—Cy2, -alkenyl(C2-C6)—Cy2, -alkynyl(C2-C6)—Cy2, —Cy2—Cy3, -alkynyl(C2-C6)—O—Cy2, —Cy2-alkyl(C0-C6)—O-alkyl(C0-C6)—Cy3, a halogen atom, a cyano group, —C(O)-R14, or —C(O)—NR14R14′,
• R10 represents 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, an arylalkyl(C1-C6) group, a cycloalkylalkyl(C1-C6) group, a linear or branched (C1-C6)polyhaloalkyl, or -alkyl(C1-C6)—O——Cy4,
• or the substituents of the pair (R9, R10), 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,
• R11 and R11′, independently of one another, represent a hydrogen atom, an optionally substituted linear or branched (C1-C6)alkyl group, or -alkyl(C0-C6)—Cy1,
• or the substituents of the pair (R11, R11′), 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 from 1 to 2 groups selected from a hydrogen atom and a linear or branched (C1-C6)alkyl group and wherein one or more of the carbon atoms of the possible substituents may be deuterated,
• R12 represents —Cy5, —Cy5-alkyl(C0-C6)—O-alkyl(C0-C6)—Cy6, —Cy5-alkyl(C0-C6)—Cy6, —Cy5-alkyl(C0-C6)—NR11-alkyl(C0-C6)—Cy6, —Cy5—Cy6—O-alkyl(C0-C6)—Cy7, —Cy5-alkyl(C0-C6)—O-alkyl(C0-C6)—Cy9, —Cy5-alkyl(C0-C6)—Cy9, —NH—C(O)—NH—R11, —Cy5-alkyl(C0-C6)—NR11-alkyl(C0-C6)—Cy9, —C(O)—NR11R11′, —NR11R11′, —OR11, —NR11—C(O)—R11′, —O-alkyl(C1-C6)—OR11, —SO2-R11, —C(O)—OR11,
• wherein the ammonium moiety may exist as a zwitterionic form or have a monovalent anionic counterion,
• R13, R13′, R14 and R14′, independently of one another, represent a hydrogen atom, or an optionally substituted linear or branched (C1-C6)alkyl group,
• Ra represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• Rb represents a —O—C(O)—O—Rc group, a —O—C(O)—NRcRc′ group, or a —O—P(O)(ORc)2 group,
• Rc and Rc′, independently of one another, represent a hydrogen atom, a linear or branched (C1-C8)alkyl group, a cycloalkyl group, a (C1-C6)alkoxy(C1-C6)alkyl group, or a (C1-C6)alkoxycarbonyl(C1-C6)alkyl group,
• or the substituents of the pair (Rc, Rc′), together with the nitrogen atom carrying them, form a 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 and nitrogen, wherein the nitrogen in question may be substituted by a linear or branched (C1-C6)alkyl group,
• Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8 and Cy10, independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
• Cy9 represents
• or Cy9 represents a heteroaryl group which is substituted by a group selected from —O—P(O)(OR20)2;
• —O—P(O)(O−M+)2;
• —(CH2)p—O—(CHR18-CHR19—O)q-R20;
• hydroxy;
• hydroxy(C1-C6)alkyl;
• —(CH2)r—U—(CH2)s-heterocycloalkyl;
• and —U—(CH2)q—NR21R21′,
• R15 represents a hydrogen atom;
• a —(CH2)p—O—(CHR18—CHR19—O)q-R20 group;
• a linear or branched (C1-C6)alkoxy(C1-C6)alkyl group;
• a —U—(CH2)q—NR21R21′ group;
• or a —(CH2)r—U—(CH2)s-heterocycloalkyl group,
• R16 represents a hydrogen atom;
• a hydroxy group;
• a hydroxy(C1-C6)alkyl group;
• a —(CH2)r—U—(CH2)s-heterocycloalkyl group;
• a (CH2)r—U—V—O—P(O)(OR20)2 group;
• a —O—P(O)(O−M+)2 group;
• a —(CH2)p—O—(CHR18—CHR19—O)q-R20 group;
• a —(CH2)p—O—C(O)—NR22R23 group;
• or a —U—(CH2)q—NR21R21′ group,
• R17 represents a hydrogen atom;
• a —(CH2)p—O—(CHR18—CHR19—O)q-R20 group;
• a —O—P(O)(OR20)2 group;
• a —O—P(O)(O−M+)2 group;
• a hydroxy group;
• a hydroxy(C1-C6)alkyl group;
• a —(CH2)r—U—(CH2)s-heterocycloalkyl group;
• a —U—(CH2)q—NR21R21′ group;
• or an aldonic acid,
• M+ represents a pharmaceutically acceptable monovalent cation,
• U represents a bond or an oxygen atom,
• V represents a —(CH2)s— group or a —C(O)— group,
• R18 represents a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group,
• R19 represents a hydrogen atom or a hydroxy(C1-C6)alkyl group,
• R20 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• R21 and R21′, independently of one another, represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, or a hydroxy(C1-C6)alkyl group,
• or the substituents of the pair (R21, R21′), 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 resulting ring may be substituted by a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• R22 represents a (C1-C6)alkoxy(C1-C6)alkyl group, a —(CH2)p—NR24R24′ group, or a —(CH2)p—O—(CHR18—CHR19—O)q-R20 group,
• R23 represents a hydrogen atom or a (C1-C6)alkoxy(C1-C6)alkyl group,
• or the substituents of the pair (R22, R23), together with the nitrogen atom carrying them, form an aromatic or non-aromatic ring having from 5 to 18 ring members, which may have, in addition to the nitrogen atom, from 1 to 5 heteroatoms selected from oxygen, sulphur and nitrogen, wherein the resulting ring may be substituted by a hydrogen atom, a linear or branched (C1-C6)alkyl group or a heterocycloalkyl group,
• R24 and R24′, independently of one another, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• or the substituents of the pair (R24, R24′), 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 resulting ring may be substituted by a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• R25 represents a hydrogen atom, a hydroxy group, or a hydroxy(C1-C6)alkyl group,
• R26 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkyl group, or a cyano group,
• R27 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• R28 represents a —O—P(O)(O−)(O−) group, a —O—P(O)(O−)(OR30) group, a —O—P(O)(OR30)(OR30′) group, a —O—SO2—O− group, a —O—SO2—OR30 group, —Cy10, a —O—C(O)-R29 group, a —O—C(O)—OR29 group or a —O—C(O)—NR29R29′ group;
• R29 and R29′ 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,
• R30 and R30′ independently of one another represent a hydrogen atom, a linear or branched (C1-C6)alkyl group or an arylalkyl(C1-C6) group,
• n is an integer equal to 0 or 1,
• p is an integer equal to 0, 1 or 2,
• q is an integer equal to 1, 2, 3 or 4,
• r and s are independently 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 composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms 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 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, may be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (C1-C6)alkyl, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-C6)alkynyl group, optionally substituted linear or branched (C1-C6)alkoxy, optionally substituted (C1-C6)alkyl-S—, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, —C(O)—OR′, —O—C(O)-R′, —C(O)—NR′R″, —NR′R″, —(C═NR′)—OR″, linear or branched (C1-C6)polyhaloalkyl, trifluoromethoxy, or halogen, wherein R′ and R″, independently of one another, represent a hydrogen atom or an optionally substituted linear or branched (C1-C6)alkyl group, and wherein one or more of the carbon atoms of the preceding possible substituents may be deuterated,
• or its enantiomers, diastereoisomers, atropisomers, or addition salts thereof with a pharmaceutically acceptable acid or base,
• and (b) a taxane compound.