Spirocyclohexane derivatives, pharmaceutical compositions containing them and their uses as anti-apoptotic inhibitors

A compound of Formula (I):

• wherein:
• X represents —S—, —O—, —CH2— or —N(R2)—,
• Y1 represents —C(R4)(R5)— or —N(R6)—,
• Y2 represents —N(R7)—, —C(R8)(R9)—, or —C(R8)(R9)—C(R14)(R15)—,
• represents a single bond or a double bond,
• Y3 represents —C(R10)— or —N—,
• Y4 represents —C(R13)— or —N—,
• R1 represents an aryl group or a heteroaryl group,
• R2 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• or the pair (R1,R2) together with the nitrogen atom to which they are attached, forms a non-aromatic or aromatic mono- or bicyclic ring having from 5 to 12 ring members, which ring may have, in addition to the nitrogen, a second heteroatom selected from oxygen, sulphur and nitrogen, and which ring may be substituted by from 1 to 2 groups selected from a hydrogen atom, a halogen atom, and a linear or branched (C1-C6)alkyl group,
• R3 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched halo(C1-C6)alkyl group, —W1—OR3A, —W1—O—C(O)—R3A, —W1—NR3AR3B, —W1—C(O)—NR3AR3B, —W1—O—C(O)—OR3A, —W1—O—C(O)—NR3AR3B, —W1—O—P(O)(OR3A)2, or —W1—SO2—OR3A, —W1—Cy1, wherein:
• W1 represents a bond or a linear or branched (C1-C4)alkylene group,
• R3A and R3B, independently of one another, represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy(C1-C6)alkyl group, or a cycloalkyl group,
• or the pair (R3A,R3B) together with the nitrogen atom to which they are attached, forms a non-aromatic ring having from 4 to 7 ring members, which ring may have, in addition to the nitrogen, a second heteroatom selected from oxygen and nitrogen,
• Cy1 represents an aryl group or a heteroaryl group,
• R4 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkyl group substituted by 2 linear or branched (C1-C6)alkoxy groups, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched (C2-C6)alkenyloxy group, a linear or branched (C1-C6)alkoxy(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy(C2-C6)alkenyl group, a linear or branched (C1-C6)alkoxy(C1-C6)haloalkyl group, a hydroxy group, a linear or branched (C1-C6)hydroxyalkyl group, a —W2-Cy2 group, a —W3-L-Cy3 group, a —W4—NR4AR4B group, or a —CO—NR4CR4D group, wherein:
• W2 represents a bond, a linear or branched (C1-C6)alkylene group, a linear or branched (C2-C6)alkenylene group, or a linear or branched (C2-C6)alkynylene group,
• W3 represents a bond, a linear or branched (C1-C6)alkylene group, a linear or branched (C2-C6)alkenylene group, a linear or branched (C2-C8)alkynylene group, a linear or branched (C1-C6)alkoxylene group, a linear or branched (C1-C4)hydroxyalkylene group, a linear or branched (C1-C4)haloalkylene group, or a —CH2—CH(R4E)—CH2— group,
• W4 represents a linear or branched (C1-C4)alkylene group,
• L represents —O—, —S—, or —SO2—,
• R4A and R4B, independently of one another, represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, a heteroaryl group, or an arylalkyl group,
• R4C and R4D, independently of one another, represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, an arylalkyl group, or a heteroarylalkyl group,
• Cy2 represents an aryl group, a heteroaryl group, a cycloalkyl group, a cycloalkenyl group, or a heterocycloalkyl group,
• Cy3 represents an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an arylalkyl group, or a heteroarylalkyl group,
• Cy4 represents an aryl group, a heteroaryl group, an arylalkyl group, or a heterocycloalkylalkyl group,
• R5 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• or the pair (R4,R5) represents an oxo group, or a cycloalkylidene group,
• or the pair (R4,R5), together with carbon atoms to which they are attached, forms a non-aromatic ring having from 3 to 6 ring members,
• R6 represents an aryl group, a —SO2-aryl group, or a —W5—O—Cy5 group, wherein:
• W5 represents a linear or branched (C1-C4)alkylene group,
• Cy5 represents an aryl group, or a heteroaryl group,
• R7 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an arylalkyl group, or a formyl group,
• R8 represents a hydrogen atom, or a linear or branched (C1-C6)alkyl group,
• or the pair (R4,R8), together with carbon atoms to which they are attached forms a non-aromatic or aromatic ring having from 3 to 7 ring members,
• R9 represents a hydrogen atom,
• or the pair (R8,R9) represents an oxo group,
• R10 represents a hydrogen atom, a halogen atom, or a linear or branched (C1-C6)alkyl group,
• or the pair (R7,R10) together with the nitrogen atom to which they are attached, forms a non-aromatic ring composed of from 4 to 7 ring members,
• R11 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkyl group, or a linear or branched (C1-C6)alkoxy group,
• R12 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkenyl group, a linear or branched (C1-C6)alkynyl group, a linear or branched (C1-C6)alkoxy group, a linear or branched (C1-C6)alkenyloxy group, a linear or branched halo(C1-C6)alkyloxy group, a linear or branched (C1-C6)alkoxy(C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy(C1-C6)alkoxy group, a hydroxy group, a linear or branched hydroxy(C1-C6)alkyl group, an acetyl group, a formyl group, a —CH2—O-tetrahydrofuranyl group, —Cy6, or —O—Cy7, wherein:
• Cy6 represents an aryl group, a heteroaryl group, a cycloalkyl group, an arylalkyl group, or an arylalkenyl group,
• Cy7 represents an aryl group, cycloalkyl group, or a cycloalkylalkyl group,
• or the pair (R11,R12), together with the carbon atoms to which they are attached, forms a non-aromatic ring having from 5 to 8 ring members, which ring may have 1 or 2 oxygen atoms, and which ring may be substituted by R18 and R18′,
• R13 represents a hydrogen atom, a halogen atom, or a linear or branched (C1-C6)alkyl group,
• R14 and R15, independently of one another, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group,
• R16 represents a —O—R3 group or a —NR17R17′ group,
• R17 and R17′ independently of one another, represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a —SO2—CF3 group, or a —SO2—CH3 group, and
• R18 and R18′ independently of one another, represent a hydrogen atom, a halogen atom, or a linear or branched (C1-C6)alkyl group,
• or the pair (R18,R18′), together with the carbon atoms to which they are attached, forms a non-aromatic ring having from 3 to 5 ring members,
• wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl groups so defined may be optionally substituted by from 1 to 4 groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched halo(C1-C6)alkyl, linear or branched halo(C1-C6)alkylidene, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkoxy(C1-C6)alkoxy, a linear or branched halo(C1-C6)alkyloxy, hydroxy, linear or branched hydroxy(C1-C6)alkyl, cyano, oxo, —NR′R″, —C(O)—OR′, cyclopropyl, 2,2-dimethylcyclopropyl, phenyl, pyridinyl, benzyl, (2,3,6-trifluorophenyl)methyl, —CH2-pyridinyl, —O-phenyl, —O-benzyl, —O-pyridinyl, —O—CH2-cyclopropyl, —O—CH2-pyridinyl, aryloxyalkyl, and heteroaryloxyalkyl, wherein R′ and R″ independently of one another, represent a hydrogen atom or linear or branched (C1-C6)alkyl,
• its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.