Pyrazolyl quinoxaline kinase inhibitors

A compound selected from the group consisting of a compound of formula (I)

• a tautomeric form, stereochemically isomeric form and isotopic form thereof, wherein
• n is an integer represents an integer equal to 0, 1, 2, 3 or 4;
• R1 is
• hydrogen,
• C1-6alkyl,
• C2-4alkenyl,
• hydroxyC1-6alkyl,
• haloC1-6alkyl,
• hydroxyhaloC1-6alkyl,
• cyanoC1-4alkyl,
• C1-6alkoxyC1-6alkyl wherein each C1-6alkyl is optionally substituted with one or two hydroxyl groups,
• C1-6alkyl substituted with —NR4R5,
• C1-6alkyl substituted with —C(═O)—NR4R5,
• —S(═O)2—C1-6alkyl,
• —S(═O)2-haloC1-6alkyl,
• —S(═O)2—NR14R15,
• C1-6alkyl substituted with —S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —S(═O)2-haloC1-6alkyl,
• C1-6alkyl substituted with —S(═O)2—NR14R15,
• C1-6alkyl substituted with —NH—S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —NH—S(═O)2-haloC1-6alkyl,
• C1-6alkyl substituted with —NR12—S(═O)2—NR14R15,
• R6,
• C1-6alkyl substituted with R6,
• C1-6alkyl substituted with —C(═O)—R6,
• hydroxyC1-6alkyl substituted with R6,
• C1-6alkyl substituted with —Si(CH3)3,
• C1-6alkyl substituted with —P(═O)(OH)2 or
• C1-6alkyl substituted with —P(═O)(OC1-6alkyl)2;
• each R1a is independently selected from
• hydrogen,
• C1-4alkyl,
• hydroxyC1-4alkyl,
• C1-4alkyl substituted with amino or mono- or di(C1-4alkyl)amino or —NH(C3-8cycloalkyl),
• cyanoC1-4alkyl,
• C1-4alkoxyC1-4alkyl, and
• C1-4alkyl substituted with one or more fluoro atoms;
• each R2 is independently selected from
• hydroxyl,
• halogen,
• cyano,
• C1-4alkyl,
• C2-4alkenyl,
• C2-4alkynyl,
• C1-4alkoxy,
• hydroxyC1-4alkyl,
• hydroxyC1-4alkoxy,
• haloC1-4alkyl,
• haloC1-4alkoxy,
• hydroxyhaloC1-4alkyl,
• hydroxyhaloC1-4alkoxy,
• C1-4alkoxyC1-4alkyl,
• haloC1-4alkoxyC1-4alkyl,
• C1-4alkoxyC1-4alkyl wherein each C1-4alkyl is optionally substituted with one or two hydroxyl groups,
• hydroxyhaloC1-4alkoxyC1-4alkyl,
• R13,
• C1-4alkyl substituted with R13,
• C1-4alkyl substituted with —C(═O)—R13,
• C1-4alkoxy substituted with R13,
• C1-4alkoxy substituted with —C(═O)—R13,
• —C(═O)—R13,
• C1-4alkyl substituted with —NR7R8,
• C1-4alkyl substituted with —C(═O)—NR7R8,
• C1-4alkoxy substituted with —NR7R8,
• C1-4alkoxy substituted with —C(═O)—NR7R8,
• —NR7R8 and
• —C(═O)—NR7R8;
• or
• when two R2 groups are attached to adjacent carbon atoms they are optionally taken together to form a radical of formula:
• —O—(C(R17)2)p—O—;
• —X—CH═CH—;
• or
• —X—CH═N—;
• wherein R17 is hydrogen or fluorine, p is 1 or 2 and X is O or S;
• R3 is
• hydroxyl,
• C1-6alkoxy,
• hydroxyC1-6alkoxy,
• C1-6alkoxy substituted with —NR10R11,
• C1-6alkyl,
• C2-6alkenyl,
• C2-6alkynyl,
• haloC1-6alkyl optionally substituted with —O—C(═O)—C1-6alkyl,
• hydroxyC1-6alkyl optionally substituted with —O—C(═O)—C1-6alkyl,
• hydroxyC2-6alkenyl,
• hydroxyC2-6alkynyl,
• hydroxyhaloC1-6alkyl,
• cyanoC1-6alkyl,
• C1-6alkyl substituted with carboxyl,
• C1-6alkyl substituted with —C(═O)—C1-6alkyl,
• C1-6alkyl substituted with —C(═O)—O—C1-6alkyl,
• C1-6alkyl substituted with C1-6alkoxyC1-6alkyl-O—C(═O)—,
• C1-6alkyl substituted with C1-6alkoxyC1-6alkyl-C(═O)—,
• C1-6alkyl substituted with —O—C(═O)—C1-6alkyl,
• C1-6alkoxyC1-6alkyl wherein each C1-6alkyl is optionally substituted with one or two hydroxyl groups or with —O—C(═O)—C1-6alkyl,
• C2-6alkenyl substituted with C1-6alkoxy,
• C2-6alkynyl substituted with C1-6alkoxy,
• C1-6alkyl substituted with R9 and optionally substituted with —O—C(═O)—C1-6alkyl,
• C1-6alkyl substituted with —C(═O)—R9,
• C1-6alkyl substituted with hydroxyl and R9,
• C2-6alkenyl substituted with R9,
• C2-6alkynyl substituted with R9,
• C1-6alkyl substituted with —NR10R11,
• C2-6alkenyl substituted with —NR10R11,
• C2-6alkynyl substituted with —NR10R11,
• C1-6alkyl substituted with hydroxyl and —NR10R11,
• C1-6alkyl substituted with one or two halogens and —NR10R11,
• —C1-6alkyl-C(R12)═N—O—R12,
• C1-6alkyl substituted with —C(═O)—NR10R11,
• C1-6alkyl substituted with —O—C(═O)—NR10R11,
• —S(═O)2—C1-6alkyl,
• —S(═O)2-haloC1-6alkyl,
• —S(═O)2—NR14R15,
• C1-6alkyl substituted with —S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —S(═O)2-haloC1-6alkyl,
• C1-6alkyl substituted with —S(═O)2—NR14R15,
• C1-6alkyl substituted with —NR12—S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —NH—S(═O)2-haloC1-6alkyl,
• C1-6alkyl substituted with —NR12—S(═O)2—NR14R15,
• R13, C1-6alkyl substituted with —P(═O)(OH)2 or
• C1-6alkyl substituted with —P(═O)(OC1-6alkyl)2;
• R4 and R5 each independently
• hydrogen,
• C1-6alkyl,
• hydroxyC1-6alkyl,
• haloC1-6alkyl,
• hydroxyhaloC1-6alkyl,
• C1-6alkoxyC1-6alkyl wherein each C1-6alkyl is optionally substituted with one or two hydroxyl groups,
• —S(═O)2—C1-6alkyl,
• —S(═O)2-haloC1-6alkyl,
• —S(═O)2—NR14R15,
• C1-6alkyl substituted with —S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —S(═O)2-haloC1-6alkyl,
• C1-6alkyl substituted with —S(═O)2—NR14R15,
• C1-6alkyl substituted with —NH—S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —NH—S(═O)2-haloC1-6alkyl,
• C1-6alkyl substituted with —NH—S(═O)2—NR14R15,
• R13 or
• C1-6alkyl substituted with R13;
• R6 is C3-8cycloalkyl, C3-8cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O and S;
• said C3-8cycloalkyl, C3-8cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclyl, each optionally and each independently being substituted by 1, 2, 3, 4 or 5 substituents, each substituent independently selected from cyano, C1-6alkyl, cyanoC1-6alkyl, hydroxyl, carboxyl, hydroxyC1-6alkyl, halogen, haloC1-6alkyl, hydroxyhaloC1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkyl-O—C(═O)—, —NR14R15, —C(═O)—NR14R15, C1-6alkyl substituted with —NR14R15, C1-6alkyl substituted with —C(═O)—NR14R15, —S(═O)2—C1-6alkyl, —S(═O)2-haloC1-6alkyl, —S(═O)2—NR14R15, C1-6alkyl substituted with —S(═O)2—C1-6alkyl, C1-6alkyl substituted with —S(═O)2-haloC1-6alkyl, C1-6alkyl substituted with —S(═O)2—NR14R15, C1-6alkyl substituted with —NH—S(═O)2—C1-6alkyl, C1-6alkyl substituted with —NH—S(═O)2-haloC1-6alkyl and C1-6alkyl substituted with —NH—S(═O)2—NR14R15;
• R7 and R8 each independently hydrogen, C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, hydroxyhaloC1-6alkyl or C1-6alkoxyC1-6alkyl;
• R9 is C3-8cycloalkyl, C3-8cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl containing at least one heteroatom selected from N, O and S, said C3-8cycloalkyl, C3-8cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl each optionally and each independently substituted with 1, 2, 3, 4 or 5 substituents, each substituent independently selected from
• ═O,
• C1-4alkyl,
• hydroxyl,
• carboxyl,
• hydroxyC1-4alkyl,
• cyano,
• cyanoC1-4alkyl,
• C1-4alkyl-O—C(═O)—,
• C1-4alkyl substituted with C1-4alkyl-O—C(═O)—,
• C1-4alkyl-C(═O)—,
• C1-4alkoxyC1-4alkyl wherein each C1-4alkyl is optionally substituted with one or two hydroxyl groups,
• halogen,
• haloC1-4alkyl,
• hydroxyhaloC1-4alkyl,
• —NR14R15,
• —C(═O)—NR14R15,
• C1-4alkyl substituted with —NR14R15,
• C1-4alkyl substituted with —C(═O)—NR14R15,
• C1-4alkoxy,
• —S(═O)2—C1-4alkyl,
• —S(═O)2-haloC1-4alkyl,
• —S(═O)2—NR14R15,
• C1-4alkyl substituted with —S(═O)2—NR14R15,
• C1-4alkyl substituted with —NH—S(═O)2—C1-4alkyl,
• C1-4alkyl substituted with —NH—S(═O)2-haloC1-4alkyl,
• C1-4alkyl substituted with —NH—S(═O)2—NR14R15,
• R13,
• —C(═O)—R13,
• C1-4alkyl substituted with R13,
• phenyl optionally substituted with R16,
• phenylC1-6alkyl wherein the phenyl is optionally substituted with R16, and
• a 5 or 6-membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O and S wherein said heterocyclyl is optionally substituted with R16;
• or when two of the substituents of R9 are attached to the same atom, they are optionally taken together to form a 4 to 7-membered saturated monocyclic heterocyclyl containing at least one heteroatom selected from N, O and S;
• R10 and R11 are each independently
• hydrogen,
• carboxyl,
• C1-6alkyl,
• cyanoC1-6alkyl,
• C1-6alkyl substituted with —NR14R15,
• C1-6alkyl substituted with —C(═O)—NR14R15,
• haloC1-6alkyl,
• hydroxyC1-6alkyl,
• hydroxyhaloC1-6alkyl,
• C1-6alkoxy,
• C1-6alkoxyC1-6alkyl wherein each C1-6alkyl is optionally substituted with one or two hydroxyl groups,
• R6,
• C1-6alkyl substituted with R6,
• —C(═O)—R6,
• —C(═O)—C1-6alkyl,
• —C(═O)-hydroxyC1-6alkyl,
• —C(═O)-haloC1-6alkyl,
• —C(═O)-hydroxyhaloC1-6alkyl,
• C1-6alkyl substituted with —Si(CH3)3,
• —S(═O)2—C1-6alkyl,
• —S(═O)2-haloC1-6alkyl,
• —S(═O)2—NR14R15,
• C1-6alkyl substituted with —S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —S(═O)2-haloC1-6alkyl,
• C1-6alkyl substituted with —S(═O)2—NR14R15,
• C1-6alkyl substituted with —NH—S(═O)2—C1-6alkyl,
• C1-6alkyl substituted with —NH—S(═O)2-haloC1-6alkyl or
• C1-6alkyl substituted with —NH—S(═O)2—NR14R15;
• R12 is hydrogen or C1-4alkyl optionally substituted with C1-4alkoxy;
• R13 is C3-8cycloalkyl or a saturated 4 to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O and S, wherein said C3-8cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxyl, C1-6alkyl, —C(═O)—C1-6alkyl, C1-6alkoxy, and —NR14R15;
• R14 and R15 are each independently
• hydrogen, or
• haloC1-4alkyl,or
• C1-4alkyl optionally substituted with a substituent selected from hydroxyl, C1-4alkoxy,
• amino and mono- or di(C1-4alkyl)amino;
• and
• R16 is hydroxyl, halogen, cyano, C1-4alkyl, C1-4alkoxy, —NR14R15 or —C(═O)NR14R15;
• or an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.