Bicyclic heterocycle compounds and their uses in therapy

摘要

The invention relates to bicyclic heterocycle compounds of formula (I): or tautomeric or stereochemically isomeric forms, N-oxides, pharmaceutically acceptable salts or the solvates thereof; wherein R1, R2, R3, A, W, U and V are as defined herein; to pharmaceutical compositions comprising said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.;

主权项

1. A compound of formula (I): or a tautomeric or stereochemically isomeric form, N-oxide, pharmaceutically acceptable salt or solvate thereof; wherein R1 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)s—C3-8 cycloalkyl and —(CH2)s—C3-8 cycloalkenyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl and C3-8 cycloalkenyl may be optionally substituted by one or more Ra groups; Ra is selected from halogen, —OH and C1-6 alkoxy; R2 is selected from hydrogen, C1-4 alkyl, haloC1-4 alkyl, C2-4 alkenyl and —(CH2)s—C3-8 cycloalkyl; R3 is selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —Y—C3-12 carbocyclyl, —Z-(3-12 membered heterocyclyl), —(CH2)s—CN, —S(O)q—Rx, —C(═O)Rx, —C(═S)Rx, —C(═N)Rx, —(CRxRy)s—C(═O)ORz, —(CRxRy)s—C(═O)NRxRy, —(CRxRy)s—C(═S)NRz, —(CRxRy)s—C(═N)NRz, and —(CH2)s—SO2NRxRy groups, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl groups may be optionally substituted by one or more Rb groups and wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more Rc groups; R4 and R4′ are independently selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, —Y—C3-12 carbocyclyl, —Z-(3-12 membered heterocyclyl), —(CRxRy)s—O—Rz, —O—(CRxRy)n—ORz, —(CH2)s—CN, —S(O)q—Rx, —C(═O)Rx, —C(═S)Rx, —C(═N)Rx, —(CRxRy)s—C(═O)ORz, —(CRxRy)s—O—C(═O)—Rz, —(CRxRy)s—C(═O)NRxRy, —(CH2)s—NRxC(═O)Ry, —(CH2)s—OC(═O)NRxRy, —(CH2)s—NRxC(═O)ORy, —(CH2)s—NRxRy, —NRx—(CH2)s—Rz, —(CRxRy)s—C(═S)NRz, —(CRxRy)s—C(═N)NRz, —(CH2)s—O—C(═O)—C1-4alkyl-NRxRy, —(C H2)s—NRx—(CH2)s—O—C(═O)—Rz, —(CH2)s—NRx—(CH2)s—SO2—Ry, —(CH2)s—NH—SO2—NRxRy and —(CH2)s—SO2NRxRy groups, or R4 and R4′ together with the carbon atom to which they are attached, can join to form a 3-10 membered carbocyclyl or heterocyclyl group, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl groups may be optionally substituted by one or more Rb groups and wherein said carbocyclyl and heterocyclyl groups may be optionally substituted by one or more Rc groups; R6 is selected from hydrogen, halogen, C1-4 alkyl, haloC1-4 alkyl, haloC1-4 alkoxy and C1-4alkoxy; Rb is independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)s—C3-8 cycloalkyl, —(CH2)s—C3-8 cycloalkenyl, —(CH2)s-phenyl, —(CH2)s-(4-7 membered saturated heterocyclyl), —(CRxRy)s—O—Rz, —O—(CRxRy)n—ORz, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkanol, ═O, ═S, nitro, Si(Rx)4, —(CH2)s—CN, —S(O)q—Rx, —C(═O)Rx, —(CRxRy)s—C(═O)ORz, —(CRxRy)s—O—C(═O)—Rz, —(CRxRy)s—C(═O)NRxRy, —(CH2)s—NRxC(═O)Ry, —(CH2)s—OC(═O)NRxRy, —(CH2)s—NRxC(═O)ORy, —(CH2)s—NRxRy, —NRx—(CH2)s—Rz, —(CH2)s—O—C(═O)—C1-4alkyl-NRxRy, —(CH2)s—NRx—(CH2)s—O—C(═O)—Rz, —(CH2)s—NRx—(CH2)s—SO2—Ry, —(CH2)s—NH—SO2—NRxRy, and —(CH2)s—SO2NRxRy groups, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl and heterocyclyl groups may be optionally substituted by one or more RX groups; Rc is independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)s—C3-8 cycloalkyl, —(CH2)s—C3-8 cycloalkenyl, —(CH2)s-phenyl, —(CH2)s-(4-7 membered saturated heterocyclyl), —(CRxRy)s—O—Rz, —O—(CRxRy)s—ORz, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkanol, ═O, ═S, nitro, Si(Rx)4, —(CH2)s—CN, —S(O)q—Rx, —C(═O)Rx, —(CRxRy)s—C(═O)ORz, —(CRxRy)s—O—C(═O)—Rz, —(CRxRy)s—C(═O)NRxRy, —(CH2)s—NRxC(═O)Ry, —(CH2)s—OC(═O)NRxRy, —(CH2)s—NRxC(═O)ORy, —(CH2)s—NRxRy, —NRx—(CH2)s—Rz, —(CH2)s—O—C(═O)—C1-4alkyl-NRxRy, —(CH2)s—NRx—(CH2)s—O—C(═O)—Rz, —(CH2)s—NRx—(CH2)s—SO2—Ry, —(CH2)s—NH—SO2—NRxRy, —(CH2)s—SO2NRxRy and —P(═O)(Rx)2 groups, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl and heterocyclyl groups may be optionally substituted by one or more Rx groups; Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)s—C3-8 cycloalkyl, —(CH2)s—C3-8 cycloalkenyl, —(CH2)s-(4-7 membered saturated heterocyclyl), C1-6 alkanol optionally substituted with one or more halo, —C(═O)OC1-6 alkyl, hydroxy, C1-6 alkoxy, haloC1-6 alkyl, —(CH2)n—O—C1-6alkyl, —C(═O)—(CH2)s—C1-6 alkoxy, —C(═O)—C1-6alkyl, —(CH2)s—CN, C1-6 alkyl-N(H)2-q(C1-6alkyl)q, —N(H)2-q(C1-6alkyl)q, —C (═O)—N(H)2-q(C1-6 alkyl)q, —(CH2)s—NH—SO2—N(H)2-q(C1-6 alkyl)q, —(CH2)s—N(C1-4 alkyl)-SO2—N(H)2-q(C1-6 alkyl)q or —(CH2)s—O—C(═O)—C1-4alkyl-N(H)2-q(C1-6 alkyl)q, and when attached to nitrogen or carbon or phosphorus or silicon atom Rx and Ry may join to form a 3-7 membered ring optionally containing one or two additional heteroatoms selected from O, N, S and oxidised forms of N or S; Y and Z are independently selected from a bond, —(CRxRy)m—, —NRx, —C(═O)NRx—, —NRxC(═O)—, —(CRxRy)q—O—, —O—(CRxRy)q— and —S(O)q—; s independently represents an integer from 0-4; n independently represents an integer from 1-4; q represents an integer from 0-2; m represents an integer from 1-2.