Farnesyl transferase inhibiting 6-heterocyclylmethyl quinolinone derivatives

A compound of formula (I):

• 33
• or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein
• r is 0, 1, 2, 3, 4 or 5;
• t is 0, 1, 2 or 3;
• >Y1—Y2 is a trivalent radical of formula
• >C═CR9— (y-2)>CH—CHR9— (y-4)
• wherein R9 is hydrogen, halo, cyano, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyloxy, halocarbonyl, hydroxycarbonyl, C1-6alkyloxycarbonyl, aryl or a group of formula —NR22R23, —C1-6alkyl-NR22R23, —C2-6alkenyl-NR R22R23, —CONR22R2 or —NR2—C1-6alkyl-NR22R23;
• p is 0 to 5;
• R20 and R21 are independently hydrogen or C1-6alkyl and are independently defined for each iteration of p in excess of 1;
• R22 and R23 are independently hydrogen, C1-6 alkyl or
• —(CR20R21)p—C3-10cycloalkyl, or together with the adjacent nitrogen atom form a 5- or 6-membered heterocyclic ring optionally containing one, two or three further heteroatoms selected from oxygen, nitrogen or sulphur and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, OCF3, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, mono- or di-(C1-6alkyl)aminocarbonyl, amino, mono- or di(C1-6alkyl)amino, C1-6alkylsulfonylamino, oxime, or phenyl;
• R1 is azido, hydroxy, halo, cyano, nitro, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, hydroxycarbonylC1-6alkyloxyC1-6alkyl, R24S C1-6alkyl, trihalomethyl, arylC1-6alkyl, Het2C1-6alkyl, —C1-6alkyl-NR22R23, —C1-6alkylNR22C1-6alkyl-NR22R23, —C1-6alkylNR22COC1-6alkyl, —C1-6alkylNR22COAlkAr2, —C1-6alkylNR22COAr2, C1-6alkylsulphonylaminoC1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, —OC1-6alkyl-NR22R23, trihalomethoxy, arylC1-6alkyloxy, Het2C1-6alkyloxy, C1-6alkylthio, C2-6alkenyl, cyanoC2-6alkenyl, —C2-6alkenyl-NR22R23, hydroxycarbonylC2-6alkenyl, C1-6alkyloxycarbonylC2-6alkenyl, C2-6alkynyl, —CHO, C1-6alkylcarbonyl, hydroxyC1-6alkylcarbonyl, hydroxycarbonyl, C1-6alkyloxycarbonyl, —CONR22R23, —CONR22—C1-6alkyl-NR22R23, —CONR22—C1-6alkyl-Het2, —CONR22—C1-6alkyl-Ar2, —CONR22—O—C1-6alkyl, —CONR22—C1-6alkenyl, —NR R22R23, —OC(O)R24, —CR24═NR25, —CR24═N—OR25NR24C(O) NR22R23—NR24SO2R25, —NR24C(O)R25, —S(O)0-2R24, —SO2NR24R25, —C(NR26R27)═NR28;
• —Sn(R24)3, —SiR24R24R25, —B(OR24)2, —P(O)OR24OR25,aryloxy, Het2-oxy, or a group of formula
• —Z, —CO—Z or —CO—NRY—Z
• in which Ry is hydrogen or C1-4alkyl and Z is phenyl or a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, the phenyl or heterocyclic ring being optionally substituted by one or two substituents each independently selected from halo, cyano, hydroxycarbonyl, aminocarbonyl, C1-6alkylthio, hydroxy, —NR22R23, C1-6alkylsulphonylamino, C1-6alkyl, haloC1-6alkyl,C1-6alkyloxy or phenyl;
• or
• two R1 substituents adjacent to one another on the phenyl ring may form together a bivalent radical of formula
• —O—CH2—O— (a-1)—O—CH2—CH2—O— (a-2)—O—CH═CH— (a-3)—O—CH2—CH2— (a-4)—O—CH2—CH2—CH2— (a-5)—CH═CH—CH═CH— (a-6)
• R24 and R25 are independently hydrogen, C1-6 alkyl, —(CR20R21)p—C3-10cycloalkyl or arylC1-6alkyl;
• R26, R27 and R28 are independently hydrogen and C1-6alkyl or C(O) C1-6alkyl;
• R2 is a mono- or bi-cyclic heterocyclic ring containing either at least one oxygen heteroatom or two or more heteroatoms selected from oxygen, sulphur and nitrogen, each such ring being optionally substituted by one or two substituents each independently selected from halo, cyano, hydroxy, nitro, C1-6alkyl, haloC1-6alkyl, -alkylNR22R23 C1-6alkyloxy, OCF3, hydroxycarbonyl, C1-6alkyloxycarbonyl, —CONR22R23, —NR22R23, C1-6alkylsulfonylamino, oxime, phenyl or benzyl;
• R3 is hydrogen, halo, cyano, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, haloC1-6alkyl, cyanoC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, arylC1-6alkyloxyC1-6alkyl,C1-6alkylthioC1-6alkyl, hydroxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, —C1-6alkyl-NR22R23, —C1-6alkyl-CONR22R23, arylC1-6alkyl, Het2C1-6alkyl, C2-6alkenyl, —C2-6alkenylNR22R23, C2-6alkynyl, hydroxycarbonyl, C1-6alkyloxycarbonyl, aryl, or Het2;
• or
• a radical of formula
• —O—R10 (b-1)—S—R10 (b-2) or—NR11R12 (b-3)
• wherein R10 is hydrogen, C1-6alkyl, —(CR2 R21)p—C3-10cycloalkyl, arylC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkylcarbonyl, aryl, a group of formula —NR22R23R or —C1-6alkylC(O)OC1-6alkyl NR22R23, or a radical of formula -Alk-OR13 or -Alk-NR14R15;
• R11 is hydrogen, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, aryl or arylC1-6alkyl;
• R12 is hydrogen, hydroxy, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, C1-6alkylcarbonylC1-6alkyl, arylC1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, C1-6alkyloxy, a group of formula —NR22R23, C1-6alkylcarbonylamino, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, arylC1-6alkylcarbonyl, Het2C1-6alkylcarbonyl, arylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkyloxyC16alkylcarbonyl, aminocarbonyl, mono- or
• di(C1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl andC1-6alkyloxycarbonyl substiuents;
• aminocarbonylcarbonyl, mono- ordi(C1-di(C1-6alkyl)aminoC1-6alkylcarbonyl, or a radical of formula -Alk-OR13 or Alk-NR14R15;
• wherein Alk is C1-6alkanediyl;
• R13 is hydrogen, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl , C2-6alkenyl, C2-6alkynyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, aryl or arylC1-6alkyl;
• R14 is hydrogen,C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, aryl or arylC1-6alkyl;
• R15 is hydrogen, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl , C2-6alkenyl, C2-6alkynyl, C1-6alkylcarbonyl, aryl or arylC1-6alkyl;
• R4 is a radical of formula
• 34
• wherein
• R16 is hydrogen, halo, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylS(O)0-2C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, a group of formula —NR22R23, hydroxycarbonyl, C1-6alkyloxycarbonyl or aryl,
• R17 is hydrogen, C1-6alkyl, —(Cr20R21)p—C3-10cycloalkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, aryl C1-6alkyl, trifluoromethyl, trifluoromethylC1-6alkyl, hydroxycarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, mono- or di (C1-6alkyl)aminosulphonyl or —C1-6alkylP(O)OR24OR25;
• R5 is cyano, hydroxy, halo, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyloxy, arylC1-6alkyloxy, Het2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, or a group of formula —NR22R23or —CONR22R23;
• R6is hydrogen, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, cyanoC1-6alkyl, —C1-6alkylCO2R24, aninocarbonylC1-6alkyl or —C1-6alkyl-NR22R23, R24SO2, R24SO2C1-6alkyl, —C1-6alkyl-OR24, —C1-6alkyl-SR24, —C1-6alkylCONR22—C1-6alky-NR22R23, —C1-6alkylCONR —Cl alkyl-Het2, —C1-6alkylCONR22—C1-6alkyl-Ar2, —C1-6alkyl CONR22-Het2, —C1-6alkylCONR22Ar2, —C1-6alkylCONR22—O—C1-6alkyl, —C1-6alkylCONR22—C1-6alkenyl, -Alk-Ar or -AlkHet2;
• R7 is oxygen or sulphur;
• Ar2 is phenyl, naphthyl or phenyl or naphthyl substituted by one to five substituents each independently selected from halo, hydroxy, cyano, nitro, C1-6alkyl, haloC1-6alkyl, -alkylNR22R23, C1-6alkyloxy, OCF3, hydroxycarbonyl, C1-6alkyloxycarbonyl, aryloxy, —NR22R23, C1-6alkylsulfonylamino, oxime or phenyl, or a bivalent substituent of formula —O—CH2—O— or —O—CH2—CH2—O—;
• Het2 is a mono- or bi-cyclic heterocyclic ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen and optionally substituted by one or two substituents each independently selected from halo, hydroxy, cyano, nitro, C1-6alkyl, haloC1-6alkyl, -alkylNR22R23, C1-6alkyloxy, OCF3, hydroxycarbonyl, C1-6alkyloxycarbonyl, —CONR22R23, —NR22R23, C1-6alkylsulfonylamino, oxime or phenyl.