Farnesyl transferase inhibiting 4-heterocyclyl-quinoline and quinazoline derivatives

A compound of formula (I):

• or a pharmaceutically acceptable salt or N-oxide or stereochemically isomeric form thereof, wherein
• s is 0, 1, 2, 3, 4 or 5;
• t is 0, 1, 2 or 3;
• >Y1—Y2— is a trivalent radical of formula
• >C═N— (y-1),
• >C═CR9— (y-2),
• >CH—NR9— (y-3), or
• >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-NR22R23, —CONR22R23 or —NR22—C1-6alkyl-NR22R23;
• R1 is a group of formula —Z-Het2
• in which Het2 is as defined below and Z is a bond, —O—, —S—, —SO—, —SO2—, —NR22—, —Alk—, C2-4alkenediyl, —O—Alk—, —Alk—O—, —S(O)0-2—Alk—, —Alk—S(O)0-2, —OC(O)—Alk—, —Alk—OC(O)—, —NR22—Alk—, —Alk—NR22—, —NR22—C(O)— or —C(O)—NR22— (in which Alk is C1-6alkanediyl) and in which the Alk or alkenediyl moiety may be optionally substituted by one or more substituents independently selected from C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl or Ar2, and where necessary to establish the configuration of any Z group, the first atom recited above in any such group being that which is linked to the Y1 grouping in formula (I);
• R2 is azido, hydroxy, halo, cyano, nitro, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl,
• cyanoC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, hydroxycarbonylC1-6alkyloxyC1-6alkyl, R24C1-6alkyl, trihalomethyl, arylC1-6alkyl, Het2C1-6alkyl, —C1-6alkyl-NR22R23, —C1-6alkylNR22-C1-6alkyl-NR22R23, —C1-6alkylNR22-Het2, —C1-6alkylNR22—C1-6alkyloxyC1-6alkyl, —C1-6alkylNR22—C6alkyl-S—C1-6alkyl-Ar2, —C1-6alkylNR22—C1-6alkyl-S—C1-6alkyl, —C1-6alkylNR22C1-6alkyl-Ar2 (in which the C1-6alkyl moiety adjacent to the Ar2 is optionally substituted by C1-6alkyloxycarbonyl), —C1-6alkylNR C1-6alkyl-Het2, —C1-6alkylNR22COC1-6alkyl, —C1-6alkylNR22COAlkAr2, —C1-6alkylNR22COAr2, C1-6alkylsulphonylaminoC1-6alkyl, C1-6alkyloxy, hydroxyC-1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, —OC1-6alkyl-NR22R23, trihalomethoxy, arylC16alkyloxy, Het2C1-6alkyloxy, C1-6alkylthio, C2-6alkenyl, cyanoC26alkenyl, —C2-6alkenyl-NR22R23, hydroxycarbonylC2-6alkenyl, C16alkyloxycarbonylC26alkenyl, C2-6alkynyl, —CHO, C1-6alkylcarbonyl, hydroxyC1-6alkylcarbonyl, hydroxycarbonyl, C1-6alkyloxycarbonyl, —CONR22R23, —CONR22—C1-6alkyl-NR22R23, —CONR22—C1-6alkyl-Het2, —CONR22—C1-6alkyl-Ar2, —CONR22-Het2, —CONR22Ar2, —CONR22—O—C1-6alkyl, —CONR22—C1-6alkenyl, —NR22R23, —OC(O)R24, —CR24═NR25, —CR24═N—OR25, —NR24C(O)NR22R23, —NR24SO2R25, —NR24C(O)R25, —S(O)0-2R24, —SO2NR24R25, —C(NR26R27)═NR28;
• —Sn(R24)3, —SiR24R24R25, —B(OR24 )2, —P(O)OR24OR25, Ar2oxy, 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, —COOR24, aminocarbonyl, C1-6alkylthio, hydroxy, —NR22R23, C1-6alkylsulphonylamino, C1-6alkyl, haloC1-6alkyl, C1-6alkyloxy or phenyl;
• or
• two R2 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), or
• —CH═CH—CH═CH— (a-6);
• p is 0 to 5;
• R20 and R21 are independently hydrogen or C1-6 alkyl 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;
• R24 and R25are independently hydrogen, C1-6 alkyl, —(CR20R21)p—C3-10cycloalkyl or arylC1-6alkyl;
• R26, R27 and R28 are independently hydrogen, C1-6alkyl or C(O)C1-6alkyl;
• 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, —C2-6alkenyl NR22R23, C2-6alkynyl, hydroxycarbonyl, C1-6alkyloxycarbonyl, aryl, or Het2;
• or a radical of formula
• —O—R10 (b-1),
• —S—R10 (b-2),
• —NR11R12 (b-3), or
• —N═CR10R11 (b-4),
• wherein R10 is hydrogen, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, arylC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkylcarbonyl, aryl, a group of formula —NR22R23 or —C1-6alkylC(O)OC1-6alkyl NR22R23 or a group 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, C1-6 alkyloxy, a group of formula —NR22R23, C1-6alkylcarbonylamino, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, arylC1-6alkylcarbonyl, Het2C1-6alkylcarbonyl, arylcarbonyl, C1-6alkyloxycarbonyl, trihaloC1-6alkyloxycarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, aminocarbonyl, mono- or di-(C1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl and C1-6alkyloxycarbonyl substituents;
• aminocarbonylcarbonyl, mono- or di-(C1-6alkyl)aminoC1-6alkylcarbonyl, or a radical of formula —Alk—OR13 or —Alk—NR14R15;
• 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
• wherein R16 is hydrogen, halo, C1-6alkyl, —(CR20R21)p—C3-10-cycloalkyl, 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—C3-10-cycloalkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, aryl C1-6alkyl, trifluoromethyl, trifluoromethylC1-6alkyl, hydroxycarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, mono- or di-(C1-6alkyl)aminosulphonyl or —C1-6alkyl P(O)OR24OR25;
• R18 is hydrogen, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl , arylC1-6alkyl or C1-6alkyloxyC1-6alkyl;
• R18a is hydrogen, —SH or —SC1-4alkyl;
• 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;
• R6 is hydrogen, C1-6alkyl, —(CR20R21)p—C3-10cycloalkyl, cyanoC1-6alkyl, —C1-6alkylCO2R24, aminocarbonylC1-6alkyl or —C1-6alkyl-NR22R23, R24SO2, R24SO2C1-6alkyl, —C1-6alkyl-OR24, —C1-6alkyl-SR24, —C1-6alkylCONR22—C1-6alkyl-NR22R23, —C1-6alkylCONR22—C1-6alkyl-Het2, —C1-6alkyl CONR22—C1-6alkyl-Ar2, —C1-6alkyl CONR22-Het2, —C1-6alkyl CONR22Ar2, —C1-6alkylCONR22-O—C1-6alkyl, —C1-6alkyl CONR22—C1-6alkenyl, —Alk—Ar2 or —AlkHet2;
• and
• R7 is oxygen or sulphur;
• or R6 and R7 together form a trivalent radical of formula:
• —CR30═CR31—N═ (x-1),
• —CR30═N—N═ (x-2),
• —C(═O)—NH—N═ (x-3),
• —N═N—N═ (x-4),
• —N═CR30—N═ (x-5),
• —CR30═CR31—CR32═ (x-6),
• —CR30═N—CR31═ (x-7),
• —C(═O)—NH—CR30═ (x-8),
• —N═N—CR30═ (x-9), or
• —CH2—(CH2)0-1—CH2—N═ (x-10),
• wherein each R30, R31 and R32 are independently hydrogen, C1-6 alkyl, —OR24, —COOR24, —NR22R23, —C1-6 alkylOR24, —C1-6 alkylSR24, R23R22NC1-6alkyl-, —CONR22R23, C2-6alkenyl, C2-6alkenylAr2, C2-6alkenylHet2, cyano, amino, thio, C1-6 alkylthio, —O—Ar2, —S—Ar2 or Ar2;
• 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, —C1-6alkylNR22R23, 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—;
• and
• Het is a monocyclic or bicyclic 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, —C1-6alkylNR22R23, C1-6alkyloxy, OCF3, hydroxycarbonyl, C1-6alkyloxycarbonyl, —CONR22R23, —NR22R23, C1-6alkylsulfonylamino, oxime or phenyl.