Farnesyl protein transferase inhibitor combinations with anti-tumor anthracycline derivatives

A combination of an anti-tumor anthracyline derivative and a farnesyl transferase inhibitor selected from compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) below:

• 10
• the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
• the dotted line represents an optional bond;
• X is oxygen or sulfur;
• R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl, or a radical of formula —Alk1—C(═O)—R9, —Alk1—S(O)—R9 or —Alk1—S(O)2—R9,
• wherein
• Alk1 is C1-6alkanediyl,
• R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or
• C1-8alkylamino substituted with C1-6alkyloxycarbonyl;
• R2, R3 and R16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl;
• or
• when on adjacent positions R2 and R3 taken together may form 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);
• R4 and R5 each independently are hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
• R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar2oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or when on adjacent positions R6 and R7 taken together may form a bivalent radical of formula
• —O—CH2—O— (c-1), or—CH═CH—CH═CH— (c-2);
• R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)-aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, or a radical of formula
• —O—R10 (b-1),—S—R10 (b-2),—N—R11R12 (b-3),
• wherein
• R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical or formula —Alk2—OR13 or —Alk2—NR14R15;
• R11 is hydrogen, C1-12alkyl, Ar1 or Ar2C1-6alkyl;
• R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, a natural amino acid, Ar1carbonyl, Ar2C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula —Alk2 OR13 or —Alk2—NR14R15;
• wherein
• Alk2 is C1-6alkanediyl;
• R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, Ar1 or Ar2C1-6alkyl;
• R14 is hydrogen, C1-6alkyl, Ar1 or Ar2C1-6alkyl;
• R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar2C1-6alkyl;
• R17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar1;
• R18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;
• R19 is hydrogen or C1-6alkyl;
• Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo;
• and
• Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.
• 11
• the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein
• the dotted line represents an optional bond;
• X is oxygen or sulfur;
• R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridyl-C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl, or a radical of formula —Alk1—C(═O)—R9, —Alk1—S(O)—R9 or —Alk1—S(O)2—R9,
• wherein Alk1 is C1-6alkanediyl,
• R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;
• R2 and R3 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, amino-C1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl;
• or
• when on adjacent positions R2 and R3 taken together may form 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);
• R4 and R5 each independently are hydrogen, Ar1, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
• R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy or Ar2oxy;
• R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkyl-carbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, hydroxy-carbonylC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)-aminoC1-6alkyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, Ar1, Ar2C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl;
• R10 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;
• R11 is hydrogen or C1-6alkyl;
• Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6akyloxy or halo,
• Ar2 is phenyl or phenyl substituted with C1-6alkyl,hydroxy,amino,C1-6alkyloxy or halo.
• 12
• the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
• the dotted line represents an optional bond;
• X is oxygen or sulfur;
• —A— is a bivalent radical of formula
• —CH═CH— (a-1), —CH2—S— (a-6),—CH2—CH2— (a-2), —CH2—CH2—S— (a-7),—CH2—CH2—CH2— (a-3), —CH═N (a-8),—CH2—O— (a-4), —N═N— (a-9), or—CH2—CH2—O— (a-5), —CO—NH— (a-10);
• wherein optionally one hydrogen atom may be replaced by C1-4alkyl or Ar1;
• R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar2, Ar2-C1-6alkyl, Ar2-oxy, Ar2-C1-6alkyloxy;
• or when on adjacent positions R1 and R2 taken together may form a bivalent radical of formula
• —O—CH2—O— (b-1),—O—CH2—CH2—O— (b-2),—O—CH═CH— (b-3),—O—CH2—CH2— (b-4),—O—CH2—CH2—CH2— (b-5), or—CH═CH—CH═CH— (b-6);
• R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar3-oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R3 and R4 taken together may form a bivalent radical of formula
• —O—CH2— (c-1)O—CH2—CH2—O— (c-2), or—CH═CH—CH═CH— (c-3);
• R5 is a radical of formula
• 13
• wherein R13 is hydrogen, halo, Ar4, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxy-C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
• R14 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;
• R6 is hydrogen, hydroxy, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar5, Ar5-C1-6alkyloxyC1-6alkyl;
• or a radical of formula
• —O—R7 (e-1),—S—R7 (e-2),—N—R8R9 (e-3),
• wherein
• R7 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar6, Ar6-C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula —Alk—OR10 or —Alk—NR11R12;
• R8 is hydrogen, C1-6alkyl, Ar7 or Ar7-C1-6alkyl;
• R9 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar8, Ar8-C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar8-carbonyl, Ar8-C1-6alkylcarbonyl, aminocarbonyl-carbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula —Alk—OR10 or —Alk—NR11R12.
• wherein
• Alk is C1-6alkanediyl;
• R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl,
• Ar9 or Ar9-C1-6alkyl;
• R11 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar10 or
• Ar10-C1-6alkyl;
• R12 is hydrogen, C1-6alkyl, Ar11 or Ar11-C1-6alkyl;
• and
• Ar1 to Ar11 are each independently selected from phenyl;
• or phenyl substituted with halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
• 14
• the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
• the dotted line represents an optional bond;
• X is oxygen or sulfur;
• R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar1C1-6alkyl, Ar1oxy or Ar1 C1-6alkyloxy;
• R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar1oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl or trihalomethoxy;
• R5 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar1, Ar1C1-6alkyloxyC1-6alkyl;
• or a radical of formula
• —O—R10 (a-1),—S—R10 (a-2),—N—R11R12 (a-3),
• wherein
• R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula —Alk—OR13 or —Alk—NR14R15;
• R11 is hydrogen, C1-6alkyl, Ar1 or Ar1 C1-6alkyl;
• R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar1carbonyl, Ar1C1-6alkylcarbonyl, aminocarbonyl-carbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula —Alk—OR13 or —Alk—NR14R15;
• wherein
• Alk is C1-6alkanediyl;
• R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxy-C1-6alkyl, Ar1 or Ar1C1-6alkyl;
• R14 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;
• R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar1C1-6alkyl;
• R6 is a radical of formula
• 15
• wherein
• R16is hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkyl-S(O)2C1-6alkyl;
• R17 is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;
• R7 is hydrogen or C1-6alkyl provided that the dotted line does not represent a bond;
• R8 is hydrogen, C1-6alkyl or Ar2CH2 or Het1CH2;
• R9 is hydrogen, C1-6alkyl , C1-6alkyloxy or halo;
• or
• R8 and R9 taken together to form a bivalent radical of formula
• —CH═CH— (c-1),—CH2—CH2— (c-2),—CH2—CH2—CH2— (c-3),—CH2—O— (c-4), or—CH2—CH2—O— (c-5);
• Ar1 is phenyl;
• or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;
• Ar2 is phenyl;
• or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;
• and
• Het1 is pyridinyl;
• pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl
• and
• 16
• or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
• ═X1—X2—X3— is a trivalent radical of formula
• ═N—CR6═CR7— (x-1),—CR6CR7═CR8— (x-6),═N—N═CR6— (x-2), ═CR6—N═CR7— (x-7),═N—NH—C(═O)— (x-3), ═CR6—NH—C(═O)— (x-8), or═N—N═N— (x-4), ═CR6—N═N— (x-9);═N—CR6═N— (x-5),
• wherein each R6, R7 and R8 are independently hydrogen, C1-4alkyl, hydroxy, C1-4alkyloxy, aryloxy, C1-4alkyloxycarbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, cyano, amino, thio, C1-4alkylthio, arylthio or aryl;
• >Y1—Y2— is a trivalent radical of formula
• >CH—CHR9— (y-1),>C═N— (y-2),>CH—NR9— (y-3), or>C═CR9— (y-4);
• wherein each R9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC1-4alkyl, cyano, carboxyl, C1-4alkyl, C1-4alkyloxy, C1-4alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl, aryl;
• r and s are each independently 0, 1, 2, 3, 4 or 5;
• t is 0,1,2 or 3;
• each R1 and R2 are independently hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkylthio. C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, aryl, arylC1-6alkyl, aryloxy or arylC1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminocarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl;
• or
• two R1 or R2 substituents adjacent to one another on the phenyl ring may independently 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);
• R3 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkyloxycarbonyl, aryl, arylC1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl;
• or a radical of formula
• —O—R10 (b-1),—S—R10 (b-2),—NR11R12 (b-3),
• wherein
• R10 is hydrogen, C1-6alkyl, C1-4alkylcarbonyl, aryl, arylC1-6alkyl, C1-6alkyloxy-carbonylC1-6alkyl, or a radical of formula —Alk—OR13 or —Alk—NR14R15;
• R11 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
• R12 is hydrogen, C1-6alkyl, aryl, hydroxy, amino, C1-6alkyloxy, C1-6alkylcarbonyl-C1-6alkyl, arylC1-6alkyl, C1-6alkylcarbonylamino, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC1-6alkylcarbonyl, arylC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, mono- or di(C1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C1-3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkylcarbonyl, or a radical or formula —Alk—OR13 or —Alk—NR14R15;
• wherein Alk is C1-6alkanediyl;
• R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, aryl or arylC1-6alkyl;
• R14 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
• R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl or arylC1-6alkyl;
• R4 is a radical of formula
• 17
• wherein
• R16 is hydrogen, halo, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-4alkyl)amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
• R16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R16 when bound to the nitrogen is limited to hydrogen, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyl-oxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;
• R17 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, arylC1-6alkyl, trifluoromethyl or di(C1-4alkyl)aminosulfonyl;
• R5 is C1-6alkyl , C1-6alkyloxy or halo;
• aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.