4-Substituted quinolines as antitumor agents

A compound of formula (I)

• or a pharmaceutically acceptable salt, pro-drug or solvate thereof
• wherein:
• n is 0;
• Y is —NH—;
• R5 is cyano, fluoro, chloro or bromo;
• R8 is a divalent phenyl ring, wherein the phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino;
• X is —O—;
• m is 0;
• p is independently selected from 0, 1, 2 or 3;
• R10 is an optionally substituted phenyl ring;
• -Z- is a direct bond or a group of sub-formula (i)
• —X12—R75—X13—(R76—X14)s—(R77—X15)s′— (i)
• where X12, X13 each X14 and each X15 are independently selected from —O—, —C(O)—, —C(O)O—, —S—, —SO—, —SO2—, —NR78C(O)—, —NR78C(O)O—, —C(O)NR79—, —C(O)ONR79—, —SO2NR80—, —NR81SO2— or —NR82— (wherein R78, R79, R80, R81 and R82 each independently represents hydrogen, C1-3alkyl optionally substituted by hydroxy, or C1-3alkoxyC2-3alkyl) and each X13, X14 and X15 may additionally be a direct bond;
• s and s′ are independently selected from 0, 1, 2 or 3,
• R75, R76 and R77 are independently selected from C1-6alkylene, C2-6alkenylene or C2-6alkylene optionally substituted by halo and hydroxy or R75, R76 and R77 can each independently be direct bonds;
• R9 is an optionally substituted divalent heterocyclic group, C1-5alkylene, or divalent C3-7cycloalkyl;
• R6 is hydrogen, amino or a group of sub-formula (ii)
• —X16—R83—(X17R84)t—X18R85 (ii)
• where X16, X18 and each X17 are each independently selected from a direct bond, —O—, —C(O)—, —S—, —SO—, —SO2—, —NR86C(O)—, —NR86C(O)O—, —C(O)NR87—, —C(O)ONR87—, —SO2NR88—, —NR89SO2— or —NR90— (wherein R86, R87, R88, R89 and R90 each independently represent hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl);
• R83 and each R84 are independently selected from C1-6alkylene, C2-6alkenylene or C2-6alkenylene;
• R85 is selected from hydrogen, C1-6alkyl, C2-6alkenyl or C2-6alkynyl;
• t is 0, 1, 2 or 3;
• R1, R2, R3, R4 are independently selected from hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, —NR11R12— (wherein R11 and R12, which may be the same or different, each represents hydrogen, or C1-3alkyl), or a group R13—X1—(CH2)x wherein x is 0 or an integer of from 1 to 3;
• X1 represents a direct bond, —O—, —CH2—, —OC(O)—, —C(O)—, —S—, —SO—, —SO2—, —NR14C(O)—, —NR14C(O)O—, —C(O)NR15—, —C(O)ONR15—, —SO2NR16—, —NR17SO2— or —NR18— (wherein R14, R15, R16, R17 and R18 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl), and R13 is hydrogen or an optionally substituted hydrocarbyl;
• provided that:
• i) where the group of sub-formula (ii) is C1-6alkyl or R6 is hydrogen and R9 is a divalent heterocycyl, Z is other than a direct bond, or the group -Z(CH2)p— is other than C2 alkylene, or the group of sub-formula (i) is other than —S—;
• ii) the group R9—R6 cannot together be C1-5 alkyl, C2-6 alkenyl, C2-6alkynyl or (C1-5 alkylene)OH unless
• a) in the group of sub-formula (i), R75 or R76 is the group —C(RARB)— where RA and RB are each independently selected from C1-3 alkyl, C2-3 alkenyl,C2-3 alkynyl and halo;
• b) in the group of sub-formula (i), where the terminal group X12, X13 or X14 linked to —(CH2)p— or —R9, is selected from —C(O)NR79—;
• —C(O)ONR79;
• —SO2NR80 and —NR78C(O);
• then R78, R79, and R80 are other than hydrogen;
• c) the group of sub-formula (i) is selected from —C(O)—NR82—O— and —O—CH2—C(O)—NR82—CH2—C(O)O—, where R82 is other than hydrogen;
• d) the group —R10-Z-(CH2)pR9—R6 is selected from
• where R99 is selected from —NC(O)CH3, —NC2H5 or —OCH3;
• R97 and R98 are each independently selected from hydrogen and fluoro, provided that at least one of R97 and R98 is fluoro;
• * denotes, the point of attachment;
• and
• p, R9 and R6 are as hereinbefore defined;
• iii) where the group of sub-formula (i) comprises the group
• —X12—R75—X13—(R76—X14)s—(R77—X15)s′—
• where X12 is selected from —O—, —NR82—, or —NR78C(O)—;
• X13 is selected from —C(O)NR79, a direct bond or —NR82—;
• R76, X14, R77, X15, s and s′ are as hereinbefore defined;
• then R75 is —C(RARB)— where RA and RB are each independently selected from C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl and halo;
• unless
• (i) R9 is piperazinyl linked through the nitrogen atoms or pyridyl;
• (ii) R75 is 1-3 alkyl substituted by hydroxy;
• or
• (iii) R79 is other than hydrogen;
• or
• iv) where the group of sub-formula (i) is selected from —(CH2)2C(O)— or —O—(CH2)2— and R9 is a divalent heterocyclic group, then R6 is other than hydrogen.