Quinoline derivatives as inhibitors of MEK enzymes

A compound of formula (IB)

• or a pharmaceutically acceptable salt thereof
• wherein
• n is 0-1;
• Y is selected from —NH—, —O—, —S—, or —NR7— where R7 is alkyl of 1-6 carbon atoms;
• R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups;
• or is a pyridinyl, pyrimidinyl, or phenyl ring;
• wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substituted with one, two or three groups selected from the group consisting of 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, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, and benzoylamino;
• or R6 is a group —R8—X—R9 where
• R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl of 1 to 6 carbon atom groups;
• or is a divalent pyridinyl, pyimidinyl, or phenyl ring;
• wherein the pyridinyl, pyrimidinyl, or 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 selected from CH2, —NH—, —O—, —S—, or —NR5— where R5 is alkyl of 1-6 carbon atoms, and
• R9 is a group (CH2)mR10 where m is 0, or an integer of from 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substituents;
• and
• at least one of R1″, R2″, R3″ or R4″ is a group R13′—X1—(CH2)x wherein x and X1 are as defined below and R13′ is alkyl substituted by chloro or bromo;
• and the remainder of the groups R1″, R2″, R3″ or R4″ are the groups of R1, R2, R3 and R4 respectively where R1, R2, R3 and R4 are each 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 to 3, X1 represents —O—, —CH2—, —OCO—, carbonyl, —S—, —SO—, —SO2—, —NR14CO—, —CONR15—, —SO2NR16—, —NR17SO2— or —NR18— (wherein R14, R15, R16, R17 and R18 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R13 is selected from one of the following sixteen groups:
• 1) C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino;
• 2) C1-5alkylX2COR19 (wherein X2 represents —O— or —NR20— (wherein R20 represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R19 represents —NR21R22— or —OR23— (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl));
• 3) C1-5alkylX3R24 (wherein X3 represents —O—, —S—, —SO—, —SO2—, —OCO—, —NR25CO—, —CONR26—, —SO2NR27—, —NR28SO2— or —NR29— (wherein R25, R26, R27, R28 and R29 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R24 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which C1-3alkyl group may bear one or two substituents selected from oxo, hydroxy, halogeno and C1-4alkoxy and which cyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
• 4) C1-5alkylX4C1-5alkylX5R30 (wherein X4 and X5 which may be the same or different are each —O—, —S—, —SO—, —SO2—, —NR31CO—, —CONR32—, —SO2NR33—, —NR34SO2— or —NR35— (wherein R31, R32, R33, R34 and R35 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R30 represents hydrogen or C1-3alkyl);
• 5) C1-5alkylR36 (wherein R36 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms, selected independently from O, S and N, which heterocyclic group may bear one or two substituents selected from oxo, hydroxy, halogeno, C1-4alkyl, C1-4hydroxyalkyl and C1-4alkoxy);
• 6) (CH2)qX6R37 (wherein q is an integer from 0 to 5, X6 represents a direct bond, —O—, —S—, —SO—, —SO2—, —NR38CO—, —CONR39—, —SO2NR40—, —NR41SO2— or —NR42— (wherein R38, R39, R40, R41 and R42 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R37 is a phenyl group, a pyridone group or a 5 or 6 membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, which phenyl, pyridone or aromatic heterocyclic group may carry up to 5 substituents selected from hydroxy, halogeno, amino, C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4hydroxyalkoxy, C1-4aminoalkyl, C1-4alkylamino, carboxy, cyano, —CONR43R44 and —NR45COR46 (wherein R43, R44, R45 and R46, which may be the same or different, each represents hydrogen, C1-4alkyl or C1-3alkoxyC2-3alkyl));
• 7) C2-6alkenylR36 (wherein R36 is as defined hereinbefore);
• 8) C2-6alkynylR36 (wherein R36 is as defined hereinbefore);
• 9) X7R47 (wherein X7 is —SO2—, —O— or —CONR48R49— (wherein R48 and R49, which may be the same or different, each represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R47 represents C1-5alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino) with the provisos that when X7 is —SO2—, X1 is —O—, when X7 is —O—, X1 is carbonyl, when X7 is —CONR48R49—, X1 is —O— or NR18 (wherein R48, R49 and R18 are as defined hereinbefore);
• 10) C2-6alkenylR37 (wherein R37 is as defined hereinbefore);
• 11) C2-6alkynylR37 (wherein R37 is as defined hereinbefore);
• 12) C2-6alkenylX8R37 (wherein X8 represents —O—, —S—, —SO—, —SO2—, —NR50CO—, —CONR51—, —SO2NR52—, —NR53SO2— or —NR54— (wherein R50, R51, R52, R53 and R54 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R37 is as defined hereinbefore);
• 13) C2-6alkynylX9R37 (wherein X9 represents —O—, —S—, —SO—, —SO2—, —NR55CO—, —CONR56—, —SO2NR57—, —NR58SO2— or —NR59— (wherein R55, R56, R57, R58 and R59 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R37 is as defined hereinbefore);
• 14) C1-3alkylX10C1-3alkylR37 (wherein X10 represents —O—, —S—, —SO—, —SO2—, —NR60CO—, —CONR61—, —SO2NR62—, —NR63SO2— or —NR64— (wherein R60, R61, R62, R63 and R64 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl) and R37 is as defined hereinbefore);
• 15) R36 (wherein R36 is as defined hereinbefore);
• and
• 16) C1-3alkylX10C1-3alkylR36 (wherein X10 and R36 are as defined hereinbefore).