Substituted quinolines as antitumor agents

摘要

The invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt, pro-drug or solvate thereof. wherein: n is 0 or 1; Y is selected from -NH-, -O-, -S-, or -NR⁷- where R⁷ is alkyl of 1-6 carbon atoms; R⁵ is cyano, fluoro, chloro or bromo; 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 optionally mono- di-, or tri-substituted; 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; and where X is selected from -NH-, -O-, -S-, CH₂ or -NR^7'- where R^7' 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 optionally substituted heterocyclic ring or an N-oxide of any nitrogen containing ring; R¹, R², R⁴ are independently selected from hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C_1-3alkyl, -NR¹¹R¹²- (wherein R¹¹ and R¹², which may be the same or different each represents hydrogen, or C_1-3alkyl), 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- -NR¹⁸- or -NR¹⁸NR¹⁸- (wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ each independently represents hydrogen, C_1-3alkyl or C_1-3alkoxyC_2-3alkyl)), and R¹³ is hydrogen, optionally substituted hydrocarbyl, or optionally substituted heterocyclyl; and R³ is selected from (i) a group of formula -X¹-R^x-(OH)_p where X¹ is as defined above, R^x is an alkylene, alkenylene or alkynylene chain, optionally interposed with a heteroatom or a heteocyclic ring and p is 1 or 2; (ii) a group of formula R^13a-(CH₂)_y-X¹-(CH₂)_x where R^{13 a} is as defined for R¹³ above, and X¹ and x are as defined above, y is 0 or an integer between 1 and 5, wherein (CH₂)_y is optionally interposed by an X¹ group; (iii) a group of formula -X¹-R^y-NR^z-R^y'-S-R^y'' where X¹ is as defined above, R^y, R^y' and R^y'' are independently selected from alkyl, alkenyl or alkynyl chains, and R^z is hydrogen or alkyl, or R^z and R^y'' are joined together to form an optionally substituted nitrogen and sulphur containing ring; (iv) a group of formula -X¹-R^x'-(C_3-6cycloalkyl) where X¹ is as defined above and R^x' is an alkylene, alkenylene or alkynylene chain, optionally interposed with a heteroatom a group of the formula -X¹-C_1-5alkyl where X¹ is as defined above and C_1-5alkyl is substituted by one more substituents independently selected from chloro and cyano; (v) a group of the formula -X¹-C_1-3alkyl-CO-NR¹⁸NR¹⁸-R²⁰ where R¹⁸ is as defined above and R²⁰ is selected from hydrogen or C_1-5alkoxycarbonyl; or (vi) a heterocyclic ring. The invention also provides a process for the preparation of a compound of Formula (Ia), pharmaceutical compositions of a compound of Formula (Ia) and methods for the treatment or prevention of cancer comprising administering an effective amount of a compound of Formula (1a).