Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives

A compound of Formula I:

• or pharmaceutically acceptable salt therof, wherein:
• R is hydrogen, PO(OH)2, P(═O)(O—(C1-C˜)alkylenephenyl))2, P(═O)(OH)(OM), or P(═O)(OM)2;
• W is benzo[d] [1,3]dioxol-4-yl, 2,3-di(C1-C18)alkoxyphenyl, 2,5-di(C1-C18)alkoxyphenyl, 2-(C1-C18)alkoxyphenyl, 4-(C1-C18)alkoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3-(C1-C18)alkoxyphenyl, 5-hydroxy-2-(C1-C18)alkoxy phenyl, 3-(O-di(C1-C18)alkylenephenyl))phenyl, 3-(O-dihydrogen phosphate)phenyl, or 2,5-dihydroxyphenyl;
• R5 is hydrogen;
• R6 hydroxyl, (C1-C18)alkoxy, N,N-di(C1-C18)alkylamino, or N—(C1-C18)cycloalkylamino;
• R7 is hydrogen.

A compound of Formula I:

• or pharmaceutically acceptable salt, thereof, wherein:
• R is hydrogen;
• W is 2-halophenyl, 3-halophenyl, 4-halophenyl;
• R5 and R6 are (C1-C18)alkylenedioxy provided that R7 is hydrogen;
• and
• R8 is hydrogen.

A compound of Formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• R is hydrogen, P(—O)(OH)2, P(═O)(O—(C1-C18)alkylenephenyl)2,
• W is naphtha-1-yl, naphtha-2-yl, quinolin-2-yl, quinolin-3-yl, anthracen-1-yl, benzo[b]furan-3-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl, 3-([bis-[((C1-C18)alkylenephenyl)oxy]]phosphoryl)oxy-5-(C1-C18)alkoxy phenyl, 3-(dihydrogen)phosphate-5-(C1-C18)alkoxy phenyl;
• and
• R6 and R7 are (C1-C18)alkylenedioxy provided that R5 is hydrogen.

A process for preparing a compound of Formula I

• (i)wherein
• R is hydrogen;
• W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, benzo[d] [1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 4-metboxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyoxyphenyl, 4-benzyloxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3-benzyoxy-5-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl, benzo[b]furan-3-yl, or naphtha-1-yl;
• R5 is methoxy, hydroxyl, or OR8, or R5 and R6 are methylenedioxy provided that R7 is hydrogen;
• R6 is N,N-dimethyamino, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;
• R7 is hydrogen, hydroxyl, or O-benzyl;
• and
• R8 is hydrogen;
• or a pharmaceutically acceptable salt thereof;
• (ii) or wherein
• R is hydrogen;
• W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, benzo[d ] [1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxphenyl, 4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl, benzo[b]furan-3-yl, or naphtha-1-yl;
• R5 is hydrogen, methoxy, hydroxyl, or OR8;
• R6 is N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;
• R7 is hydroxyl, or O-benzyl;
• or R6 and R7 are methylenedioxy provided that R5 is hydrogen;
• and
• R8 is hydrogen,
• the method comprising;
• ai) reacting a compound of Formula II
• wherein R5 is hydroxyl, methoxy, or OR8, or R5 and R6 are methylenedioxy provided that R7 is hydrogen;
• R6 is hydroxyl, N,N-dimethylamino, methoxy, N-morpholino, or N-pyrrolindino;
• R7 is hydrogen, halo, OR8, hydroxyl, or O-benzyl;
• and
• R8 is hydrogen;
• (aii) or reacting a compound of Formula II
• wherein
• R5 is hydrogen, hydroxyl, methoxy, or OR8;
• R6 hydroxyl, N,N-dimethylamino, methoxy, N-morpholino, or N-pyrrolindino;
• R7 is halo, OR8, hydroxyl, or O-benzyl;
• or R6 and R7 are methylenedioxy provided that R5 is hydrogen;
• and
• R8 is hydrogen;
• with a compound of Formula III
• in the presence of a base;
• wherein W is 2-fluorophenyl, 3-fluorophenyl, 4fluorophenyl, benzo[d] [1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl,4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl, benzo[b]furan-3-yl, or naphtha-1-yl;
• to afford a compound of Formula IV
• (1) wherein
• R is hydrogen;
• W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, benzo[d ] [1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxvphenyl, 4-benzyloxphenyl, 4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl, benzo[b]furan-3-yl, or naphtha-1-yl;
• R5 is methoxy, hydroxyl, or OR8, or R5 and R6 are methylenedioxy provided that R7 is hydrogen;
• R6 is N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;
• R7 is hydrogen, hydroxyl, or O-benzyl;
• and
• R8 is hydrogen;
• (2) or wherein
• R is hydrogen;
• W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, benzo[d ] [1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxphenyl, 4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl, benzo[b]furan-3-yl, or naphtha-1-yl;
• R5 is hydrogen, methoxy, hydroxyl, or OR8,
• R6 is N,N-dimethydroxyl, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;
• R7 is hydroxyl or O-benzyl;
• or R6 and R7 are methylenedioxy provided that R5 is hydrogen;
• and
• R8 is hydrogen;
• (b) and reacting the compound of Formula IV with a base to afford the compound of Formula I.