Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,

(i) wherein:

R is hydrogen, PO(OH) 2 , P(═O)(O—(C 1 -C 18 )alkylenephenyl)) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 ;

W is 2-halophenyl, 3-halophenyl, -halophenyl;

R 5 is (C 1 -C 18 )alkoxy, hydrogen, hydroxyl, OR 8 ;

R 6 is hydroxyl, or (C 1 -C 18 )alkoxy;

R 7 is hydrogen, hydroxyl, or O—(C 1 -C 18 )alkylenephenyl;

R 8 is hydrogen, PO(OH) 2 , P(═O)(O—(C 1 -C 18 )alkylenephenyl) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 , and

M is a monovalent or divalent metal ion, or alkylammonium ion;

(ii) or wherein;

R is hydrogen, PO(OH) 2 , P(═O)(O—(C 1 -C 18 )alkylenephenyl) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 ;

W is 2-halophenyl, 3-halophenyl, 4-halophenyl;

R 5 is hydrogen, (C 1 -C 18 )alkoxy, hydroxyl, or OR 8 ;

R 6 is hydroxyl or (C 1 -C 18 )alkoxy;

R 7 hydroxyl, or O—(C 1 -C 18 )alkylenephenyl;

R 8 hydrogen, PO(OH) 2 , P(═O)(O—(C 1 -C 18 )alkylenephenyl) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 ; and

M is a monovalent or divalent metal ion, or alkylammonium ion.

2. The compound of claim 1 ,

(i) wherein;

R is hydrogen, P(═O)(OH) 2 , P(═O)(O-benzyl) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 ;

W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,

R 5 is methoxy, hydroxyl, halo or OR 8 ;

R 6 is hydroxyl or methoxy;

R 7 is hydrogen, hydroxyl, or O-benzyl;

R 8 is hydrogen PO(OH) 2 , P(═O)(O-benzyl) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 , and

M is a sodium ion;

(ii) or wherein

R is hydrogen, PO(OH) 2 , P(═O)(O-benzyl) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 ;

W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,

R 5 is methoxy, hydroxyl, halo or OR 8 ;

R 6 is hydroxyl or methoxy;

R 7 is hydrogen, hydroxyl, or O-benzyl;

R 8 is hydrogen PO(OH) 2 , P(═O)(O-benzyl) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 , and

M is a sodium ion.

3. The compound of claim 2 , wherein the compound is selected from the group consisting of

2-(2-Fluorophenyl)-5,6-dimethoxyquinolin-4-one;

2-(3-Fluorophenyl)-5,6-dimethoxyquinolin-4-one;

2-(4-Fluorophenyl)-5,6-dimethoxyquinolin-4-one;

7-Benzyloxy-2-(2-fluorophenyl)-6-methoxyquinolin-4-one;

7-Benzyloxy-2-(3-fluorophenyl)-6-methoxyquinolin-4-one;

7-Benzyloxy-2-(4-fluorophenyl)-6-methoxyquinolin-4-one;

2-(2-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one;

2-(3-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one;

2-(4-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one;

2-(2-Fluorophenyl)-5,6-dihydroxyquinolin-4-one;

2-(3-Fluorophenyl)-5,6-dihydroxyquinolin-4-one;

2-(4-Fluorophenyl)-5,6-dihydroxyquinolin-4-one;

2-(2-Fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-one;

2-(3-Fluorophenyl)-6-methoxyquinolin-4,5-diyl bis(dibenzyl phosphate),

2-(3-Fluorophenyl)-6-methoxyquinolin-4,5-diyl bis(dihydrogen phosphate),

2-(3-Fluorophenyl)-6-methoxyquinolin-4,5-diyl bis(disodium phosphate),

Dibenzyl 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate,

2-(3-Fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl dihydrogen phosphate, and

Sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate.

4. The compound of claim 2 , wherein the compound comprises is selected from the group consisting of

5. A compound of Formula I:

or pharmaceutically acceptable salt therof, wherein:

R is hydrogen, PO(OH) 2 , P(═O)(O—(C 1 -C ˜ )alkylenephenyl)) 2 , P(═O)(OH)(OM), or P(═O)(OM) 2 ;

W is benzo[d] [1,3]dioxol-4-yl, 2,3-di(C 1 -C 18 )alkoxyphenyl, 2,5-di(C 1 -C 18 )alkoxyphenyl, 2-(C 1 -C 18 )alkoxyphenyl, 4-(C 1 -C 18 )alkoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3-(C 1 -C 18 )alkoxyphenyl, 5-hydroxy-2-(C 1 -C 18 )alkoxy phenyl, 3-(O-di(C 1 -C 18 )alkylenephenyl))phenyl, 3-(O-dihydrogen phosphate)phenyl, or 2,5-dihydroxyphenyl;

R 5 is hydrogen;

R 6 hydroxyl, (C 1 -C 18 )alkoxy, N,N-di(C 1 -C 18 )alkylamino, or N—(C 1 -C 18 )cycloalkylamino;

R 7 is hydrogen.

6. The compound of claim 5 , wherein:

R is hydrogen;

W is benzo[d] [1,3]dioxo 1 -4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3-metboxyphenyl, 5-hydroxy-2-methoxyphenyl, 3-(O-dibenzylphosphate)phenyl, 3-(O-dihydrogen phosphate)phenyl, or 2,5-dihydroxyphenyl;

R 5 is hydrogen;

R 6 is hydroxyl, methoxy, N,N-dimethylamino, N-morpholino, or N-pyrrolindino; and R 7 is hydrogen.

7. The compound of claim 6 , wherein the compound is selected from the group consisting of

2-(benzo[d] [1,3]dioxol-1-yl)-6-morpholinoquinolin-4-one,

2-(benzo[d] [1,3]dioxol-4-yl)-6-pyrrolidinoquinolin-4-one,

2-(2,3-dimethoxyphenyl)-6-morpholinoquinolin-4-one,

2-(2,3-dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(2,5-dimethoxyphenyl)-6-morpholinoquinolin-4-one,

2-(2,5-dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(2-methoxyphenyl)-6-morpholinoquinolin-4-one,

2-(2,5-dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(4-methoxyphenyl)-6-morpholinoquinolin-4-one,

2-(4-methoxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(2-Hydroxyphenyl)-6-morpholinoquinolin-4-one,

2-(2-hydroxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(2-hydroxyphenyl)-6-dimethylaminoquinolin-4-one,

2-(3-Hydroxyphenyl)-6-morpholinoquinolin-4-one,

2-(3-hydroxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(3-hydroxyphenyl)-6-dimethyaminoquinolin-4-one,

2-(4-Hydroxyphenyl)-6-morpholinoquinolin-4-one,

2-(4-hydroxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(4-hydroxyphenyl)-6-dimethylaminoquinolin-4-one,

2-(4-hydroxy-3-methoxyphenyl)-6-morpholinoquinolin-4-one,

2-(5-hydroxy-2-methoxyphenyl)-6-morpholinoquinolin-4-one,

2-(5-hydroxy-2-methoxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(4-hydroxy-3-methoxyphenyl)-6-pyrrolidinoquinolin-4-one,

2-(2,5-dihydroxy-phenyl)-6-morpholinoquinolin-4-one,

2-(2,5dihydroxy-phenyl)-6-pyrrolidinoquinolin-4-one,

Dibenzyl 3-(4-oxo-6-(pyrrolidin-1-yl)- 1,4-dihydroquinolin-2-yl)phenyl phosphate, and

3-(4-Oxo-6-(pyrrolidin-1-yl)-1,4-dihydroquinolin-2-yl)phenyl dihydrogen phosphate.

8. The compound of claim 6 , wherein the compound is selected from the group consisting of

9. A compound of Formula I:

or pharmaceutically acceptable salt, thereof, wherein:

R is hydrogen;

W is 2-halophenyl, 3-halophenyl, 4-halophenyl;

R 5 and R 6 are (C 1 -C 18 )alkylenedioxy provided that R 7 is hydrogen; and

R 8 is hydrogen.

10. The compound of claim 9 , wherein:

R is hydrogen;

W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl;

R 5 and R 6 are methylenedioxy provided that R 7 is hydrogen; and

R 8 is hydrogen.

11. The compound of claim 10 , wherein the compound is selected from the group consisting of

2-(2-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one,

2-(3-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one, and

2-(4-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one.

12. The compound of claim 10 , wherein the compound is selected from the group consisting of

13. A compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein:

R is hydrogen, P(—O)(OH) 2 , P(═O)(O—(C 1 -C 18 )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-[((C 1 -C 18 )alkylenephenyl)oxy]]phosphoryl)oxy-5-(C 1 -C 18 )alkoxy phenyl, 3-(dihydrogen)phosphate-5-(C 1 -C 18 )alkoxy phenyl; and

R 6 and R 7 are (C 1 -C 18 )alkylenedioxy provided that R 5 is hydrogen.

14. The compound of claim 13 ,

wherein:

R is hydrogen, P(═O)(OH) 2 , P(═O)(O-benzyl) 2 ,

W is naphtha-1-yl, naphtha-2-yl, quinolin-2-yl, quinolin-3-yl, quinolin-5-yl, anthracen-1-yl, benzo[b]furan-3-yl, benzo[b]thiophen-3-yl , benzo[b]thiophen-2-yl, 3-([bis-[(benzyl)oxy]]phosphoryl)oxy-5-methoxyphenyl, 3-(dihydrogen)phosphate-5-methoxyphenyl, and

R 6 and R 7 are methylenedioxy provided that R 5 is hydrogen.

15. The compound of claim 13 , wherein the compound is selected from the group consisting of

Dibenzyl 2-(1-naphthalenyl)-6,7-methylenedioxyquinolin-4-yl phosphate,

2-(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-yl dihydrogen phosphate,

Dibenzyl 2-(3-benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl phosphate,

2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl dihydrogen phosphate,

2-(3-Hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one,

Dibenzyl 2-(3-([bis-[(benzyl)oxy]]phosphoryl)oxy-5-methoxyphenyl) -6,7-methylenedioxyquinolin-4-yl phosphate,

2-(3-([bis-[(benzyl)oxy]]phosphoryl)oxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one,

2-(3-(dihydrogen)phosphate-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one,

2(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-one,

2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one,

2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one,

2-(2-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one,

2-(2-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one,

2-(2-Naphthalenyl)-6,7-methylenedioxyquinolin-4-one,

2-(4-Quinolinyl)-6,7-methylenedioxyquinolin-4-one,

2-(3-Quinolinyl)-6,7-methylenedioxyquinolin-4-one,

2-(2-Quinolinyl)-6,7-methylenedioxyquinolin-4-one,

2-(5-Quinolinyl)-6,7-methylenedioxyquinolin-4-one, and

2-(1-Anthracenyl)-6,7-methylenedioxyquinolin-4-one.

16. The compoundof claim 13 , wherein the compound is selected from the group consisting of

17. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. The method of claim 17 , wherein the cancer is at least one selected from the group consisting of lung cancer, colon cancer, breast cancer, liver cancer, prostate cancer, ovarian cancer, leukemia, lymphoma, pancreatic cancer, skin cancer, brain tumor, kidney cancer, bladder cancer, esophagus cancer, gastric cancer, head and neck cancer, cervical cancer, endometrial cancer, thyroid cancer, bone cancer, and soft tissue sarcoma.

19. 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;

R 5 is methoxy, hydroxyl, or OR 8 , or R 5 and R 6 are methylenedioxy provided that R 7 is hydrogen;

R 6 is N,N-dimethyamino, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;

R 7 is hydrogen, hydroxyl, or O-benzyl; and

R 8 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;

R 5 is hydrogen, methoxy, hydroxyl, or OR 8 ;

R 6 is N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;

R 7 is hydroxyl, or O-benzyl;

or R 6 and R 7 are methylenedioxy provided that R 5 is hydrogen; and

R 8 is hydrogen,

the method comprising;

ai) reacting a compound of Formula II

wherein R 5 is hydroxyl, methoxy, or OR 8 , or R 5 and R 6 are methylenedioxy provided that R 7 is hydrogen;

R 6 is hydroxyl, N,N-dimethylamino, methoxy, N-morpholino, or N-pyrrolindino;

R 7 is hydrogen, halo, OR 8 , hydroxyl, or O-benzyl; and

R 8 is hydrogen;

(aii) or reacting a compound of Formula II

wherein

R 5 is hydrogen, hydroxyl, methoxy, or OR 8 ;

R 6 hydroxyl, N,N-dimethylamino, methoxy, N-morpholino, or N-pyrrolindino;

R 7 is halo, OR 8 , hydroxyl, or O-benzyl;

or R 6 and R 7 are methylenedioxy provided that R 5 is hydrogen; and

R 8 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;

R 5 is methoxy, hydroxyl, or OR 8 , or R 5 and R 6 are methylenedioxy provided that R 7 is hydrogen;

R 6 is N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;

R 7 is hydrogen, hydroxyl, or O-benzyl; and

R 8 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;

R 5 is hydrogen, methoxy, hydroxyl, or OR 8 ,

R 6 is N,N-dimethydroxyl, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino;

R 7 is hydroxyl or O-benzyl;

or R 6 and R 7 are methylenedioxy provided that R 5 is hydrogen; and

R 8 is hydrogen;

(b) and reacting the compound of Formula IV with a base to afford the compound of Formula I.

20. The process of claim 19 , further comprising dealkylating the compound of Formula I to afford the 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-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;

R 5 is hydroxyl, or methoxy;

R 6 is N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or N-pyrrolindino; and

R 7 is hydrogen;

(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;

R 5 is hydrogen, hydroxyl, or methoxy;

R 6 is N,N-dimethylamino, hydroxyl, N-morpholino, or N-pyrrolindino, provided that R 7 is hydrogen, or R 6 and R 7 are methylenedioxy provided that R 5 is hydrogen.