Quinoline derivatives

• US 7,381,824 B2
• Filed: 12/16/2004
• Issued: 06/03/2008
• Est. Priority Date: 12/23/2003
• Status: Expired due to Fees

• Current Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.), Pfizer Inc.
• Original Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Hong, Yufeng, Kania, Robert Steven
• Primary Examiner(s): Seaman; D. Margaret
• Application Number:
  US11/015,508
• Publication Number:
  US 20050137395A1
• Time in Patent Office: 1,265 Days
• Field of Search: 546/153, 546/159, 546/160
• US Class Current: 546/160
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The invention relates to compounds represented by Formula (I):

and to pharmaceutically acceptable salts or solvates of said compounds, wherein each of A, R^3-8, X³, X⁵, m, and n are defined herein. The invention also relates to pharmaceutical compositions containing the compounds of Formula (I) and to methods of treating hyperproliferative disorders in a mammal by administering compounds of Formula (I).

Claims

1. A compound having the structure of Formula (I):

2. A compound according to claim 1, wherein R^2a is CH₃.

3. A compound according to claim 1, wherein R⁴ and R⁷ are both H;

R^2a is CH₃; and

n and m are both 0.

4. A compound according to claim 1, wherein X² is either O, N, or S.

5. A compound according to claim 3, wherein X² is either O, N, or S.

6. A compound according to claim 1, wherein R⁴, R⁵, and R⁷ are H.

7. A compound according to claim 6, wherein R^2a is CH₃;

n and m are both 0; and

X² is either O or S.

8. A compound according to claim 7, wherein R⁶ is —

X⁴(CR¹⁰R¹¹)_j-heterocyclyl and X⁴ is a bond or O.

9. A compound according to claim 7, wherein R⁶ is —

X⁴(C₁-C₈) alkyl and X⁴ is a bond or O.

10. A compound of claim 1 that is selected from the group consisting of:

6-[(7-iodoquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide,

N-2-dimethyl-6-[(7-pyridin-4-ylquinolin-4-yl)oxy]-1-benzofuran-3-carboxamide,

N-2-dimethyl-6-[(7-pyridin-3-ylquinolin-4-yl)oxy]-1-benzofuran-3-carboxamide,

N-2-dimethyl-6-[(7-pyridin-2-ylquinolin-4-yl)oxy]-1-benzofuran-3-carboxamide,

N-2-dimethyl-6-[(7-pyridin-4-ylquinolin-4-yl)oxy]-1-benzothiophene-3-carboxamide,

6-{[7-(2-furyl)quinolin-4-yl]oxy}-N,2-dimethyl-1-benzofuran-3-carboxamide,

N-2dimethyl-6-[(7-pyridin-3-ylquinolin-4-yl)oxy]-1-benzothiophene-3-carboxamide,

6-[(7-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}quinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide,

6-[(7-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}quinolin-4-yl)oxy]-N,2-dimethyl-1-benzothiophene-3-carboxamide,

N,2-dimethyl-6-[(7-pyrimidin-2-ylquinolin-4-yl)oxy]-1-benzothiophene-3-carboxamide,

N,2-dimethyl-6-[(7-pyrimidin-2-ylquinolin-4-yl)oxy]-1-benzofuran-3-carboxamide,

6-[(7-bromoquinolin-4-yl)oxy]-N,2-dimethy-1-benzofuran-3-carboxamide,

6-[(7-bromoquinolin-4-yl)oxy]-N,2-dimethy-1-benzothiophene-3-carboxamide,

6-[(6-iodoquinolin-4-yl)oxy]-N,2-dimethyl-1-benzothiophene-3-carboxamide,

6-[(6-iodoquinolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide,

N,2-dimethyl-6-[(6-pyridin-4-ylquinolin-4-yl)oxy]-1-benzofuran-3-carboxamide,

6-[(6-methoxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzothiophene-3-carboxamide,

6-[(6-hydroxyquinolin-4-yl)oxy]-N,2-dimethyl-1-benzothiophene-3-carboxamide,

N,2-dimethyl-6-({6-[2-(1-methylpyrrolidinyl-2-yl)ethoxy]quinolin-4-yl}oxy)-1-benzothiophene-3-carboxamide,

6-[(7-methoxyquinoline-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide,

6-[(7-hydroxyquinoline-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide,

N,2-dim ethyl-6-{(7-1,3-thiazol-2-yl)quinolin-4-yl)oxy}-1-benzofuran-3-carboxamide,

N,2-dimethyl-6-[(7-pyridin-2-yl)quinolin-4-yl)oxy}-1-benzothiaphene-3-carboxamide,

N,2-dimethyl-5-[(7-pyridin-2-yl)quinolin-4-yl)amino]-1H-indole-1-carboxamide,

N,2-dimethyl-6-{[7-(2-piperidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N,2-dimethyl-6-{[7-(pyridin-2-ylmethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N,2-dimethyl-6-{[7-(thiazol-2-ylmethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N,2-dimethyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N,2-dimethyl-6-{[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

6-({7-[2-(dimethylamino)ethoxy]quinolin-4-yl}oxy)-N,2-dimethyl-1-benzofuran-3-carboxamide,

N-butyl-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-pyridin-2-yl-1-benzofuran-3-carboxamide,

N-butyl-6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

6-{[7-(allyloxy)quinolin-4-yl]oxy}-N,2-dimethyl-1-benzofuran-3-carboxamide,

N-isopropyl-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

N-butyl-2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N-butyl-2-methyl-6-{[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N-butyl-6-({7-[2-(dimethylamino)ethoxy]quinolin-4-yl}oxy)-2-methyl-1-benzofuran-3-carboxamide,

N-butyl-2-methyl-6-{[7-(2-piperidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N-cyclopropyl-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N-[2-(dimethylamino)ethyl]-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-propyl-1-benzothiophene-3-carboxamide,

N-[3-(dimethylamino)propyl]-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N-cyclohexyl-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N-cyclopentyl-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-(pyridin-3-ylmethyl)-1-benzothiophene-3-carboxamide,

6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-N-propyl-1-benzothiophene-3-carboxamide,

N-[2-(dimethylamino)ethyl]-6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N-cyclopentyl-6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N-[3-(dimethylamino)propyl]-6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-N-(pyridin-3-ylmethyl)-1-benzothiophene-3-carboxamide,

N,2-dimethyl-6-{[7-(trifluoromethyl)quinolin-4-yl]oxy}-1-benzothiophene-3-carboxamide,

N,2-dimethyl-6-{[7-(trifluoromethyl)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-(3-morpholin-4-ylpropyl)-1-benzothiophene-3-carboxamide,

N-cyclopropyl-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-(3-morpholin-4-ylpropyl)-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-(pyridin-2-ylmethyl)-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-benzofuran-3-carboxylic acid (3-dimethylamino-propyl)-amide,

N-(3-hydroxypropyl)-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

N-(5-hydroxy-1H-pyrazol-3-yl)-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

6-[(7-hydroxyquinolin-4-yl)oxy]-N-isopropyl-2-methyl-1-benzofuran-3-carboxamide,

6-[(7-hydroxyquinolin-4-yl)oxy]-N-isopropyl-2-methyl-1-benzothiophene-3-carboxamide,

N-isopropyl-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

[(7-methoxyquinolin-4-yl)oxy]-N,1,2-trimethyl-1H-indole-3-carboxamide,

N-isopropyl-2-methyl-6-{[7-(trifluoromethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-{[7-(trifluoromethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N-butyl-2-methyl-6-{[7-(trifluoromethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-N,1,2-trimethyl-1H-indole-3-carboxamide,

N,1,2-trimethyl-6-{[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy}-1H-indole-3-carboxamide

N,1,2-trimethyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1H-indole-3-carboxamide

N-(2-hydroxypropyl)-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N-(2-hydroxybutyl)-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N-(3-hydroxybutyl)-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzothiophene-3-carboxamide,

N,1,2-trimethyl-6-{[7-(2-piperidin-1-ylethoxy)quinolin-4-yl]oxy}-1H-indole-3-carboxamide

6-{[7-(1,3-dioxolan-2-ylmethoxy)quinolin-4-yl]oxy}-N,2-dimethyl-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-[(2R)-tetrahydrofuran-2-ylmethyl]-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-[ethoxy-ethyl]-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-[2-methoxy-1-methyl-ethyl]-1-benzofuran-3-carboxamide,

N-(2-methoxyethyl)-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-[(7-pyrimidin-2-ylquinolin-4-yl)oxy]-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-({7-[2-(methylamino)ethoxy]quinolin-4-yl}oxy)-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-({7-[2-(diethylamino)ethoxy]quinolin-4-yl}oxy)-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-({7-[2-hydroxy-ethoxy]quinolin-4-yl}oxy)-1-benzofuran-3-carboxamide,

6-{[7-(2-bromoethoxy)quinolin-4-yl]oxy}-N-cyclopropyl-2-methyl-1-benzofuran-3-carboxamide, N-cyclopropyl-2-methyl-6-{7-[2-(4-ethyl-piperazin-1-yl)-ethoxy]quinolin-4-yloxy}-1-benzofuran-3-carboxamide,

N-cyclopropyl-6-({7-[2-(isopropylamino)ethoxy]quinolin-4-yloxy)-2-methyl-1-benzofuran-3-carboxamide,

N-cyclopropyl-6-({7-[2-(cyclopropylamino)ethoxy]quinolin-4-yl}oxy)-2-methyl-1-benzofuran-3-carboxamide,

N-cyclopropyl-6-[(7-{2-[(2-methoxy-1-methylethyl)amino]ethoxy}quinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

6-(7-[2-(tert-butylamino)ethoxy]quinolin-4-yloxy)-N-cyclopropyl-2-methyl-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-{[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

6-({7-[2-(cyclobutylamino)ethoxy]quinolin-4-yl}oxy)-N-cyclopropyl-2-methyl-1-benzofuran-3-carboxamide,

6-{[7-(benzyloxy)quinolin-4-yl]oxy}-N-(4,6-dimethylpyridin-2-yl)-2-methyl-1-benzofuran-3-carboxamide,

N-(4,6-dimethylpyridin-2-yl)-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

N-(4,6-dimethylpyridin-2-yl)-6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-{[7-(2-piperazin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

N-cyclopropyl-6-({7-[2-(dimethylamino)ethoxy]quinolin-4-yl}oxy)-2-methyl-1-benzofuran-3-carboxamide,

6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-{6-[(3-methylbutyl)amino]pyridin-3-yl}-1-benzofuran-3-carboxamide,

7-[(7-hydroxyquinolin-4-yl)oxy]-N,2-dimethylimidazo[1,2-α

]pyridine-3-carboxamide,

N,2-dimethyl-7-{[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy}imidazo[1,2-α

]pyridine-3-carboxamide,

N,2-dimethyl-6-({7-[(2-oxo-1,3-dioxolan-4-yl)methoxy]quinolin-4-yl}oxy)-1-benzofuran-3-carboxamide, 6-hydroxy-N, 2-dimethy-1-benzofuran-3-carboxamide,

N,2-dimethyl-6-[(6-pyridin-4-ylquinolin-4-yl)oxy]-1-benzothiophene-3-carboxamide,

N-cyclopropyl-6-({7-[2-(ethylamino)ethoxy]quinolin-4-yl}oxy)-2-methyl-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-{[7-(2-piperidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxamide,

7-fluoro-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-(6-morpholin-4-ylpyridin-3-yl)-1-benzofuran-3-carboxamide,

7-fluoro-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-N-(3-morpholin-4-ylpropyl)-1-benzofuran-3-carboxamide,

N-cyclopropyl-2-methyl-6-{[7-(2-piperazin-1-ylethoxy)quinolin-4-yl]oxy}-1benzofuran-3-carboxamide,

6-{[7-(2,3-dihydroxypropoxy)quinolin-4-yl]oxy}-N,2-dimethyl-1-benzofuran-3-carboxamide,

N-[5-(aminomethyl)pyridin-2-yl]-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

N-[6-(aminomethyl)pyridin-3-yl]-6-[(7-methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide,

4-{[4-({2-methyl-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}oxy)quinolin-7-yl]oxy}butanoic acid,

{[4-({2-methyl-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}oxy)quinolin-7-yl]oxy}acetic acid,

N-(4,6-dimethylpyridin-2-yl)-2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy]-1-benzofuran-3-carboxamide,

methyl 2-methyl-6-{[7-(2-morpholin-4-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxylate,

6-({7-[2-hydroxy-3-(methylamino)propoxy]quinolin-4-yl}oxy)-N,2-dimethyl-1-benzofuran-3-carboxaminde, and

methyl 4-{[4-({2-methyl-3-[(methylamino)carbonyl]-1-benzofuran-6-yl}oxy)quinolin-7-yl]oxy}butanoate,

or a pharmaceutically acceptable solvate or pharmaceutically acceptable salt thereof.

11. A compound of claim 1 that is selected from the following group:

12. A method of producing a compound having the formula of claim 1, wherein

13. The method of claim 12, wherein the activating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, and HATU.

14. A compound of formula

15. A compound of formula

16. A compound of formula