IP Library › Patent Application 10594978
Patent Application
App. No. 10/594,978

Quinolone Carboxylic Acid Derivatives for Treatment of Hyperproliferative Conditions

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Patent No.
US None
App. No.
10/594,978
Abstract

Quinolone carboxylic acid derivatives of formula (I) wherein Ar is an optionally substituted phenyl, pyridyl, or pyrimidinyl group and the substituent groups R 1 , R 4 , R 10 , R 11 , R 19 , and R 20 are as defined in the specification, pharmaceutical compositions containing them, and methods of using them in treatment of hyperproliferative diseases such as cancer are disclosed and claimed.

Claims (662)

1 . A compound having the structure (I)

wherein

R 1 represents

—F,

—Cl,

—Br,

—NO 2 ,

—(C 1-3 alkyl) optionally substituted with halogen, or

—NR 2 R 3 , wherein

R 2 and R 3 are independently H or C 1-3 alkyl optionally substituted with halogen;

R 4 represents —F, —Cl, —Br, or —(C 1-3 alkyl) optionally substituted with halogen;

Ar represents:

wherein

R 5 represents

—F,

—Cl,

—Br,

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen,

—S(C 1-3 alkyl) optionally substituted with halogen

—CN,

—C(O)NH 2 ,

—SO 2 NH 2 ,

—C(O)CH 3 ,

—NO 2 ; or

—NR 6 R 7 , wherein

R 6 and R 7 are independently H or —(C 1-3 alkyl) optionally substituted with halogen;

wherein

R 8 represents

—CN

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen,

—C(O)NH 2 , or

—SO 2 NH 2 ; or

wherein

R 9 represents —F, —Cl, or —Br;

R 10 represents

—Cl,

—Br,

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen, or

—CN;

Z represents C or N;

when Z is C, R 11 is located on one of the two ring atoms encompassed by the bracket and the other of the two ring atoms encompassed by the bracket bears a H or an R 19 substituent, and

when Z is C, R 11 represents

wherein

R 12 represents

—F, —Cl —Br,

—OH,

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen, or —CH 2 OR 13 ; wherein

R 13 represents H or —(C 1-3 alkyl) optionally substituted with halogen;

wherein

R 14 represents H or —(C 1-3 alkyl) optionally substituted with halogen;

R 15 represents —(CH 2 ) 0-2 (C 3-6 cycloalkyl) wherein said cycloalkyl moiety is optionally substituted with up to two substituents independently selected from the group of —F, —Cl, —Br, —OH, —(C 1-3 alkyl) optionally substituted with halogen, —O(C 1-3 alkyl) optionally substituted with halogen, and —CH 2 OR 16 wherein

R 16 represents H or —(C 1-3 alkyl) optionally substituted with halogen; and

wherein

R 17 represents H or —(C 1-3 alkyl) optionally substituted with halogen,

and

R 18 represents —(C 1-3 alkyl) optionally substituted with halogen; or

with the proviso that when R 11 is —CH 2 —NR 17 R 18 ,

R 10 is —Br, —CN, —O(C 1-3 alkyl), —OCF 3 , —OCF 2 Cl, or —(C 1-3 alkyl) optionally substituted with halogen;

when Z is N, R 11 is located on the carbon atom encompassed by the bracket and R 11 represents

wherein

R 12 is as defined above;

R 19 represents

—F, —Cl, —Br,

—(C 1-3 alkyl) optionally substituted with halogen, or

—O(C 1-3 alkyl) optionally substituted with halogen;

R 20 represents

—NHR 21 , or

—OR 22 ; wherein

R 21 and R 22 are each independently H or —(C 1-3 alkyl) optionally substituted with halogen;

or a pharmaceutically acceptable salt or hydrate thereof.

2 . The compound of claim 1 wherein

R 1 represents

—F,

—Br, or

—(C 1-3 alkyl) optionally substituted with halogen;

R 4 is absent;

Ar represents:

wherein

R 5 represents

—F,

—Cl,

—Br,

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen,

—S(C 1-3 alkyl) optionally substituted with halogen

—CN,

—C(O)NH 2 ,

—SO 2 NH 2 ,

—C(O)CH 3 ,

—NO 2 ; or

—NR 6 R 7 , wherein

R 6 and R 7 are independently H or —(C 1-3 alkyl) optionally substituted with halogen;

wherein

R 8 represents

—CN

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen,

—C(O)NH 2 , or

—SO 2 NH 2 ; or

wherein

R 9 represents —F, —Cl, or —Br;

R 10 represents

—Cl,

—O(C 1-3 alkyl) optionally substituted with halogen, or

—CN;

Z represents C;

R 11 is located on one of the two ring atoms encompassed by the bracket and the other of the two ring atoms encompassed by the bracket bears a H or an R 19 substituent,

R 11 represents

wherein

R 12 represents

—F, —Cl—Br,

—OH,

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen, or

—CH 2 OR 13 ; wherein

R 13 represents H or —(C 1-3 alkyl) optionally substituted with halogen;

wherein

R 14 represents H or —(C 1-3 alkyl) optionally substituted with halogen;

R 15 represents —(CH 2 ) 0-2 (C 3-6 cycloalkyl) wherein said cycloalkyl moiety is optionally substituted with up to two substituents independently selected from the group of —F, —Cl, —Br, —OH, —(C 1-13 alkyl) optionally substituted with halogen, —O(C 1-3 alkyl) optionally substituted with halogen, and —CH 2 OR 16 wherein

R 16 represents H or —(C 1-3 alkyl) optionally substituted with halogen; or

wherein

R 17 represents H or —(C 1-3 alkyl) optionally substituted with halogen,

and

R 18 represents —(C 1-3 alkyl) optionally substituted with halogen;

with the proviso that when R 11 is —CH 2 —NR 17 R 18 ,

R 10 is —Br, —CN, —(C 1-3 alkyl), —OCF 3 , —OCF 2 Cl, or —(C 1-13 alkyl) optionally substituted with halogen;

R 19 represents

—F, —Cl, —Br,

—(C 1-3 alkyl) optionally substituted with halogen, or

—O(C 1-3 alkyl) optionally substituted with halogen; and

R 20 represents

—OR 22 ; wherein

R 22 is H or —(C 1-3 alkyl) optionally substituted with halogen.

3 . The compound of claim 1 wherein

R 1 is absent or represents a single substituent selected from

—F,

—Cl, and

—Br;

R 4 is absent;

Ar represents:

wherein

R 5 represents

—F,

—Cl,

—Br,

—(C 1-3 alkyl) optionally substituted with halogen,

—O(C 1-3 alkyl) optionally substituted with halogen, or

—CN;

wherein

R 8 represents

—CN

—(C 1-3 alkyl) optionally substituted with halogen, or

—O(C 1-3 alkyl) optionally substituted with halogen; or

wherein

R 9 represents —F, —Cl, or —Br;

R 10 represents

—Cl, or

—O(C 1-3 alkyl) optionally substituted with halogen;

Z represents C;

R 11 is located on one of the two ring atoms encompassed by the bracket and the other of the two ring atoms encompassed by the bracket bears a H or an R 19 substituent,

R 11 represents

wherein

R 14 represents H or —(C 1-3 alkyl) optionally substituted with halogen;

R 15 represents —(CH 2 ) 0-2 (C 3-6 cycloalkyl) wherein said cycloalkyl moiety is optionally substituted with up to two substituents independently selected from the group of —F, —Cl, —Br, —OH, —(C 1-3 alkyl) optionally substituted with halogen, —O(C 1-3 alkyl) optionally substituted with halogen, and —CH 2 OR 16 wherein

R 16 represents H or —(C 1-3 alkyl) optionally substituted with halogen; or

wherein

R 17 represents H or —(C 1-3 alkyl) optionally substituted with halogen,

and

R 18 represents —(C 1-3 alkyl) optionally substituted with halogen;

with the proviso that when R 11 is —CH 2 —NR 17 R 18 ,

R 10 is —Br, —CN, —O(C 1-3 alkyl), —OCF 3 , —OCF 2 Cl, or —(C 1-3 alkyl) optionally substituted with halogen;

R 19 represents

—F, —Cl, or —Br; and

R 20 represents

—OR 22 ; wherein

R 22 is H.

4 . A compound selected from the group consisting of:

Example

Number

Chemical Name

1

8-chloro-6-fluoro-4-oxo-7-(4-pyridin-2-yl-piperazin-1-yl)-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

2

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

4

8-chloro-6-fluoro-7-[4-(2-cyanophenyl)-piperazin-1-yl]-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

6

8-chloro-6-fluoro-4-oxo-7-(4-pyrimidin-2-ylpiperazin-1-yl)-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

7

8-chloro-7-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]-6-fluoro-4-oxo-1-

[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

13

8-chloro-6-fluoro-7-[4-(6-methylpyridin-2-yl)-piperazin-1-yl]-4-oxo-1-

[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

15

8-chloro-7-[4-(2-cyanophenyl)piperazin-1-yl]-6-fluoro-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

17

8-chloro-6-fluoro-1-{4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}-4-

oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

18

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-1-{4-[(2-

methylpyrrolidin-1-yl)methyl]phenyl}-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

19

8-chloro-1-{4-[(2,5-dimethylpyrrolidin-1-yl)methyl]phenyl}-6-fluoro-

4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylic acid

21

8-chloro-6-fluoro-1-(4-{[(2R)-2-(methoxy-methyl)pyrrolidin-1-

yl]methyl}phenyl)-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-

dihydroquinoline-3-carboxylic acid

23

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-1-(4-{[(2R)-2-

(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

24

8-chloro-6-fluoro-1-(4-{[(2S)-2-(methoxy-methyl)pyrrolidin-1-

yl]methyl}phenyl)-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-

dihydroquinoline-3-carboxylic acid

25

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-1-(4-{[(2S)-2-

(methoxymethyl)pyrrolidin-1-yl]methyl}phenyl)-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

26

8-chloro-6-fluoro-1-(4-{[(2S)-2-(methoxy-methyl)pyrrolidin-1-

yl]methyl}phenyl)-4-oxo-7-(4-pyrimidin-2-ylpiperazin-1-yl)-1,4-

dihydroquinoline-3-carboxylic acid

27

8-chloro-6-fluoro-1-(4-{[(3S)-3-hydroxy-pyrrolidin-1-

yl]methyl}phenyl)-4-oxo-7-(4-pyrimidin-2-ylpiperazin-1-yl)-1,4-

dihydroquinoline-3-carboxylic acid

28

8-chloro-6-fluoro-1-(4-{[(3S)-3-hydroxy-pyrrolidin-1-

yl]methyl}phenyl)-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-

dihydroquinoline-3-carboxylic acid

29

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-1-(4-{[(3S)-3-

hydroxypyrrolidin-1-yl]methyl}phenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

30

8-chloro-7-[4-(2-cyanophenyl)piperazin-1-yl]-6-fluoro-1-(4-{[(3S)-3-

hydroxypyrrolidin-1-yl]methyl}phenyl)-4-oxo-1,4-dihydro-quinoline-

3-carboxylic acid

31

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-1-(4-{[(3R)-3-

hydroxypyrrolidin-1-yl]methyl}phenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

32

8-chloro-7-[4-(2-cyanophenyl)piperazin-1-yl]-6-fluoro-1-(4-{[(3R)-3-

hydroxypyrrolidin-1-yl]methyl}phenyl)-4-oxo-1,4-dihydro-quinoline-

3-carboxylic acid

35

8-chloro-7-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]-6-fluoro-4-oxo-1-

[6-(pyrrolidin-1-ylmethyl)pyridin-3-yl]-1,4-dihydroquinoline-3-

carboxylic acid

37

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-4-oxo-1-[6-

(pyrrolidin-1-ylmethyl)pyridin-3-yl]-1,4-dihydroquinoline-3-

carboxylic acid

38

8-chloro-7-[4-(4-chlorophenyl)piperazin-1-yl]-6-fluoro-4-oxo-1-[6-

(pyrrolidin-1-ylmethyl)pyridin-3-yl]-1,4-dihydroquinoline-3-

carboxylic acid

39

8-chloro-7-[4-(2-cyanophenyl)piperazin-1-yl]-6-fluoro-1-[2-fluoro-4-

(pyrrolidin-1-ylmethyl)phenyl]-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

40

8-chloro-6-fluoro-1-[2-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-4-oxo-

7-(4-pyrimidin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic

acid

41

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazin-1-yl]-1-[2-fluoro-4-

(pyrrolidin-1-ylmethyl)phenyl]-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

42

8-chloro-7-[4-(4-chlorophenyl)piperazin-1-yl]-6-fluoro-1-[2-fluoro-4-

(pyrrolidin-1-ylmethyl)phenyl]-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

43

8-chloro-6-fluoro-1-[2-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-4-oxo-

7-(4-phenylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

44

8-chloro-6-fluoro-1-[2-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-7-[4-

(3-methylpyridin-2-yl)piperazin-1-yl]-4-oxo-1,4-dihydro-quinoline-3-

carboxylic acid

45

8-chloro-7-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]-6-fluoro-1-[2-

fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-4-oxo-1,4-dihydro-quinoline-

3-carboxylic acid

48

8-chloro-7-[4-(4-cyanophenyl)piperazin-1-yl]-6-fluoro-1-[2-fluoro-4-

(pyrrolidin-1-ylmethyl)phenyl]-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

56

8-chloro-1-{4-[(cyclopentylamino)-methyl]phenyl}-6-fluoro-4-oxo-7-

(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylic acid

57

8-chloro-1-{4-[(cyclopentylamino)methyl]-phenyl}-6-fluoro-4-oxo-7-

(4-pyrimidin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic

acid

58

8-chloro-1-{4-[(cyclobutylamino)methyl]-phenyl}-6-fluoro-4-oxo-7-

(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

59

8-chloro-1-{4-[(cyclopropylamino)-methyl]phenyl}-6-fluoro-4-oxo-7-

(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylic acid

60

8-chloro-1-{4-[(cyclopropylamino)methyl]-phenyl}-6-fluoro-4-oxo-7-

(4-pyrimidin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic

acid

61

8-chloro-1-(4-{[cyclohexyl(methyl)amino]-methyl}phenyl)-6-fluoro-4-

oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydro-quinoline-3-

carboxylic acid

62

8-chloro-1-(4-{[cyclohexyl(methyl)amino]-methyl}phenyl)-6-fluoro-

4-oxo-7-(4-pyrimidin-2-ylpiperazin-1-yl)-1,4-dihydro-quinoline-3-

carboxylic acid

69

8-chloro-1-{4-[2-(dimethylamino)ethyl]phenyl}-6-fluoro-4-oxo-7-(4-

pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

72

6-fluoro-8-methoxy-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

73

6-fluoro-8-methoxy-4-oxo-7-(4-pyrimidin-2-ylpiperazin-1-yl)-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

74

6-fluoro-7-[4-(4-fluorophenyl)piperazin-1-yl]-8-methoxy-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

77

7-[4-(4-cyanophenyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

79

7-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-

1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic

acid

85

6-fluoro-7-[4-(3-fluorophenyl)piperazin-1-yl]-8-methoxy-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

88

6-fluoro-8-methoxy-7-{4-[2-(methylthio)phenyl]-piperazin-1-yl}-4-

oxo-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-

carboxylic acid

89

7-[4-(2-cyanophenyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1-[4-

(piperidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

90

7-[4-(4-chlorophenyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1-[4-

(piperidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-3-carboxylic acid

92

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-7-

(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

93

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-7-[4-(4-

fluorophenyl)piperazin-1-yl]-8-methoxy-4-oxo-1,4-dihydroquinoline-

3-carboxylic acid

96

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-7-

(4-pyrimidin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic

acid

97

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-7-

(4-phenylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

98

7-[4-(3-chlorophenyl)piperazin-1-yl]-1-{4-

[(dimethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

102

7-[4-(4-cyanophenyl)piperazin-1-yl]-1-{4-

[(dimethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

105

1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-7-[4-(4-

fluorophenyl)piperazin-1-yl]-8-methoxy-4-oxo-1,4-dihydroquinoline-

3-carboxylic acid

106

1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-7-(4-

pyrimidin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

108

7-[4-(4-cyanophenyl)piperazin-1-yl]-1-{4-

[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

110

1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-7-[4-(2-

methoxyphenyl)piperazin-1-yl]-4-oxo-1,4-dihydro-quinoline-3-

carboxylic acid

113

7-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]-1-{4-

[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

114

1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-7-[4-(2-

fluorophenyl)piperazin-1-yl]-8-methoxy-4-oxo-1,4-dihydroquinoline-

3-carboxylic acid

115

7-[4-(3-chlorophenyl)piperazin-1-yl]-1-{4-

[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

116

7-[4-(4-acetylphenyl)piperazin-1-yl]-1-{4-

[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

117

7-[4-(2-cyanophenyl)piperazin-1-yl]-1-{4-

[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

118

7-[4-(4-chlorophenyl)piperazin-1-yl]-1-{4-

[(diethylamino)methyl]phenyl}-6-fluoro-8-methoxy-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

119

7-[4-(3-chlorophenyl)piperazin-1-yl]-6-fluoro-4-oxo-1-[4-(pyrrolidin-

1-ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-dihydroquinoline-3-

carboxylic acid

120

6-fluoro-7-[4-(6-methylpyridin-2-yl)piperazin-1-yl]-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-

dihydroquinoline-3-carboxylic acid

121

6-fluoro-7-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1-[4-(pyrrolidin-

1-ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-dihydroquinoline-3-

carboxylic acid

122

6-fluoro-7-[4-(3-methylpyridin-2-yl)-piperazin-1-yl]-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-

dihydroquinoline-3-carboxylic acid

123

6-fluoro-4-oxo-7-(4-pyrimidin-2-yl-piperazin-1-yl)-1-[4-(pyrrolidin-1-

ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-dihydroquinoline-3-

carboxylic acid

124

6-fluoro-4-oxo-7-(4-pyridin-2-yl-piperazin-1-yl)-1-[4-(pyrrolidin-1-

ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-dihydroquinoline-3-

carboxylic acid

125

7-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]-6-fluoro-4-oxo-1-[4-

(pyrrolidin-1-ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-

dihydroquinoline-3-carboxylic acid

126

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-4-oxo-7-(4-pyridin-2-

ylpiperazin-1-yl)-8-(trifluoromethoxy)-1,4-dihydro-quinoline-3-

carboxylic acid

127

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-7-[4-(6-methylpyridin-

2-yl)piperazin-1-yl]-4-oxo-8(trifluoromethoxy)-1,4-dihydroquinoline-

3-carboxylic acid

128

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-4-oxo-7-(4-pyrimidin-

2-ylpiperazin-1-yl)-8-(trifluoromethoxy)-1,4-dihydro-quinoline-3-

carboxylic acid

130

7-[4-(3-chlorophenyl)piperazin-1-yl]-1-{4-

[(dimethylamino)methyl]phenyl}-6-fluoro-4-oxo-8-(trifluoromethoxy)-

1,4-dihydroquinoline-3-carboxylic acid

131

1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-7-[4-(4-

fluorophenyl)piperazin-1-yl]-4-oxo-8-(trifluoromethoxy)-1,4-dihydro-

quinoline-3-carboxylic acid

132

1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-4-oxo-7-(4-pyridin-2-

ylpiperazin-1-yl)-8-(trifluoromethoxy)-1,4-dihydro-quinoline-3-

carboxylic acid

133

ethyl 1-{4-[(diethylamino)methyl]-phenyl}-6-fluoro-4-oxo-7-(4-

pyrimidin-2-ylpiperazin-1-yl)-8-(trifluoromethoxy)-1,4-

dihydroquinoline-3-carboxylate

135

1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-7-[4-(2-

fluorophenyl)piperazin-1-yl]-4-oxo-8-(trifluoromethoxy)-1,4-dihydro-

quinoline-3-carboxylic acid

136

7-[4-(3-chlorophenyl)piperazin-1-yl]-1-{4-

[(diethylamino)methyl]phenyl}-6-fluoro-4-oxo-8-(trifluoromethoxy)-

1,4-dihydro-quinoline-3-carboxylic acid

137

1-{4-[(diethylamino)methyl]phenyl}-7-[4-(2,4-

difluorophenyl)piperazin-1-yl]-6-fluoro-4-oxo-8-(trifluoromethoxy)-

1,4-dihydro-quinoline-3-carboxylic acid

138

1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-4-oxo-7-(4-

phenylpiperazin-1-yl)-8-(trifluoromethoxy)-1,4-dihydroquinoline-3-

carboxylic acid

139

6-fluoro-1-(4-{[(2S)-2-methylpiperidin-1-yl]methyl}phenyl)-4-oxo-7-

(4-pyrimidin-2-ylpiperazin-1-yl)-8-(trifluoromethoxy)-1,4-

dihydroquinoline-3-carboxylic acid

146

8-[chloro(difluoro)methoxy]-6-fluoro-4-oxo-7-(4-pyridin-2-

ylpiperazin-1-yl)-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-

dihydroquinoline-3-carboxylic acid

147

8-[chloro(difluoro)methoxy]-6-fluoro-7-[4-(4-fluorophenyl)piperazin-

1-yl]-4-oxo-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydroquinoline-

3-carboxylic acid

148

8-[chloro(difluoro)methoxy]-7-[4-(4-chlorophenyl)piperazin-1-yl]-6-

fluoro-4-oxo-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-

dihydroquinoline-3-carboxylic acid

149

8-[chloro(difluoro)methoxy]-7-[4-(3-cyanopyridin-2-yl)piperazin-1-

yl]-6-fluoro-4-oxo-1-[4-(pyrrolidin-1-ylmethyl)-phenyl]-1,4-

dihydroquinoline-3-carboxylic acid

151

8-[chloro(difluoro)methoxy]-7-[4-(3,4-dimethylphenyl)piperazin-1-yl]-

6-fluoro-4-oxo-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-

dihydroquinoline-3-carboxylic acid

152

8-[chloro(difluoro)methoxy]-6-fluoro-4-oxo-7-(4-phenylpiperazin-1-

yl)-1-[4-(pyrrolidin-1-ylmethyl)phenyl]-1,4-dihydro-quinoline-3-

carboxylic acid

153

6-fluoro-4-oxo-7-(4-pyrimidin-2-yl-piperazin-1-yl)-1-[4-(pyrrolidin-1-

ylmethyl)phenyl]-8-(trifluoromethoxy)-1,4-dihydroquinoline-3-

carboxylic acid

154

8-[chloro(difluoro)methoxy]-1-{4-[(dimethylamino)methyl]phenyl}-6-

fluoro-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-

carboxylic acid

155

8-[chloro(difluoro)methoxy]-1-{4-[(dimethylamino)methyl]phenyl}-6-

fluoro-7-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

156

8-[chloro(difluoro)methoxy]-7-[4-(4-chlorophenyl)piperazin-1-yl]-1-

{4-[(dimethylamino)methyl]phenyl}-6-fluoro-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

158

8-[chloro(difluoro)methoxy]-7-[4-(3-cyanopyridin-2-yl)piperazin-1-

yl]-1-{4-[(dimethylamino)methyl]phenyl}-6-fluoro-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

159

8-[chloro(difluoro)methoxy]-1-{4-[(diethylamino)methyl]phenyl}-6-

fluoro-4-oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-

carboxylic acid

161

8-[chloro(difluoro)methoxy]-7-[4-(3-cyanopyridin-2-yl)piperazin-1-

yl]-1-{4-[(diethylamino)methyl]phenyl}-6-fluoro-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

162

8-[chloro(difluoro)methoxy]-7-[4-(2-cyanophenyl)piperazin-1-yl]-1-

{4-[(diethylamino)methyl]phenyl}-6-fluoro-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

163

8-[chloro(difluoro)methoxy]-1-{4-[(diethylamino)methyl]phenyl}-6-

fluoro-7-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

164

8-[chloro(difluoro)methoxy]-7-[4-(4-chlorophenyl)piperazin-1-yl]-1-

{4-[(diethylamino)methyl]phenyl}-6-fluoro-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

165

8-[chloro(difluoro)methoxy]-1-(4-

{[ethyl(methyl)amino]methyl}phenyl)-6-fluoro-4-oxo-7-(4-pyrimidin-

2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

166

8-[chloro(difluoro)methoxy]-7-[4-(3-cyanopyridin-2-yl)piperazin-1-

yl]-1-(4-{[ethyl(methyl)amino]methyl}phenyl)-6-fluoro-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

167

8-[chloro(difluoro)methoxy]-1-(4-

{[ethyl(methyl)amino]methyl}phenyl)-6-fluoro-7-[4-(4-

fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic

acid

168

8-[chloro(difluoro)methoxy]-7-[4-(4-chlorophenyl)piperazin-1-yl]-1-

(4-{[ethyl(methyl)amino]methyl}phenyl)-6-fluoro-4-oxo-1,4-

dihydroquinoline-3-carboxylic acid

170

8-chloro-1-(4-{[(cyclopropylmethyl)amino]methyl}phenyl)6-fluoro-4-

oxo-7-(4-pyridin-2-ylpiperazin-1-yl)-1,4-dihydroquinoline-3-

carboxylic acid

171

8-chloro-1-(4-cyclohexylaminomethyl-phenyl)-6-fluoro-4-oxo-7-(4-

pyridin-2-yl-piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

172

8-chloro-6-fluoro-1{4-[(2-hydroxycyclopentylamino)-methyl]-

phenyl}-4-oxo-7-(4-pyridin-2-yl-piperazine-1-yl)-1,4-dihydro-

quinoline-3-carboxylic acid

174

8-chloro-1-{4-[(2-cyclohexyl-isopropyl-amino)-methyl]-phenyl}-6-

fluoro-4-oxo-7-(4-pyridin-2-yl-piperazine-1-yl)-1,4-dihydro-quinoline-

3-carboxylic acid

175

8-chloro-6-fluoro-1-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-7-[4-(6-

methylpyridine-2-yl)-piperazine-1-yl]-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

176

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazine-1-yl]-1-(2-

methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-4-oxo-1,4-dihydroquinoline-

3-carboxylic acid

177

8-chloro-6-fluoro-7-[4-(4-fluorophenyl)-piperazine-1-yl]-1-(2-

methoxy-4-piperidine-1-ylmethyl-phenyl)-4-oxo-1,4-dihydroquinoline-

3-carboxylic acid

178

8-chloro-1-(4-cyclobutylaminomethyl-2-methoxyphenyl)-6-fluoro-7-

[4-(4-fluorophenyl)-piperazine-1-yl]-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

180

8-(chloro-difluoromethoxy)-1-(4-cyclopentylaminomethyl-phenyl)-6-

fluoro-4-oxo-7-(4-pyridin-2-yl-piperazin-1-yl)-1,4-dihyroquinoline-3-

carboxylic acid

181

8-(chloro-difluoromethoxy)-1-(4-cyclopentylaminomethyl-phenyl)-6-

fluoro-4-oxo-7-[4(4-fluorophenyl)piperazine-1-yl]-1,4-

dihyroquinoline-3-carboxylic acid

182

1-(4-cyclopentylaminomethyl-phenyl)-6-fluoro-7-[4-(4-fluorophenyl)-

piperazine-1-yl]-4-oxo-8-trifluoromethoxy-1,4-dihyroquinoline-3-

carboxylic acid

183

1-(4-cyclopentylaminomethyl-phenyl)-6-fluoro-7-(4-pyridin-2-yl-

piperazine-1-yl]-4-oxo-8-chlorodifluoromethoxy-1,4-dihyroquinoline-

3-carboxylic acid

184

8-chloro-7-[4-(3-cyanopyridin-2-yl)-piperazine-1-yl]-6-fluoro-1-(3-

fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

185

8-chloro-7-[4-(2-cyanophenyl)-piperazine-1-yl]-6-fluoro-1-(3-fluoro-4-

pyrrolidin-1-ylmethyl-phenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

186

8-chloro-7-[4-(4-fluorophenyl)-piperazine-1-yl]-6-fluoro-1-(3-fluoro-4-

pyrrolidin-1-ylmethyl-phenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

187

8-chloro-7-[4-(4-chlorophenyl)-piperazine-1-yl]-6-fluoro-1-(3-fluoro-

4-pyrrolidin-1-ylmethyl-phenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

188

8-chloro-7-[4-(4-cyanophenyl)-piperazine-1-yl]-6-fluoro-1-(3-fluoro-4-

pyrrolidin-1-ylmethyl-phenyl)-4-oxo-1,4-dihydroquinoline-3-

carboxylic acid

189

8-chloro-1-(4-cyclohexylaminomethyl-phenyl)-6-fluoro-4-oxo-7-(4-

pyrimidin-2-yl-piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

191

8-chloro-1-(4-cyclobutylaminomethyl-phenyl)-6-fluoro-4-oxo-7-(4-

pyrimidin-2-yl-piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid

192

7-[4-(4-cyanophenyl)-piperazine-1-yl]-6-fluoro-8-methoxy-4-oxo-1-(4-

piperidin-1-ylmethyl-phenyl)-1,4-dihydroquinoline-3-carboxylic acid

193

6-fluoro-8-methoxy-4-oxo-1-(4-piperidin-1-ylmethyl-phenyl)-7-(4-

pyrimidine-2-yl-piperazine-1-yl]-1,4-dihydroquinoline-3-carboxylic

acid

194

6-fluoro-8-methoxy-4-oxo-1-(4-piperidin-1-ylmethyl-phenyl)-7-(4-

pyridin-2-yl-piperazine-1-yl]-1,4-dihydroquinoline-3-carboxylic acid

5 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

6 . A method of treating a hyperproliferative disorder comprising administering to a mammalian subject an effective amount of a compound of claim 1.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 27, 2009
From: BAYER PHARMACEUTICALS CORPORATION
To: BAYER HEALTHCARE LLC
Reel/Frame 023027/0804 →