IP Library › Granted Patent US 7,465,746

Granted Patent B2

US 7,465,746 · App. 10/915,743 · Granted Dec 16, 2008

Fluorinated 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP

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Quick Facts

Patent No.: US 7,465,746
App. No.: 10/915,743
Granted: Dec 16, 2008
Kind: B2

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Abstract

The present invention relates to dihydropyrrole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention is also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Claims (680)

1. The compound of Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

b is 0 or 1;

m is 0, 1, or 2;

n is 0, 1, 2 or 3;

r is 0 or 1;

s is 0 or 1;

t is 0 or 1;

R 1 and R 2 are independently selected from: H or (C 1 -C 6 )alkyl, optionally substituted with one, two or three substituents selected from R7;

R 3 is selected from:

1) hydrogen; or

3) CH 2 —O—R d ,

R 4 is independently selected from:

1) halo,

2) OH, and

3) O b C 1 -C 6 perfluoroalkyl;

R 5 is selected from:

1) hydrogen and

2) halo,

R 7 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

2) O r (C 1 -C 3 )perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C 2 -C 10 )alkenyl,

8) (C 2 -C 10 )alkynyl,

13) C(O)R a ,

14) (C 0 -C 6 )alkylene-CO 2 R a ,

15) C(O)H,

16) (C 0 -C 6 )alkylene-CO 2 H,

17) C(O)N(R b ) 2 ,

18) S(O) m R a ,

19) S(O) 2 N(R b ) 2 ; and

20) —OPO(OH) 2 ;

said alkyl, alkenyl, alkynyl, and alkylene is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6 alkyl, oxo, NO 2 and N(R b ) 2 ;

R 10 is selected from: F and —CH 2 F;

R 13 is selected from: H and CH 2 F, provided that if t is 1, R 13 is H, and if t is 0, R 13 is —CH 2 F;

R ox is absent or is oxo;

R a is (C 1 -C 6 )alkyl;

R b H or (C 1 -C 6 )alkyl;

R d is selected from: H or (C1-C6)alkyl.

2. The compound according to claim 1 of the Formula III:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

b is 0or 1;

m is 0, 1, or 2;

n is 0, 1 or 2;

r is 0 or 1;

s is 0 or 1;

R 1 and R 2 are independently selected from: H or (C 1 -C 6 )alkyl, optionally substituted with one, two or three substituents selected from R 7 ;

R 4 is independently selected from:

1) halo,

2) OH,

3) O b C 1 -C 6 perfluoroallcyl,

R 5 is selected from:

1) hydrogen, or

2) halo,

R 7 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

2) O r (C 1 -C 3 )perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C 2 -C 10 )alkenyl,

8) (C 2 -C 10 )alkynyl,

13) C(O)R a ,

14) (C 0 -C 6 )alkylene-CO 2 R a ,

15) C(O)H,

16) (C 0 -C 6 )alkylene-CO 2 H, and

17) C(O)N(R b ) 2 ,

18) S(O) m R a , and

19) S(O) 2 N(R b ) 2 ;

said alkyl, alkenyl, alkynyl and aikylene are optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6 alkyl, oxo, NO 2 and N(R b ) 2 ;

R a is independently selected from: (C 1 -C 6 )alkyl;

R b is H or (C 1 -C 6 )alkyl.

3. The compound according to claim 2 of the Formula IV:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

b is

m is 0, 1, or 2;

r is 0 or 1;

s is 0 or 1;

R 1 and R 2 are independently selected from: H and (C 1 -C 6 )alkyl, optionally substituted with one, two or three substituents selected from R 7 ;

R 4 is independently selected from:

1) halo,

2) OH,

3) O b C 1 -C 6 perfluoroalkyl,

R7 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

2) O r (C 1 -C 3 )perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C 2 -C 10 )alkenyl,

8) (C 2 -C 10 )alkynyl,

13) C(O)R a ,

14) (C 0 -C 6 )alkylene-CO 2 R a ,

15) C(O)H,

16) (C 0 -C 6 )alkylene-CO 2 H, and

17) C(O)N(R b ) 2 ,

18) S(O) m R a , and

19) S(O) 2 N(R b ) 2 ;

R a is (C 1 -C 6 )alkyl;

R b is H or (C 1 -C 6 )alkyl.

4. The compound according to claim 3 of the Formula V:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

R 1 and R 2 are independently selected from: H and (C 1 -C 6 )alkyl.

5. The compound according to claim 1 of the formula VI:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

R 1 and R 2 are independently selected from: H and (C 1 -C 6 )alkyl.

6. A compound according to claim 1 selected from:

(2S)-4-(2,5-Difluorophenyl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yf]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3R,4R)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3S,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3R,4R)-3-fluoro-1-methylpiperidin-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(2R,4R)-2-(fluoromethyl)-1-methylpiperidin-4-yl]-2-(hydromethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(2S,4S)-2-(fluoromethyl)-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3S,4R)-3-fluoro-1-methyl-1-oxidopiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3S,4R)-3-fluoropiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3S,4R)-3-fluoro-1-isopropylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-Difluorophenyl)-N-[(3S,4S)-3-fluoropiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide