IP Library › Granted Patent US 7,666,862

Granted Patent B2

US 7,666,862 · App. 10/567,249 · Granted Feb 23, 2010

Mitotic Kinesin Inhibitors

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Quick Facts

Patent No.: US 7,666,862
App. No.: 10/567,249
Granted: Feb 23, 2010
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 (1430)

1. A compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

a is 0 or 1;

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, 1 or 2;

u is 0, 1, or 2;

R 1 and R 2 are independently selected from: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl and (C 3 -C 6 )cycloalkyl, optionally substituted with one, two or three substituents selected from R 7 ;

R 3 is selected from:

1) hydrogen,

2) C 1 -C 10 alkyl;

3) C 1 -C 10 alkyl-O—R d ,

4) C 2 -C 10 alkenyl-O—R d ,

5) C 2 -C 10 alkynyl-O—R d ,

6) (C 1 -C 6 -alkylene) n C 3 -C 8 cycloalkyl-O—R d ,

7) C 1 -C 10 alkyl-(C═O) b —NR c R c ′,

8) C 2 -C 10 alkenyl-(C═O) b NR c R c ′,

9) C 2 -C 10 alkynyl-(C═O) b NR c R c ′,

10) (C 1 -C 6 -alkylene) n C 3 -C 8 cycloalkyl-(C═O) b NR c R c ′,

11) C 1 -C 10 alkyl-S(O) m —R d ,

12) C 2 -C 10 alkenyl-S(O) m —R d ,

13) C 2 -C 10 alkynyl-S(O) m —R d ,

14) (C 1 -C 6 -alkylene) n C 3 -C 8 cycloalkyl-S(O) m —R d ,

said alkyl alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from R 6 ;

R 4 is independently selected from:

1) (C═O) a O b C 1 -C 10 alkyl,

2) (C═O) a O b aryl,

3) CO 2 H,

4) halo,

5) CN,

6) OH,

7) O b C 1 -C 6 perfluoroalkyl,

8) O a (C═O) b NR 8 R 9 ,

9) S(O) m R a ,

10) S(O) 2 NR 8 R 9 ,

11) —OPO(OH) 2 ;

said alkyl and aryl optionally substituted with one, two or three substituents selected from R 7 ;

R 5 is selected from:

1) hydrogen;

2) (C═O) a O b C 1 -C 10 alkyl,

3) (C═O) a O b aryl,

4) CO 2 H,

5) halo,

6) CN,

7) OH,

8) O b C 1 -C 6 perfluoroalkyl,

9) O a (C═O) b NR 8 R 9 ,

10) S(O) m R a ,

11) S(O) 2 NR 8 R 9 ,

12) —OPO(OH) 2 ;

said alkyl and aryl optionally substituted with one, two or three substituents selected from R 7 ;

R 6 is independently selected from:

1) (C═O) a O b C 1 -C 10 alkyl,

2) (C═O) a O b aryl,

3) C 2 -C 10 alkenyl,

4) C 2 -C 10 alkynyl,

5) (C═O) a O b heterocyclyl,

6) CO 2 H,

7) halo,

8) CN,

9) OH,

10) O b C 1 -C 6 perfluoroalkyl,

11) O a (C═O) b NR 8 R 9 ,

12) S(O) m R a ,

13) S(O) 2 NR 8 R 9 ,

14) oxo,

15) CHO,

16) (N═O)R 8 R 9 , or

17) (C═O) a O b C 3 -C 8 cycloalkyl,

18) —OPO(OH) 2 ;

said alkyl aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 7 ;

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,

9) (C═O) r O s (C 3 -C 6 )cycloalkyl,

10) (C═O) r O s (C 0 -C 6 )alkylene-aryl,

11) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,

12) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 ,

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) r 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, cycloalkyl, aryl, alkylene and heterocyclyl 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 8 and R 9 are independently selected from:

1) H,

2) (C═O)O b C 1 -C 10 alkyl,

3) (C═O)O b C 3 -C 8 cycloalkyl,

4) (C═O)O b aryl,

5) (C═O)O b heterocyclyl,

6) C 1 -C 10 alkyl,

7) aryl,

8) C 2 -C 10 alkenyl,

9) C 2 -C 10 alkynyl,

10) heterocyclyl,

11) C 3 -C 8 cycloalkyl,

12) SO 2 R a , and

13) (C═O)NR b 2 ,

said alkyl cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R 7 , or

R 8 and R 9 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 ;

R 10 is selected from: H and F;

R 11 and R 12 are independently selected from: F and —CH 2 F;

R 13 and R 14 are independently selected from: H and —CH 2 F;

R ox is absent or is oxo;

R a is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl, optionally substituted with one, two or three substituents selected from R 7 ;

R b is independently selected from: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6 alkyl, (C═O)C 1 -C 6 alkyl, (C═O)aryl, (C═O)heterocyclyl, (C═O)NR e R e ′ or S(O) 2 R a ;

R c and R c ′ are independently selected from: H, (C 1 -C 6 )alkyl, aryl, NH 2 , OH, OR a , —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C═O)OC 1 -C 6 alkyl, (C═O)C 1 -C 6 alkyl, (C═O)aryl, (C═O)heterocyclyl, (C═O)NR e R e ′, S(O) 2 R a and —(C 1 -C 6 )alkyl-N(R b ) 2 , wherein the alkyl is optionally substituted with one, two or three substituents selected from R 7 ; or

R c and R c′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 ;

R d is selected from: H, (C 1 -C 6 )alkyl, —(C 2 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl and —(C 1 -C 6 )alkyl-N(R b ) 2 , wherein the alkyl is optionally substituted with one, two or three substituents selected from R 7 ;

R e and R e′ are independently selected from: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl and (C 3 -C 6 )cycloalkyl; or

R e and R e′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 .

2. The compound according to claim 1 of Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

a is 0 or 1;

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;

u is 0 or 1;

R 1 and R 2 are independently selected from: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl and (C 3 -C 6 )cycloalkyl, optionally substituted with one, two or three substituents selected from R 7 ;

R 3 is selected from:

1) hydrogen;

2) C 1 -C 10 alkyl;

3) C 1 -C 10 alkyl-O—R d ,

4) C 2 -C 10 alkenyl-O—R d ,

5) C 2 -C 10 alkynyl-O—R d ,

6) (C 1 -C 6 -alkylene) n C 3 -C 8 cycloalkyl-O—R d ,

7) C 1 -C 10 alkyl-(C═O) b —NR c R c ′,

8) C 2 -C 10 alkenyl-(C═O) b NR c R c ′,

9) C 2 -C 10 alkynyl-(C═O) b NR c R c ′,

10) (C 1 -C 6 -alkylene) n C 3 -C 8 cycloalkyl-(C═O) b NR c R c ′,

11) C 1 -C 10 alkyl-S(O) m —R d ,

12) C 2 -C 10 alkenyl-S(O) m —R d ,

13) C 2 -C 10 alkynyl-S(O) m —R d ,

14) (C 1 -C 6 -alkylene) n C 3 -C 8 cycloalkyl-S(O) m —R d ,

said alkyl alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from R 6 ;

R 4 is independently selected from:

1) (C═O) a O b C 1 -C 10 alkyl,

2) (C═O) a O b aryl,

3) CO 2 H,

4) halo,

5) CN,

6) OH,

7) O b C 1 -C 6 perfluoroalkyl,

8) O a (C═O) b NR 8 R 9 ,

9) S(O) m R a ,

10) S(O) 2 NR 8 R 9 , and

11) —OPO(OH) 2 ;

said alkyl and aryl optionally substituted with one, two or three substituents selected from R 7 ;

R 5 is selected from:

1) hydrogen;

2) (C═O) a O b C 1 -C 10 alkyl,

3) (C═O) a O b aryl,

4) CO 2 H,

5) halo,

6) CN,

7) OH,

8) O b C 1 -C 6 perfluoroalkyl,

9) O a (C═O) b NR 8 R 9 ,

10) S(O) m R a ,

11) S(O) 2 NR 8 R 9 ,

said alkyl and aryl optionally substituted with one, two or three substituents selected from R 7 ;

R 6 is independently selected from:

1) (C═O) a O b C 1 -C 10 alkyl,

2) (C═O) a O b aryl,

3) C 2 -C 10 alkenyl,

4) C 2 -C 10 alkynyl,

5) (C═O) a O b heterocyclyl,

6) CO 2 H,

7) halo,

8) CN,

9) OH,

10) O b C 1 -C 6 perfluoroalkyl,

11) O a (C═O) b NR 8 R 9 ,

12) S(O) m R a ,

13) S(O) 2 NR 8 R 9 ,

14) oxo,

15) CHO,

16) (N═O)R 8 R 9 , or

17) (C═O) a O b C 3 -C 8 cycloalkyl, and

18) —OPO(OH) 2 ;

said alkyl aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 7 ;

R 7 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

2) Or(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,

9) (C═O) r O s (C 3 -C 6 )cycloalkyl,

10) (C═O) r O s (C 0 -C 6 )alkylene-aryl,

11) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,

12) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 ,

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 ;

R 8 and R 9 are independently selected from:

1) H,

2) (C═O)O b C 1 -C 10 alkyl,

3) (C═O)O b C 3 -C 8 cycloalkyl,

4) (C═O)O b aryl,

5) (C═O)O b heterocyclyl,

6) C 1 -C 10 alkyl,

7) aryl,

8) C 2 -C 10 alkenyl,

9) C 2 -C 10 alkynyl,

10) heterocyclyl,

11) C 3 -C 8 cycloalkyl,

12) SO 2 R a , and

13) (C═O)NR b 2 ,

said alkyl cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R 7 , or

R 11 and R 12 are independently selected from: F and —CH 2 F;

R 13 and R 14 are independently selected from: H and —CH 2 F, provided that when t is 1, R 14 Is H; and when u is 1, R 13 is H;

R ox is absent or is oxo;

R a is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl, optionally substituted with one, two or three substituents selected from R 7 ;

R c and R c ′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 ;

R e and R e ′ are independently selected from: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl and (C 3 -C 6 )cycloalkyl; or

R e and R e ′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 .

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

a is 0 or 1;

b is 0 or 1;

m is 0, 1, or 2;

n is 0, 1 or 2;

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, (C 1 -C 6 )alkyl, aryl and (C 3 -C 6 )cycloalkyl, 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,

R 5 is selected from:

1) hydrogen,

2) halo,

3) OH,

4) O b C 1 -C 6 perfluoroalkyl,

R 7 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

2) Or(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,

9) (C═O) r O s (C 3 -C 6 )cycloalkyl,

10) (C═O) r O s (C 0 -C 6 )alkylene-aryl,

11) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,

12) (C═O) r O s (C 0 -C 6 )alkylene-N(R b )

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 8 and R 9 are independently selected from:

1) H,

2) (C═O)O b C 1 -C 10 alkyl,

3) (C═O)O b C 3 -C 8 cycloalkyl,

4) (C═O)O b aryl,

5) (C═O)O b heterocyclyl,

6) C 1 -C 10 alkyl,

7) aryl,

8) C 2 -C 10 alkenyl,

9) C 2 -C 10 alkynyl,

10) heterocyclyl,

11) C 3 -C 8 cycloalkyl,

12) SO 2 R a , and

13) (C═O)NR b 2 ,

said alkyl cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R 7 , or

R 12 is selected from: F and —CH 2 F;

R 14 is selected from: H and —CH 2 F, provided that when t is 1, R 14 is H;

R a is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl, optionally substituted with one, two or three substituents selected from R 7 ;

R c and R c′ are independently selected from: H, (C 1 -C 6 )alkyl, aryl, NH 2 , OH, OR a , —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C═O)OC 1 -C 6 alkyl, (C═O)C 1 -C 6 alkyl, (C═O)aryl, (C═O)heterocyclyl, (C═O)NR e R e′ , S(O) 2 R a and —(C 1 -C 6 )alkyl-N(R b ) 2 , wherein the alkyl is optionally substituted with one, two or three substituents selected from R 7 ; or

R c and R c ′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 ;

R e and R e ′ are independently selected from: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl and (C 3 -C 6 )cycloalkyl; or

R e and R e ′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 .

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

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

a is 0 or 1;

b is 0 or 1;

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,

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,

9) (C═O) r O s (C 3 -C 6 )cycloalkyl,

10) (C═O) r O s (C 0 -C 6 )alkylene-aryl,

11) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,

12) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 ,

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 8 and R 9 are independently selected from:

1) H,

2) (C═O)O b C 1 -C 10 alkyl,

3) (C═O)O b C 3 -C 8 cycloalkyl,

4) (C═O)O b aryl,

5) (C═O)O b heterocyclyl,

6) C 1 -C 10 alkyl,

7) aryl,

8) C 2 -C 10 alkenyl,

9) C 2 -C 10 alkynyl,

10) heterocyclyl,

11) C 3 -C 8 cycloalkyl,

12) SO 2 R a , and

13) (C═O)NR b 2 ,

said alkyl cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R 7 , or

R a is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl, optionally substituted with one, two or three substituents selected from R 7 ;

R c and R c ′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 ;

R e and R e ′ are independently selected from: H, (C 1 -C 6 )alkyl, aryl, heterocyclyl and (C 3 -C 6 )cycloalkyl; or

R e and R e ′ can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 7 .

5. A compound selected from:

(2S)-4-(2,5-difluorophenyl)-N-[(4R,6S)-6-fluoro-1-methylazepan-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2, 5-dihydro-1H-pyrrole-1-carboxamide

(2S)-4-(2,5-difluorophenyl)-N-[(4S,6R)-6-fluoro-1-methylazepan-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2, 5-dihydro-1H-pyrrole-1-carboxamide

or a pharmaceutically acceptable salt thereof.

6. The compound which is selected from:

R 1

R 2

R 3

R 4

R 5

CH 2 OH

CF 3

CH 2 OH

NO 2

CH 2 OH

NH 2

CH 2 OH

R 1

R 2

R 3

R 4

R 5

CH 2 OH

CF 3

CH 2 OH

NO 2

CH 2 OH

NH 2

CH 2 OH

R 1

R 2

R 3

R 4

R 5

CH 2 OH

CF 3

CH 2 OH

NO 2

CH 2 OH

NH 2

CH 2 OH

R 1

R 2

R 3

R 4

R 5

CH 2 OH

CF 3

CH 2 OH

NO 2

CH 2 OH

NH 2

CH 2 OH

or a pharmaceutically acceptable salt or stereoisomer thereof.

7. A pharmaceutical composition that is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

Assignments (1)

CHANGE OF NAME Recorded Jan 22, 2010

From: MERCK & CO., INC.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 023834/0029 →