IP Library › Granted Patent US 7,348,440

Granted Patent B2

US 7,348,440 · App. 10/517,559 · Granted Mar 25, 2008

Mitotic kinesin inhibitors

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Quick Facts

Patent No.: US 7,348,440
App. No.: 10/517,559
Granted: Mar 25, 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 also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Claims (624)

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 or 1;

r is 0 or 1;

s is 0 or 1;

R 1 is:

1) (C 1 -C 6 -alkylene) n (C═X)NR c R c′ ,

said alkylene is optionally substituted with one or more substituents selected from R 10 ;

R 2 and R 6 are independently selected from:

1) phenyl,

said phenyl is optionally substituted with one or more substituents selected from R 10 ;

R 3 , R 4 , R 8 , and R 9 are independently selected from:

1) H, and

2) C 1 -C 10 alkyl;

R 10 is independently selected from:

1) C 1 -C 10 alkyl,

7) halo,

8) CN, and

9) OH,

said alkyl is optionally substituted with one or more halo;

R 11 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

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

3) (C 0 -C 6 )alkylene-S(O) m R a ,

4) oxo,

5) OH,

6) halo,

7) CN,

8) (C═O) r O s (C 2 -C 10 )alkenyl,

9) (C═O) r O s (C 2 -C 10 )alkynyl,

10) (C═O) r O s (C 3 -C 6 )cycloalkyl,

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

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

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

14) C(O)R a ,

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

16) C(O)H,

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

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

19) S(O) m R a , and

20) S(O) 2 N(R b ) 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, and N(R b ) 2 ;

R 12 and R 13 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 or more substituents selected from R 11 , or

R 12 and R 13 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 or more substituents selected from R 11 ;

R 14 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 12 R 13 ,

12) S(O) m R a ,

13) S(O) 2 NR 12 R 13 ,

14) oxo,

15) CHO,

16) (N═O)R 12 R 13 , or

17) (C═O) a O b C 3 -C 8 cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R 11 ;

R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl, optionally substituted with one to three substituents selected from R 14 ;

R b is 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 or S(O) 2 R a , optionally substituted with one to three substituents selected from R 14 ;

R c and R c′ are independently selected from: H, morpholine, piperazine, pyrrolidine, phenyl, pyridine, oxazole, pyrazole, oxadiazole, thiazole, triazole, oxopyridine, piperidine, tetrahydrofuran, dioxane, and (C 3 -C 6 )cycloalkyl, optionally substituted with one, two or three substituents selected from C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, NR 12 R 13 or S(O) m R a wherein said alkyl is optionally substituted with OH, —CO 2 H, alkoxy, (C═O)morpholine (which is optionally substituted with alkyl), O(C═O)piperazine, O(C═O)piperidine, O(C═O)morpholine, phenyl, pyridine, oxazole, pyrazole, oxadiazole, thiazole, triazole, oxopyridine, piperidine, piperazine, tetrahydrofuran, dioxane or pyrrolidinyl,

R c and R c′ can be taken together with the nitrogen to which they are attached to form morpholine, azetidine or pyrrolidine;

X is O.

2. The compound according to claim 1 of the 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 or 1;

r is 0 or 1;

s is 0 or 1;

R 1 is;

1) (C 1 -C 6 -alkylene) n (C═X)NR c R c′ ,

said alkylene is optionally substituted with one or more substituents selected from R 10 ;

R 2 and R 6 are independently selected from:

1) phenyl,

said phenyl, is optionally substituted with one or more substituents selected from R 10 ;

R 3 , R 4 , R 8 , and R 9 are independently selected from:

1) H, and

2) C 1 -C 10 alkyl;

R 10 is independently selected from:

1) C 1 -C 10 alkyl,

7) halo,

8) CN, and

9) OH,

said alkyl is optionally substituted with one or more halo;

R 11 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

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

3) (C 0 -C 6 )alkylene-S(O) m R a ,

4) oxo,

5) OH,

6) halo,

7) CN,

8) (C═O) r O s (C 2 -C 10 )alkenyl,

9) (C═O) r O s (C 2 -C 10 )alkynyl,

10) (C═O) r O s (C 3 -C 6 )cycloalkyl,

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

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

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

14) C(O)R a ,

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

16) C(O)H,

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

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

19) S(O) m R a , and

20) S(O) 2 N(R b ) 2

R 12 and R 13 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 or more substituents selected from R 11 , or

R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl;

R b is 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 or S(O) 2 R a ;

R c and R c′ are independently selected from: H, morpholine, piperazine, pyrrolidine, phenyl, pyridine, oxazole, pyrazole, oxadiazole, thiazole, triazole, oxopyridine, piperidine, tetrahydrofuran, dioxane, and (C 3 -C 6 )cycloalkyl, optionally substituted with one, two or three substituents selected from, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, NR 12 R 13 or S(O) m R a , wherein said alkyl is optionally substituted with OH, —CO 2 H, alkoxy, (C═O)morpholine (which is optionally substituted with alkyl), O(C═O)piperazine, O(C═O)piperidine, O(C═O)morpholine, phenyl, pyridine, oxazole, pyrazole, oxadiazole, thiazole, triazole, oxopyridine, piperidine, piperazine, tetrahydrofuran, dioxane or pyrrolidinyl,

R c and R c′ can be taken together with the nitrogen to which they are attached to form morpholine, azetidine or pyrrolidine;

and

X is O.

3. The compound according to claim 2 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 or 1;

r is 0 or 1;

s is 0 or 1;

R 1 is;

1) (C 1 -C 6 -alkylene) n (C═X)NR c R c′ ,

said alkylene is optionally substituted with one or more substituents selected from R 10 ;

R 2 and R 6 are independently selected from:

1) phenyl,

said phenyl, is optionally substituted with one or more substituents selected from R 10 ;

R 3 , R 4 , R 8 , and R 9 are independently selected from:

1) H, and

2) C 1 -C 10 alkyl;

R 10 is independently selected from:

1) C 1 -C 10 alkyl,

7) halo,

8) CN, and

9) OH,

said alkyl is optionally substituted with one or more halo;

R 11 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

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

3) (C 0 -C 6 )alkylene-S(O) m R a ,

4) oxo,

5) OH,

6) halo,

7) CN,

8) (C═O) r O s (C 2 -C 10 )alkenyl,

9) (C═O) r O s (C 2 -C 10 )alkynyl,

10) (C═O) r O s (C 3 -C 6 )cycloalkyl,

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

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

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

14) C(O)R a ,

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

16) C(O)H,

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

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

19) S(O) m R a , and

20) S(O) 2 N(R b ) 2

R 12 and R 13 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 or more substituents selected from R 11 , or

R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl;

R b is 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 or S(O) 2 R a ;

R c and R c′ can be taken together with the nitrogen to which they are attached to form morpholine, azetidine or pyrrolidine;

and

X is O.

4. The compound according to claim 2 of the 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;

r is 0 or 1;

s is 0 or 1;

R 1 is;

1) (C 1 -C 6 -alkylene) n (C═X)NR c R c′ ,

said alkylene is optionally substituted with one or more substituents selected from R 10 ;

R 2 and R 6 are independently selected from:

1) phenyl,

said phenyl, is optionally substituted with one or more substituents selected from R 10 ;

R 3 , R 4 , R 8 , and R 9 are independently selected from:

1) H, and

2) C 1 -C 10 alkyl;

R 10 is independently selected from:

1) C 1 -C 10 alkyl,

7) halo,

8) CN, and

9) OH,

said alkyl is optionally substituted with halo;

R 11 is selected from:

1) (C═O) r O s (C 1 -C 10 )alkyl,

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

3) (C 0 -C 6 )alkylene-S(O) m R a ,

4) oxo,

5) OH,

6) halo,

7) CN,

8) (C═O) r O s (C 2 -C 10 )alkenyl,

9) (C═O) r O s (C 2 -C 10 )alkynyl,

10) (C═O) r O s (C 3 -C 6 )cycloalkyl,

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

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

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

14) C(O)R a ,

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

16) C(O)H,

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

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

19) S(O) m R a , and

20) S(O) 2 N(R b ) 2

R 12 and R 13 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 11 , or

R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl; or heterocyclyl;

R b is 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 or S(O) 2 R a ;

R c and R c′ are independently selected from: H, morpholine, piperazine, pyrrolidine, phenyl, pyridine, oxazole, pyrazole, oxadiazole, thiazole, triazole, oxopyridine, piperidine, tetrahydrofuran, dioxane, and (C 3 -C 6 )cycloalkyl, or R c and R c′ can be taken together with the nitrogen to which they are attached to form morpholine, azetidine or pyrrolidine.

5. A compound 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;

r is 0 or 1;

s is 0 or 1;

R 1 is selected from:

1) (C═O)NR c R c′ ;

R 2 is selected from:

1) phenyl,

said phenyl, is optionally substituted with one or more substituents selected from R 10 ;

R 3 , R 4 , R 8 , and R 9 are independently selected from:

1) H, and

2) C 1 -C 10 alkyl;

R 10 is independently selected from:

1) C 1 -C 10 alkyl,

7) halo,

8) CN, and

9) OH,

said alkyl is optionally substituted with halo;

R 10′ is halogen;

R 11 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 ;

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 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, and N(R b ) 2 ;

R 12 and R 13 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 11 , or

R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl; or heterocyclyl

R b is 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 or S(O) 2 R a ;

or R c and R c′ can be taken together with the nitrogen to which they are attached to form morpholine, azetidine or pyrrolidine.

6. The compound according to claim 4 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 is selected from:

1) (C═O)NR c R c′ ;

R 2 is selected from:

1) phenyl,

said phenyl, is optionally substituted with one or more substituents selected from R 10 ;

R 3 , R 4 , R 8 , and R 9 are independently selected from:

1) H, and

2) C 1 -C 10 alkyl;

R 6 is selected from:

1) phenyl,

said phenyl, is optionally substituted with one or more substituents selected from R 10 ;

R 10 is independently selected from:

1) C 1 -C 10 alkyl,

7) halo,

8) CN, and

9) OH,

said alkyl is optionally substituted with halo;

R 11 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)N(R b ) 2 ,

18) S(O) m R a , and

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

R 12 and R 13 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 11 , or

R a is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl; and heterocyclyl;

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 or S(O) 2 R a ; and

R c and R c′ can be taken together with the nitrogen to which they are attached to form morpholine, azetidine or pyrrolidine.

7. The compound according to claim 6 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

R 2 and R 6 are phenyl optionally substituted with one or two substituents selected from R 10 .

8. A compound selected from:

4-(2-chloro-5-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(+)-4-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(−)-4-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(5-chloro-2-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2-fluoro-5-methylphenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(5-bromo-2-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-{[4-(5-chloro-2-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}morpholine;

4-{[4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}morpholine;

N,N-dimethyl-2,4-diphenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(4-fluorophenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(2-fluorophenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

2-(3-bromophenyl)-4-(2,5-difluorophenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

2-(3-aminophenyl)-4-(2,5-difluorophenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-methylphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(5-chloro-2-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2-fluoro-5-isocyanophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-Difluorophenyl)-N-methyl-2-phenyl-N-piperidin-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-Difluorophenyl)-N-methyl-2-phenyl-N-(piperidin-4-ylmethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(5-Chloro-2-fluorophenyl)-N-methyl-2-phenyl-N-[(3R)-pyrrolidin-3-yl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(5-chloro-2-fluorophenyl)-N-methyl-2-phenyl-N-piperidin-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(5-chloro-2-fluorophenyl)-N-methyl-2-phenyl-N-[(3S)-pyrrolidin-3-yl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-methyl-2-phenyl-N-pyrrolidin-3-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-methyl-N-[(3S)-1-methylpyrrolidin-3-yl]-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-methyl-N-[(3R)-1-methylpyrrolidin-3-yl]-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-methyl-N-[(1-methyl-5-oxopyrrolidin-2-yl)methyl]-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-(1,3-dioxolan-2-ylmethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-methyl-2-phenyl-N-tetrahydrofuran-3-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-N-(1-allylpiperidin-4-yl)-4-(2,5-difluorophenyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

allyl 4-[{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]piperidine-1-carboxylate;

allyl 4-{[{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]methyl}piperidine-1-carboxylate;

(2S)-4-(2,5-difluorophenyl)-N-methyl-N-(1-methylpiperidin-4-yl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

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

4-(2,5-difluorophenyl)-N-methyl-2-phenyl-N-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide;

N-benzyl-4-(2,5-difluorophenyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-(2-hydroxyethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-isobutyl-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-methyl-2-phenyl-N-(2-pyridin-2-ylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-(2-methoxyethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-(2,3-dihydroxypropyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-methyl-2-phenyl-N-(2-phenylethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-phenyl-N-propyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(5-chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-piperidin-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-piperidin-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N,N,2-trimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(5-chloro-2-fluorophenyl)-N,N,2-trimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(5-chloro-2-fluorophenyl)-2-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(5-chloro-2-fluorophenyl)-N-ethyl-2-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

N-(tert-butyl)-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]acetamide;

2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N-isopropylacetamide;

(2S)-1-(2-azetidin-1-yl-2-oxoethyl)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole;

(2S)-4-(2,5-difluorophenyl)-1-(2-oxo-2-pyrrolidin-1-ylethyl)-2-phenyl-2,5-dihydro-1H-pyrrole;

4-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]acetyl}morpholine;

1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]acetyl}piperazine;

1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]acetyl}-4-methylpiperazine;

2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N-isopropylbutanamide;

4-{2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]butanoyl}morpholine;

2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N-ethylacetamide;

N-cyclobutyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]acetamide;

2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N-ethylpropanamide;

N-cyclobutyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanamide;

2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N-methylpropanamide;

2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N-isopropylpropanamide;

N-(tert-butyl)-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanamide;

4-{2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanoyl}morpholine;

2-({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)-N-isopropylacetamide;

2-(dimethylamino)ethyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate;

1-methylpiperidin-4-yl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-(2-hydroxyethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

N-{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-N-methyl-beta-alanine;

methyl N-{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-N-methyl-beta-alaninate;

4-{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]acetyl}-morpholin-4-ium;

3-[4-(2,5-difluorophenyl)-1-(morpholin-4-ylcarbonyl)-2,5-dihydro-1H-pyrrol-2-yl]phenol;

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-tetrahydrofuran-3-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-(2-methoxyethyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-tetrahydro-2H-pyran-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-[1-(2-fluoroethyl)piperidin-4-yl]-2-(3-hydroxyphenyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]piperidinium trifluoroacetate;

2-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]ethyl 4-methylpiperazine-1-carboxylate;

3-{4-(2,5-difluorophenyl)-1-[(4-methylpiperazin-1-yl)carbonyl]-2,5-dihydro-1H-pyrrol-2-yl}phenol;

2-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]ethyl morpholine-4-carboxylate;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-(isoxazol-5-ylmethyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

2-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]ethyl dimethylaminocarboxylate;

2-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]ethyl piperidine-1-carboxylate;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[2-(2-oxopyrrolidin-1-yl)ethyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-{[5-(methoxymethyl)-1H-pyrazol-3-yl]methyl}-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-(1,3-thiazol-4-ylmethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-(1,3-thiazol-2-ylmethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-(isoxazol-3-ylmethyl)-N-methyl-2,5,-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[2-(1H-pyrazol-1-yl)ethyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[(1-methyl-5-oxopyrrolidin-2-yl)methyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-(1-isoxazol-3-ylethyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-(1,3-dioxolan-2-ylmethyl)-2-(3-hydroxyphenyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-(1,4-dioxan-2-ylmethyl)-2-(3-hydroxyphenyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-[2-(methylsulfonyl)ethyl]-2,5-dihydro-1H-pyrrole-1-carboxamide 2-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]ethanesulfonic acid;

3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N-methylpropanamide;

3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N,N-dimethylpropanamide;

3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-N,N,2-trimethyipropanamide;

4-{3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanoyl}morpholine;

1-{3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanoyl}-4-(methylsulfonyl)piperazine;

1-{3-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]propanoyl}piperidin-4-ol;

or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The compound according to claim 8 which is selected from:

(−)-4-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(5-chloro-2-fluorophenyl)-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide; and

(2S)-4-(2,5-difluorophenyl)-N-methyl-2-phenyl-N-piperidin-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

or a pharmaceutically acceptable salt or stereoisomer thereof.

10. The compound according to claim 8 which is selected from:

(2S)-4-(2,5-difluorophenyl)-N-methyl-2-phenyl-N-piperidin-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-N-methyl-N-(1-methylpiperidin-4-yl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide; or

or a pharmaceutically acceptable salt or stereoisomer thereof.

11. A compound selected from:

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-tetrahydrofuran-3-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-(2-methoxyethyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N-methyl-N-tetrahydro-2H-pyran-4-yl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-(2,5-difluorophenyl)-N-[1-(2-fluoroethyl)piperidin-4-yl]-2-(3-hydroxyphenyl)-N-methyl-2,5-dihydro-1H-pyrrole-1-carboxamide;

4-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]piperidinium trifluoro acetate; 2-[{[4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}(methyl)amino]ethyl 4-methylpiperazine-1-carboxylate;