Mitotic kinesin inhibitors

1. A compound as illustrated by Formula II:

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)C 1 -C 10 alkyl;

6) (C═O)NR c R c ′;

7) SO 2 NR c R c ′;

8) SO 2 C 1 -C 10 alkyl;

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

R 2 and R 3 are H;

R 4 , R 5 and R 9 are independently selected from:

1) H;

2) (C 1 -C 10 )alkyl;

3) (C 1 -C 10 )alkylamino;

4) (C 1 -C 10 )alkylhydroxy;

R 7 is H;

R 10 is:

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 11 R 12 ;

12) S(O) m R a ;

13) S(O) 2 NR 11 R 12 ;

14) oxo;

15) CHO;

16) (N═O)R 11 R 12 ; 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 13 ;

R 10a and R 10b are independently selected from:

1) H;

2) C 1 -C 10 alkyl;

3) C 2 -C 10 alkenyl;

4) C 2 -C 10 alkynyl;

5) OH;

6) CN;

7) halo;

8) CHO;

9) CO 2 H;

10) (C 1 -C 6 )alkyl amino; and

11) (C 1 -C 6 )alkyl hydroxy;

R 11 and R 12 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 ;

13) (C═O)NR b 2 ;

14) oxo; and

15) OH;

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 13 ; or

R 11 and R 12 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 4-7 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 13 ;

R 13 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 a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl;

said alkyl, cycloalkyl, aryl or heterocylyl is optionally substituted with one or more substituents selected from R f ,

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 ;

said alkyl, cycloalkyl, aryl or heterocylyl is optionally substituted with one or more substituents selected from R f ,

R c and R c′ 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 13 , 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 4-7 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 13 ;

R e is selected from: H and (C 1 -C 6 )alkyl; and

R f is selected from: heterocyclyl, amino substituted heterocyclyl, (C 1 -C 6 )alkyl, amino (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl amino, hydroxy (C 1 -C 6 )alkyl, OH and NH 2 ;

or a pharmacuetically acceptable salt or stereoisomer thereof.

2. A compound selected from:

3-[1-Acetyl-4-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol;

1-acetyl-4-(2,5-difluorophenyl)-6-phenyl-1,2,3,6-tetrahydropyridine;

4-(2,5-difluorophenyl)-6-phenyl-3,6-dihydropyridine-1(2H)-carboxamide;

N-1-[4-(2,5-difluorophenyl) -6-(3-hydroxyphenyl)-1-L-valyl-1,2,3,6-tetrahydropyridin-2-yl]-L-valinamide; and

4-(2,5-difluorophenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[2-methyl-3-(methylamino)propyl]-3,6-dihydropyridine-1(2H)-carboxamide;

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. A TFA salt selected from:

N-1-[4-(2,5-difluorophenyl)-6-(3-hydroxyphenyl)-1-L-valyl- 1,2,3,6-tetrahydropyridin-2-yl]-L-valinamide; and

4-(2,5-difluorophenyl)-6-(3-hydroxyphenyl)-N-methyl-N-[2-methyl-3-(methylamino)propyl]-3,6-dihydropyridine-1(2H)-carboxamide;

or a stereoisomer thereof.

4. The compound according to claim 2 which is selected from:

3-[1-Acetyl-4-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol; and

N-1-[4-(2,5-difluorophenyl)-6-(3-hydroxyphenyl)-1-L-valyl-1,2,3,6-tetrahydropyridin-2-yl]-L-valinamide;

or a pharmaceutically acceptable salt or stereoisomer thereof.

5. A compound according to claim 1 which is selected from:

6-(2-aminoethyl)-4-(2,5 -difluorophenyl)-N,N-dimethyl-6-phenyl-3,6-dihydropyridine-1(2H)-carboxamide;

6-(3-aminopropyl)-4-(2,5-difluorophenyl)-N,N-dimethyl-6-phenyl-3,6-dihydropyridine-1(2H)-carboxamide;

6-(4-aminobutyl)-4-(2,5-difluorophenyl)-N,N-dimethyl-6-phenyl -3,6-dihydropyridine-1(2H)-carboxamide;

4-(2,5-difluorophenyl)-6-(hydroxymethyl)-6-(3-hydroxyphenyl) -N-methyl-N-(1-methylpiperidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide;

3-[l-[(2S)-2-amino-2-cyclopropylethanoyl]-4-(2,5-difluorophenyl)-2-(hydroxymethyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol;

4-(2,5-difluorophenyl)-6-(hydroxymethyl)-6-(3-hydroxyphenyl)-N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide;

6-(3-aminopropyl)-4-isopropyl-N,N-dimethyl-6-phenyl-3,6-dihydropyridine-1(2H)-carboxamide;

6-(3-aminopropyl)-6-(3-hydroxyphenyl)-4-isopropyl-N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide;

2-[1-acetyl-4-(2,5-difluorophenyl)-2-phenyl-1,2,5,6-tetrahydropyridin-2-yl]ethanamine;

3-[1-acetyl-4-(2,5-difluorophenyl)-2-phenyl-1,2,5,6-tetrahydropyridin-2-yl]propan-1-amine;

4-[1-acetyl-4-(2,5-difluorophenyl)-2-phenyl-1,2,5,6-tetrahydropyridin-2-yl]butan-1-amine;

3-[1-acetyl-2-(2-aminoethyl)-4-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol;

3-[1-acetyl-2-(3-aminopropyl)-4-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol;

3-[1-acetyl-2-(4-aminobutyl)-4-(2,5-difluorophenyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol;

3-[1-acetyl-2-(2-aminoethyl)-4-(2,5 -difluorophenyl)-1,2,5,6-tetrahydropyridin-2-yl]phenol;

1′-acetyl-4′-(2,5-difluorophenyl)-1′,2′,5′,6′-tetrahydro-2,2′-bipyridin-6(1H)-one; and

1-acetyl-4-(2,5-difluorophenyl)-1,2,5,6-tetrahydro-2,4′-bipyridin-2′(1′H )-one;

or a pharmaceutically acceptable salt or stereoisomer thereof.

6. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .

7. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.

8. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.

9. The composition of claim 6 further comprising a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist; an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, and an apoptosis inducing agent.

10. The composition of claim 9 , wherein the second compound is an angiogenesis inhibitor selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, or an antibody to VEGF.

11. The composition of claim 9 , wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.