IP Library › Granted Patent US 7,192,949

Granted Patent B2

US 7,192,949 · App. 11/410,341 · Granted Mar 20, 2007

Substituted bicyclic pyrimidinones as a mitotic kinesin KSP inhibitors

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Quick Facts

Patent No.: US 7,192,949
App. No.: 11/410,341
Granted: Mar 20, 2007
Kind: B2

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Abstract

The present invention relates to cycloalkylpyrimidinone 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 (832)

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 1 to 3;

r is 0 to 3;

u is 2, 3, 4 or 5;

R 1 is selected from:

1) H,

2) C 1 –C 10 alkyl,

3) aryl,

4) C 2 –C 10 alkenyl,

5) C 2 –C 10 alkynyl,

6) C 1 –C 6 perfluoroalkyl,

7) C 1 –C 6 aralkyl,

8) C 3 –C 8 cycloalkyl, and

9) heterocyclyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;

R 2 and R 2′ are independently selected from:

1) H,

2) (C═O) a O b C 1 –C 10 alkyl,

3) (C═O) a O b aryl,

4) (C═O) a O b C 2 –C 10 alkenyl,

5) (C═O) a O b C 2 –C 10 alkynyl,

6) CO 2 H,

7) C 1 –C 6 perfluoroalkyl,

8) (C═O) a O b C 3 –C 8 cycloalkyl,

9) (C═O) a O b heterocyclyl,

10) SO 2 NR 7 R 8 , and

11) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ; or

R 2 and R 2′ are combined to form —(CH 2 ) u — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —NC(O)—, and —N(R b )—, and wherein the ring formed when R 2 and R 2′ are combined is optionally substituted with one, two or three substituents selected from R 5 ;

R 3 and R 3′ are independently selected from:

1) H,

2) (C═O) a O b C 1 –C10 alkyl,

3) (C═O) a O b aryl,

4) (C═O) a O b C 2 –C 10 alkenyl,

5) (C═O) a O b C 2 –C 10 alkynyl,

6) CO 2 H,

7) C 1 –C 6 perfluoroalkyl,

8) (C═O) a O b C 3 –C 8 cycloalkyl,

9) (C═O) a O b heterocyclyl,

10) SO 2 NR 7 R 8 , and

11) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;

or R 3 and R 3′ along with the nitrogen to which they are attached are combined to form ring

which is a 5–12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;

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) (C═O) a O b C 2 –C 10 alkenyl,

4) (C═O) a O b C 2 –C 10 alkynyl,

5) CO 2 H,

6) halo,

7) OH,

8) O b C 1 –C 6 perfluoroalkyl,

9) (C═O) a NR 7 R 8 ,

10) CN,

11) (C═O) a O b C 3 –C 8 cycloalkyl,

12) (C═O) a O b heterocyclyl,

13) SO 2 NR 7 R 8 , and

14) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;

R 5 is:

1) (C═O) a O b C 1 –C10 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 7 R 8 ,

12) oxo,

13) CHO,

14) (N═O)R 7 R 8 , or

15) (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 6 ;

R 6 is selected from:

1) (C═O) r O s (C 1 –C 10 )alkyl, wherein r and s are independently 0 or 1,

2) O r (C 1 –C 3 )perfluoroalkyl, wherein r is 0 or 1,

3) (C 0 –C 6 )alkylene-S(O) m R a , wherein m is 0, 1, or 2,

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, and

18) C(O)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 7 and R 8 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, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6 , or

R 7 and R 8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5–7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R 6 ;

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

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 .

2. A compound 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 1 to 3;

r is 0 to 3;

u is 2, 3, 4 or 5;

R 1 is selected from:

1) H,

2) C 1 –C 10 alkyl,

3) aryl,

4) C 2 –C 10 alkenyl,

5) C 2 –C 10 alkynyl,

6) C 1 –C 6 perfluoroalkyl,

7) C 1 –C 6 aralkyl,

8) C 3 –C 8 cycloalkyl, and

9) heterocyclyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;

R 2 and R 2′ are independently selected from:

1) H,

2) (C═O) a O b C 1 –C 10 alkyl,

3) (C═O) a O b aryl,

4) (C═O) a O b C 2 –C 10 alkenyl,

5) (C═O) a O b C 2 –C 10 alkynyl,

6) CO 2 H,

7) C 1 –C 6 perfluoroalkyl,

8) (C═O) a O b C 3 –C 8 cycloalkyl,

9) (C═O) a O b heterocyclyl,

10) SO 2 NR 7 R 8 , and

11) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ; or

R 3 and R 3′ are independently selected from:

1) H,

2) (C═O) a O b C 1 –C 10 alkyl,

3) (C═O) a O b aryl,

4) (C═O) a O b C 2 –C 10 alkenyl,

5) (C═O) a O b C 2 –C 10 alkynyl,

6) CO 2 H,

7) C 1 –C 6 perfluoroalkyl,

8) (C═O) a O b C 3 –C 8 cycloalkyl,

9) (C═O) a O b heterocyclyl,

10) SO 2 NR 7 R 8 , and

11) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;

or R 3 and R 3′ along with the nitrogen to which they are attached are combined to form ring

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) (C═O) a O b C 2 –C 10 alkenyl,

4) (C═O) a O b C 2 –C 10 alkynyl,

5) CO 2 H,

6) halo,

7) OH,

8) O b C 1 –C 6 perfluoroalkyl,

9) (C═O) a NR 7 R 8 ,

10) CN,

11) (C═O) a O b C 3 –C 8 cycloalkyl,

12) (C═O) a O b heterocyclyl,

13) SO 2 NR 7 R 8 , and

14) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;

R 5 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 7 R 8 ,

12) oxo,

13) CHO,

14) (N═O)R 7 R 8 , or

15) (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 6 ;

R 6 is selected from:

1) (C═O) r O s (C 1 –C 10 )alkyl, wherein r and s are independently 0 or 1,

2) O r (C 1 –C 3 )perfluoroalkyl, wherein r is 0 or 1,

3) (C 0 –C 6 )alkylene-S(O) m R a , wherein m is 0, 1, or 2,

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, and

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

R 7 and R 8 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, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6 , or

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

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 .

3. The compound according to claim 2 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 to 2;

R 1 is selected from:

1) H,

2) C 1 –C 10 alkyl,

3) aryl,

4) C 1 –C 6 aralkyl,

5) C 3 –C 8 cycloalkyl, and

6) heterocyclyl,

said alkyl, aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;

R 2 and R 2′ are independently selected from:

1) H,

2) (C═O) a O b C 1 –C 10 alkyl,

3) (C═O) a O b aryl,

4) CO 2 H,

5) C 1 –C 6 perfluoroalkyl,

6) (C═O) a O b C 3 –C 8 cycloalkyl, and

7) (C═O) a O b heterocyclyl,

said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;

R 3 and R 3′ are independently selected from:

1) H,

2) (C═O) a O b C 1 –C 10 alkyl,

3) (C═O) a O b aryl,

4) (C═O) a O b C 2 –C 10 alkenyl,

5) (C═O) a O b C 2 –C 10 alkynyl,

6) CO 2 H,

7) C 1 –C 6 perfluoroalkyl,

8) (C═O) a O b C 3 –C 8 cycloalkyl,

9) (C═O) a O b heterocyclyl,

10) SO 2 NR 7 R 8 , and

11) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;

or R 3 and R 3′ along with the nitrogen to which they are attached are combined to form ring

which is a 5–12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to three R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;

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) OH,

6) O b C 1 –C 6 perfluoroalkyl,

7) (C═O) a NR 7 R 8 ,

8) CN,

9) (C═O) a O b heterocyclyl,

10) SO 2 NR 7 R 8 , and

11) SO 2 C 1 –C 10 alkyl,

said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;

R 5 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 7 R 8 ,

12) oxo,

13) CHO,

14) (N═O)R 7 R 8 , or

15) (C═O) a O b C 3 –C 8 cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 6 ;

R 6 is selected from:

1) (C═O) r O s (C 1 –C 10 )alkyl, wherein r and s are independently 0 or 1,

2) O r (C 1 –C 3 )perfluoroalkyl, wherein r is 0 or 1,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C 2 –C 10 )alkenyl,

8) (C 2 –C10)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 ,

R 7 and R 8 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, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R 6 , or

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

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 .

4. The compound according to claim 3 , or the pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is selected from: (C 1 –C 6 )alkyl, aryl and benzyl, optionally substituted with one or more substituents selected from R 5 .

5. The compound according to claim 3 , or the pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is selected from: (C 1 –C 6 )alkyl; R 2′ is defined as H; R 1 is selected from: (C 1 –C 6 )alkyl, aryl and benzyl, optionally substituted with one or more substituents selected from R 5 .

6. A compound which is selected from:

N-[1-(3-benzyl-4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide

N-[1-(2-benzyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide

or a pharmaceutically acceptable salt or stereoisomer thereof.

7. A compound selected from:

R 1

R 2

R 2′

R 3

R 3′

R 1

R 2

R 2′

R 3

R 3′

(R 4 ) r

6-Cl

7-Cl

6-Cl

7-Cl

6-Cl

7-Cl

7-Me

6-Me

6,7-dihydroxy

7-amino-6-hydroxy

6-methyl-7-amino

R 1

R 2

R 4

6-Cl

6-F

7-F

7-Cl

5-F

or a pharmaceutically acceptable salt or stereoisomer thereof.

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

9. The composition of claim 8 further comprising a second compound selected from:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor,

10) an angiogenesis inhibitor, and

11) a PPAR-γ agonist.

Assignments (2)

CHANGE OF NAME Recorded Jan 28, 2010

From: MERCK & CO., INC.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 023861/0349 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 25, 2006

From: FRALEY, MARK E.; GARBACCIO, ROBERT M.

To: MERCK & CO., INC.

Reel/Frame 018002/0167 →