Mitotic kinesin inhibitors
View Patent ↗The present invention relates to bicyclic 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.
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;
u is 2, 3, 4 or 5;
a dashed line represents an optional double bond, provided that one and only one double bond is present in the ring;
X is —CH 2 ;
Y is O;
Z is —C(═O)—,
R 1 and R 5 are independently selected from:
1) aryl,
2) C 1 -C 6 aralkyl,
3) C 3 -C 8 cycloalkyl, and
4) heterocyclyl,
said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 10 ;
R 2 , R 3 , R 4 , R 6 and R 7 are independently 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 10 ; or
R 3 and R 4 attached to the same carbon atom 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 ,
—N(R a )C(O)—, —N(R b )— and —N(COR a )—;
R 10 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 ,
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 or more substituents selected from R 11 ;
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 ,
20) S(O) 2 N(R b ) 2 and
21) —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, 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 ,
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 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 .
2. The compound according to claim 1 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;
n is 0 or 1;
r is 0 or 1;
s is 0 or 1;
X is —CH 2 —;
Y is O;
Z is —C(═O)—,
R 1 and R 5 are independently selected from:
1) aryl,
2) C 1 -C 6 aralkyl,
3) C 3 -C 8 cycloalkyl, and
4) heterocyclyl,
said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 10 ;
R 2 and R 3 are independently 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 10 ;
R 10 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 ,
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 11 ;
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 ,
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, 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 12 and R 13 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 monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 11 ;
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 .
3. The compound according to claim 2 of 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;
X is —CH 2 —;
Y is O;
Z is —C(═O)—,
R 1 is selected from:
1) aryl,
2) C 1 -C 6 aralkyl,
3) C 3 -C 8 cycloalkyl, and
4) heterocyclyl,
said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 10 ;
R 2 and R 3 are independently 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 10 ;
R 10 is independently selected from:
1) (C═) 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 ,
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 11 ;
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,
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, 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 12 and R 13 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 monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 11 ;
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, (C 1 -C 6 )alkyl, aryl, heterocyclyl and (C 3 -C 6 )cycloalkyl.
4. The compound according to claim 3 of the Formula III, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
X is —CH 2 —;
Y is O;
Z is —C(═O)—;
R 1 is selected from:
1) aryl, and
2) heteroaryl,
said aryl and heteroaryl is optionally substituted with one or more substituents selected from R 10 ;
R 2 and R 3 are independently selected from:
1) H, and
2) C 1 -C 10 alkyl,
said alkyl is optionally substituted with one or more substituents selected from R 10 ; and
X, Y, Z, R 10 , R 10′ , R 11 , R 12 , R 13 , R a , R b , R c and R c′ are as described in claim 3 .
5. 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;
X is —CH 2 —;
Y is O;
Z is —C(═O)—;
R 1 is selected from:
1) aryl,
2) C 1 -C 6 aralkyl,
3) C 3 -C 8 cycloalkyl, and
4) heterocyclyl,
said aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 10 ;
R 2 is independently 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 10 ;
R 3 is H;
R 10 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 ,
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 11 ;
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,
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, 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 12 and R 13 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 monocyclic or bicyclic heterocycle optionally substituted with one, two or thee substituents selected from R 11 ;
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 .
6. A compound selected from:
(±)-(5S,7aR and 5R,7aS)-7-(2,5-Difluorophenyl)-5-phenyl-2,7a-dihydro-1H-pyrrole[1,2-c][1,3]oxazol-3-one;
(±)-(5S,7aS and 5R,7aR)-7-(2,5-Difluorophenyl)-5-phenyl-2,7a-dihydro-1H-pyrrole[1,2-c][1,3]oxazol-3-one;
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.