Mitotic kinesin inhibitors
View Patent ↗The present invention relates to dihydropyrazole 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;
p is 0, 1, 2 or 3;
q is 0, 1, or 2;
u is 1, 2, 3, 4 or 5;
R 1 is selected from:
1) (C 1 -C 6 -alkylene) n (C═X)O b C 1 -C 10 alkyl,
2) (C 1 -C 6 -alkylene) n (C═X)O b aryl,
3) (C 1 -C 6 -alkylene) n (C═X)O b C 2 -C 10 alkenyl,
4) (C 1 -C 6 -alkylene) n (C═X)O b C 2 -C 10 alkynyl,
5) (C 1 -C 6 -alkylene) n (C═X)O b C 3 -C 8 cycloalkyl,
6) (C 1 -C 6 -alkylene) n (C═X)O b heterocyclyl,
7) (C 1 -C 6 -alkylene) n (C═X)NR c R c′ ,
8) (C 1 -C 6 -alkylene) n SO 2 NR c R c′ ,
9) (C 1 -C 6 -alkylene) n SO 2 C 1 -C 10 alkyl,
10) (C 1 -C 6 -alkylene) n SO 2 C 2 -C 10 alkenyl,
11) (C 1 -C 6 -alkylene) n SO 2 C 2 -C 10 alkynyl,
12) (C 1 -C 6 -alkylene) n SO 2 -aryl,
13) (C 1 -C 6 -alkylene) n SO 2 -heterocyclyl,
14) (C 1 -C 6 -alkylene) n SO 2 —C 3 -C 8 cycloalkyl,
15) aryl;
16) heterocyclyl; and
17) C 1 -C 10 alkyl;
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents selected from R 7 ;
R 2 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 9 R 10 ,
9) S(O) m R a ,
10) S(O) 2 NR 9 R 10 , and
11) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 7 ;
R 3 and R 4 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, and
10) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 7 ; 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 9 )C(O)—, and —N(COR 10 )—;
R 5 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,
9) heterocyclyl, and
10) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 7 ;
R 6 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 9 R 10 ,
10) S(O) m R a ,
11) S(O) 2 NR 9 R 10 , and
12) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 7 ;
R 7 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 9 R 10 ,
12) S(O) m R a ,
13) S(O) 2 NR 9 R 10 ,
14) oxo,
15) CHO,
16) (N═O)R 9 R 10 ,
17) (C═O) a O b C 3 -C 8 cycloalkyl, or
18) Si(R c C) 3 ;
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R 8 ;
R 8 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 )
12) (C═O) r O s (C 0 -C 6 )allylene-heterocyclyl,
13) (CO) 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)NR 9 R 10 ,
19) S(O) m R a ,
20) S(O) 2 NR 9 R 10 ,
21) C(NH)NH 2 ; and
22) Si(R c ) 3 ;
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 9 and R 10 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 8 , or
R 9 and R 10 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 8 ;
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 ; said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 7 ,
R c is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heterocyclyl, OH or OR a ; said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 7 ,
X is selected from O, NR e and S; and
W is selected from: a bond, C═O, C═S and CH(OH);
provided that at least one silicon atom is present in the compound, and further provided that —W—R 5 is not —(C 1 -C 6 )alkyl-O—Si[(C 1 -C 6 )alkyl] 3 .
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;
p is 0, 1, 2 or 3;
q is 0 or 1;
R 1′ is selected from: CF 3 , NH 2 , O b (C 1 -C 10 )alkyl, O b (C 2 -C 10 )alkenyl, O b (C 2 -C 10 )alkynyl, O b (C 3 -C 8 )cycloalkyl, O b (C 0 -C 6 )alkylene-aryl, O b (C 0 -C 6 )alkylene-heterocyclyl, O b (C 0 -C 6 )alkylene-NR 9 R 10 , O b (C 1 -C 3 )perfluoroalkyl, (C 0 -C 6 )alkylene-CO 2 R a and (C 0 -C 6 )alkylene-CO 2 H; said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one to three substituents selected from R 7 ; or
R 2 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 9 R 10 ,
9) S(O) m R a ,
10) S(O) 2 NR 9 R 10 , and
11) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 7 ;
R 5 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,
9) heterocyclyl, and
10) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one to three substituents selected from R 7 ; or
R 6 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 , and
12) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 7 ;
R 7 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 9 R 10 ,
12) S(O) m R a ,
13) S(O) 2 NR 9 R 10 ,
14) oxo,
15) CHO,
16) (N═O)R 9 R 10 ,
17) (C═O) a O b C 3 -C 8 cycloalkyl, or
18) Si(R c ) 3 ;
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one to three substituents selected from R 8 ;
R 8 is selected from:
1) (CO) 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) (CO) 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 NR 9 R 10 ,
21) C(NH)NH 2 , and
22) Si(R c ) 3 ;
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 9 and R 10 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 to three substituents selected from R 8 , or
R 9 and R 10 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 to three substituents selected from R 8 ;
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 ; said alkyl, aryl, cycloalkyl and heterocyclyl is optionally substituted with one to three substituents selected from R 7 ;
R c is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heterocyclyl, OH or OR a ; said alkyl, aryl, cycloalkyl and heterocyclyl is optionally substituted with one to three substituents selected from R 7 ;
W is selected from: a bond and CH(OH);
provided that at least one silicon atom is present in the compound, and further provided that —W—R 5 is not —(C 1 -C 6 )alkyl-O—Si[(C 1 -C 6 )alkyl] 3 .
3. A compound selected from:
{2-[1-acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]ethyl}(dimethyl)silanol;
{4-[1-acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]butyl}(dimethyl)silanol; and
1-acetyl-4-(3-{(5S)-1-acetyl-3-[2-fluoro-5-(trimethylsilyl)phenyl]-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl}propyl)piperazine
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. A pharmaceutical composition that is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.