Mitotic kinesin inhibitors
View Patent ↗The present invention relates to fluorinated 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. The compound of the Formula II:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
a is independently 0 or 1;
b is independently 0 or 1;
m is independently 0, 1, or 2;
R 1 is selected from:
1) C 1 -C 10 alkyl, and
2) C 3 -C 8 cycloalkyl;
R 2 is selected from:
1) H,
2) C 1 -C 4 alkyl,
3) halo, and
4) OH,
said alkyl optionally substituted with one, two or three substituents selected from R 6 ;
R 3 is selected from chloro, fluoro and bromo;
R 5 is F;
R 6 independently 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 8 R 9 ,
12) S(O) m R a ,
13) S(O) 2 NR 8 R 9 ,
14) oxo,
15) CHO,
16) (N═O)R 8 R 9 , 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 7 ;
R 7 is independently selected from:
1) (C═O) a O b (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1,
2) O b (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 -C 10 )alkynyl,
9) (C═O) a O b (C 3 -C 6 )cycloalkyl,
10) (C═O) a O b (C 0 -C 6 )alkylene-aryl,
11) (C═O) a O b (C 0 -C 6 )alkylene-heterocyclyl,
12) (C═O) a O b (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 NR 8 R 9 ;
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 ; or
two R 7 s, attached to the same carbon atom are combined to form —(CH 2 ) u — wherein u is 3 to 6 and one or two 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 8 and R 9 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 ,
or
R 8 and R 9 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;
R a is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, and heterocyclyl; and
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 .
2. The compound according to claim 1 of the Formula III:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
a is independently 0 or 1;
b is independently 0 or 1;
m is independently 0, 1, or 2;
R 1 is selected from:
1) C 1 -C 10 alkyl, and
2) C 3 -C 8 cycloalkyl;
R 2 is selected from:
1) H,
2) C 1 -C 4 alkyl,
3) halo, and
4) OH,
said alkyl optionally substituted with one, two or three substituents selected from R 6 ;
R 3 is selected from chloro, fluoro and bromo;
R 5 is CH 2 F;
R 6 independently 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 8 R 9 ,
12) S(O) m R a ,
13) S(O) 2 NR 8 R 9 ,
14) oxo,
15) CHO,
16) (N═O)R 8 R 9 , 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 7 ;
R 7 is independently selected from:
1) (C═O) a O b (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1,
2) O b (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 -C 10 )alkynyl,
9) (C═O) a O b (C 3 -C 6 )cycloalkyl,
10) (C═O) a O b (C 0 -C 6 )alkylene-aryl,
11) (C═O) a O b (C 0 -C 6 )alkylene-heterocyclyl,
12) (C═O) a O b (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 NR 8 R 9 ;
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 ; or
two R 7 s, attached to the same carbon atom are combined to form —(CH 2 ) u — wherein u is 3 to 6 and one or two 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 8 and R 9 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 ,
R 8 and R 9 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;
R a is independently selected from: (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, and heterocyclyl; and
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 .
3. A compound selected from:
(2S)-3-[(5R)-1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
(2R)-3-[(5R)-1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
(2S)-3-[(5R)-1-Acetyl-3-(2-fluoro-5-chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
(2S)-3-[(5R)-1-Acetyl-3-(2-fluoro-5-bromophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
(2S)-3-[(5R)-1-Cyclopropylacyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
(2S)-3-[(5R)-1-Cyclobutylacyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
[(1R)-3-[(5S)-1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-1-(fluoromethyl)propyl]amine
[(1S)-3-[(5S)-1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-1-(fluoromethyl)propyl]amine
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound of claim 3 which is:
(2S)-3-[(5R)-1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The compound of claim 3 which is:
(2S)-3-[(5R)-1-Acetyl-3-(2-fluoro-5-bromophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-fluoropropan-1-amine
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. The compound of claim 3 which is:
[(1S)-3-[(5S)-1-Acetyl-3-(2,5-difluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-1-(fluoromethyl)propyl]amine
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.