Tyrosine kinase inhibitors
View Patent ↗The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like 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;
s is 0 or 1;
t is 0 or 1
R 1 and R4 are independently:
6) halo,
R 2 and R 3 are independently:
1) H,
2) (C═O)O a C 1 –C 6 alkyl, optionally substituted with aryl,
3) (C═O)O a aryl,
4) C 1 –C 6 alkyl, optionally substituted with aryl, or
5) SO 2 R a ;
R 5 and R 7 are independently H, halo, or C 1 –C 6 alkyl;
R 8 and R 9 are independently:
1) H,
5) C 1 –C 10 alkyl,
6) aryl,
9) heterocyclyl,
12) C 1 –C 10 alkyl-NR b 2 , or
R 8 and R 9 are taken together with the nitrogen to which they are attached to form a monocyclic 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, wherein said monocyclic heterocycle is optionally substituted with one or more substituents selected from R c ;
R a is C 1 –C 6 alkyl, aryl, or benzyl;
R b is H, C 1 –C 6 alkyl, aryl, or benzyl;
R c is:
1) (C═O) a O b (C 1 –C 1 O)alkyl, optionally substituted with NR b 2 ,
2) oxo,
3) OH,
4) halo,
5) CN,
6) SO m R a ,
7) aryl,
8) NR b 2 ,
9) C(O)R a ,
10) (C 0 –C 6 )alkyl-CO 2 R a ,
11) C(O)H, or
12) (C 0 –C 6 )alkyl-CO 2 .
2. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
s is 0 or 1;
t is 0 or 1;
R 1 and R 4 are independently:
6) halo,
R 2 and R 3 are independently:
1) H,
2) (C═O)O a C 1 –C 3 alkyl, optionally substituted with aryl,
3) (C═O)O a aryl,
4) C 1 –C 3 alkyl, optionally substituted with aryl, or
5) SO 2 R a ;
R 5 and R 7 are independently H, halo, or C 1 –C 6 alkyl;
R 8 and R 9 are independently:
1) H,
5) C 1 –C 6 alkyl,
6) aryl,
9) heterocyclyl,
12) C 1 –C 6 alkyl-NR b 2 , or
R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5–7 membered heterocycle optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, and optionally substituted with one to three substituents selected from R c ;
R a is C 1 –C 6 alkyl, aryl, or benzyl;
R b is H, C 1 –C 6 alkyl, aryl, or benzyl;
R c is:
1) (C═O) a O b (C 1 –C 6 )alkyl, optionally substituted with NR b 2 ,
2) oxo,
3) OH,
4) halo,
5) CN,
6) SO m R a ,
7) aryl,
8) NR b 2 ,
9) C(O)R a ,
10) (C 0 –C 6 )alkyl-CO 2 R a ,
11) C(O)H, or
12) (C 0 –C 6 )alkyl-CO 2 H.
3. The compound according to claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
R 1 and R 4 are independently:
5) halo,
R 2 and R 3 are independently H or C 1 –C 3 alkyl;
R 5 is H, C 1 –C 3 alkyl, or halogen;
R 7 is H;
R 8 and R 9 are independently:
1) H,
5) C 1 –C 6 alkyl,
6) aryl,
9) heterocyclyl,
12) C 0 –C 6 alkyl-NR b 2 , or
R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5–7 membered heterocycle optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, and optionally substituted with one to three substituents selected from R c ;
R a is C 1 –C 6 alkyl, aryl, or benzyl;
R b is H, C 1 –C 6 alkyl, aryl, or benzyl;
R c is:
1) (C═O) a O b (C 1 –C 6 )alkyl, optionally substituted with NR b 2 ,
2) oxo,
3) OH,
4) halo,
5) CN,
6) SO m R a ,
7) aryl,
8) NR b 2 ,
9) C(O)R a ,
10) (C 0 –C 6 )alkyl-CO 2 R a ,
11) C(O)H, or
12 ) ( 0 –C 6 ) alkyl-CO 2 H.
4. A compound according to claim 1 selected from:
3-{5-[(4-methylpiperazin-1-yl)sulfonyl]-1H-indol-2-yl}quinolin-2(1H)-one;
3-[5-(piperazin-1-ylsulfonyl)-1H-indol-2-yl]quinolin-2(1H)-one;
3-{5-[(3-aminopyrrolidin-1-yl)sulfonyl]-1H-indol-2-yl }quinolin-2(1H)-one;
N-[2-(dimethylamino)ethyl]-2-(2-oxo-1,2-dihydroquinolin-3-yl)-1H-indole-5-sulfonamide; and
N-methyl-2-(2-oxo-1,2-dihydroquinolin-3-yl)-N-pyrrolidin-3-yl-1H-indole-5-sulfonamide,
or a pharmaceutically acceptable salt or stereoisomer thereof.
5. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
6. A method of treating acute myeloid leukemia which comprises administering a therapeutically effective amount of a compound of claim 1 .