Tyrosine kinase inhibitors
View Patent ↗The present invention relates to imidazopyridine 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;
R 1 is selected from:
1) aryl,
2) C 3 –C 5 cycloalkyl;
3) C 2 –C 3 alkenyl;
4) C 2 –C 3 alkynyl and
5) heteroaryl,
said aryl, cycloalkyl and heteroaryl is optionally substituted with one or more substituents selected from R 3 ;
R 2 is selected from:
1) aryl,
2) C 3 –C 8 cycloalkyl and
3) heterocyclyl,
said aryl, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 4 ;
R 3 is:
1) (C═O) a O b C 1 –C 3 alkyl,
2) CO 2 H,
3) halo,
4) CN,
5) OH,
6) O b C 1 –C 3 perfluoroalkyl,
7) O a (C═O) b NH 2 ,
8) oxo,
9) CHO, or
10) (N═O)H 2 ;
R 4 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 6 R 7 ,
12) oxo,
13) CHO,
14) (N═O)R 6 R 7 , 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 5 ;
R 5 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 2 –C 10 )alkenyl,
9) (C 2 –C 10 )alkynyl,
10) (C 3 –C 6 )cycloalkyl,
11) (C 0 –C 6 )alkylene-aryl,
12) (C 0 –C 6 )alkylene-heterocyclyl,
13) (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, and
17) (C 0 –C 6 )alkylene-CO 2 H,
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 6 and R 7 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 5 , or
R 6 and R 7 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 or more substituents selected from R 5 ;
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. The compound according to claim 1 of the 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;
R 1 is selected from: phenyl, thienyl, pyridyl, cyclopropyl and cyclobutyl; said phenyl, thienyl and pyridyl is optionally substituted with one or two substituents selected from R 3 ;
R 2 is selected from:
1) aryl,
2) C 3 –C 8 cycloalkyl and
3) heterocyclyl,
said aryl, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 4 ;
R 3 is:
1) (C═O) a O b C 1 –C 3 alkyl,
2) CO 2 H,
3) halo,
4) CN,
5) OH,
6) O b C 1 –C 3 perfluoroalkyl,
7) O a (C═O) b NH 2 ,
8) oxo,
9) CHO, or
10) (N═O)H 2 ;
R 4 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 –C6 perfluoroalkyl,
11) O a (C═O) b NR 6 R 7 ,
12) oxo,
13) CHO,
14) (N═O) 6 R 7 , 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 5 ;
R 5 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 2 –C 10 )alkenyl,
9) (C 2 –C 10 )alkynyl,
10) (C 3 –C 6 )cycloalkyl,
11) (C 0 –C 6 )alkylene-aryl,
12) (C 0 –C 6 )alkylene-heterocyclyl,
13) (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, and
17) (C 0 –C 6 )alkylene-CO 2 H,
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 6 and R 7 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 5 , or
R 6 and R 7 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 or more substituents selected from R 5 ;
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
R 1 is selected from phenyl and pyridyl, optionally substituted with one or more substituents selected from R 3 ; and
R 2 is selected from phenyl, pyridyl and 1,2-dihydropyridinyl, optionally substituted with one to three substituents selected from R 4 .
4. The compound according to claim 1 selected from:
3,7-diphenylimidazo[1,2-a]pyridine
7-phenyl-3-pyridin-4-ylimidazo[1,2-a]pyridine
7-phenyl-3-pyridin-3-ylimidazo[1,2-a]pyridine
[4-(3-phenylimidazo[1,2-a]pyridin-7-yl)phenyl]methanol
7-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)-3-phenylimidazo[1,2-a]pyridine
4-methyl-1-[4-(3-phenylimidazo[1,2-a]pyridin-7-yl)benzyl]-1,4-diazepan-5-one
7-{4-[(4-acetylpiperazin-1-yl)methyl]phenyl}-3-phenylimidazo[1,2-a]pyridine
N-methyl-4-[4-(3-phenylimidazo[1,2-a]pyridin-7-yl)benzyl]piperazine-1-carboxamide
4-[4-(3-phenylimidazo[1,2-a]pyridin-7-yl)benzyl]piperazine-1-carboxamide
1-[4-(3-phenylimidazo[1,2-a]pyridin-7-yl)benzyl]-1,4-diazepan-5-one
7-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)-3-phenylimidazo[1,2-a]pyridine
3-phenyl-7-(4-pyridyl)imidazo[1,2-a]pyridine
7-(1-oxy-pyridin-4-yl)-3-phenyl-imidazo[1,2-a]pyridine
4-(3-phenyl-imidazo[1,2-a]pyridin-7-yl)-1H-pyridin-2-one
3-(6-methoxypyridin-2-yl)-7-phenylimidazo[1,2-a]pyridine
6-(7-phenylimidazo[1,2-a]pyridine-3-yl)pyridine-2(1H)-one
3-(6-methoxypyridin-3-yl)-7-phenylimidazo[1,2-a]pyridine
7-phenyl-3-(1,3-thiazol-2-yl)imidazo[1,2-a]pyridine
4-(3-phenylimidazo[1,2-a]pyridine-7-yl)-1-(3-piperidin-1-ylpropyl)pyridine-2(1H)-one
1-[3-(4-methylpiperazin-1-yl)propyl]-4-(3-phenylimidazo[1,2-a]pyridine-7-yl)pyridine-2(1H)-one
1-(3-hydroxypropyl)-4-(3-phenylimidazo[1,2-a]pyridine-7-yl)pyridine-2(1H)-one
1-(3-morpholin-4-ylpropyl)-4-(3-phenylimidazo[1,2-a]pyridin-2(1H)-one
1-(3,3-diethoxypropyl)-4-(3-phenylimidazo[1,2-a]pyridine-2(1H)-one
1-(3-{3-[(dimethylamino)methyl]piperidin-1-yl}propyl)-4-(3-phenylimidazo[1,2-a]pyridine-7-yl)pyridine-2(1H)-one
7-phenyl-3-(1,3-thiazol-5-yl)imidazo[1,2-a]pyridine
3-(1,3-oxazol-5-yl)-7-phenylimidazo[1,2-a]pyridine
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition which is comprised of a therapeutically effective amount of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
6. A pharmaceutical composition made by combining a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
7. A method of treating acute myeloid leukemia which comprises administering a therapeutically effective amount of a compound of claim 1 .