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
W is N or C;
X═Y is C═N, N═C, or C═C;
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
t is 1,2, or 3;
R 1 , R 2 and R 5 are independently selected from:
1) H,
2) (C═O) a O b C 1 –C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 –C 10 alkenyl,
5) (C═O) a O b C 2 –C 10 alkynyl,
6) CO 2 H,
7) halo,
8) OH,
9) O b C 1 –C 6 perfluoroalkyl,
10) (C═O) a NR 7 R 8 ,
11) CN,
12) (C═O) a O b C 3 –C 8 cycloalkyl,
13) (C═O) a O b heterocyclyl,
14) SO 2 NR 7 R 8 , and
15) SO 2 C 1 –C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
R 3 is selected from:
1) H,
2) (C═O)O a C 1 –C 6 alkyl,
3) (C═O)O a aryl,
4) C 1 –C 6 alkyl,
5) SO 2 R a , and
6) aryl;
R 4 is selected from:
1) (C═O) a O b C 1 –C 10 alkyl,
2) (C═O) a O b aryl,
3) (C═O) a O b C 2 –C 10 alkenyl,
4) (C═O) a O b C 2 –C 10 alkynyl,
5) CO 2 H,
6) halo,
7) OH,
8) O b C 1 –C 6 perfluoroalkyl,
9) (C═O) a NR 7 R 8 ,
10) CN,
11) (C═O) a O b C 3 –C 8 cycloalkyl,
12) (C═O) a O b heterocyclyl,
13) SO 2 NR 7 R 8 , and
14) SO 2 C 1 –C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
R 6 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 7 R 8 ,
12) oxo,
13) CHO,
14) (N═O)R 7 R 8 , 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 6a ;
R 6a 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,
17) (C 0 –C 6 )alkylene-CO 2 H, and
18) C(O)N(R b ) 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 7 and R 8 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 6a , or
R 7 and R 8 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 monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R 6a ;
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 of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
3. A compound of Formula I
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
a is 0 or 1;
b is 0 or 1; and
t is 1 or 2;
R 1 , R 2 and R 5 are independently selected from:
1) H,
2) (C═O) a O b C 1 –C 6 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 –C 6 alkenyl,
5) (C═O) a O b C 2 –C 6 alkynyl,
6) CO 2 H,
7) halo,
8) OH,
9) O b C 1 –C 3 perfluoroalkyl,
10) (C═O) a NR 7 R 8 ,
11) CN,
12) (C═O) a O b C 3 –C 6 cycloalkyl,
13) (C═O) a O b heterocyclyl,
14) SO 2 NR 7 R 8 , and
15) SO 2 C 1 –C 6 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
R 4 is selected from:
1) (C═O) a O b C 1 –C 6 alkyl,
2) (C═O) a O b aryl,
3) (C═O) a O b C 2 –C 6 alkenyl,
4) (C═O) a O b C 2 –C 6 alkynyl,
5) CO 2 H,
6) halo,
7) OH,
8) O b C 1 –C 3 perfluoroalkyl,
9) (C═O) a NR 7 R 8 ,
10) CN,
11) (C═O) a O b C 3 –C 6 cycloalkyl,
12) (C═O) a O b heterocyclyl,
13) SO 2 NR 7 R 8 , and
14) SO 2 C 1 –C 6 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 6 ;
R 6 is:
1) (C═O) a O b C 1 –C 6 alkyl,
2) (C═O) a O b aryl,
3) C 2 –C 6 alkenyl,
4) C 2 –C 6 alkynyl,
5) (C═O) a O b heterocyclyl,
6) CO 2 H,
7) halo,
8) CN,
9) OH,
10) O b C 1 –C 3 perfluoroalkyl,
11) O a (C═O) b NR 7 R 8 ,
12) oxo,
13) CHO,
14) (N═O)R 7 R 8 , or
15) (C═O) a O b C 3 –C 6 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl is optionally substituted with one or more substituents selected from R 6a ;
R 6a is selected from:
1) (C═O) r O s (C 1 –C 6 )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 6 )alkenyl,
9) (C 2 –C 6 )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 ; and
R 7 and R 8 are independently selected from:
1) H,
2) (C═O)O b C 1 –C 6 alkyl,
3) (C═O)O b C 3 –C 6 cycloalkyl,
4) (C═O)O b aryl,
5) (C═O)O b heterocyclyl,
6) C 1 –C 6 alkyl,
7) aryl,
8) C 2 –C 6 alkenyl,
9) C 2 –C 6 alkynyl,
10) heterocyclyl,
11) C 3 –C 6 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 R6 a , or
R 7 and R 8 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 monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R 6a ;
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 .
4. The compound of claim 3 , wherein R 2 , R 3 , and R 5 are H.
5. The compound of claim 4 , wherein t is 1.
6. The compound of claim 5 wherein R 4 is selected from:
1) OC 1 –C 6 alkyleneNR 7 R 8 ,
2) (C═O) a C 0 –C 6 alkylene-Q, wherein Q is H, OH, CO 2 H, or OC 1 –C 6 alkyl,
3) OC 0 –C 6 alkylene-heterocyclyl, optionally substituted with one to three substituents selected from R6 a ,
4) C 0 –C 6 alkyleneNR 7 R 8 ,
5) (C═O)NR 7 R 8 , and
6) OC 1 –C 3 alkylene-(C═O)NR 7 R 8 .
7. A compound selected from:
6-Chloro-3-(1H-indol-2-yl)-1H-indazole
3-(1H-Indol-2-yl)-1H-indazole
3-(1H-Indol-2-yl)-1H-indazol-5-ylamine
3-(1H-Indol-2-yl)-6-methyl-1H-indazole
3-(1H-Indol-2-yl)-4-chloro-1H-indazole
3-(1H-Indol-2-yl)-7-chloro-1H-indazole
3-(1H-Indol-2-yl)-4-fluoro-1H-indazole
3-(1H-Indol-2-yl)-5-fluoro-1H-indazole
3-(1H-Indol-2-yl)-5-methyl-1H-indazole
3-(1H-Indol-2-yl)-6-trifluoromethyl-1H-indazole
3-(1H-Indol-2-yl)-5,6-dimethyl-1H-indazole
3-(1H-Indol-2-yl)-1H-indazole-6-sulfonic acid amide
3-(1H-indol-2-yl)-1H-indazole-5-sulfonamide
3-(1H-Indol-2-yl)-6-bromo-1H-indazole
3-(1H-Indol-2-yl)-1H-indazole-6-carbonitrile
3-[5-(piperazin-1-ylsulfonyl)-1H-indol-2-yl]-1H-indazole
6-(2-Fluoro-pyridin-4-yl)-3(1H-indol-2-yl)-1H-indazole
4-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H-pyridin-2-one
3-(1H-Indol-2-yl)-6-(1-oxy-pyridin-3-yl)-1H-indazole
3-(1H-Indol-2-yl)-6-(1H-pyrrol-2-yl)-1H-indazole
3-(1H-Indol-2-yl)-6-(1H-pyrrol-3-yl)-1H-indazole
5-[3-(1H-Indol-2-yl)-1H-indazol-6-yl]-1H-pyridin-2-one
3-(1H-Indol-2-yl)-6-(1-oxy-pyridin-4-yl)-1H-indazole
3-(1H-Indol-2-yl)-6-(1H-tetrazol-5-yl)-1H-indazole
3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H-indol-2-yl}-1H-indazole
1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]-1-(4-methyl-piperazin-1-yl)-methanone
1-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-yl]-1-piperazin-1-yl-methanone
1-[2-(1H-Indazol-3-yl)-1H-indol-5-yl]-1-piperazin-1-yl-methanone
2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide
Methyl [2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-yl]sulfone
2-(6-Chloro-1H-indazol-3-yl)-7-fluoro-1H-indole-5-sulfonic acid amide
2-(6-Chloro-1H-indazol-3-yl)-6-fluoro-1H-indole-5-sulfonic acid amide
2-(6-Chloro-1H-indazol-3-yl)-4-fluoro-1H-indole-5-sulfonic acid amide
7-Chloro-2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide
2-(6-Chloro-5-fluoro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide
2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-carboxylic acid methyl ester
2-(6-chloro-1H-indazol-3-yl)-1H-indole-5-carboxylic acid
6-Chloro-3-(5-fluoro-1H-indol-2-yl)-1H-indazole
6-Chloro-3-(5-methyl-1H-indol-2-yl)-1H-indazole
3-[5-(4-Methyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole
3-[5-(4-Methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole
6-Chloro-3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole
6-Chloro-3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole
1-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-4-methyl-[1,4]diazepan-5-one
1-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-2-hydroxy-ethanone
3-{4-[2-(6-Chloro-1H-indazol-3yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-butyric acid
6-Chloro-3-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole
3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-4-ylmethyl]-piperazin-1-yl}-butyric acid
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7 selected from:
2-(6-Chloro-1H-indazol-3-yl)-1H-indole-5-sulfonic acid amide
6-Chloro-3-[5-(4-acetyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole
1-{(4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-2-hydroxy-ethanone
3-{4-[2-(6-Chloro-1H-indazol-3-yl)-1H-indol-5-ylmethyl]-piperazin-1-yl}-butyric acid
6-Chloro-3-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-indazole
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
10. A method of treating cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.
11. A method of treating cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma.
12. A method of treating cancer wherein is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx, lung, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a compound selected from:
1) an estrogen receptor modulator,
2) an androgen receptor modulator,
3) retinoid receptor modulator,
4) a cytotoxic agent,
5) an antiproliferative agent,
6) a prenyl-protein transferase inhibitor,
7) an HMG-CoA reductase inhibitor,
8) an HIV protease inhibitor,
9) a reverse transcriptase inhibitor, and
10) another angiogenesis inhibitor.