Tyrosine kinase inhibitors
The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises a sulfonyl indole moiety. The present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.
1 . A compound of Formula I:
wherein:
Y is selected from:
R a is independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) Halogen,
4) Aryl,
5) Heterocycle,
6) C 3 -C 10 cycloalkyl, and
7) OR 4 ;
said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent selected from R 7 ;
R 1 is independently selected from:
1) H,
2) (CR a 2 ) n R 6 ,
3) (CR a 2 ) n C(O)R 4 ,
4) C(O)N(R 4 ) 2 ,
5) (CR a 2 ) n OR 4 ,
6) (CR a 2 ) n N(R 4 ) 2 ,
7) S(O) m R 6 ,
8) S(O) m R 6 OR 4 ,
9) C(O)N(R 4 )(CR a 2 ) n R 6 ,
10) C(O)N(R 4 )(CR a 2 ) n OR 4 ,
11) C(O)R 6 (CR a 2 ) n R 6 ,
12) C(O)N(R 4 )(CR a 2 ) n S(O) m (CR a 2 ) n R 6 ,
13) C(O)N(R 4 )(CR a 2 ) n C(O)R 6 ,
14) C(O)N(R 4 )(CR a 2 ) n N(R 4 ) 2 ,
15) Halogen,
16) N(R 4 )S(O) m R 6 , and
(CR a 2 ) n C(O)OR 4 ;
R 2 is:
1) H,
2) unsubstituted or substituted C 1 -C 10 alkyl,
3) N(R 4 ) 2 ,
4) OR 4 ,
5) unsubstituted or substituted aryl, and
6) unsubstituted or substituted C 3 -C 10 cycloalkyl;
R 4 is independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 10 cycloalkyl,
4) Aryl,
5) Heterocycle,
6) CF 3 ,
7) C 2 -C 6 alkenyl, and
8) C 2 -C 6 alkynyl;
said alkyl, cycloalkyl, aryl, heterocycle, alkenyl and alkynyl is optionally substituted with at least one substituent selected from R 7 ;
R 5 is independently selected from:
1) H,
2) Halogen,
3) NO 2 ,
4) CN,
5) CR 4 ═C(R 4 ) 2 ,
6) C≡CR 4
7) (CR a 2 ) n OR 4 ,
8) (CR a 2 ) n N(R 4 ) 2 ,
9) C(O)R 4 ,
10) C(O)OR 4 ,
11) (CR a 2 ) n R 4 ,
12) S(O) m R 6 ,
13) S(O) m N(R 4 ) 2 ,
14) OS(O) m R 6 ,
15) N(R 4 )C(O)R 4 ,
16) N(R 4 )S(O) m R 6 ,
17) (CR a 2 ) n N(R 4 )R 6 ,
18) (CR a 2 ) n N(R 4 )R 6 OR 4 ,
19) (CR a 2 ) n N(R 4 )(CR a 2 ) n C(O)N(R 4 ) 2 ,
20) N(R 4 )(CR a 2 ) n R 6 ,
21) N(R 4 )(CR a 2 ) n N(R 4 ) 2 ,
22) (CR a 2 ) n C(O)N(R 4 ) 2 ,
23) O(CR a 2 ) n C(O)OR 4 , and
24) O(CR a 2 ) n C(O)N(R 4 ) 2 ;
R 6 is independently selected from:
1) C 1 -C 6 alkyl,
2) Aryl,
3) Heterocycle, and
4) C 3 -C 10 cycloalkyl;
said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent of R 7 ;
R 7 is independently selected from:
1) Unsubstituted or substituted C 1 -C 6 alkyl,
2) Halogen,
3) OR 4 ,
4) CF 3 ,
5) Unsubstituted or substituted aryl,
6) Unsubstituted or substituted C 3 -C 10 cycloalkyl,
7) Unsubstituted or substituted heterocycle,
8) S(O) m N(R 4 ) 2 ,
9) C(O)OR 4 ,
10) C(O)R 4 ,
11) CN,
12) C(O)N(R 4 ) 2 ,
13) N(R 4 )C(O)R 4 ,
14) NO 2 ; and
15) S(O) m R 6 ;
m is independently 0, 1 or 2;
n is independently 0, 1, 2, 3, 4, 5 or 6;
s is 0 to 6;
t is 0, 1, or 2;
v is 0, 1 or 2;
w is 0, 1, 2, 3, or 4;
z is 1 or 2;
or a pharmaceutically acceptable salt or stereoisomer thereof.
2 . The compound according to claim 1 ,
wherein:
R a is independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) Halogen,
4) Aryl,
5) Heterocycle,
6) C 3 -C 10 cycloalkyl, and
7) OR 4 ;
said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent selected from R 7 ;
R 1 is independently selected from:
1) H,
2) (CR a 2 ) n R 6 ,
3) (CR a 2 ) n C(O)R 4 ,
4) C(O)N(R 4 ) 2 ,
5) (CR a 2 ) n OR 4 ,
6) (CR a 2 ) n N(R 4 ) 2 ,
7) S(O) m R 6 ,
8) S(O) m R 6 OR 4 ,
9) C(O)N(R 4 )(CR a 2 ) n R 6 ,
10) C(O)N(R 4 )(CR a 2 ) n OR 4
11) C(O)R 6 (CR a 2 ) n R 6 ,
12) C(O)N(R 4 )(CR a 2 ) n S(O) m (CR a 2 ) n R 6
13) C(O)N(R 4 )(CR a 2 ) n C(O)R 6 ,
14) C(O)N(R 4 )(CR a 2 ) n N(R 4 ) 2 ,
15) Halogen,
16) N(R 4 )S(O) m R 6 , and
17) (CR a 2 ) n C(O)OR 4 ;
R 2 is:
1) H,
2) Unsubstituted or substituted C 1 -C 10 alkyl,
3) N(R 4 ) 2 , or
4) OR 4 ;
R 4 is independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) C 3 -C 10 cycloalkyl,
4) Aryl,
5) Heterocycle,
6)CF 3 ,
7) C 2 -C 6 alkenyl, and
8) C 2 -C 6 alkynyl;
said alkyl, cycloalkyl, aryl, heterocycle, alkenyl and alkynyl is optionally substituted with at least one substituent selected from R 7 ;
R 5 is independently selected from:
1) H,
2) Halogen,
3) NO 2 ,
4) CN,
5) CR 4 ═C(R 4 ) 2 ,
6) C≡CR 4
7) (CR a 2 ) n OR 4 ,
8) (CR a 2 ) n N(R 4 ) 2 ,
9) C(O)R 4 ,
10) C(O)OR 4 ,
11) (CR a 2 ) n R 4 ,
12) S(O) m R 6 ,
13) S(O) m N(R 4 ) 2 ,
14) OS(O) m R 6 ,
15) N(R 4 )C(O)R 4 ,
16) N(R 4 )S(O) m R 6 ,
17) (CR a 2 ) n N(R 4 )R 6 ,
18) (CR a 2 ) n N(R 4 )R 6 OR 4 ,
19) (CR a 2 ) n N(R 4 )(CR a 2 ) n C(O)N(R 4 ) 2 ,
20) N(R 4 )(CR a 2 ) n R 6 ,
21) N(R 4 )(CR a 2 ) n N(R 4 ) 2 , and
22) (CR a 2 ) n C(O)N(R 4 ) 2 ;
R 6 is independently selected from:
1) C 1 -C 6 alkyl,
2) Aryl,
3) Heterocycle, and
4) C 3 -C 10 cycloalkyl;
said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent of R 7 ;
R 7 is independently selected from:
1) Unsubstituted or substituted C 1 -C 6 alkyl,
2) Halogen,
3) OR 4 ,
4) CF 3 ,
5) Unsubstituted or substituted aryl,
6) Unsubstituted or substituted C 3 -C 10 cycloalkyl,
7) Unsubstituted or substituted heterocycle,
8) S(O) m N(R 4 ) 2 ,
9) C(O)OR 4 ,
10) C(O)R 4 ,
11) CN,
12) C(O)N(R 4 ) 2 ,
13) N(R 4 )C(O)R 4 ,
14) S(O) m R 6 , and
15) NO 2 ;
m is independently 0, 1 or 2;
n is independently 0, 1, 2, 3, 4, 5 or 6;
s is 0 to 6;
w is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
3 . The compound according to claim 2 wherein:
R a is independently selected from:
1) H,
2) C 1 -C 6 alkyl,
3) Aryl, and
4) C 3 -C 10 cycloalkyl;
said alkyl, aryl, and cycloalkyl is optionally substituted with at least one substituent selected from R 7 ;
R 1 is independently selected from:
1) H,
2) (CR a 2 ) n R 6 ,
3) (CR a 2 ) n C(O)R 4 ,
4) C(O)N(R 4 ) 2 ,
5) (CR a 2 ) n OR 4 ,
6) (CR a 2 ) n N(R 4 ) 2 ,
7) S(O) m R 6 ,
8) S(O) m R 6 OR 4 ,
9) C(O)N(R 4 )(CR a 2 ) n R 6 ,
10) C(O)N(R 4 )(CR a 2 ) n OR 4 ,
11) N(R 4 )S(O) m R 6 , and
12) (CR a 2 ) n C(O)OR 4 ,
R 2 is:
1) N(R 4 ) 2 , or
2) OR 4 ;
s is 0 to 3;
or a pharmaceutically acceptable salt or stereoisomer thereof.
4 . The compound according to claim 3 wherein:
R 1 is independently selected from:
1) H,
2) (CR a 2 ) n R 6 ,
3) (CR a 2 ) n C(O)R 4 ,
4) C(O)N(R 4 ) 2 ,
5) (CR a 2 ) n OR 4 ,
6) (CR a 2 ) n N(R 4 ) 2 ,
7) S(O) m R 6 , and
8) S(O) m R 6 OR 4 ;
or a pharmaceutically acceptable salt or stereoisomer thereof.
5 . (canceled)
6 . (canceled)
7 . A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
8 . (canceled)
9 . (canceled)
10 . (canceled)
11 . (canceled)
12 . (canceled)
13 . A method of treating cancer in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 .
14 . (canceled)
15 . A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a second 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) an angiogenesis inhibitor.
16 . The method of claim 15 , wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.
17 . (canceled)
18 . The method of claim 15 wherein radiation therapy is also administered.
19 . (canceled)
20 . (canceled)
21 . (canceled)
22 . (canceled)