US2005182256A1PendingUtilityA1
Inhibitors of akt activity
Priority: Apr 8, 2002Filed: Apr 4, 2003Published: Aug 18, 2005
Est. expiryApr 8, 2022(expired)· nominal 20-yr term from priority
A61P 35/00C07D 401/14C07D 241/18A61P 43/00
50
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Claims
Abstract
The present invention is directed to compounds comprising a 2,3-diphenylpyrazine moiety which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.
Claims
exact text as granted — not AI-modified1 . A compound of the Formula A:
wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
r is 0 or 1;
s is 0 or 1;
t is 2, 3, 4, 5 or 6;
R 1 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) oxo,
18) CHO,
19) NO 2 ,
20) NR c (C═O)O b R a ,
21) O(C═O)O b C 1 -C 10 alkyl,
22) O(C═O)O b C 3 -C 8 cycloalkyl,
23) O(C═O)O b aryl, and
24) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ;
R 2 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) CHO,
18) NO 2 ,
19) NR c (C═O)O b R a ,
20) O(C═O)O b C 1 -C 10 alkyl,
21) O(C═O)O b C 3 -C 8 cycloalkyl,
22) O(C═O)O b aryl, and
23) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R z ;
R 3 and R 4 are independently selected from: H, C 1 -C 6 -alkyl and C 1 -C 6 -perfluoroalkyl, or
R 3 and R 4 are combined to form —(CH 2 ) t — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —N(R b )C(O)—, and —N(COR a )—;
R 5 and R 6 are independently selected from:
1) H,
2) (C═O)O b R a ,
3) C 1 -C 10 alkyl,
4) aryl,
5) C 2 -C 10 alkenyl,
6) C 2 -C 10 alkynyl,
7) heterocyclyl,
8) C 3 -C 8 cycloalkyl,
9) SO 2 R a , and
10) (C═O)NR b 2 ,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z , or
R 5 and R 6 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 Q and also optionally substituted with one or more substituents selected from R z ;
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 z , 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 monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R z ;
R z is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl,
2) Or(C 1 -C 3 )perfluoroalkyl,
3) (C 0 -C 6 )alkylene-S(O) m R a ,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (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,
18) C(O)N(R b ) 2 ,
19) S(O) m R a ,
20) S(O) 2 N(R b ) 2
21) NR c (C═O)O b R a ,
22) O(C═O)O b C 1 -C 10 alkyl,
23) O(C═O)O b C 3 -C 8 cycloalkyl,
24) O(C═O)O b aryl, and
25) O(C═O)O b -heterocycle,
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 a is substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 2 -C 6 )alkenyl, substituted or unsubstituted (C 2 -C 6 )alkynyl, substituted or unsubstituted (C 3 -C 6 )cycloalkyl, substituted or unsubstituted aryl, (C 1 -C 6 )perfluoroalkyl, 2,2,2-trifluoroethyl, or substituted or unsubstituted heterocyclyl; and
R b is H, (C 1 -C 6 )alkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted 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 ;
R c is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
5) C 2 -C 10 alkynyl,
6) heterocyclyl,
7) C 3 -C 8 cycloalkyl,
8) C 1 -C 6 perfluoroalkyl,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z ;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
2 . A compound of the Formula B:
wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 0, 1, 2, 3 or 4;
r is 0 or 1;
s is 0 or 1;
t is 2, 3, 4, 5 or 6;
Q is selected from: —NR 7 R 8 , aryl and heterocyclyl, said aryl and heterocyclyl optionally substituted with one to three substituents selected from R z ;
R 1 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) oxo,
18) CHO,
19) NO 2 ,
20) NR c (C═O)O b R a ,
21) O(C═O)O b C 1 -C 10 alkyl,
22) O(C═O)O b C 3 -C 8 cycloalkyl,
23) O(C═O)O b aryl, and
24) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ;
R 2 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) CHO,
18) NO 2 ,
19) NR c (C═O)O b R a ,
20) O(C═O)O b C 1 -C 10 alkyl,
21) O(C═O)O b C 3 -C 8 cycloalkyl,
22) O(C═O)O b aryl, and
23) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R z ;
R 3 and R 4 are independently selected from: H, C 1 -C 6 -alkyl and C 1 -C 6 -perfluoroalkyl, or
R 3 and R 4 are combined to form —(CH 2 ) t — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —N(R b )C(O)—, and —N(COR a )—;
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 z , 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 monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R z ;
R z is selected from:
1) (C═O) r OS(C 1 -C 10 )alkyl,
2) O r (C 1 -C 3 )perfluoroalkyl,
3) (C 0 -C 6 )alkylene-S(O) m R a ,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (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,
18) C(O)N(R b ) 2 ,
19) S(O) m R a ,
20) S(O) 2 N(R b ) 2
20) NR c (C═O)O b R a ,
21) O(C═O)O b C 1 -C 10 alkyl,
22) O(C═O)O b C 3 -C 8 cycloalkyl,
23) O(C═O)O b aryl, and
24) O(C═O)O b -heterocycle,
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 a is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, substituted or unsubstituted aryl, (C 1 -C 6 )perfluoroalkyl, 2,2,2-trifluoroethyl, or substituted or unsubstituted 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 ;
R c is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
5) C 2 -C 10 alkynyl,
6) heterocyclyl,
7) C 3 -C 8 cycloalkyl,
8) C 1 -C 6 perfluoroalkyl,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z ;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
3 . The compound according to claim 2 of the Formula C:
wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
r is 0 or 1;
s is 0 or 1;
Q is selected from: —NR 7 R 8 and heterocyclyl, the heterocyclyl optionally substituted with one or two R z ;
R 1 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) oxo,
18) CHO,
19) NO 2 ,
20) NR c (C═O)O b R a ,
21) O(C═O)O b C 1 -C 10 alkyl,
22) O(C═O)O b C 3 -C 8 cycloalkyl,
23) O(C═O)O b aryl, and
24) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ;
R 2 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) CHO,
18) NO 2 ,
19) NR c (C═O)O b R a ,
20) O(C═O)O b C 1 -C 10 alkyl,
22) O(C═O)O b C 3 -C 8 cycloalkyl,
23) O(C═O)O b aryl, and
24) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R z ;
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 z , 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 monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R z ;
R z is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl,
2) O r (C 1 -C 3 )perfluoroalkyl,
3) (C 0 -C 6 )alkylene-S(O) m R a ,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (C 0 -C 6 )alkylene-N(R b )
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,
18) C(O)N(R b ) 2 ,
19) S(O) m R a ,
20) S(O) 2 NR 9 R 10
21) NR c (C═O)O b R a ,
22) O(C═O)O b C 1 -C 10 alkyl,
23) O(C═O)O b C 3 -C 8 cycloalkyl,
24) O(C═O)O b aryl, and
25) O(C═O)O b -heterocycle,
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 a is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, substituted or unsubstituted aryl, (C 1 -C 6 )perfluoroalkyl, 2,2,2-trifluoroethyl, or substituted or unsubstituted 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 ;
R c is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
5) C 2 -C 10 alkynyl,
6) heterocyclyl,
7) C 3 -C 8 cycloalkyl,
8) C 1 -C 6 perfluoroalkyl,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z ;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
4 . The compound according to claim 2 of the Formula C:
wherein:
a is 0 or 1;
bis 0 or 1;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
r is 0 or 1;
s is 0 or 1;
Q is selected from: —NR 7 R 8 , phenyl, benzimidazolyl, benzimidazolonyl, quinolinyl and isoquinolinyl, the benzimidazolyl, benzimidazolonyl, quinolinyl and isoquinolinyl optionally substituted with R z ;
R 1 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) oxo,
18) CHO,
19) NO 2 ,
20) NR c (C═O)O b R a ,
21) O(C═O)O b C 1 -C 10 alkyl,
22) O(C═O)O b C 3 -C 8 cycloalkyl,
23) O(C═O)O b aryl, and
24) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ;
R 2 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) CHO,
18) NO 2 ,
19) NR c (C═O)O b R a ,
20) O(C═O)O b C 1 -C 10 alkyl,
21) O(C═O)O b C 3 -C 8 cycloalkyl,
22) O(C═O)O b aryl, and
23) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R z ;
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 z , 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 monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R z ;
R z is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl,
2) O r (C 1 -C 3 )perfluoroalkyl,
3) (C 0 -C 6 )alkylene-S(O) m R a ,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (C 0 -C 6 )alkylene-N(R b )
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,
18) C(O)N(R b ) 2 ,
19) S(O) m R a ,
20) S(O) 2 NR 9 R 10
21) NR c (C═O)O b R a ,
22) O(C═O)O b C 1 -C 10 alkyl,
23) O(C═O)O b C 3 -C 8 cycloalkyl,
24) O(C═O)O b aryl, and
25) O(C═O)O b -heterocycle,
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 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 ;
R c is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
5) C 2 -C 10 alkynyl,
6) heterocyclyl,
7) C 3 -C 8 cycloalkyl,
8) C 1 -C 6 perfluoroalkyl,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z ;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
5 . The compound according to claim 4 of the Formula D:
wherein:
a is 0 or 1;
bis 0 or 1;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
r is 0 or 1;
s is 0 or 1;
Q is selected from: —NR 7 R 8 ,
R 1 is independently selected from:
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) (C═O) a O b C 3 -C 8 cycloalkyl,
7) CO 2 H,
8) halo,
9) CN,
10) OH,
11) O b C 1 -C 6 perfluoroalkyl,
12) O a (C═O) b NR 7 R 8 ,
13) NR c (C═O)NR 7 R 8 ,
14) S(O) m R a ,
15) S(O) 2 NR 7 R 8 ,
16) NR c S(O) m R a ,
17) oxo,
18) CHO,
19) NO 2 ,
20) NR c (C═O)O b R a ,
21) O(C═O)O b C 1 -C 10 alkyl,
22) O(C═O)O b C 3 -C 8 cycloalkyl,
23) O(C═O)O b aryl, and
24) O(C═O)O b -heterocycle,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R z ;
R 2 is independently selected from:
1) C 1 -C 6 alkyl,
2) aryl,
3) heterocyclyl,
4) CO 2 H,
5) halo,
6) CN,
7) OH,
8) S(O) 2 NR 7 R 8 ,
said alkyl, aryl and heterocyclyl optionally substituted with one, two or three substituents selected from R z ;
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 z , 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 monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R z ;
R z is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl,
2) Or(C 1 -C 3 )perfluoroalkyl,
3) (C 0 -C 6 )alkylene-S(O) m R a ,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (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,
18) C(O)N(R b ) 2 ,
19) S(O) m R a , and
20) S(O) 2 N(R b ) 2
21) NR c (C═O)O b R a ,
22) O(C═O)O b C 1 -C 10 alkyl,
23) O(C═O)O b C 3 -C 8 cycloalkyl,
24) O(C═O)O b aryl, and
25) O(C═O)O b -heterocycle,
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 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 ;
R c is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
5) C 2 -C 10 alkynyl,
6) heterocyclyl,
7) C 3 -C 8 cycloalkyl,
8) C 1 -C 6 perfluoroalkyl,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z ;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
6 . The compound according to claim 1 which is selected from:
1-{1-[4-(6-hydroxy-5-isobutyl-3-phenylpyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4-(5-hydroxy-6-isobutyl-3-phenylpyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1-(1-{4-[5-hydroxy-6-(1H-indol-3-ylmethyl)-3-phenylpyrazin-2-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; and 1-(1-{4-[6-hydroxy-5-(1H-indol-3-ylmethyl)-3-phenylpyrazin-2-yl]benzyl} piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; or a pharmaceutically acceptable salt thereof.
7 . The TFA salts according to claim 1 selected from:
1-{1-[4-(6-hydroxy-5-isobutyl-3-phenylpyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4-(5-hydroxy-6-isobutyl-3-phenylpyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1-(1-{4-[5-hydroxy-6-(1H-indol-3-ylmethyl)-3-phenylpyrazin-2-yl]benzyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one; and 1-(1-{4-[6-hydroxy-5-(1H-indol-3-ylmethyl)-3-phenylpyrazin-2-yl]benzyl piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one.
8 . The compound according to claim 1 which is selected from:
R″
R′′′
—OH
—CH 2 CH(CH 3 ) 2
—CH 2 CH(CH 3 ) 2
—OH
—OH
H
H
—OH
—OH
—CH 2 Ph
—CH 2 Ph
—OH
—CH 2 Ph
—OH
—OH
—OH
—OH
—CH 2 OH
—CH 2 OH
—OH
—OH
—OH
—OH
—CH 3
—CH 3
—OH
or a pharmaceutically acceptable salt or a stereoisomer thereof.
9 . The TFA salt according to claim 1 selected from:
R″
R′′′
—OH
—CH 2 CH(CH 3 ) 2
—CH 2 CH(CH 3 ) 2
—OH
—OH
H
H
—OH
—OH
—CH 2 Ph
—CH 2 Ph
—OH
—CH 2 Ph
—OH
—OH
—OH
—OH
—CH 2 OH
—CH 2 OH
—OH
—OH
—OH
—OH
—CH 3
—CH 3
—OH
or a stereoisomer thereof.
10 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .
11 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 6 .
12 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 8 .
13 . A method of inhibiting one or more of the isoforms of Akt in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1 .
14 . A method of inhibiting one or more of the isoforms of Akt in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 6 .
15 . A method of inhibiting one or more of the isoforms of Akt in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of claim 8 .
16 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
17 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 6 .
18 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 8 .
19 . A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.
20 . (canceled)
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 . (canceled)
25 . A method of treating or preventing cancer 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, 10) an angiogenesis inhibitor, 11) a PPAR-γ agonists, 12) a PPAR-δ agonists, 13) an inhibitor of inherent multidrug resistance, 14) an anti-emetic agent, 15) an agent useful in the treatment of anemia, 16) an agent useful in the treatment of neutropenia, 17) an immunologic-enhancing drug, 18) an inhibitor of cell proliferation and survival signaling, and 19) an agent that interfers with a cell cycle checkpoint.
26 . (canceled)
27 . (canceled)Join the waitlist — get patent alerts
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