Inhibitors of Akt activity

1. A compound of the formula A:

wherein:

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

r is 0 or 1;

s is 0 or 1;

m is 0 or 1;

a is 0 or 1;

b is 0 or 1;

X, Y and Z are independently selected from: C, N, S or O provided that at least one of X, Y or Z is N, S or O;

heterocycle, optionally substituted with one to three R z ;

Q is selected from: H, —NR 5 R 6 and heterocycle, said heterocycle which is optionally substituted with one to three R z ;

R 1 and R 2 are 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 alkynyl,

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 3 R 4 ,

13) NR c (C═O)NR 3 R 4 ,

14) S(O) m R a ,

15) S(O) 2 NR 3 R 4 ,

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 3 and R 4 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 2 -C 10 alkenyl,

5) C 2 -C 10 alkynyl,

6) (C═O) a O b heterocyclyl,

7) (C═O) a O b C 3 -C 8 cycloalkyl,

8) OH,

9) C 1 -C 6 perfluoroalkyl,

10) S(O) m R a , and

11) CHO,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R z , or

R 3 and R 4 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 4-7 members in each ring and optionally containing, in addition to the nitrogen, 1-3 heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R z ;

R 5 and R 6 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 2 -C 10 alkenyl,

5) C 2 -C 10 alkynyl,

6) (C═O) a O b heterocyclyl,

7) (C═O) a O b C 3 -C 8 cycloalkyl,

8) OH,

9) C 1 -C 6 perfluoroalkyl,

10) (C═O)NR 3 R 4 ,

11) S(O) m R a ,

12) S(O) 2 NR 3 R 4 , and

13) CHO,

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 4-7 members in each ring and optionally containing, in addition to the nitrogen, 1-3 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 ) 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) 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 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. The compound according to claim 1 wherein:

n is 0 or 1;

heterocycle selected from 2-azepinone, benzimidazolyl, benzimidazolonyl, 2-diazapinone, imidazolyl, 2-imidazolidinone, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinone, 2-pyrimidinone, 2-pyrollidinone, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl, said heterocycle optionally substituted with one to three R z ;

Q is selected from: H and —NR 5 R 6 ;

R 1 and R 2 are 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,

1) O b C 1 -C 6 perfluoroalkyl,

2) S(O) m R a ,

3) NR c S(O) m R a ,

4) oxo,

5) CHO,

6) NO 2 ,

7) NR c (C═O)O b R a ,

8) O(C═O)O b C 1 -C 10 alkyl,

9) O(C═O)O b C 3 -C 8 cycloalkyl,

10) O(C═O)O b aryl,

11) O(C═O)O b -heterocycle, and

12) NH 2 ,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl 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 wherein:

heterocycle selected from

said heterocycle optionally substituted with one to three R z ;

Q is selected from: —NR 5 R 6 ;

R 5 and R 6 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 2 -C 10 alkenyl,

5) C 2 -C 10 alkynyl,

6) (C═O) a O b heterocyclyl,

7) (C═O) a O b C 3 -C 8 cycloalkyl,

8) OH,

9) C 1 -C 6 perfluoroalkyl,

10) S(O) m R a , and

11) CHO,

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 4-7 members in each ring and optionally containing, in addition to the nitrogen, 1-3 heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle 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 3 wherein:

Q is selected from:

wherein R z can attach anywhere on the bicyclic structure;

R 1 and R 2 are independently selected from:

1) (C 1 -C 6 )alkyl,

2) (C 1 -C 10 )alkyl-OH

3) CO 2 H,

4) halo,

5) CN,

6) OH,

7) oxo,

8) CHO,

9) NO 2 , and

10) NH 2

R z is independently selected from:

1) (C 1 -C 6 )alkyl,

2) (C 1 -C 10 )alkyl-OH

3) CO 2 H,

4) halo,

5) CN,

6) OH,

7) oxo,

8) CHO,

9) NO 2 , and

10) NH 2

or a pharmaceutically acceptable salt or a stereoisomer thereof.

5. A compound which is selected from:

1-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one;

N-ethyl-N′-{(3R)-1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]pyrrolidin-3-yl}urea;

N-{(3R)-1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]pyrrolidin-3-yl}-1,3-thiazole-5-carboxamide;

9-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-9H-purin-6-amine;

2-(4-{[4-(3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl]methyl}phenyl)-3-phenylthieno[3,4-b]pyrazine;

9-{(1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-9H-purine;

{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]-1H-benzimidazol-2-yl}methanol;

2-{4-[(2-methyl-1H-benzimidazol-1-yl)methyl]phenyl}-3-phenylthieno[3,4-b]pyrazine;

1-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]-1,2,3,6-tetrahydropyridin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one;

N-{(3R)-1-[4-(3-hydroxy-5-phenyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)benzyl]pyrrolidin-3-yl}-1,3-thiazole-5-carboxamide; and

1-{1-[4-(3-hydroxy-5-phenyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

6. The TFA salt of a compound according to claim 1 which is:

1-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one;

N-ethyl-N′-{(3R)-1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]pyrrolidin-3-yl}urea;

N-{(3R)-1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]pyrrolidin-3-yl}-1,3-thiazole-5-carboxamide;

9-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-9H-purin-6-amine;

2-(4-{[4-(3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl]methyl}phenyl)-3-phenylthieno[3,4-b]pyrazine;

9-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-9H-purine;

{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]-1H-benzimidazol-2-yl}methanol;

2-{4-[(2-methyl-1H-benzimidazol-1-yl)methyl]phenyl}-3-phenylthieno[3,4-b]pyrazine;

1-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]-1,2,3,6-tetrahydropyridin-4-yl }-1,3-dihydro2H-benzimidazol-2-one;

N-{(3R)-1-[4-(3-hydroxy-5-phenyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)benzyl]pyrrolidin-3-yl}-1,3-thiazole-5-carboxamide; and

1-{1-[4-(3-hydroxy-5-phenyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one;

or a stereoisomer thereof.

7. A compound according to claim 5 which is selected from:

1-{1-[4-(3-phenylthieno[3,4-b]pyrazin-2-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

8. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .

9. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 6 .