Isoindolinone and pyrrolopyridinone derivatives as Akt inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 4 ;

Y is N or CR 5 ;

Z is N or CR 6 , provided at least one of X, Y, and Z comprises a carbon atom;

A is C 6-10 aryl, 5-10 membered heteroaryl, or C 3-7 cycloalkyl, wherein said C 6-10 aryl, 5-10 membered heteroaryl, and C 3-7 cycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Q;

R 1 is H, F, Cl, Br, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c (O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d , wherein no more than one of said 1, 2, or 3 substituents is Cy;

R 2 is H, C 1-6 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl is optionally substituted by 1, 2, or 3 substituents independently selected from R A ;

R 3 is H or C 1-3 alkyl;

or R 2 and R 3 together with the nitrogen atom to which they are both attached form a 4-6 membered heterocycloalkyl group optionally substituted by 1 or 2 substituents independently selected from R A ;

R 4 is H, F, Cl, CN, or C 1-3 alkyl;

R 5 is H, F, Cl, CN, or C 1-3 alkyl;

R 6 is H, F, Cl, CN, or C 1-3 alkyl;

R 7 is C 1-3 alkyl;

Q is independently selected from Cy 1 , -L-Cy 1 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR g )NR c1 R d1 , NR c1 C(═NR g )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein no more than two Q are independently selected from Cy 1 and -L-Cy 1 , and wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR g )NR c1 R d1 , NR c1 C(═NR g )NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

L is C 1-3 alkylene, (C 1-3 alkylene) p O(C 1-3 alkylene) q , (C 1-3 alkylene) p S(C 1-3 alkylene) q , (C 1-3 alkylene) p C(O)(C 1-3 alkylene) q , (C 1-3 alkylene) p C(O)NR e (C 1-3 alkylene) q , (C 1-3 alkylene) p C(O)O(C 1-3 alkylene) q , (C 1-3 alkylene) p OC(O)(C 1-3 alkylene) q , (C 1-3 alkylene) p OC(O)NR e (C 1-3 alkylene) q , (C 1-3 alkylene) p NR e (C 1-3 alkylene) q , (C 1-3 alkylene) p NR e C(O)NR f (C 1-3 alkylene) q , (C 1-3 alkylene) p S(O)(C 1-3 alkylene) q , (C 1-3 alkylene) p S(O)NR e (C 1-3 alkylene) q , (C 1-3 alkylene) p S(O) 2 (C 1-3 alkylene) q , or (C 1-3 alkylene) p S(O) 2 NR e (C 1-3 alkylene) q , wherein said C 1-3 alkylene occurring in any of the options for L is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, CN, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ;

Cy is C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein said C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from Cy 2 and R B , wherein no more than one of said 1, 2, or 3 substituents is Cy 2 ;

Cy 1 is C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein said C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R C ;

Cy 2 is C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein said C 3-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R D ;

R A , R B , R C , and R D are each independently selected from halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , NR c1 R dl , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

R a , R b , R c , R d , R a1 , R b1 , R c1 , and R d1 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl, and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl, and 4-10 membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, halo, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR g )NR c3 R d3 , NR c3 C(═NR g )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;

or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, halo, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR g )NR c3 R d3 , NR c3 C(═NR g )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;

or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, halo, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR g )NR c3 R d3 , NR c3 C(═NR g )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;

R a2 , R b2 , R c2 , and R d2 are each independently selected from H, C 1-3 alkyl, and C 3-6 cycloalkyl;

or R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl group or 5-membered heteroaryl group;

R a3 , R b3 , R c3 , and R d3 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl, and 4-10 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl C 6-10 aryl-C 1-3 alkyl, 5-10 membered heteroaryl-C 1-3 alkyl, C 3-7 cycloalkyl-C 1-3 alkyl, and 4-10 membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

or R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R e and R f are each independently selected from H and C 1-4 alkyl;

R g is H, CN, or NO 2 ;

n is 0 or 1;

p is 0 or 1; and

q is 0 or 1.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 4 ; Y is CR 5 ; and Z is CR 6 .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N; Y is CR 5 ; and Z is CR 6 .

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 4 ; Y is N; and Z is CR 6 .

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 4 ; Y is CR 5 ; and Z is N.

6. The compound according claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H, C 1-6 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl, wherein said 4-6 membered heterocycloalkyl is optionally substituted by C 1-3 alkyl.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H or C 1-6 alkyl.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are both H.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, F, Cl, Br, CN, C 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, 4-6 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with one substituent selected from halo, C 1-6 alkyl, OR a , SR a , and C(O)NR c R d .

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, F, Cl, Br, CN, methyl, methoxymethyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, cyclobutyloxymethyl, cyclopropylmethyloxymethyl, methylthiomethyl, ethylthiomethyl, phenyl, thienyl, pyridinyl, methylpyrazolyl, thiazolyl, naphthyl, pyrimidinyl, fluoropyridinyl, methoxypyridinyl, methylaminocarbonylpyridinyl, and hydroxymethylbutynyl.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, F, Cl, Br, CN, and methyl.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Q.

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Q.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from pyridinyl, thienyl, thiazolyl, and pyrazolyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Q.

17. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is C 3-7 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Q.

18. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is cyclohexyl or cyclopropyl.

19. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is independently selected from Cy 1 , halo, C 2-6 alkynyl, C 1-6 haloalkyl, CN, and OR a1 .

20. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is independently selected from F, trifluoromethyl, methoxy, CN, acetylene, methylpyrazolyl, thienyl, pyridinyl, and pyrimidinyl.

21. The compound according to any claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , and R 6 are each H.

22. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl, or ethyl,.

23. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.

24. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

25. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

26. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

Y is N or CH;

Z is N or CH, provided at least two of X, Y, and Z are CH;

R 1 is H, F, Cl, Br, CN, methyl, methoxymethyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, cyclobutyloxymethyl, cyclopropylmethyloxymethyl, methylthiomethyl, ethylthiomethyl, phenyl, thienyl, pyridinyl, methylpyrazolyl, thiazolyl, naphthyl, pyrimidinyl, fluoropyridinyl, methoxypyridinyl, methylaminocarbonylpyridinyl, or hydroxymethylbutynyl;

R 2 is H or methyl;

R 3 is H or methyl;

R 7 is methyl;

A is phenyl, pyridinyl, thienyl, thiazolyl, pyrazolyl, cyclohexyl, or cyclopropyl, each optionally substituted with 1, 2, or 3 substituents independently selected from F, trifluoromethyl, methoxy, CN, acetylene, methylpyrazolyl, thienyl, pyridinyl, and pyrimidinyl; and

n is 0 or 1.

27. The compound according to claim 1 , having Formula IIa or IIb:

or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 1 , having Formula III:

or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1 , having Formula IV:

or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 1 , having Formula V:

or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 1 , selected from:

2-[(1S)-2-Amino-1-(3-fluorobenzyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-methyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-methoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-ethoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(2-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(1-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-cyclobutoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-cyclopropylmethoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[(methylthio)methyl-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-fluoro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-cyano-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(4-phenyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[1-methyl-4-(2-thienyl)-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[1-methyl-4-(3-thienyl)-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(1′,2-dimethyl-1′H,2H-3,4′-bipyrazol-5′-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[1-methyl-4-(1,3-thiazol-2-yl)-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[1-methyl-4-(2-naphthyl)-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[1-methyl-4-(1-naphthyl)-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(1-methyl-4-pyrimidin-5-yl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(2-fluoropyridin-3-yl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(6-fluoropyridin-3-yl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(5-fluoropyridin-3-yl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(2-methoxypyridin-3-yl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-[4-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

5-(5-{2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-1-methyl-1H-pyrazol-4-yl)-N-methylpyridine-2-carboxamide;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-1-(3-fluorobenzyl)-2-(methylamino)-ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-2-(ethylamino)-1-(3-fluorobenzyl)-ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-1-(3-fluorobenzyl)-2-(isopropylamino)ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-2-(cyclopropylamino)-1-(3-fluorobenzyl)ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-2-(cyclobutylamino)-1-(3-fluorobenzyl)ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-2-(cyclopentylamino)-1-(3-fluorobenzyl)ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-1-(3-fluorobenzyl)-2-(tetrahydro-2H-pyran-4-ylamino)ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-{(1S)-1-(3-fluorobenzyl)-2-[(1-methylpiperidin-4-yl)amino]ethyl}isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-2-(dimethylamino)-1-(3-fluorobenzyl)ethyl]isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[(1S)-2-(diethylamino)-1-(3-fluorobenzyl)ethyl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(4-methyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(4-methoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(4-ethoxymethyl-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-[4-(2-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-[4-(1-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-[4-(cyclobutoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-[4-(cyclopropylmethoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-[4-(methylthio)methyl-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-[4-(ethylthio)methyl-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(4-fluoro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(4-cyano-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-[4-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-benzyl-ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-benzyl-ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-benzyl-ethyl]-5-(4-bromo-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-benzyl-ethyl]-5-[4-(2-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-benzyl-ethyl]-5-[4-(methylthiomethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[2-amino-1-(2-fluorobenzyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-{2-amino-1-[3-(trifluoromethyl)benzyl]ethyl}-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

3-{(2S)-3-amino-2-[5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}benzonitrile;

4-{(2S)-3-amino-2-[5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}benzonitrile;

2-{(1S)-2-amino-1-[(2-methoxypyridin-4-yl)methyl]ethyl}-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(pyridin-3-ylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(pyridin-2-ylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(2-thienylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-thienylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(1,3-thiazol-4-ylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-{(1S)-2-amino-1-[3-(1-methyl-1H-pyrazol-4-yl)benzyl]ethyl}-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-{(1S)-2-amino-1-[3-(3-thienyl)benzyl]ethyl}-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-pyridin-4-ylbenzyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-pyridin-3-ylbenzyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-pyrimidin-5-ylbenzyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

3-{(2S)-3-amino-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}benzonitrile;

2-[(1S)-2-amino-1-(1-benzothien-3-ylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-{(1S)-2-amino-1-[(2-methoxypyridin-4-yl)methyl]ethyl}-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(pyridin-3-ylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(pyridin-2-ylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(2-thienylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-thienylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(1,3-thiazol-4-ylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-{(1S)-2-amino-1-[3-(1-methyl-1H-pyrazol-4-yl)benzyl]ethyl}-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-{(1S)-2-amino-1-[3-(3-thienyl)benzyl]ethyl}-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-pyridin-4-ylbenzyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-pyridin-3-ylbenzyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-pyrimidin-5-ylbenzyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-ethynylbenzyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-ethynylbenzyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

6-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one;

6-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-(4-methyl-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-[4-(2-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-[4-(1-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-[4-(cyclobutoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-[4-(ethylthiomethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-6-[4-(methylthiomethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-((1S)-2-amino-1-benzylethyl)-6-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1, 2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-(4-methyl-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-(4-broro-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-(4-methoxymethyl-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-[4-(2-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-[4-(1-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-6-[4-(cyclobutoxymethyl)-1-methyl-1H-pyrazol-5-yl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

6-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;

6-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-2-(1-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;

6-[(1S)-2-amino-1-benzylethyl]-2-(1-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-pyrrolo[3, 4-b]pyridin-5-one;

6-[(1S)-2-amino-1-benzylethyl]-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;

6-[(1S)-2-amino-1-benzyl-ethyl]-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;

2-[(1R)-2-amino-1-phenylethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(2-(dimethylamino)-1-phenylethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1R)-2-amino-1-phenylethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[2-amino-1-(3-fluorophenyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[2-amino-1-(4-fluorophenyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[2-amino-1-(3-methoxyphenyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[2-amino-1-(4-methoxyphenyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-[2-(dimethylamino)-1-phenylethyl]isoindolin-1-one;

2-[(1R)-2-amino-1-phenylethyl]-5-[4-(2-propoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[2-amino-1-(3-fluorophenyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[2-amino-1-(4-fluorophenyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[2-amino-1-(3-methoxyphenyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[2-amino-1-(4-methoxyphenyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3-fluorobenzyl)ethyl]-5-(1-ethyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(3,5-difluorobenzyl)ethyl]-5-(1-ethyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-[4-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]isoindolin-1-one;

2-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-6-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-6-(4-chloro-1-methyl-1H-pyrazol-5-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one;

2-[(1S)-2-amino-1-(cyclopropylmethyl)ethyl]-5-(1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

2-[(1S)-2-amino-1-(cyclopropylmethyl)ethyl]-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)isoindolin-1-one;

or a pharmaceutically acceptable salt thereof .

32. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

33. A method of therapeutically treating cancer comprising administering to a patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

34. The method of claim 33 wherein said cancer is selected from ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, colon cancer, brain cancer, lung cancer, head and neck cancer, melanoma, gastric cancer, and hepatocellular carcinoma (HCC).

35. A method of therapeutically treating Cowden syndrome comprising administering to a patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.