GDF-8 inhibitors

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

X is C(H);

R 1 is hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R 10 , or —C 1-6 alkyl-R 10 ,

R 2 is halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R 10 , or —C 1-6 alkyl-R 10 ,

wherein

R 10 is —OR, —SR, —NR a R a , —C(O)R, —C(O)OR, —C(O)NR a R a , —S(O) 2 NR a R a , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —O(CH 2 ) m C(O)NR a R a , —N(R)C(O)OR, —N(R)C(O)NR a R a , —N(R)S(O) 2 NR a R a or —N(R)S(O) 2 R;

or when R 1 and R 2 are attached to adjacent carbon atoms they are optionally taken together with the atoms to which they are attached to form a 5- or 6-membered ring optionally substituted with one or two groups that are each independently halogen, oxo, oxime, imino, C 1-6 alkyl, C 1-6 haloalkyl, or —R 10 ;

each R a is independently R or, two R a together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl group, optionally including 1-4 additional heteroatoms selected from O, N and S and optionally substituted with 1-4 R groups;

each R b is independently halogen, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, or —OR;

m is 0, 1 or 2;

n is 1, 2, 3 or 4;

R 5 is hydrogen, halogen, C 1-6 alkyl, —OR 50 , —NR 50 R 50 , —N(R 50 )C(O)R 50 , or —N(R 50 )S(O) 2 R 50 , wherein each R 50 is independently hydrogen or C 1-6 alkyl;

R 6 is hydrogen, halogen, C 1-6 alkyl, —OR 60 , —NR 60 R 60 , —N(R 60 )C(O)R 60 , or —N(R 60 )S(O) 2 R 60 , wherein each R 60 is indepcndently hydrogen or C 1-6 alkyl;

Z is a fused bicyclic ring of the formula,

 wherein

ring A is a phenyl or 5- or 6-membered heteroaryl,

ring B is a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl;

wherein

Z is optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), —R Z , or —C 1-6 alkyl-R z , wherein the C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), and heteroaryl(C 1-6 alkyl) are each optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, or —R Z ;

and R Z is cyano, —CF 3 , —OR, —SR, —NR a R a , —C(O)R, —C(O)OR, —C(O)NR a R a , —S(O) 2 NR a R a , —S(O) 2 R 0 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR a R a , —N(R)C(O)OR, —N(R)C(O)NR a R a , —N(R)S(O) 2 R, or —OP(O)(OR) 2 ;

wherein each R is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl(heteroaryl)-, heterocyclyl(aryl)-, heteroaryl(heterocyclyl)-, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), or heteroaryl(C 1-6 alkyl), each optionally substituted by 1-5 groups that are each independently R b , —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 ,—S(O) 2 N(R 0 ) 2 , —OC(O)R 0 , —N(R 0 )C(O)R 0 , —OC(O)OR 0 , —O(CH 2 ) m C(O)N(R 0 ) 2 , —N(R 0 )C(O)OR 0 , —N(R 0 )C(O)N(R 0 ) 2 , or) —N(R 0 )S(O) 2 R 0

and each R 0 is independently hydrogen, C 1-6 haloalkyl, C 1-6 alkyl optionally substituted with 1-3 R b , C 3-8 cycloalkyl optionally substituted with one or two R b or, alternatively two R 0 together with a nitrogen atom to which they are bound form a 3-8 membered heterocyclyl group, optionally including 1-4 additional heteroatoms selected from O, N and S and optionally substituted with 0-3 R b and R groups.

2. The compound or pharmaceutically acceptable salt of claim 1 of the formula,

3. The compound or pharmaceutically acceptable salt of claim 1 of the formula,

4. The compound or pharmaceutically acceptable salt of claim 1 of the formula

5. The compound or pharmaceutically acceptable salt of claim 1 of the formula

6. The compound or pharmaceutically acceptable salt of claim 1 of the formula

7. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl,

C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R 10 , or —C 1-6 alkyl-R 10 ,

R 2 is halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, -R 10 , or -C 1-6 alkyl-R 10 ,

wherein R 10 is —OR, —SR, —NR 2 ,—C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R.

8. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is hydrogen, halogen, or C 1-6 alkyl, and R 2 is halogen, or C 1-6 alkyl.

9. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is fluoro and R 2 is methyl.

10. The compound or pharmaceutically acceptable salt of claim 1 of the formula

provided R 1 is not H.

11. The compound or pharmaceutically acceptable salt of claim 1 of the formula,

provided R 1 is not H.

12. The compound or pharmaceutically acceptable salt of claim 1 of the formula,

provided R 1 is not H.

13. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is hydrogen, halogen, cyano, nitro, C 1-8 alkyl, C 1-8 haloalkyl,

C 3-8 cycloalkyl, C 3-8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, —R 10 , or —C 1-6 alkyl-R 10 , wherein R 10 is —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R.

14. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is halogen or C 1-6 alkyl.

15. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is of the formula,

wherein

each is optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), —R z , or —C 1-6 alkyl-R z ,wherein the C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), and heteroaryl(C 1-6 alkyl) are each optionally substituted by one or two groups that are each independently C 1-6 alkyl or —R z .

16. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is of the formula,

wherein each is optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl), —R z ,or —C 1-6 alkyl-R z ,wherein the C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), and heteroaryl(C 1-6 alkyl) are each optionally substituted by one or two groups that are each independently C 1-6 alkyl or —R z .

17. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is

wherein R zl is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or —C 1-6 alkyl-R z ; and R Z2 is hydrogen, halogen, or C 1-6 alkyl.

18. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is

wherein

Q is —O—, —S—, or —N(R z1 )—; and

R zl is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, or —C 1-6 alkyl-R z ; and

R Z2 is hydrogen, halogen, or C 1-6 alkyl.

19. The compound of claim 1 according to the formula,

or a pharmaceutically acceptable sail thereof, wherein

R 1 is hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C -8 cycloalkyl, C 3-8 cycloalkcnyl, hcterocyclyl, aryl, hcteroaryl, —R 10 , or —C 1-6 alkyl-R 10 , wherein R 10 is —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

R 2 is hatogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 cycoalkenyl, hetcrocyclyl, aryl, heteroaryl, —R 10 , or —C 1-6 alkyl-R 10 , wherein R 10 is —OR, —SR,

—NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

R 5 is hydrogen, halogen, C 1-6 alkyl, —OR 50 , —NR 50 R 50 , —N(R 50 )C(O)R 50 , or —N(R 50 )S(O) 2 R 50 , wherein each R 50 is independently hydrogen or C 1-6 alkyl;

R 6 is hydrogen, halogen, C 1-6 alkyl, —OR 60 , —NR 60 R 60 , —N(R 60 )C(O)R 60 , or —N(R 60 )S(O) 2 R 60 , wherein each R 60 is independently hydrogen or C 1-6 alkyl;

R Z1 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, helerocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), heleroaryl(C 1-6 alkyl), —R Z3 , —C 1-6 alkyl-R Z3 or —C 1-6 alkyl-R Z4 , wherein the C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), and heteroaryl(C 1-6 alkyl) are each optionally substituted by one or two groups that are each independently halogen, C 1-6 alkyl, —R Z3 , or —R Z4 , wherein

R Z3 is —C(O)R, —C(O)OR, —C(O)NR 2 , or —S(O) 2 NR 2 ; and

R Z4 is —OR, —SR, —NR 2 , —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, N(R)C(O)NR 2 , —N(R)S(O) 2 R, or —OP(O)(OR) 2 ;

R Z2 is hydrogen, halogen, or C 1-6 alkyl; and

and each R is independently hydrogen or C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-6 alkyl), heterocyclyl(C 1-6 alkyl), aryl(C 1-6 alkyl), or heteroaryl(C 1-6 alkyl), each optionally substituted by one or two groups that are each independently —OR 0 , —SR 0 , —N(R 0 ) 2 , —C(O)R 0 , —C(O)OR 0 , —C(O)N(R 0 ) 2 , —S(O) 2 N(R 0 ) 2 , —OC(O)R 0 , —N(R 0 )C(O)R 0 , —OC(O)OR 0 , —OC(O)N(R 0 ) 2 , —N(R 0 )C(O)OR 0 , —N(R 0 )C(O)N(R 0 ) 2 , or —N(R 0 )S(O) 2 R 0 , wherein each R 0 independently hydrogen or C 1-6 alkyl.

20. A pharmaceutical composition comprising a compound or pharmaccutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.

21. A method for inhibiting GDF-8 in a cell, the method comprising contacting the cell with an effective amount of a compound or pharmaceutically acceptable salt according to claim 1 .