Compositions and methods for modulating a kinase cascade

1. A compound according to Formula I

or a salt thereof, wherein:

T is a bond;

X y is CY, N, or N—O;

X z is CZ;

Y is selected from hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 )alkyl-aryl, (C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 )cycloalkyl-aryl, and O-benzyl;

X a is CR a ;

X b is CR b ;

X c is CR c ;

X d is CR d ;

X e is CR e ;

R a , R d , R e , R 4 , and R 6 are, independently, hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O—(C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 ) cycloalkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl-OH, COOH, COO—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 —(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,

wherein W is H, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl, C 3 , C 4 , C 5 , C 6 , C 7 or C 8 cycloalkyl-aryl; V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —O—CH 2 —, —OCH 2 CH 2 — or —OCH 2 CH 2 CH 2 —; R b is hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O—(C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 ) cycloalkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl-OH, COOH, COO—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 —(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,

wherein W is H, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl, C 3 , C 4 , C 5 , C 6 , C 7 or C 8 cycloalkyl-aryl; V is a bond, —CH 2 —,

—CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —O—CH 2 —, —OCH 2 CH 2 — or —OCH 2 CH 2 CH 2 —;

or T is OCH 2 , or CH 2 O; wherein R b is hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O—(C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 ) cycloalkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl-OH, COOH, COO—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 —(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,

wherein W is H, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl, C 3 , C 4 , C 5 , C 6 , C 7 or C 8 cycloalkyl-aryl; V is a bond, —CH 2 —,

—CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —O—CH 2 —, —OCH 2 CH 2 — or —OCH 2 CH 2 CH 2 —;

R c and R 5 are, independently, hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O—(C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 ) cycloalkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl-OH, COO—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 —(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,

wherein W is H, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl, C 3 , C 4 , C 5 , C 6 , C 7 or C 8 cycloalkyl-aryl; V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —O—CH 2 —, —OCH 2 CH 2 — or —OCH 2 CH 2 CH 2 —;

R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring;

Z is —(CR 1 R 1′ ) n —NR 2 —C(O)—(CR 3 R 3′ ) m —B,

B is Ar or —(CR 22 R 23 ) s -J;

Ar is unsubstituted aryl, unsubstituted nitrogen-containing heteroaryl group, aryl substituted with D, or nitrogen-containing heteroaryl group substituted with D;

J is selected from C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, non-aromatic heterocycle, partially unsaturated carbocycle, COOH, COOR 30 , and CONR 31 R 32 ; further wherein alkyl, cycloalkyl, non-aromatic heterocycle, and partially unsaturated carbocycle are optionally substituted with D;

D is selected from halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, non-aromatic heterocycle, partially unsaturated carbocycle, (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 )alkyl-non-aromatic heterocycle, (C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 )cycloalkyl-non-aromatic heterocycle, (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 )alkyl-partially unsaturated carbocycle, (C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 )cycloalkyl-partially unsaturated carbocycle, —OR 26 , —SR 27 , —NR 28 R 29 , and —(CR 24 R 25 ) t —U;

U is cyano, —OR 26 , —SR 27 , C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, non-aromatic heterocycle, partially unsaturated carbocycle, C(O)NR 28 R 29 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , or glycoside;

R 22 and R 23 are independently selected from H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, and C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl;

R 24 and R 25 are independently selected from H C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, and C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl;

R 26 , R 27 , R 28 , and R 29 are independently selected from H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, and C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, or together R 28 and R 29 form a ring;

R 30 , R 31 and R 32 are independently selected from H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, and C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl, or together R 31 and R 32 form a ring;

s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

t is 0, 1, 2, 3, 4, 5, or 6;

p is 0, 1 or 2;

m is 1 or 2;

n is 0, 1 or 2; and

R 1 , R 1′ , R 2 , R 3 , and R 3′ are independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 3 , C 4 , C 5 , C 6 , C 7 , or C 8 cycloalkyl.

2. The compound of claim 1 , wherein m and n are independently selected from 1 and 2.

3. The compound of claim 1 , wherein R 1 and R 1′ are both hydrogen.

4. The compound of claim 1 , wherein R 2 is hydrogen.

5. The compound of claim 1 , wherein R 3 and R 3′ are both hydrogen.

6. The compound of claim 1 , wherein X y is N.

7. The compound of claim 1 , wherein T is a bond.

8. The compound of claim 1 , wherein B is Ar.

9. The compound of claim 1 , wherein B is —(CR 22 R 23 ) s -J.

10. The compound of claim 9 , wherein J is non-aromatic heterocycle.

11. A composition comprising a compound of claim 1 and at least one pharmaceutically acceptable carrier or excipient.

12. The compound of claim 1 , wherein T is OCH 2 , or CH 2 O, and R b is hydrogen.

13. The compound of claim 1 , wherein Xy is CY, further wherein Y is hydrogen.

14. The compound of claim 1 , wherein n and m are both 1.

15. The compound of claim 1 , wherein R 4 , R 5 , and R 6 are each hydrogen.

16. The compound of claim 1 , wherein R 2 is hydrogen.

17. The compound of claim 8 , wherein Ar is substituted with D, wherein D is selected from halogen, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkyl and non-aromatic heterocycle.

18. A compound selected from

or a salt thereof.