Compositions and methods for modulating a kinase cascade

A compound according to Formula I

• or a salt thereof, wherein:
• T is a bond;
• Xy is CY, N, or N—O;
• Xz is CZ;
• Y is selected from hydrogen, hydroxyl, halogen, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7 or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O—(C1, C2, C3, C4, C5, or C6)alkyl-aryl, (C3, C4, C5, C6, C7, or C8)cycloalkyl-aryl, and O-benzyl;
• Xa is CRa;
• Xb is CRb;
• Xc is CRc;
• Xd is CRd;
• Xe is CRe;
• Ra, Rd, Re, R4, and R6 are, independently, hydrogen, hydroxyl, halogen, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O—(C1, C2, C3, C4, C5, or C6) alkyl-aryl, O—(C3, C4, C5, C6, C7, or C8) cycloalkyl-aryl, O-benzyl, C1, C2, C3, C4, C5, or C6 alkyl-OH, C3, C4, C5, C6, C7, or C8 cycloalkyl-OH, COOH, COO—(C1, C2, C3, C4, C5, or C6) alkyl, SO2H, SO2—(C1, C2, C3, C4, C5, or C6) alkyl,
• wherein W is H, or C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkyl-aryl, C3, C4, C5, C6, C7 or C8 cycloalkyl-aryl;
• V is a bond, —CH2—, —CH2CH2—, —CH2CH2CH2—, —O—CH2—, —OCH2CH2— or —OCH2CH2CH2—;
• Rb is hydroxyl, halogen, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O—(C1, C2, C3, C4, C5, or C6) alkyl-aryl, O—(C3, C4, C5, C6, C7, or C8) cycloalkyl-aryl, O-benzyl, C1, C2, C3, C4, C5, or C6 alkyl-OH, C3, C4, C5, C6, C7, or C8 cycloalkyl-OH, COOH, COO—(C1, C2, C3, C4, C5, or C6) alkyl, SO2H, SO2—(C1, C2, C3, C4, C5, or C6) alkyl,
• wherein W is H, or C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkyl-aryl, C3, C4, C5, C6, C7 or C8 cycloalkyl-aryl;
• V is a bond, —CH2—,
• —CH2CH2—, —CH2CH2CH2—, —O—CH2—, —OCH2CH2— or —OCH2CH2CH2—;
• or T is OCH2, or CH2O;
• wherein Rb is hydrogen, hydroxyl, halogen, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O—(C1, C2, C3, C4, C5, or C6) alkyl-aryl, O—(C3, C4, C5, C6, C7, or C8) cycloalkyl-aryl, O-benzyl, C1, C2, C3, C4, C5, or C6 alkyl-OH, C3, C4, C5, C6, C7, or C8 cycloalkyl-OH, COOH, COO—(C1, C2, C3, C4, C5, or C6) alkyl, SO2H, SO2—(C1, C2, C3, C4, C5, or C6) alkyl,
• wherein W is H, or C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkyl-aryl, C3, C4, C5, C6, C7 or C8 cycloalkyl-aryl;
• V is a bond, —CH2—,
• —CH2CH2—, —CH2CH2CH2—, —O—CH2—, —OCH2CH2— or —OCH2CH2CH2—;
• Rc and R5 are, independently, hydrogen, hydroxyl, halogen, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O—(C1, C2, C3, C4, C5, or C6) alkyl-aryl, O—(C3, C4, C5, C6, C7, or C8) cycloalkyl-aryl, O-benzyl, C1, C2, C3, C4, C5, or C6 alkyl-OH, C3, C4, C5, C6, C7, or C8 cycloalkyl-OH, COO—(C1, C2, C3, C4, C5, or C6) alkyl, SO2H, SO2—(C1, C2, C3, C4, C5, or C6) alkyl,
• wherein W is H, or C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkyl-aryl, C3, C4, C5, C6, C7 or C8 cycloalkyl-aryl;
• V is a bond, —CH2—, —CH2CH2—, —CH2CH2CH2—, —O—CH2—, —OCH2CH2— or —OCH2CH2CH2—;
• R19, R20 and R21 are independently C1, C2, C3, C4, C5, or C6 alkyl or R19 and R20 taken together with the attached nitrogen atom form a five membered ring;
• Z is —(CR1R1′)n—NR2—C(O)—(CR3R3′)m—B,
• B is Ar or —(CR22R23)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 C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, non-aromatic heterocycle, partially unsaturated carbocycle, COOH, COOR30, and CONR31R32;
• further wherein alkyl, cycloalkyl, non-aromatic heterocycle, and partially unsaturated carbocycle are optionally substituted with D;
• D is selected from halogen, C1, C2, C3, C4, C5, or C6 alkoxy, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, non-aromatic heterocycle, partially unsaturated carbocycle, (C1, C2, C3, C4, C5, or C6)alkyl-non-aromatic heterocycle, (C3, C4, C5, C6, C7, or C8)cycloalkyl-non-aromatic heterocycle, (C1, C2, C3, C4, C5, or C6)alkyl-partially unsaturated carbocycle, (C3, C4, C5, C6, C7, or C8)cycloalkyl-partially unsaturated carbocycle, —OR26, —SR27, —NR28R29, and —(CR24R25)t—U;
• U is cyano, —OR26, —SR27, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, non-aromatic heterocycle, partially unsaturated carbocycle, C(O)NR28R29, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, or glycoside;
• R22 and R23 are independently selected from H, C1, C2, C3, C4, C5, or C6 alkyl, and C3, C4, C5, C6, C7, or C8 cycloalkyl;
• R24 and R25 are independently selected from H C1, C2, C3, C4, C5, or C6 alkyl, and C3, C4, C5, C6, C7, or C8 cycloalkyl;
• R26, R27, R28, and R29 are independently selected from H, C1, C2, C3, C4, C5, or C6 alkyl, and C3, C4, C5, C6, C7, or C8 cycloalkyl, or together R28 and R29 form a ring;
• R30, R31 and R32 are independently selected from H, C1, C2, C3, C4, C5, or C6 alkyl, and C3, C4, C5, C6, C7, or C8 cycloalkyl, or together R31 and R32 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
• R1, R1′, R2, R3, and R3′ are independently H or C1, C2, C3, C4, C5, or C6 alkyl, or C3, C4, C5, C6, C7, or C8 cycloalkyl.