Compositions and methods for modulating a kinase cascade

A method of treating or preventing a disease or disorder by administering to a subject a compound of Formula I,

• or a salt, solvate, hydrate, or prodrug thereof, wherein:
• T is a bond, CR12R13, C(O), O, S, S(O), S(O)2, NR14, C(R15R16)C(R17R18), CH2O, or OCH2;
• Xy is CZ, CY, N, or N—O;
• Xz is CZ, CY, N, or N—O;
• at least one of Xy and 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, N, or N—O;
• Xb is CRb, N, or N—O;
• Xc is CRc, N, or N—O;
• Xd is CRd, N, or N—O;
• Xe is CRd, N, or N—O;
• Ra, Rb, Rc, Rd, Re, R4, R5, and R6 are, independently, hydrogen, hydroxyl, halogen, G, 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—;
• R12, R13, R14, R15, R16, R17, and R18, are, independently, H or C1, C2, C3, C4, C5, or C6 alkyl, or C3, C4, C5, C6, C7, or C8 cycloalkyl;
• G is SO3H, OSO3H, OPO3H2, OPO3H2, NH2, NHR19, NR20R21,
• tetrazole, O—(C1, C2, C3, C4, C5, or C6) alkyl-K, O—(C3, C4, C5, C6, C7, or C8)cycloalkyl-K, O—C(O)—(C1, C2, C3, C4, C5, or C6) alkyl-L, O—C(O)(C3, C4, C5, C6, C7, or C8)cycloalkyl-L, NH—(C1, C2, C3, C4, C5, or C6) alkyl-M, NH—(C3, C4, C5, C6, C7, or C8)cycloalkyl-M or O-aryl-Q, further wherein (C1, C2, C3, C4, C5, or C6) alkyl is linear or branched alkyl;
• K is aryl, heteroaryl, C(O)NR28R29, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, C1, C2, C3, C4, C5, C6 alkoxy, or
• L is aryl, heteroaryl, OH, C(O)NR28R29, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• M is aryl, heteroaryl, OH, C(O)NR28R29 COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• Q is aryl, heteroaryl, OH, C(O)NR28R29, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• 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—C(O)—NR2(CR3R3′)m—B, —(CR1R1′)n—NR2—C(O)—(CR3R3′)m—B, —(CR1R1′)n—NR2—C(O)—NR2′(CR3R3′)m—B, —(CR1R1′)n—S(O)p—NR2—(CR3R3′)m—B, —(CR1R1′)n—NR2—S(O)p—(CR3R3′)m—B, —(CR1R1′)n—O—C(O)—NR2—(CR3R3′)m—B, —(CR1R1′)n—NR2—C(O)—O—(CR3R3′)m—B, —(CR1R1′)n—CH(OH)—CR2R2′—NR2(CR3R3′)m—B, —(CR1R1′)n—S—C(O)—NR2(CR3R3′)m—B, —(CR1R1′)n—O—(CR3R3′)m—B, —(CR1R1′)n—C(S)—NR2(CR3R3′)m—B, —(CR1R1′)n—NR2—C(S)—(CR3R3′)m—B, —(CR1R1′)n—P(═O)(O—)—CH2—NR2(CR3R3′)m—B, —(CR1R1′)n—P(═O)(OH)—CH2—(CR3R3′)m—B, —(CR1R1′)nNR2—CH2—P(═O)(O—)(CR3R3′)m—B, —(CR1R1′)n—P(═O)(O—)NR2(CR3R3′)m—B, —(CR1R1′)n—NR2P(═O)(O—)(CR3R3′)m—B, —(CR1R1′)n—CH(CN)—NR2(CR3R3′)m—B, —(CR1R1′)n—CH2—(CR3R3′)m—B, —(CR1R1′)n—C(O)—CHF—(CR3R3′)m—B, —(CR1R1′)n—CR2(OH)—CR2′(OH)—(CR3R3′)m—B, —(CR1R1′)n—CR2(OH)—CR2′(NH2)—(CR3R3′)m—B, —(CR1R1′)n—CH(OH)—C(O)NR2(CR3R3′)m—B,
• —(CR1R1′)n—NR2—(CR3R3′)m—B, —(CR1R1′)n—C(O)C(OH)R2—(CR3R3′)m—B, —(CR1R1′)n—C(O)—(CR3R3′)—B, —(CR1R1′)n—S(O)p—(CR3R3′)—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 hydrogen, OH, CN, CF3, NR31R32, C1, C2, C3, C4, C5, or C6 alkyl, C3, C4, C5, C6, C7, or C8 cycloalkyl, C1, C2, C3, C4, C5, or C6 alkoxy, 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, NHR19g, 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 R3, 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;
• n and m are, independently 0, 1, or 2;
• and
• R1, R1′, R2, 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.
• wherein the disorder or disease is selected from a cell proliferation disorder, pre-cancer, microbial infection, an immune disease, osteoporosis, hearing loss, ophthalmic disease, macular edema, a cardiovascular disorder, stroke, athrosclerosis, type II diabetes, obesity, immune system dysfunction, chronic neuropathic pain, and transplant rejection.