Biaryl Compositions and Methods for Modulating a Kinase Cascade

A method of protecting against or treating hearing loss or osteoporosis in a subject comprising administering a compound having the Formula I:

• or a salt, solvate, hydrate, or prodrug thereof, wherein:
• T is absent, 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, lower (C1, C2, C3, C4, C5, or C6) alkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O-lower (C1, C2, C3, C4, C5, or C6) alkyl-aryl, and O-benzyl;
• Xa is CRa or N, or N—O;
• Xb is CRb, N, or N—O;
• Xc is CRc or N, or N—O;
• Xd is CRd or N, or N—O;
• Xe is CRe, N, or N—O;
• Ra, Rb, Rc, Rd, Re, R4, R5, and R6 are, independently, hydrogen, hydroxyl, halogen, P, C1, C2, C3, C4, C5, or C6 alkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O-lower (C1, C2, C3, C4, C5, or C6) alkyl-aryl, O-benzyl, C1, C2, C3, C4, C5, or C6 alkyl-OH, COOH, COO-lower (C1, C2, C3, C4, C5, or C6) alkyl, SO2H, SO2-lower (C1, C2, C3, C4, C5, or C6) alkyl,
• where W is H, or C1, C2, C3, C4, C5, or C6 alkyl, C1, C2, C3, C4, C5, or C6 alkyl-aryl;
• P is SO3H, OSO3H, OPO3H2, OPO3H2, NH2, NHR19, NHR20R21,
• tetrazole, O-lower (C1, C2, C3, C4, C5, or C6) alkyl-K, O—C(O)-lower (C1, C2, C3, C4, C5, or C6) alkyl-L, NH-lower (C1, C2, C3, C4, C5, or C6) alkyl-M, or O-aryl-Q, further wherein lower alkyl is linear or branched alkyl;
• K is C(O)NH2, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• L is aryl, OH, C(O)NH2, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• M is aryl, OH, C(O)NH2, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• Q is aryl, OH, C(O)NH2, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• R19, R20 and R21 are C1, C2, C3, C4, C5, or C6 alkyl or R19 and R20 taken together with the attached nitrogen atom form a five membered ring;
• 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;
• and
• Z is (CHR1)n—C(O)—NR2(CHR3)m—Ar, where Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, R1, R2, and R3 are independently H or C1, C2, C3, C4, C5, or C6 alkyl;
• and
• n and m are independently 0, 1, or 2.

A method of preventing or treating a cell proliferation disorder comprising administering to a subject in need thereof a compound having the formula IA:

• or a salt, solvate, hydrate, or prodrug thereof, wherein:
• T is absent, 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, lower (C1, C2, C3, C4, C5, or C6) alkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O-lower (C1, C2, C3, C4, C5, or C6) alkyl-aryl, and O-benzyl;
• Xa is CRa or N, or N—O;
• Xb is CRb, N, or N—O;
• Xc is CRc or N, or N—O;
• Xd is CRd or N, or N—O;
• Xe is CRe, N, or N—O;
• Ra, Rb, Rc, Rd, Re, R4, R5, and R6 are, independently, hydrogen, hydroxyl, halogen, P, C1, C2, C3, C4, C5, or C6 alkyl, C1, C2, C3, C4, C5, or C6 alkoxy, O-lower (C1, C2, C3, C4, C5, or C6) alkyl-aryl, O-benzyl, C1, C2, C3, C4, C5, or C6 alkyl-OH, COOH, COO-lower (C1, C2, C3, C4, C5, or C6) alkyl, SO2H, SO2-lower (C1, C2, C3, C4, C5, or C6) alkyl,
• wherein W is H, or C1, C2, C3, C4, C5, or C6 alkyl, C1, C2, C3, C4, C5, or C6 alkyl-aryl;
• P is SO3H, OSO3H, OPO3H2, OPO3H2, NH2, NHR19, NHR20R21
• tetrazole, O-lower (C1, C2, C3, C4, C5, or C6) alkyl-K, O—C(O)-lower (C1, C2, C3, C4, C5, or C6) alkyl-L, NH-lower (C1, C2, C3, C4, C5, or C6) alkyl-M, or O-aryl-Q, further wherein lower (C1, C2, C3, C4, C5, or C6) alkyl is linear or branched alkyl;
• K is C(O)NH2, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• L is aryl, OH, C(O)NH2, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• M is aryl, OH, C(O)NH2, COOH, SO3H, OSO3H, PO3H2, OPO3H2, NH2, NHR19, NR19R20, SO2R21, glycoside, lower C1, C2, C3, C4, C5, C6 alkoxy, or
• Q is aryl, OH, C(O)NH2, 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;
• 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;
• and
• Z is (CHR1)n—C(O)—NR2(CHR3)m—Ar, where Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, R1, R2, and R3 are independently H or C1, C2, C3, C4, C5, or C6 alkyl;
• and n and m are, independently 0, 1, or 2;
• provided that at least one of Ra, Rb, Rc, Rd, Re, R4, R5, and R6 is P.