BIARYL COMPOSITIONS AND METHODS FOR MODULATING A KINASE CASCADE

1 .- 3 . (canceled)

4 . A method of inhibiting or relieving a disease or disorder selected from hearing loss, osteoporosis, type II diabetes, obesity, transplant rejection, stroke, atherosclerosis, chronic neuropathic pain, hepatitis B, a cardiovascular disorder, an immune system dysfunction, and an ophthalmic disorder in a subject, comprising administering to the subject a compound having Formula I:

or a salt, solvate, hydrate, or prodrug thereof, wherein:

T is a bond, CR 12 R 13 , C(O), O, S, S(O), S(O) 2 , NR 14 , C(R 15 R 16 )C(R 17 R 18 ), CH 2 O, or OCH 2 ;

X y is CZ, CY, N, or N—O;

X z is CZ, CY, N, or N—O;

at least one of X y and X z is CZ;

Y is H, hydroxyl, halogen, lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, or O-benzyl;

X a is CR a N, or N—O;

X b is CR b , N, or N—O;

X c is CR, N, or N—O;

X d is CR d N, or N—O;

X e is Me, N, or N—O;

R a , R b , R c , R d , R e , R 4 , R 5 , and R 6 are independently H, hydroxyl, halogen, P, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH, COO-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,

W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 6 , or C 6 alkyl-aryl;

P is SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NHR 20 R 21 ,

tetrazole, O-lower (C 1 , C 2 , C 3 , C 4 , CS, or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , CS, or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;

K is C(O)NH 2 , 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 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or

L is aryl, OH, C(O)NH 2 , 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 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or

M is aryl, OH, C(O)NH 2 , 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 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or

Q is aryl, OH, C(O)NH 2 , 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 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or

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;

V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —;

R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl;

Z is (CHR 1 ) n —C(O)—NR 2 (CHR 3 ) m —Ar, wherein Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group;

R 2 , and R 3 are independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; and

n and m are independently 0, 1, or 2.

5 . The method of claim 4 , wherein T is a bond.

6 . The method of claim 4 , wherein at least one of X a , X b , X c , X d , X e , X y , and X z is N.

7 . The method of claim 4 , wherein X y is CY, N, or N—O and X z is CZ.

8 . The method of claim 7 , wherein X y is N.

9 . The method of claim 7 , wherein X y is CY.

10 . The method of claim 7 , wherein Z is

wherein:

R 7 , R 8 , R 9 , R 10 , and R 11 are independently H, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O—C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl,

W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl; and

V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —.

11 . The method of claim 10 , wherein at least one of R 7 , R 8 , R 9 , R 10 and R 11 is halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or O-benzyl.

12 . The method of claim 10 , wherein m and n are each 1 and R 2 and R 3 are each H.

13 . The method of claim 4 , wherein X b is CR b ; X c is CR c ; and X d is CR d .

14 . The method of claim 4 , wherein the compound is selected from:

15 . The method of claim 4 , wherein the compound is selected from:

16 . The method of claim 4 , wherein the disease or disorder is selected from hearing loss, osteoporosis, type II diabetes, obesity, transplant rejection, stroke, atherosclerosis, chronic neuropathic pain, and hepatitis B.

17 . The method of claim 4 , wherein the compound is administered orally.

18 . The method of claim 4 , wherein the compound is administered with a pharmaceutically acceptable carrier.