Bicyclic compositions and methods for modulating a kinase cascade

1. A method of relieving osteoporosis in a subject comprising administering a compound of Formula VII:

or a salt or prodrug thereof,

wherein R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are independently H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, benzyl, heteroaryl, biaryl, heterobiaryl, heterocycle, or branched, unbranched, or cyclic alkyl;

one of R 6 or R 7 is (CH 2 ) t —Z and the remaining R 6 or R 7 is H;

Z is aryl, heteroaryl, or biaryl;

t is 1;

R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, or branched, unbranched, or cyclic alkyl;

P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , 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 , C 5 , 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;

wherein any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R a , R b , and R c is substituted or unsubstituted.

2. The method of claim 1 , wherein the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.

3. The method of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , or R 5 is halogen.

4. The method of claim 1 , wherein R 3 is halogen.

5. The method of claim 4 , wherein R 3 is fluorine.

6. The method of claim 1 , wherein Z is optionally substituted aryl or heteroaryl.

7. The method of claim 6 , wherein Z is phenyl.

8. The method of claim 6 , wherein aryl is substituted with alkoxy, hydroxyl, halogen, aldehyde, O-benzyl, trifluoromethyl, alkylhydroxy, nitro, —OCF 3 , or alkoxycarbonyloxy.

9. The method of claim 1 , wherein R 2 and R 4 are each H.

10. The method of claim 1 , wherein R 5 is H.

11. The method of claim 1 , wherein R 1 is optionally substituted aryl.

12. The method of claim 11 , wherein R 1 is phenyl or phenyl substituted with halogen, alkoxy, ethyl, hydroxyl, or alkylhydroxy.

13. The method of claim 11 , wherein R 3 is fluorine.

14. The method of claim 13 , wherein Z is phenyl substituted with fluorine.

15. The method of claim 1 , wherein the subject is a human.

16. A method of relieving osteoporosis in a subject comprising administering a compound selected from:

or a salt or prodrug thereof.

17. The method of claim 16 , wherein the subject is a human.

18. A method of relieving osteoporosis in a subject comprising administering a compound of the formula:

wherein

R 1 is phenyl or phenyl substituted with halogen, alkoxy, ethyl, hydroxyl, or alkylhydroxy;

R 2 , R 3 , R 4 , and R 5 are the same or different and are independently H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b —, P(O)OR a OR b , halogen, or branched, unbranched, or cyclic alkyl;

R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, or branched, unbranched, or cyclic alkyl;

Z is phenyl or phenyl substituted with alkoxy, hydroxyl, halogen, aldehyde, O-benzyl, trifluoromethyl, alkylhydroxy, nitro, —OCF 3 , or alkoxycarbonyloxy.