MACROCYCLIC PRODRUG COMPOUNDS USEFUL AS THERAPEUTICS

1 . A compound of formula IA, or a pharmaceutically acceptable salt, solvate, or ester thereof:

wherein:

R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, arylalkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, NR 2 , SR, S(O)R, S(O) 2 R, —SO 2 N(R) 2 , —N(R)SO 2 R, —N(CO)R, —N(CO)NR 2 , —N(CO)OR, —O(CO)R, —(CO)R, —(CO)OR, —(CO)NR 2 , —O(CO)OR, —O(CO)NR 2 , or a structural formula of

provided that at least one of R 1 , R 2 , R 3 , and R 4 have a structural formula, wherein each R can be the same or different;

L 1 and L 2 are each independently a covalent bond, —O—, or —NR 3a —;

p is 0, 1, or 2;

R 1a and R 2a are each independently hydrogen, alkyl, heteroalkyl, heteroaryl, heterocyclyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, -alkylene-C(O)—O—R 4a , or -alkylene-O—C(O)—O—R 4a ; and

R 3a and R 4a are each independently hydrogen, alkyl, heteroalkyl, cyclylalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, arylalkyl, heterocyclylalkyl, or heteroarylalkyl;

R 5 is hydrogen, halogen, nitro, cyano, alkyl, alkenyl, alkynyl, arylalkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OR, NR 2 , SR, S(O)R, S(O) 2 R, —SO 2 N(R) 2 , —N(R)SO 2 R, —N(CO)R, —N(CO)NR 2 , —N(CO)OR, —O(CO)R, —(CO)R, —(CO)OR, —(CO)NR 2 , —O(CO)OR, or —O(CO)NR 2 ; wherein each R can be the same or different;

A 1 and A 2 together are —CH═CH;

X 1 is hydrogen, halogen, OR, NR 2 , NH—OR, SR, S(O)R, S(O) 2 R, —N—O—(CH 2 ) n —CO 2 —R; or X 1 together with X 2 or X 3 represents a covalent bond; wherein each R can be the same or different;

X 2 and X 3 are both hydrogen, or one of X 2 and X 1 is hydrogen and the other together with X 1 represents a covalent bond;

R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CONR 2 , ═N—NR 2 , ═N—N—SOR or ═N—N—SO 2 R;

each R is independently hydrogen, alkyl, acyl, aryl, alkaryl, arylalkyl, heteroalkyl, heteroaryl, heterocyclyl, a protecting group; or when two R groups are bonded to the same nitrogen, the two R groups taken together with the nitrogen form a 5-8 membered heterocyclic or heteroaryl ring; and

n is 1, 2 or 3.

2 . (canceled)

3 . The compound of claim 2 , wherein R 1 is H, halogen or heterocyclyl.

4 . The compound of claim 2 , wherein R 5 is hydrogen, alkyl, aryl, heteroaryl or arylalkyl.

5 - 9 . (canceled)

10 . The compound of claim 2 , wherein:

R 1 is H, Cl or heterocyclyl;

R 5 is hydrogen, alkyl, lower alkyl, aryl or arylalkyl;

A 1 and A 2 together are —CH═CH;

X 1 together with X 2 represent a bond; and

R 7 is ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CONR 2 , ═N—NR 2 , ═N—N—SOR, ═N—N—SO 2 R.

11 . (canceled)

12 . The compound of claim 10 , wherein:

R 1 is H or Cl;

R 5 is hydrogen, methyl, propyl, isopropyl or phenyl; and

R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, or ═N—O—(CH 2 ) n CONR 2 .

13 . (canceled)

14 . The compound of claim 12 , wherein n is 1.

15 . The compound of claim 12 , wherein R 5 is hydrogen and R 7 is ═N—O—(CH 2 ) n COOR, or ═N—O—(CH 2 ) n CONR 2 .

16 - 44 . (canceled)

45 . The compound of claim 1 , wherein one of R 2 and R 4 has structural formula (Ia), at least one of L 1 and L 2 is —O—, and p is 0 or 1.

46 . The compound of claim 45 , wherein L 1 and L 2 are both —O—.

47 - 51 . (canceled)

52 . A Compound having a structural formula selected from the group consisting of

or a pharmaceutically acceptable salt, solvent, or ester thereof.

53 - 76 . (canceled)

77 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof; and a pharmaceutically acceptable carrier.

78 - 89 . (canceled)

90 . A method of treating a HSP90-mediated disorder comprising administering to a patient in need thereof with at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof.

91 . The method of claim 90 , wherein the HSP90-mediated disorder is selected from the group consisting of an autoimmune disease, an inflammatory disease, a neurological or neurodegenerative disease, cancer, a cardiovascular disease, allergy, asthma, a hormone-related disease, and tumors or symptoms resulting from neurofibromatosis.

92 . A method of inhibiting or reducing the growth or number of NF2-deficient tumor cells or NF1-deficient tumor cells comprising contacting said NF2-deficient tumor cells or NF1-deficient tumor cells with at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof.

93 - 103 . (canceled)

104 . The compound of claim 1 , wherein R 3 is hydrogen.

105 . The compound of claim 104 , wherein p is 0.