C-terminal HSP90 inhibitors

1. A compound according to Formula I, or a pharmaceutically acceptable salt thereof:

wherein

R 1 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, alkoxy, sulfanyl, sulfenyl, sulfonyl, or ether;

R 2 is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or —R 9 —O—R 10 , wherein

R 9 is a covalent bond or alkylene, and

R 10 is hydrogen, alkyl, C-amido or acyl; or

R 2 together with R 3 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

R 3 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or —R 11 —O—R 12 , wherein

R 11 is a covalent bond or alkylene, and

R 12 is alkyl, C-amido or acyl; or

R 3 together with R 2 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen; or R 3 is absent when Y is ═N—;

R 4 is hydrogen, hydroxy, alkyl, arylalkoxy, carboxyl, —R 13 —O—R 14 , or —R 13 —R 15 ; and wherein

R 13 is a covalent bond or alkylene, and

R 14 is hydrogen, C-amido or acyl, and

R 15 is N-amido, —POR 16 R 17 , —SO 2 R 18 , or sulfonamido, and wherein

R 16 , R 17 , R 18 are independently alkoxy;

R 5 is hydrogen, hydroxy, alkyl, arylalkoxy, alkenyl, alkynyl, aryl, or aralkyl;

R 6 is hydrogen, hydroxy, sulfanyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, aryloxy, or arylalkoxy;

R 7 is hydrogen, hydroxyl, arylalkoxy, alkyl, or absent;

R 8 is hydrogen, hydroxyl, or arylalkoxy;

R 22 is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen, trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl, aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl, sulfanyl, sulfenyl, ether, R 25 —OR 26 , or R 25 —NHR 26 ; wherein

R 25 is a covalent bond or alkylene; and

R 26 is a hydrogen, alkyl, C-amido, or acyl;

R 23 is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen, trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl, aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl, sulfanyl, sulfenyl, ether, R 27 —OR 28 , or R 27 —NHR 28 ; wherein

R 27 is a covalent bond or alkylene and

R 28 is a hydrogen, alkyl, C-amido, or acyl; or

R 24 is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen, trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl, aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl, sulfanyl, sulfenyl, ether, R 29 —OR 30 , or R 29 —NHR 30 , wherein

R 29 is a covalent bond or alkylene and

R 30 is a hydrogen, alkyl, C-amido, or acyl; or

X 1 is —CHR 19 — or —CR 19 ═, and wherein R 19 is selected from hydrogen, halo, alkyl, alkenyl, or alkynyl; or X 1 together with X 2 form a carbocyclic ring having 3 to 7 ring members; or wherein X 1 -X 2 is —C≡C—;

X 2 is —CHR 20 — or ═CR 20 —, and wherein R 20 is selected from hydrogen, halo, alkyl, alkenyl, or alkynyl; or X 2 together with X 1 form a carbocyclic ring having 3 to 7 ring members; or wherein X 1 -X 2 is —C≡C—;

X 3 is O or CH 2 ;

X is ═CR 21 — or ═N—, wherein

R 21 is hydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;

R′ is H or alkyl;

R″ is alkyl, alkoxy, haloalkyl, alkylcycloalkyl or alkylamidoalkyl;

Y is ═CR 3 — or ═N—;

Z is CH, or Z-Z 1 is —C═C—;

Z 1 is CH, O, or Z-Z 1 is —C═C—; and

n is 0, 1, 2, or 3.

2. The compound according to claim 1 wherein

X 1 is —CHR 19 — and

R 19 is hydrogen or alkyl; or

X 1 together with X 2 form a carbocyclic ring having 3 to 7 ring members; and

X 2 is —CHR 20 — and wherein

R 20 is hydrogen or alkyl; or

X 2 together with X 1 form a carbocyclic ring having 3 to 7 ring members.

3. The compound according to claim 1 wherein

R′ is H,

R″ is CH 3 ,

X 1 is CH 2 , and

X 2 is CH 2 .

4. The compound according to claim 1 wherein R 4 and R 5 are independently methyl or hydrogen.

5. The compound according to claim 1 wherein R 6 is selected from hydrogen, hydroxy, methoxy, sulfanyl, or alkyl.

6. The compound according to claim 1 wherein R 7 and R 8 are hydroxy.

7. The compound of claim 1 further defined by formula (II):

wherein

R 1 is hydrogen, halo, hydroxy, trifluoroalkyl, alkoxy, or sulfanyl;

R 2 is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, or alkyl, or R 2 together with R 3 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

R 3 is hydrogen, halo, hydroxy, trifluoroalkyl, alkoxy, sulfanyl, alkyl; or R 3 together with R 2 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen, or R 3 is absent when Y is ═N—;

X is ═CR 21 — or ═N—, wherein R 21 is hydrogen, halo, or trifluoromethyl; and

Y is ═CR 3 — or ═N—;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 wherein

R 1 is hydrogen, halo, alkoxy, or sulfanyl;

R 2 is hydrogen, hydroxy, halo, trifluoromethyl, or alkoxy;

R 3 is hydrogen, hydroxy, halo, trifluoroalkyl, alkoxy, or sulfanyl;

X is ═CR 21 —, wherein R 21 is hydrogen, halo, or trifluoromethyl; and

Y is ═CR 3 —;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 further defined by formula (III):

wherein one of R 22 , R 23 , and R 24 is not H;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 selected from the group consisting of

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11a);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11b);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11c);

N-(2-(2′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11d);

N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11e);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11f);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11g);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-(methylthio)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11h);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11i);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11j);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11k);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(morpholinomethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11l);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11m);

N-(2-(benzo[d][1,3]dioxol-5-yl)-4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)phenethyl)acetamide (11n);

N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-3-yl)phenethyl)acetamide (11o);

N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-4-yl)phenethyl)acetamide (11p);

N-(4′-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3″-fluoro-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide (20a);

N-(4′-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3″-(trifluoromethyl)-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide (20b);

N-(2-(5-((4-(benzyloxy)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (24);

N-(2-(5-((4-(benzyloxy)cyclohex-2-en-1-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (36);

N-(2-(5-((4-(benzyloxy)-2,3-dihydroxycyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (37);

N-(2-(5-((4-(tert-butyl)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (39);

N-(2-(3′-fluoro-5-((4-(piperidin-4-yl)cyclohexyl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (40);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-6-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (41);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-3-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (42); and

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-4-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide (43);

or a pharmaceutically salt thereof.

11. The compound claim 10 which is

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11b);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11c);

N-(2-(2′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11d);

N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11e);

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11f); or

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11g);

or a pharmaceutically salt thereof.

12. The compound of claim 11 which is

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11b);

N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11e); or

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (11f);

or a pharmaceutically salt thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier.

14. A method for treating or preventing diabetic peripheral neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 7 .

15. The method of claim 14 , wherein the compound exhibits neuroprotective effects by upregulation of Hsp70.

16. The method of claim 14 , wherein the composition is administered in an amount effective to alleviate or prevent symptoms of neuronal glucotoxicity.

17. The method of claim 16 , wherein the composition is administered in an amount effective to alleviate symptoms of neuronal glucotoxicity.

18. The compound of claim 1 , further defined by the formula IV, or a pharmaceutically acceptable salt thereof:

wherein

R 1 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, alkoxy, trifluoromethyl, sulfanyl, sulfenyl, sulfonyl, or ether;

R 2 is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or —R 9 —O—R 10 , wherein

R 9 is a covalent bond or alkylene, and

R 10 is hydrogen, alkyl, C-amido or acyl; or

R 2 together with R 3 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

R 3 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or —R 11 —O—R 12 , wherein

R 11 is a covalent bond or alkylene, and

R 12 is alkyl, C-amido or acyl; or

R 3 together with R 2 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen; or R 3 is absent when Y is ═N—;

R 4 is hydrogen, hydroxy, alkyl, arylalkoxy, carboxyl, —R 13 —O—R 14 , or —R 13 —R 15 ; and wherein

R 13 is a covalent bond or alkylene, and

R 14 is hydrogen, C-amido or acyl, and

R 15 is N-amido, —POR 16 R 17 , —SO 2 R 18 , or sulfonamido, and wherein

R 16 , R 17 , R 18 are independently alkoxy;

R 5 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, or aralkyl;

R 6 is hydrogen, hydroxy, sulfanyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, aryloxy, or arylalkoxy;

R 7 is hydrogen or hydroxyl;

R 8 is hydrogen or hydroxyl;

X 1 is —CHR 19 — or —CR 19 ═, and wherein

R 19 is selected from hydrogen, halo, alkyl, alkenyl, or alkynyl; or

X 1 together with X 2 form a carbocyclic ring having 3 to 7 ring members; or wherein X 1 -X 2 is —C≡C—;

X 2 is —CHR 20 — or ═CR 20 —, and wherein

R 20 is selected from hydrogen, halo, alkyl, alkenyl, or alkynyl; or

X 2 together with X 1 form a carbocyclic ring having 3 to 7 ring members; or wherein X 1 -X 2 is —C≡C—;

X is ═CR 21 — or ═N—, wherein

R 21 is hydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;

R′ is H or alkyl;

R″ is alkyl, alkoxy, haloalkyl, alkylcycloalkyl or alkylamidoalkyl;

Y is ═CR 3 — or ═N—; and

n is 0, 1, 2, or 3.

19. The compound of claim 12 wherein the compound is:

or a pharmaceutically acceptable salt thereof.