C-terminal Hsp90 inhibitors

Patent metadata

Field	Value
Publication number	US-10030041-B2
Application number	US-201615227230-A
Country	US
Kind code	B2
Filing date	Aug 3, 2016
Priority date	Feb 9, 2012
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

Hsp90 C-terminal inhibitors and pharmaceutical compositions containing such compounds are provided. The compounds of the disclosure are useful for the treatment and/or prevention of neurodegenerative disorders such as diabetic peripheral neuropathy.

First claim

What is claimed is:

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

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 —OR 10 , wherein R 9 is a covalent bond or alkyl, 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 —OR 12 , wherein R 11 is a covalent bond or alkyl, 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;
R 4 is hydrogen or alkyl;
R 5 is hydrogen or alkyl;
R 6 is hydrogen, hydroxy, sulfanyl, alkyl, or alkoxy;
R 7 is hydrogen or hydroxyl;
R 8 is hydrogen or hydroxyl;
X 1 is —CHR 19 —, and wherein R 19 is selected from hydrogen, halo, alkyl, alkenyl, and alkynyl;
X 2 is —CHR 20 —, and wherein R 20 is selected from hydrogen, halo, alkyl, alkenyl, and alkynyl;
X is ═CR 21 — or ═N—, wherein R 21 is hydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;
R′ is hydrogen or alkyl;
R″ is alkyl;
Y is ═CR 3 — or ═N—;
Z is CH or Z—Z 1 is —C═C—;
Z 1 is CH or Z—Z 1 is —C═C—; and
n is 0, 1, 2, or 3.

2. The compound or salt according to claim 1 , wherein
X 1 is —CHR 19 —, and wherein R 19 is hydrogen or alkyl; and
X 2 is —CHR 20 —, and wherein R 20 is hydrogen or alkyl.

3. The compound or salt according to claim 1 , wherein
R′ is hydrogen,
R″ is CH 3 ,
X 1 is CH 2 , and
X 2 is CH 2 .

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

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

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

7. The compound or salt of claim 1 , 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 —.

8. The compound or salt 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); and
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).

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

10. A method for treating or preventing a neurodegenerative disorder, wherein inhibition of Hsp90 would be beneficial, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 1 .

11. The method of claim 10 , wherein the neurodegenerative disorder is diabetic peripheral neuropathy.

12. The method of claim 10 , wherein the compound exhibits neuroprotective effects by upregulation of Hsp70.

13. The compound of claim 7 , wherein R 1 is hydrogen.

14. The compound of claim 7 , wherein R 2 is halo.

15. The compound of claim 14 , wherein R 2 is fluoro.

16. The compound of claim 7 , wherein R 3 is hydrogen.

17. The compound of claim 7 , wherein R 21 is hydrogen.

18. The pharmaceutical composition of claim 9 , wherein the compound is further defined as:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 10 , wherein the compound or pharmaceutically acceptable salt is formulated as a pharmaceutical composition.

20. The method of claim 10 , wherein the neurodegenerative disorder is associated with oxidative stress.

Assignees

• Univ Kansas

Inventors

• Blagg Brian S J
• Kusuma Bhaskar Reddy
• Sundstrom Teather

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title