Substituted heterocycles for targeting Hsp90

Patent metadata

Field	Value
Publication number	US-10927115-B2
Application number	US-201916550715-A
Country	US
Kind code	B2
Filing date	Aug 26, 2019
Priority date	Aug 6, 2012
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

Substituted indazoles linked to a substituted adenine with a polyethylene glycol moiety selectively bind to Hsp90. The compounds include detection moieties such as fluorophores and are useful in methods and kits for selective detection of Hsp90 in a sample.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
A is formula (II):

wherein:
X is CR 9 or N;
Y is CR 3 or N;
R 1 is H or C 1-8 -alkyl;
R 2 is H or C 1-8 -alkyl;
R 3 is H, F, or OCH 3 ;
R 4 is H, F, or OCH 3 ;
R 5 is H, F, or OCH 3 ;
R 6 is C 1-8 -alkyl, halo-C 1-8 -alkyl, hydroxy-C 1-8 -alkyl, C 3-8 -cycloalkyl-C 1-8 -alkyl, C 3-8 -cycloalkenyl-C 1-8 -alkyl, heterocyclyl-C 1-8 -alkyl, aryl-C 1-8 -alkyl, heteroaryl-C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
R 7 is H or C 1-8 -alkyl;
R 8 is H or C 1-8 -alkyl; or
R 7 and R 8 , taken together with the carbon atom to which they are attached, form a C 3-8 -cycloalkyl;
R 9 is H or C 1-8 -alkyl; and
is the point of attachment in formula (I);
X 1 is —C(O)—, —NH—, —O—, —S—, or —S(O) 2 —;
L is a divalent linker of the following formula:
—(CH 2 ) m —(OCH 2 CH 2 ) n —O—(CH 2 ) p —,

wherein:
m is 2 or 3;
n is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and
p is 2 or 3;

X 2 is —NR—;
R is a detection moiety; and
B is formula (III):

wherein:
R is alkylenyl or heteroalkylenyl;
each Y 1 is independently CH or N;
each Z 1 , taken together with the carbon atoms to which they are attached, form a heterocyclyl;
Z 2 is H or halo;
Z 3 is —CH 2 —, —NH—, —O—, or —S—;
Z 4 is H or halo; and
is the point of attachment in formula (I);
wherein the detection moiety comprises a fluorophore or a radioactive compound;
wherein the fluorophore is a fluorescein, a rhodamine, a coumarin, a cyanine, or a boron-dipyrromethene; and
wherein the radioactive compound is a radioisotope.

2. The compound of claim 1 , wherein:
X is N;
Y is CR 3 ;
R 1 is H;
R 2 is H;
R 3 is H;
R 4 is H;
R 5 is H;
R 6 is C 1-8 -alkyl or halo-C 1-8 -alkyl;
R 7 is C 1-8 -alkyl; and
R 8 is C 1-8 -alkyl.

3. The compound of claim 1 , wherein A is:

4. The compound of claim 1 , wherein:
m is 3; and
p is 3.

5. The compound of claim 1 , wherein n is 4.

6. The compound of claim 1 , wherein the detection moiety comprises a fluorophore.

7. The compound of claim 6 , wherein the fluorophore is a fluorescein.

8. The compound of claim 6 , wherein the detection moiety is:

9. The compound of claim 1 , wherein B is:

10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

11. A kit comprising a compound of claim 1 .

12. A method for detecting heat shock protein 90 in a sample, wherein the method comprises the following steps:
a) contacting the sample with the compound of claim 1 ; and
b) detecting a signal from the detection moiety.

13. A method for detecting cancer in a subject, wherein the method comprises the following steps:
a) contacting a biological sample from the subject with the compound of claim 1 ; and
b) detecting a signal from the detection moiety.

14. A method for detecting human immunodeficiency virus in a subject, wherein the method comprises the following steps:
a) contacting a biological sample from the subject with the compound of claim 1 ; and
b) detecting a signal from the detection moiety.

Assignees

• Univ Duke

Inventors

• Haystead Timothy
• Hughes Philip Floyd

Classifications

• G01N33/57595

  involving intracellular compounds · CPC title

• G01N33/575

  for cancer · CPC title

• C07D231/54 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title