Small molecule inhibitors of PI3-kinase signaling

Patent metadata

Field	Value
Publication number	US-9701646-B2
Application number	US-201414777630-A
Country	US
Kind code	B2
Filing date	Mar 18, 2014
Priority date	Mar 18, 2013
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

Provided are certain 1,2,3-triazole and 1,2,3-triazole dimer analogs of DM-PIT-1 which are second-generation selective non-phosphoinositide small molecule inhibitors of phosphatidylinositol-3,4,5-trisphosphate (PIP3), including 1,2,3-triazoles represented by formula (I)

where:
Ar represents aryl or heteroaryl; X represents O or S; each of R a , R b , R c , and R d independently represents hydrogen, halogen, C 1 -C 10 alkyl, —OH, —CF 3 , aryl, amino, or nitro; and Ar is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1 -C 10 alkyl, —OH, —CF 3 , amino, and nitro. Also provided are pharmaceutical compositions comprising compounds of the invention and a pharmaceutical carrier. Also provided are methods of inhibiting PIP3-mediated signaling in a cell and treating cancer using compounds of the invention.

First claim

We claim:

1. A compound represented by formula (II), or a pharmaceutically acceptable salt thereof

wherein:
R 1 represents methyl or —CF 3 ;
R 2 represents hydrogen, halogen, —OH, methyl, or —CF 3 ; and
X represents O or S.

2. The compound of claim 1 , wherein X is O.

3. The compound of claim 1 , wherein X is S.

4. The compound of claim 1 , wherein R 1 is —CF 3 .

5. The compound of claim 1 , wherein each of R 1 and R 2 is —CF 3 .

6. The compound represented by formula (III), or a pharmaceutically acceptable salt thereof

7. A compound represented by formula (V) or formula (VI), or a pharmaceutically acceptable salt thereof

8. A pharmaceutical composition, comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition, comprising the compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition, comprising the compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is O; each of R 1 and R 2 is methyl, or each of R 1 and R 2 is —CF 3 ; and the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.

12. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.

13. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.

14. A method of treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by formula (IV), or a pharmaceutically acceptable salt thereof

wherein the subject has a cancer selected from the group consisting of ovarian cancer, glioblastoma, breast cancer, and prostate cancer.

Assignees

• Univ Tufts
• Council Scient Ind Res

Inventors

• Degterev Alexei
• Ramana Chepuri V
• Lee Jinbo
• Kommagalla Yadagiri

Classifications

• C07D249/06 Primary

  with aryl radicals directly attached to ring atoms · CPC title