Oxadiazole inhibitors of hipk2 for treating kidney fibrosis

Patent metadata

Field	Value
Publication number	US-2019352292-A1
Application number	US-201816473878-A
Country	US
Kind code	A1
Filing date	Jan 5, 2018
Priority date	Jan 6, 2017
Publication date	Nov 21, 2019
Grant date	—

Abstract

in which Z is an oxadiazole. The compounds disclosed are useful in treatment of fibrotic disease, particularly renal fibrosis, and similar diseases associated with the dysregulation of the HIPK2/Smad3 signaling pathway.

First claim

1 . A compound of formula I

wherein
Z is an oxadiazole;
X is chosen from N and CH;
R 1 and R 2 are chosen independently from —(C 1 -C 8 )hydrocarbyl, OH, —O(C 1 -C 8 )hydrocarbyl, halogen, nitro, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )acylamino, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylthio, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )haloalkylthio, —COOH, —C(═O)O(C 1 -C 3 )alkyl, —B(OR 3 ) 2 , and —BF 3 K; and
R 3 is H or (C 1 -C 8 )hydrocarbyl; or (OR 3 ) 2 , taken together with the boron to which they are attached form a dioxaborolane or dioxaborinane ring optionally substituted with from one to four (C 1 -C 8 )hydrocarbyl.

2 . A compound according to claim 1 wherein Z is

3 . A compound according to claim 1 wherein Z is

4 . A compound according to claim 2 of formula

5 . A compound according to claim 1 wherein R 1 is chosen from halogen, —COOH, —C(═O)O(C 1 -C 3 )alkyl, —B(OR 3 ) 2 , and —BF 3 K.

6 . A compound according to claim 1 wherein R 2 is chosen from halogen, (C 1 -C 3 )haloalkyl, —O(C 1 -C 3 )alkyl, —B(OR 3 ) 2 , and —BF 3 K.

7 . A compound according to claim 1 wherein R 1 is chosen from bromine, COOEt, and —BF 3 K.

8 . A compound according to claim 1 wherein R 2 is chosen from bromine, CF 3 and —OCH 3 .

9 . A compound according to claim 1 wherein X is nitrogen.

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

11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 9 .

12 . A method for inhibiting the interaction of homeodomain interacting protein kinase 2 (HIPK2) with Smad3, said method comprising bringing HIPK2 into contact with a compound of claim 1 .

13 . A method for inhibiting Smad3 activation, said method comprising bringing Smad3 into contact with a compound of claim 1 .

14 . An in vitro method according to claim 12 .

15 . An in vivo method according to claim 12 .

16 . An in vitro method according to claim 13 .

17 . An in vivo method according to claim 13 .

18 . A method for treating a fibrotic disease comprising administering a compound of claim 1 to a subject suffering from a fibrotic disease.

19 . A method according to claim 18 wherein said disease is renal fibrosis.

Assignees

• Icahn School Med Mount Sinai
• Univ Kansas

Inventors

• He John Cijiang
• Liu Ruijie
• Das Bhaskar
• Xiao Wenzhen
• Li Zhengzhe
• Lee Kyung

Classifications

• A61P13/12

  of the kidneys · CPC title

• C07D271/06

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• C07D271/107

  with two aryl or substituted aryl radicals attached in positions 2 and 5 · CPC title

• C07F5/025

  Boronic and borinic acid compounds · CPC title

• C07F5/04

  Esters of boric acids · CPC title