Hydrazone derivative in which terminal amine group is substituted with aryl group or heteroaryl group, and use thereof

Patent metadata

Field	Value
Publication number	US-12590071-B2
Application number	US-201817415382-A
Country	US
Kind code	B2
Filing date	Dec 26, 2018
Priority date	Dec 19, 2018
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

A compound represented by Formula 3 as described herein, or a pharmaceutically acceptable salt thereof, and a method of making a Formula 3 compound.
In Formula 3: R 1 is hydrogen; and
Cy is unsubstituted benzothiazol-6-yl, benzothiazol-5-yl, quinolin-3-yl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, or oxodihydrobenzoxazolyl; or substituted benzothiazol-6-yl, benzothiazol-5-yl, indazolyl, quinolin-3-yl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, oxodihydrobenzoxazolyl, or oxodihydrobenzoimidazolyl, each of which is substituted with: (i) methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoroethyl, difluoromethyl, trifluoromethoxy, dimethylcarbamoyl, phenoxy, isopropoxy, methylamino or dimethylamino; or (ii) phenyl, pyridinyl, furanyl, or thiophenyl unsubstituted or substituted with at least one of methyl, fluoro, and dimethylamino.

A compound of Formula 4 as described herein, or a pharmaceutically salt thereof.

First claim

The invention claimed is:

1 . A compound represented by Formula 3 or a pharmaceutically acceptable salt thereof:

in Formula 3 above,
R 1 is hydrogen;
Cy is unsubstituted benzothiazol-6-yl, unsubstituted benzothiazol-5-yl, unsubstituted quinolin-3-yl, indolyl, unsubstituted pyrrolopyridinyl, unsubstituted oxodihydrobenzothiazolyl, or unsubstituted oxodihydrobenzoxazolyl; or
substituted benzothiazol-6-yl, substituted benzothiazol-5-yl, substituted indazolyl, substituted quinolin-3-yl, substituted indolyl, substituted pyrrolopyridinyl, substituted oxodihydrobenzothiazolyl, substituted oxodihydrobenzoxazolyl, or substituted oxodihydrobenzoimidazolyl; each of which is substituted with
(i) methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoroethyl, difluoromethyl, trifluoromethoxy, dimethylcarbamoyl, phenoxy, isopropoxy, methylamino or dimethylamino, or
(ii) phenyl, pyridinyl, furanyl, or thiophenyl unsubstituted or substituted with at least one selected from the group consisting of methyl, fluoro, and dimethylamino.

2 . A compound is represented by Formula 4, or a pharmaceutically salt thereof:

in Formula 4 above,
X 1 to X 3 are different from each other, are each selected from C, N, O, and S, and are each connected to a carboxamido group through a C site;
R 1 is hydrogen or C 1-6 alkyl; and
R 2 ″ is C 1-6 alkyl, or aryl or heteroaryl unsubstituted or substituted with at least one selected from the group consisting of C 1-6 alkoxy, hydroxy, cyano, and C 1-6 alkyl.

3 . The compound of claim 2 or pharmaceutically acceptable salt thereof,
wherein X 1 to X 3 are sequentially N, C, and S or O, N, and C, and are connected to a carboxamido group through a C site;
R 1 is hydrogen; and
R 2 ″ is methyl, or phenyl, pyridinyl, pyrazinyl, or pyrimidinyl unsubstituted or substituted with at least one selected from the group consisting of methoxy, hydroxy, cyano, and methyl.

4 . The compound of claim 1 or pharmaceutically acceptable salt thereof,
benzo[d]thiazol-6-ylcarbonohydrazonoyl dicyanide,
benzo[d]thiazol-5-ylcarbonohydrazonoyl dicyanide,
(1-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide,
quinolin-3-ylcarbonohydrazonoyl dicyanide,
(2-methyl-2H-indazol-6-yl)carbonohydrazonoyl dicyanide,
(1-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide,
(1-methyl-1H-indol-5-yl)carbonohydrazonoyl dicyanide,
(1H-indol-5-yl)carbonohydrazonoyl dicyanide,
(1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(3-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide,
(3-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide,
(1H-indol-4-yl)carbonohydrazonoyl dicyanide,
(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,
(2-phenylbenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(4-fluorophenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(pyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(furan-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(thiophen-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-(pyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide,
(2-(5-methylpyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide,
(2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-methoxybenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,
(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide,
(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide,
(3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,
(3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,
(2-isopropoxybenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,
(3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyl dicyanide,
(3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyl dicyanide,
(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide,
(1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide,
(1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydraz onoyl dicyanide,
(2-(methylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide, or
(2-(dimethylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide.

5 . A method of preparing the compound of claim 1 , comprising the step of reacting sodium nitrite, a 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclyl derivative containing an amine group, and malononitrile in the presence of acid to form an imine bond.

6 . The method of claim 5 ,
wherein, when the 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclyl contains a nitrogen bondable thereto other than an amine group, it comprises a protecting group at the nitrogen site, and the method further comprises a step of removing the protection group after the step of forming the imine bond.

7 . The method of claim 5 ,
wherein the 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclyl is prepared by reducing a nitrophenyl derivative containing a nitro group instead of an amine group in the same skeleton.

8 . A method of preparing the compound of claim 2 , comprising the steps of:
reacting carboxylic acid of R 2 ″ or an anhydride thereof with

 wherein Y is an unprotected or protected amine or nitro group to form an amide bond; and
reacting sodium nitrite, a heterocycle derivative comprising R 2 ″ connected to a carboxamido group obtained from the previous step, and malononitrile in the presence of acid to form an imine bond.

9 . The method of claim 8 ,
wherein, when Y is a protected amine group or nitro group, the method further comprises a step of converting the protected amine group or nitro group into an amine group before the step of forming the imine group.

10 . A composition for inhibiting the aggregation of tau protein comprising the compound according to claim 1 as an active ingredient.

11 . A composition for inhibiting the hyperphosphorylation of tau protein comprising the compound according to claim 1 as an active ingredient.

12 . The

Assignees

• Korea Inst Sci & Tech

Inventors

• Pae Ae Nim
• Kim Yun Kyung
• Lim Sang Min
• Lim Sungsu
• Seong Jihye
• Lee Jae Wook
• Song Ji Yeon
• Shin Seulgi
• Jeong Hyean Jeong
• Son Woo Seung
• Lee Haeun
• Lim Da Mi
• Kim Seok Kyu
• Ahn Jee Yun
• Kim Chae Won
• Londhe Ashwini Machhindra
• Gotina Lizaveta
• Kim Hyojin
• Lee Hye Yeon
• Kim Nam Gyung
• Cha Eunji
• Kim Kunhee
• Lim Ji Woong

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/12

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

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D277/82

  Nitrogen atoms · CPC title