Compound having ERK kinase inhibitory activity and use thereof

Patent metadata

Field	Value
Publication number	US-11465984-B2
Application number	US-201816652148-A
Country	US
Kind code	B2
Filing date	Sep 29, 2018
Priority date	Sep 30, 2017
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The invention relates to a compound of formula (I):wherein variables are as defined in the specification. The compound is an inhibitor of an ERK kinase, e.g. ERK1 and/or ERK2 kinase. The invention also relates to the use of the compound and a method for preparing the compound, and a pharmaceutical composition containing the compound.

First claim

The invention claimed is:

1. A compound of Formula (Ie), or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

wherein,
X 1 is selected from the group consisting of CH, CD, and N;
R 1 is selected from the group consisting of H and D;
R 2 is selected from the group consisting of C 1-6 alkyl optionally substituted with one or more hydroxyl, C 3-8 cycloalkyl optionally substituted with one or more hydroxyl, 3-8 membered heterocyclyl, and 5-7 membered heteroaryl optionally substituted with one or more substituents selected from —CD 3 , C 1-6 alkyl and hydroxylC 1-6 alkyl;
R 3 is selected from the group consisting of halo and C 1-6 alkyl;
R 4 is —CO(CR 10 R 11 ) m R 12 ; wherein m is 0, 1, 2 or 3, and wherein
R 10 and R 11 are each independently selected from the group consisting of H, D, and C 1-4 alkyl optionally substituted with hydroxyl; and
R 12 is each independently selected from optionally substituted phenyl and optionally substituted pyridinyl, wherein the optional substituent is one or more substituents independently selected from the group consisting of D, halo, C 1-4 alkyl, cyano, and C 3-8 heterocyclyl-(CH 2 ) 0-4 —; and
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of —H, and C 1-6 alkyl optionally substituted with hydroxyl or —OC 1 -C 6 alkyl,

provided that the compound is not
2-(2-chloropyridin-3-yl)-1-(7-fluoro-2-(hydroxylmethyl)-5-(2-(isopropylamino)pyrimidin-4-yl)indolin-1-yl)ethan-1-one.

2. The compound according to claim 1 , wherein
R 2 is selected from the group consisting of C 1-4 alkyl optionally substituted with one or more hydroxyl;

 which are optionally substituted with one or more hydroxyl;

 which are optionally substituted with one or more substituents independently selected from the group consisting of C 1-4 alkyl, —CD 3 and hydroxylC 1-4 alkyl.

3. The compound according to claim 1 , wherein R 3 is selected from the group consisting of fluoro, chloro, bromo, iodo, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , and —CH 2 CH 2 CH 3 .

4. The compound according to claim 1 , wherein
R 12 is selected from the group consisting of

wherein Rc is selected from the group consisting of halo, C 1-4 alkyl,

wherein R d is selected from the group consisting of H, C 1-4 alkyl, and

wherein R e is selected from the group consisting of halo, and p is 1 or 2; and

wherein R f is selected from the group consisting of

5. The compound according to claim 1 , wherein R 4 is selected from the group consisting of —CO(CR 10 R 11 ) m R 12 , wherein m is 0, 1, 2 or 3, and wherein
R 10 and R 11 are each independently H; and
R 12 is selected from the group consisting of

6. The compound according to claim 1 , wherein R 4 is selected from the group consisting of —CO(CR 10 R 11 ) m R 12 , wherein m is 0, 1, 2 or 3, and wherein R 10 and R 11 are each independently H; R 12 is selected from the group consisting of 2-cyanophenyl, 5-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2,5-difluorophenyl, 3-chloropyridin-2-yl, 6-chloropyridin-2-yl, 3-chloropyridin-4-yl, or 4-chloropyridin-3-yl.

7. The compound according to claim 1 , wherein
R 5 and R 6 are each independently selected from the group consisting of H and C 1-6 alkyl; and R 7 and R 8 are each independently selected from the group consisting of H and C 1-6 alkyl optionally substituted with hydroxyl or —OC 1 -C 6 alkyl.

8. A compound selected from the group consisting of Examples P1-P20, P23-P25, P28-51, P53-P64, or a pharmaceutically acceptable salt thereof,

P1 

P2 

P3 

P4 

P5 

P6 

P7 

P8 

P9 

P10

Assignees

• Shanghai Haihe Pharmaceutical Co Ltd
• Shanghai Inst Materia Medica Cas

Inventors

• Li Lei
• Geng Meiyu
• Huang Ying
• Ding Jian
• Zhang Qiong
• Huang Min
• Tang Shuai
• Shen Ning
• Chen Yi

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title