Benzopyrazole compound used as RHO kinase inhibitor

Patent metadata

Field	Value
Publication number	US-11345678-B2
Application number	US-201917047840-A
Country	US
Kind code	B2
Filing date	Apr 18, 2019
Priority date	Apr 18, 2018
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

The invention relates to a benzopyrazole compound used as RHO kinase inhibitor, a pharmaceutical composition and uses thereof for preparing an RHO kinase inhibiting drug, and more specifically to said compound of formula (I-1), a pharmaceutically acceptable salt and isomer thereof.

First claim

What is claimed is:

1. A compound represented by formula (I-1), a pharmaceutically acceptable salt thereof or an isomer thereof,

T 1 is N or CR 1 ; T 2 is N or CR 2 ; T 3 is N or CR 3 ;
R 1 , R 2 and R 3 are each independently H, F, Cl, Br, CN, —OR a , —C(═O)NR b R c or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , —CN, —NH 2 , —NO 2 or 5-membered heterocycloalkyl;
or, R 2 and R 3 with the carbon atoms to which they are attached are linked together so that the moiety

R 4 , R 5 , R 6 and R 7 are each independently H, F, Cl, Br, CN, —OR a , —C(═O)NR b R c , —NR d R e , C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , —CN, —NO 2 or C 1-4 alkyl;
R 8 and R 9 are each independently H, F, Cl, C 1-6 alkyl, or R 8 and R 9 together with the carbon atom to which they are attached form a 5- to 6-membered heterocycloalkyl, wherein the C 1-6 alkyl and 5- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, CN, —OR a or —NR d R e ;
each of R 10 is independently F, Cl, Br, CN, —OR a , C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , —CN, —NH 2 , —NO 2 or C 1-4 alkyl;
R a , R b and R e are each independently H, C 1-6 alkyl or C 3-4 cycloalkyl, wherein the C 1-6 alkyl and C 3-4 cycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, —OH, —OCH 3 , —CN, —NH 2 or —NO 2 ;
R d and R e are each independently H, C 1-6 alkyl, —S(═O) 2 C 1-3 alkyl, or R d and R e together with the N atom to which they are attached form a 4- to 8-membered heterocycloalkyl, wherein the C 1-6 alkyl and 4- to 8-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, —OH, —OCH 3 , —CN, —NH 2 , C 1-6 alkylamino or —NO 2 ;
n is 0, 1, 2, 3 or 4;
the 5-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl and 4- to 8-membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from N, —O—, —S— and —NH—.

2. The compound, the pharmaceutically acceptable salt thereof or the isomer thereof as defined in claim 1 , wherein R a , R b and R e are each independently H, methyl, ethyl, n-propyl, isopropyl or cyclopropyl, wherein the methyl, ethyl, n-propyl, isopropyl and cyclopropyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , CN, —NH 2 or —NO 2 ;
and/or, R 4 , R 5 , R 6 and R 7 are each independently H, F, Cl, Br, CN, —OH, —OCH 3 , —OCH 2 CH 3 , —C(═O)NH 2 , —NH 2 , methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , CN, —NH 2 , —NO 2 , methyl, ethyl or propyl;
and/or, R 1 , R 2 and R 3 are each independently H, F, Cl, Br, CN, —OH, —OCH 3 , —OCHF 2 , —OCF 3 , —C(═O)NH 2 , methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , CN, —NH 2 , —NO 2 or pyrrolidyl;
and/or, the moiety

and/or, R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl,

or R d and R e together with the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl, wherein the methyl, ethyl, n-propyl, isopropyl, and 5- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , CN, —NH 2 , C 1-3 alkylamino or —NO 2 ;
and/or, each of R 10 is independently F, Cl, Br, CN, —OH, —OCH 3 , methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , CN, —NH 2 , —NO 2 , methyl, ethyl or propyl;
and/or, the moiety

3. The compound, the pharmaceutically acceptable salt thereof or the isomer thereof as defined in claim 2 , wherein, R a , R b and R c are each independently H, methyl, ethyl, n-propyl, isopropyl,

and/or, R 4 , R 5 , R 6 and R 7 are each independently H, F, Cl, Br, CN, —OH, —OCH 3 , —OCH 2 CH 3 , —C(═O)NH 2 , —NH 2 , methyl, ethyl, n-propyl, isopropyl,

cyclopropyl, cyclopentyl, cyclohexyl,

and/or, R 1 , R 2 and R 3 are each independently H, F, Cl, Br, CN, —OH, —OCH 3 , —OCHF 2 , —OCF 3 , —C(═O)NH 2 , methyl, ethyl, n-propyl, isopropyl,

and/or, the moiety

and/or, R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl,

or R d and R e together with the N atom to which they are attached form a pyrrolidyl, piperazinyl or piperidyl, wherein the pyrrolidyl, piperazinyl and piperidyl are optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, —OH, —OCH 3 , CN, —NH 2 , C 1-3 alkylamino or —NO 2 ;
and/or, each of R 10 is independently F, Cl, Br, CN, —OH, —OCH 3 , —OCH 2 CH 3 ,

methyl, ethyl, n-propyl, isopropyl,

cyclopropyl, cyclopentyl, cyclohexyl,

and/or, the moiety

4. The compound, the pharmaceutically acceptable salt thereof or the isomer thereof as defined in claim 1 , wherein R 8 and R 9 are each independently H, F, Cl, methyl, ethyl, n-propyl, isopropyl,

or R 8 and R 9 toget

Assignees

• Medshine Discovery Inc

Inventors

• Wu Lingyun
• Yin Jun
• Wang Cailin
• Xiao Zheming
• Li Jian
• Chen Shuhui

Classifications

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D403/04

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D401/04 Primary

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

• C07D403/12 Primary

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