Isoquinoline derivatives as MGAT2 inhibitors

Patent metadata

Field	Value
Publication number	US-10065945-B2
Application number	US-201515104537-A
Country	US
Kind code	B2
Filing date	Jan 20, 2015
Priority date	Jan 24, 2014
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

The compounds of Formula I act as MGAT2 inhibitors and can be useful in preventing, treating or acting as a remedial agent for hyperlipidemia, diabetes mellitus and obesity.

First claim

What is claimed is:

1. A compound of formula (I):

or pharmaceutically acceptable salts thereof, wherein X is —N— or —CH—;
R 1 is a nitrogen containing heterocycle, wherein the nitrogen containing heterocycle is substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkene, halogen, halogen-substitutedC 1 -C 6 alkyl, COOC 1 -C 6 alkyl, CONH 2 , CONHC 1 -C 6 alkyl, CON(C 1 -C 6 alkyl) 2 , CONHhalogen-substitutedC 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkoxy, NHC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedC 3 -C 6 cycloalkyl, —OH, C 1 -C 6 alkylOH, pyrrole, phenyl, halogen-substituted phenyl, pyrazole, N-methyl pyrazole, pyrroline, CO-pyrrolidine, azetidine and CO-azetidine;
R 2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkyl, halogen-substitutedC 1 -C 6 alkoxy, —OH and C 1 -C 6 alkylOH;
R 3 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkyl, halogen-substitutedC 1 -C 6 alkoxy, —OH and C 1 -C 6 alkylOH;
R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkyl, halogen-substitutedC 1 -C 6 alkoxy, —OH and C 1 -C 6 alkylOH;
R 5 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkyl, halogen-substitutedC 1 -C 6 alkoxy, —OH and —C 1 -C 6 alkylOH; and
R 6 is selected from the group consisting of phenyl or a nitrogen containing heterocycle, wherein the phenyl or nitrogen containing heterocycle is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkene, halogen, halogen-substitutedC 1 -C 6 alkyl, —COOC 1 -C 6 alkyl, CONH 2 , CONHC 1 -C 6 alkyl, CON(C 1 -C 6 alkyl) 2 , CONH-halogen-substitutedC 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedC 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-halogen-substitutedC 3 -C 6 cycloalkyl, OH, —C 1 -C 6 alkylOH, —OC 1 -C 6 alkyl-O—C 1 -C 6 alkyl, SC 1 -C 6 alkyl, —S-halogen-substitutedC 1 -C 6 alkyl, pyrrole, phenyl, halogen-substituted phenyl, pyrazole, N-methyl pyrazole, pyrroline, CO-pyrrolidine, azetidine and CO-azetidine.

2. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein X is —N—.

3. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein X is —CH—.

4. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of isoxazole, pyrazine, oxadiazole and pyridazine, wherein the isoxazole, pyrazine, oxadiazole or pyridazine is substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkene, halogen, halogen-substitutedC 1 -C 6 alkyl, COOC 1 -C 6 alkyl, CONH 2 , CONHC 1 -C 6 alkyl, CON(C 1 -C 6 alkyl) 2 , CONHhalogen-substitutedC 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkoxy, NHC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedC 3 -C 6 cycloalkyl, —OH, C 1 -C 6 alkylOH, pyrrole, phenyl, halogen-substituted phenyl, pyrazole, N-methyl pyrazole, pyrroline, CO-pyrrolidine, azetidine and CO-azetidine.

5. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is isoxazole, wherein the isoxazole is substituted with one or two substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkene, halogen, halogen-substitutedC 1 -C 6 alkyl, COOC 1 -C 6 alkyl, CONH 2 , CONHC 1 -C 6 alkyl, CON(C 1 -C 6 alkyl) 2 , CONHhalogen-substitutedC 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkoxy, NHC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedC 3 -C 6 cycloalkyl, —OH, C 1 -C 6 alkylOH, pyrrole, phenyl, halogen-substituted phenyl, pyrazole, N-methyl pyrazole, pyrroline, CO-pyrrolidine, azetidine and CO-azetidine.

6. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or C 1 -C 6 alkyl.

7. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

8. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is phenyl, wherein the phenyl is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkene, halogen, halogen-substitutedC 1 -C 6 alkyl, —COOC 1 -C 6 alkyl, CONH 2 , CONHC 1 -C 6 alkyl, CON(C 1 -C 6 alkyl) 2 , CONH-halogen-substitutedC 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedC 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-halogen-substitutedC 3 -C 6 cycloalkyl, OH, —C 1 -C 6 alkylOH, —OC 1 -C 6 alkyl-O—C 1 -C 6 alkyl, SC 1 -C 6 alkyl, —S-halogen-substitutedC 1 -C 6 alkyl, pyrrole, phenyl, halogen-substituted phenyl, pyrazole, N-methyl pyrazole, pyrroline, CO-pyrrolidine, azetidine and CO-azetidine.

9. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of pyrimidine, pyridine, thiazole and pyrazine, wherein the pyrimidine, pyridine, thiazole or pyrazine is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkene, halogen, halogen-substitutedC 1 -C 6 alkyl, —COOC 1 -C 6 alkyl, CONH 2 , CONHC 1 -C 6 alkyl, CON(C 1 -C 6 alkyl) 2 , CONH-halogen-substitutedC 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedC 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-halogen-substitutedC 3 -C 6 cycloalkyl, OH, —C 1 -C 6 alkylOH, —OC 1 -C 6 alkyl-O—C 1 -C 6 alkyl, SC 1 -C 6 alkyl, —S-halogen-substitutedC 1 -C 6 alkyl, pyrrole, phenyl, halogen-substituted phenyl, pyrazole, N-methyl pyrazole, pyrroline, CO-pyrrolidine, azetidine and CO-azetidine.

10. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is unsubstituted.

11. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkene, halogen, halogen-substitutedC 1 -C 6 alkyl, —COOC 1 -C 6 alkyl, —CONH 2 , —CONHC 1 -C 6 alkyl, —CON(C 1 -C 6 alkyl) 2 , —CONHhalogen-substitutedC 1 -C 6 alkyl, —C 1 -C 6 alkoxy, halogen-substitutedC 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substitutedC 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl-halogen-substitutedC 3 -C 6 cycloalkyl, —OH, —C 1 -C 6 alkylOH, —O—C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, SC 1 -C 6 alkyl, S-halogen-substitutedC 1 -C 6 alkyl, pyrrole, phenyl, halogen-substituted phenyl, pyrazole, N-methyl pyrazole, pyrroline, CO-pyrrolidine, azetidine and CO-azetidine.

12. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:

Assignees

• Merck Sharp & Dohme

Inventors

• Berger Richard
• Blizzard Timothy A
• Campbell Brian T
• Chen Helen Y
• Debenham John S
• Dewnani Sunita V
• Dubois Byron
• Gude Candido
• Guo Zack Zhiqiang
• Harper Bart
• Hu Zhiyong
• Lin Songnian
• Liu Ping
• Wang Ming
• Ujjainwalla Feroze
• Xu Jiayi
• Xu Libo
• Zhang Rui

Classifications

• C07D401/12

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

• C07D413/12

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

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title