IP Library › Granted Patent US 10,065,945
Granted Patent B2
US 10,065,945 · App. 15/104,537 · Granted Sep 4, 2018

Isoquinoline derivatives as MGAT2 inhibitors

Inventors: Richard Berger (Harleysville, PA); Timothy A. Blizzard (Princeton, NJ); Brian T. Campbell (Burlington, NJ); Helen Y. Chen (Marlboro, NJ); John S. Debenham (Scotch Plains, NJ); Sunita V. Dewnani (Secaucus, NJ); Byron Dubois (New York, NY); Candido Gude (Staten Island, NY); Zack Zhiqiang Guo (Morganville, NJ); Bart Harper (New York, NY); Zhiyong Hu (Livingston, NJ); Songnian Lin (Holmdel, NJ); Ping Liu (Westfield, NJ); Ming Wang (Belle Mead, NJ); Feroze Ujjainwalla (Hoboken, NJ); Jiayi Xu (Marlboro, NJ); Libo Xu (Bridgewater, NJ); Rui Zhang (Plainsboro, NJ)
Assignee: Merck Sharp & Dohme Corp.
C07D413/14C07D401/12C07D413/12C07D417/14C07D471/04
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Quick Facts
Patent No.
US 10,065,945
App. No.
15/104,537
Granted
Sep 4, 2018
Kind
B2
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.

Claims (28)

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:

13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method for the treatment of a condition selected from the group consisting of obesity and diabetes comprising administering to an individual a pharmaceutical composition comprising 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, or when combined with R 5 is an oxo group;

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, or when combined with R 4 is an oxo group; 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.

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 15, 2016
From: BERGER, RICHARD; BLIZZARD, TIMOTHY A.; CAMPBELL, BRIAN T.; CHEN, HELEN Y.; DEBENHAM, JOHN S.; DEWNANI, SUNITA V.; DUBOIS, BYRON; GUDE, CANDIDO; GUO, ZHIQIANG; HARPER, BART; HU, ZHIYONG; LIN, SONGNIAN; LIU, PING; WANG, MING; UJJAINWALLA, FEROZE; XU, JIAYI; XU, LIBO; ZHANG, RUI
To: MERCK SHARP & DOHME CORP.
Reel/Frame 039023/0001 →
Continuity (2)
Provisional Application 61931005 · Jan 24, 2014
Related Publication 20180009796A1 · Jan 11, 2018