Compound useful for altering the levels of bile acids for the treatment of diabetes and cardiometabolc disease

Patent metadata

Field	Value
Publication number	US-10414774-B2
Application number	US-201716324596-A
Country	US
Kind code	B2
Filing date	Aug 10, 2017
Priority date	Aug 15, 2016
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

Abstract

Described herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula I act as Cyp8b1 inhibitors and can be useful in preventing, treating or acting as a remedial agent for diabetes and cardiovascular disease.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the dashed lines in Formula I indicate the possibility of aromaticity or no aromaticity in the ring depending on the substitution of the ring and wherein:
A is N or CR 17 ;
B is N or NO;
D is N, NR 12 or CR 2 ;
E is N or CR 3 ;
T is N, NR 12 or CR 12 , wherein T is not CR 12 when W is C and Z is CR 14 and U is CR 13 ;
U is N, NH or CR 13 , wherein U is not CR 13 when W is C and T is CR 12 and Z is CR 14 ;
Z is N, NH, S, O or CR 14 , wherein Z is not CR 14 when W is C and T is CR 12 and U is CR 13 ;
W is N or C, wherein W is not C when T is CR 12 and U is CR 13 and Z is CR 14 ;
X is N or CR 11 ;
Y is N or CH;
R 1 is selected from the group consisting of hydrogen, halogen, CN, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 alkylC 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, COOC 1 -C 6 alkyl, COOC 1 -C 6 alkylC 3 -C 6 cycloalkyl, phenyl and oxazole;
R 2 is selected from the group consisting of hydrogen, halogen, CN, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 alkylC 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 6 alkoxy, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, COOC 1 -C 6 alkyl, COOC 1 -C 6 alkylC 3 -C 6 cycloalkyl, phenyl and oxazole;
R 3 is selected from the group consisting of hydrogen, halogen, CN, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 6 alkoxy, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, COOC 1 -C 6 alkyl, COOC 1 -C 6 alkylC 3 -C 6 cycloalkyl, phenyl and oxazole;
R 4 is selected from the group consisting of hydrogen, halogen, CN, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkoxy, C 1 -C 6 alkylC 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 6 alkoxy, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, COOC 1 -C 6 alkyl, COOC 1 -C 6 alkylC 3 -C 6 cycloalkyl, phenyl and oxazole;
R 5 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkyl or when taken with R 10 forms a C 3 -C 6 cycloalkyl;
R 6 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkyl or when taken with R 7 forms a C 3 -C 6 cycloalkyl, or when taken with R 11 forms a C 3 -C 6 cycloalkyl;
R 7 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkyl or when taken with R 6 forms a C 3 -C 6 cycloalkyl;
R 8 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkyl;
R 9 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkyl;
R 10 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkyl or when taken with R 5 forms a C 3 -C 6 cycloalkyl;
R 11 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl or when taken with R 6 forms a C 3 -C 6 cycloalkyl;
R 12 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, COOC 1 -C 6 alkylC 3 -C 6 cycloalkyl, and haloC 1 -C 6 alkyl;
R 13 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and haloC 1 -C 6 alkyl;
R 14 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and haloC 1 -C 6 alkyl;
R 15 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl;
R 16 is selected from the group consisting of hydrogen, halogen, OH, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl; and
R 17 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and haloC 1 -C 6 alkyl.

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

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is N.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 11 , wherein R 11 is hydrogen.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is CR 14 , wherein R 14 is trifluoromethyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is N.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is N.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U is N.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is CR 17 , wherein R 17 is hydrogen.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is CR 3 , wherein R 3 is hydrogen.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is CR 2 .

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of halogen and haloC 1 -C 6 alkyl.

13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2 is haloC 1 -C 6 alkyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl and R 5 , R 7 , R 8 , R 9 , R 10 , R 15 and R 16 are hydrogen.

15. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
7-chloro-8-fluoro-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
8-fluoro-7-methoxy-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
6-chloro-8-(difluoromethyl)-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
7-bromo-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
7-hydroxy-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
7-fluoro-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
6,7,8-trifluoro-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
7,8-difluoro-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
6-methoxy-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}piperidin-1-yl]quinoline-3-carbonitrile;
6,8-difluoro-2-methyl-4-[(3S,4S)-3-methyl-4-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]p

Assignees

• Merck Sharp & Dohme
• Cumming Jared N
• Dykstra Kevin D
• Hruza Alan
• Li Derun
• Liu Hong
• Tang Haiqun
• Taoka Brandon M
• Verras Andreas
• Walsh Shawn P
• Wu Wen Lian

Inventors

• Cumming Jared N
• Dykstra Kevin D
• Hruza Alan
• Li Derun
• Liu Hong
• Tang Haiqun
• Taoka Brandon M
• Verras Andreas
• Walsh Shawn P
• Wu Wen-Lian

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title