IP Library › Granted Patent US 10,414,775
Granted Patent B2
US 10,414,775 · App. 16/324,604 · Granted Sep 17, 2019

Compounds useful for altering the levels of bile acids for the treatment of diabetes and cardiometabolic disease

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Quick Facts
Patent No.
US 10,414,775
App. No.
16/324,604
Granted
Sep 17, 2019
Kind
B2
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.

Claims (48)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is N or CR 17 ;

B is N or NO;

D is N, NR 2 or CR 2 ;

E is N or CR 3 ;

T is N 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, O 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, 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 1 ;

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, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, COOC1-C 6 alkyl, COOC 1 -C 6 alkylC 3 -C 6 cycloalkyl 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 1 -C 6 alkoxyC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, —OC 1 -C 6 alkylC 3 -C 6 cycloalkyl, COOC 1 -C 6 alkyl, COC 1 -C 6 alkyl, COC 3 -C 6 cycloalkyl, COOC 1 -C 6 alkylC 3 -C 6 cycloalkyl, CONH(C 1 -C 6 alkyl), CONH(C 1 -C 6 alkyl C 3 -C 6 cycloalkyl), CONH(C 3 -C 6 cycloalkyl), SO 2 (C 1 -C 6 alkyl), pyridine, C 1 -C 6 alkoxypyridine, triazole, and oxazole, wherein the oxazole may be substituted with one or more C 1 -C 6 alkyl substituents;

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 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, COOC1-C 6 alkylC 3 -C 6 cycloalkyl 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, COOC1-C 6 alkylC 3 -C 6 cycloalkyl 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 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;

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; and

R 18 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, NO 2 , CONH 2 , haloC 1 -C 6 alkyl and COOC 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 which is:

or a pharmaceutically acceptable salt thereof.

16. A method of treating diabetes comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of claim 1 .

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

18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

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 Feb 11, 2019
From: CALDWELL, JOHN P.; CAPLEN, MARY ANN; CUMMING, JARED N.; DYKSTRA, KEVIN D.; HRUZA, ALAN; LANKIN, CLAIRE; LI, DERUN; LIU, HONG; MCCRACKEN, AMY; MCKITTRICK, BRIAN; RAO, ASHWIN; TAGAT, JAYARAM R.; TANG, HAIQUN; TAOKA, BRANDON M.; VERRAS, ANDREAS; WALSH, SHAWN P.; WU, WEN-LIAN; ZHANG, TIANYUAN
To: MERCK SHARP & DOHME
Reel/Frame 048301/0486 →