Substituted bicyclic compounds as farnesoid X receptor modulators

Patent metadata

Field	Value
Publication number	US-11254663-B2
Application number	US-202016789551-A
Country	US
Kind code	B2
Filing date	Feb 13, 2020
Priority date	Feb 15, 2019
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

Abstract

Disclosed are compounds of Formula (I):or a stereoisomer, a tautomer, or a salt or solvate thereof, wherein all the variables are as defined herein. These compounds modulate the activity of farnesoid X receptor (FXR), for example, as agonists. Also disclosed are pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, or a salt or solvate thereof, wherein:
X 1 is CH;
X 2 is CH or N;
X 3 is CH;
X 4 is CH;
Z 1 and Z 2 are each CH 2 ;
a is 1;
b is 1;
d is 1;
Q is phenyl substituted with R 1 ;
R 1 is C 1-4 alkyl, C 1-2 fluoroalkyl, —CH 2 Cl, C 1-4 hydroxyalkyl, —C(CH 3 ) 2 CN, or —CH(OH)CHF 2 ;
R 2 is:
(i) C 1-4 alkyl, C 1-5 alkoxy, or —NH(C 1-6 alkyl), wherein each of said alkyl and alkoxy is substituted with zero to 4 R 2a ; or
(ii) C 3-6 cycloalkyl substituted with zero to 3 R 2b ;

each R 2a is independently F, cyano, hydroxyl, C 1-2 alkoxy, or —NH 2 ;
each R 2b is independently F, cyano, hydroxyl, C 1-3 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-2 alkoxy, C 1-2 fluoroalkoxy, or —NH 2 ;
R 3a is hydrogen;
R 3b is hydrogen;
A is oxadiazolyl substituted with R 4a ;
R 4a is C 1-4 alkyl substituted with zero to 4 R 4d ; and
each R 4d is independently F, Cl, hydroxyl, —NH 2 , cyano, C 1-3 alkoxy, or C 1-3 fluoroalkoxy.

2. The compound according to claim 1 or a stereoisomer, or a salt or solvate thereof, having the structure:

3. The compound according to claim 1 or a stereoisomer, or a salt or solvate thereof, having the structure:

4. A compound having the structure:

5. A pharmaceutically acceptable salt of a compound having the structure:

6. A compound having the structure:

7. A pharmaceutically acceptable salt of a compound having the structure:

8. A compound having the structure:

9. A pharmaceutically acceptable salt of a compound having the structure:

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 , or a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and said compound according to claim 4 .

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and said pharmaceutically acceptable salt of the compound according to claim 5 .

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and said compound according to claim 6 .

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and said pharmaceutically acceptable salt of the compound according to claim 7 .

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and said compound according to claim 8 .

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and said pharmaceutically acceptable salt of the compound according to claim 9 .

17. A method of treating a disease or disorder, comprising administering to a mammalian patent a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said disease or disorder is pathological fibrosis, metabolic disorders, or cholestatic disorders.

18. The method according to claim 17 , wherein the pathological fibrosis is liver fibrosis, renal fibrosis, biliary fibrosis, or pancreatic fibrosis.

19. The method according to claim 17 , wherein said disease or disorder is nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

20. The method according to claim 17 , wherein said disease or disorder is idiopathic pulmonary fibrosis (IPF).

21. A method of treating a disease or disorder, comprising administering to a mammalian patent the compound according to claim 4 , wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

22. A method of treating a disease or disorder, comprising administering to a mammalian patent the pharmaceutically acceptable salt of the compound according to claim 5 , wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

23. A method of treating a disease or disorder, comprising administering to a mammalian patent the compound according to claim 6 , wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

24. A method of treating a disease or disorder, comprising administering to a mammalian patent the pharmaceutically acceptable salt of the compound according to claim 7 , wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

25. A method of treating a disease or disorder, comprising administering to a mammalian patent the compound according to claim 8 , wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

26. A method of treating a disease or disorder, comprising administering to a mammalian patent the pharmaceutically acceptable salt of the compound according to claim 9 , wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).

Assignees

• Bristol Myers Squibb Co

Inventors

• Wacker Dean A
• Nara Susheel Jethanand
• Cheruku Srinivas
• Sarkunam Kandhasamy
• Jaipuri Firoz Ali
• Thangavel Soodamani
• Jogi Srinivas
• Kathi Pavan Kalyan

Classifications

• C07D403/12

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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D417/12

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

• A61K31/4245

  Oxadiazoles · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title