Substituted bicyclic compounds as farnesoid X receptor modulators
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.
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).