Isoxazole derivatives as FXR agonists and methods of use therof

• US 10,138,228 B2
• Filed: 05/17/2017
• Issued: 11/27/2018
• Est. Priority Date: 05/18/2016
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Or, Yat Sun, He, Yong, Shen, Ruichao, Xing, Xuechao, Granger, Brett, Wang, Bin, Ma, Jun, He, Jing, Long, Jiang, Wang, Guoqiang
• Primary Examiner(s): Shterengarts, Samantha L
• Application Number:
  US15/597,423
• Publication Number:
  US 20170334894A1
• Time in Patent Office: 559 Days
• Field of Search: None
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides compounds of Formula I:

and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated as FXR modulators. Specifically, the present invention relates to isoxazole derivatives useful as agonists for FXR, and methods for their preparation and use.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group set forth below:

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group set forth below:

5. The compound of claim 1, represented by Formula (Ia), (Ib), (Ic), or a pharmaceutically acceptable salt thereof:

6. The compound of claim 1, represented by Formula (II) or a pharmaceutically acceptable salt thereof:

7. The compound of claim 1, represented by Formula (III) or a pharmaceutically acceptable salt thereof:

8. The compound of claim 1, selected from the compounds set forth below,

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

10. A method for treating an FXR-mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of according to claim 1, or a pharmaceutically acceptable salt thereof.

11. The method according to claim 10, wherein the FXR-mediated disease or condition is selected from the group consisting of chronic liver disease, gastrointestinal disease, renal disease, cardiovascular disease, and metabolic disease.

12. The method according to claim 11, wherein the chronic liver disease is selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis, bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren'"'"'s syndrome, Sarcoidosis, Wilson'"'"'s disease, Gaucher'"'"'s disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

13. The method according to claim 11, wherein the renal disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis, hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.

14. The method according to claim 11, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.

15. The method according to claim 11, wherein the metabolic disease is selected from the group consisting of insulin resistance, type I and type II diabetes, and obesity.

16. The method of claim 12, wherein the chronic liver disease is primary biliary cirrhosis.

17. The method of claim 12, wherein the chronic liver disease is nonalcoholic fatty liver disease.

18. The method of claim 12, wherein the chronic liver disease is nonalcoholic steatohepatitis.