Isoxazole analogs as FXR agonists and methods of use thereof

• US 10,450,306 B2
• Filed: 10/04/2017
• Issued: 10/22/2019
• Est. Priority Date: 10/04/2016
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Ma, Jun, Wang, Guoqiang, Wang, Bin, Xing, Xuechao, Shen, Ruichao, He, Jing, Or, Yat Sun
• Primary Examiner(s): Stockton, Laura L
• Application Number:
  US15/724,919
• Publication Number:
  US 20180099957A1
• Time in Patent Office: 748 Days
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

The present invention provides compounds of Formula I,

pharmaceutical compositions comprising these compounds and methods of using these compounds to prevent or treat FXR-mediated or TGR5-mediated diseases or conditions.

Claims

1. A compound represented by Formula (I):

2. The compound of claim 1, wherein R² is selected from the group consisting of

3. The compound of claim 1, wherein A is

4. The compound of claim 1, wherein B is selected from the group consisting of

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

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

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

9. The compound of claim 1, represented by Formula (X), or Formula (XI), or a pharmaceutically acceptable salt thereof:

10. The compound according to claim 1, selected from:

(A) Compounds according to Formula (X), wherein A, B, and Z—

R⁴ are delineated for each compound in Table 3;

11. The compound of claim 1, represented by Formula (XII), or Formula (XIII), or a pharmaceutically acceptable salt thereof:

12. The compound according to claim 1, selected from:

(A) Compounds according to Formula (XII), wherein A, B, and Z—

R⁴ are delineated for each compound in Table 5;

13. The compound of claim 1, wherein R¹ is optionally substituted cyclopropyl;

R² is selected from the group consisting of

14. The compound of claim 1, selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

15. 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 according to claim 1.

16. The method according to claim 15, wherein the FXR-mediated disease or condition is selected from the group consisting of chronic liver disease, gastrointestinal disease, renal disease, cardiovascular disease, fibrotic diseases, and metabolic disease.

17. The method according to claim 16, wherein the fibrotic diseases is selected from primary biliary cirrhosis, primary sclerosing cholangitis, pulmonary fibrosis, renal fibrosis, and liver fibrosis.

18. The method according to claim 16, wherein the chronic liver disease is selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), 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.

19. The method according to claim 16, wherein the renal disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.

20. The method according to claim 16, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.

21. The method according to claim 16, wherein the metabolic disease is selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.

22. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

8. A compound selected from:

(A) Compounds according to Formula (VIII), wherein A, B, and Z—

R⁴ are delineated for each compound in Table 1;