IP Library › Granted Patent US 11,718,619
Granted Patent B2
US 11,718,619 · App. 17/224,518 · Granted Aug 8, 2023

Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators

Inventors: Jianhua Chao (Fremont, CA); Rakesh Jain (Fremont, CA); Lily Hu (Fremont, CA); Jason Gustaf Lewis (Fremont, CA); Helene Baribault (Fremont, CA); Jeremy Caldwell (Fremont, CA)
Assignee: Ardelyx, Inc.
C07D471/08A61P1/16
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Quick Facts
Patent No.
US 11,718,619
App. No.
17/224,518
Granted
Aug 8, 2023
Kind
B2
Abstract

The disclosure relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): wherein L 1 , L 2 , A, B, R 1 , R 2 , R 3 , and R 4 are described herein.

Claims (64)

1. A method of treating or preventing a disease in which farnesoid X receptor (FXR) plays a role, comprising administering to a subject in need thereof an effective amount of a compound

selected from the group consisting of:

methyl 2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

(1R,3R,5S)-8-(6-carbamoyl-4-fluoro-1,3-benzothiazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

2-({2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}formamido)acetic acid;

2-({2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}formamido)ethane-1-sulfonic acid;

(1R,3R,5S)-8-[4-fluoro-6-(methanesulfonylcarbamoyl)-1,3-benzothiazol-2-yl]-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-5-methoxy-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethyl)-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic acid;

4-cyclopropyl-2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-(5-cyclopropyl-3-phenyl-1,2-oxazole-4-carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-{5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole-4-carbonyloxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-{3-[2-chloro-6-(difluoromethoxy)phenyl]-5-cyclopropyl-1,2-oxazole carbonyloxy}-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-5-methoxy-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-(5-cyclopropyl-3-{spiro[2.5]octan-6-yl}-1,2-oxazole-4-carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-(3-{bicyclo[2.2.2]octan-1-yl}-5-cyclopropyl-1,2-oxazole-4-carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-(3-{bicyclo[2.2.2]octan-1-yl}-5-cyclopropyl-1,2-oxazole-4-carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-methoxy-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-(3-{bicyclo[2.2.2]octan-1-yl}-5-cyclopropyl-1,2-oxazole-4-carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-5-methoxy-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3S,5S)-3-[3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[5-cyclobutyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3S,5S)-3-[5-tert-butyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3S,5S)-3-[3-(2,6-dichlorophenyl)-5-(1-methylcyclopropyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

6-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1H-indole-3-carboxylic acid;

6-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-1,2-benzoxazole-3-carboxylic acid;

(1R,3R,5S)-8-(2,2-difluoro-1-methyl-3-oxo-2,3-dihydro-1H-indol-6-yl)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1-methyl-1H-1,3-benzodiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-({2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]acetyl}oxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3R,5S)-3-({2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]acetyl}oxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1-methyl-1H-1,3-benzodiazole-6-carboxylic acid;

4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]benzoic acid;

4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid;

3-chloro-4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]benzoic acid;

4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-2-(trifluoromethyl)benzoic acid;

4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-3-(trifluoromethyl)benzoic acid;

4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-2-methoxybenzoic acid;

4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-3-methoxybenzoic acid;

4-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-2-fluorobenzoic acid;

3-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-5-fluorobenzoic acid;

4-[(1R,3R,5S)-3-{3-[2-chloro-6-(difluoromethoxy)phenyl]-5-cyclopropyl-1,2-oxazole carbonyloxy}-8-azabicyclo[3.2.1]octan-8-yl]-3-fluorobenzoic acid;

(1R,3R,5S)-8-[4-(methanesulfonylcarbamoyl)phenyl]-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

(1R,3R,5S)-8-{4-[(propane-1-sulfonyl)carbamoyl]phenyl}-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate

(1R,3R,5S)-8-{4-[(pentane-1-sulfonyl)carbamoyl]phenyl}-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

(1R,3R,5S)-8-{4-[(propane-2-sulfonyl)carbamoyl]phenyl}-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

(1R,3S,5S)-8-{4-[(cyclopropanesulfonyl)carbamoyl]phenyl}-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

(1R,3S,5S)-8-[4-(cyclopropylmethanesulfonylcarbamoyl)phenyl]-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate; (1R,3R,5S)-8-{4-[(3-hydroxypropanesulfonyl)carbamoyl]phenyl}-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

(1R,3R,5S)-8-[2-fluoro-4-(methanesulfonylcarbamoyl)phenyl]-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

(1R,3R,5S)-8-[2-chloro-4-(methanesulfonylcarbamoyl)phenyl]-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

(1R,3R,5S)-8-(4-cyano-3-hydroxyphenyl)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl (2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate;

5-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]pyrimidine-2-carboxylic acid;

3-{[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]sulfonyl}benzoic acid;

3-{[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]sulfonyl}-5-fluorobenzoic acid;

2-[(1R,3R,5S)-3-(3-{bicyclo[2.2.2]octan-1-yl}-5-cyclopropyl-1,2-oxazole-4-carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid;

2-[(1R,3S,5S)-3-(5-cyclopropyl-3-{4-methoxybicyclo[2.2.2]octan-1-yl}-1,2-oxazole-4-carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid; and

2-[(1R,3R,5S)-3-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-methyl-1,3-benzothiazole-6-carboxylic acid

wherein the disease is liver disease, intestinal disease, kidney disease or an autoimmune disorder.

2. The method of claim 1 , wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, intra-cholestasis, extra-cholestasis, or portal vein hypertension.

3. The method of claim 1 , wherein the intestinal disease is inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, Celiac's disease or bile acid diarrhea.

4. The method of claim 1 , wherein the autoimmune disorder is inflammatory bowel disease, autoimmune liver disease, autoimmune hepatitis, or multiple sclerosis.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: CHAO, JIANHUA; JAIN, RAKESH; HU, LILY; LEWIS, JASON G; BARIBAULT, HELENE; CALDWELL, JEREMY
To: ARDELYX, INC.
Reel/Frame 061315/0596 →
Continuity (4)
Division 16327790
Provisional Application 62419452 · Nov 8, 2016
Provisional Application 62378531 · Aug 23, 2016
Related Publication 20210300927A1 · Sep 30, 2021