IP Library › Granted Patent US 11,091,482
Granted Patent B2
US 11,091,482 · App. 16/327,790 · Granted Aug 17, 2021

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 11,091,482
App. No.
16/327,790
Granted
Aug 17, 2021
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 (60)

1. 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-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-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-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,5 S)-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-4-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-4-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-3-(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.

Continuity (3)
Provisional Application 62419452 · Nov 8, 2016
Provisional Application 62378531 · Aug 23, 2016
Related Publication 20190308973A1 · Oct 10, 2019
Cited By (1)
US 12,209,088