Claims for Patent: 8,323,671

Summary for Patent: 8,323,671

Title:	Prolyl hydroxylase inhibitors and methods of use
Abstract:	The present disclosure relates to HIF-1α prolyl hydroxylase inhibitors, compositions which comprise the HIF-1α prolyl hydroxylase inhibitors described herein and to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.
Inventor(s):	Wu Shengde, Warshakoon Namal C., Evdokimov Artem G., Greis Kenneth D., Boyer Angelique Sun, Kawamoto Richard Masaru
Assignee:	Akebia Therapeutics Inc.
Application Number:	US12860136
Patent Claims:	2. The method according to claim 1 , wherein R is substituted or unsubstituted phenyl.3. The method according to claim 1 , wherein R is chosen from 2-fluorophenyl claim 1 , 3-fluorophenyl claim 1 , 4-fluorophenyl claim 1 , 2-chlorophenyl claim 1 , 3-chlorophenyl claim 1 , and 4-chlorophenyl.4. The method according to claim 1 , wherein R is chosen from 2-methoxyphenyl claim 1 , 3-methoxyphenyl claim 1 , 4-methoxyphenyl claim 1 , 2-ethoxyphenyl claim 1 , 3-ethoxyphenyl claim 1 , 4-ethoxyphenyl claim 1 , 2-iso-propoxyphenyl claim 1 , 3-iso-propoxyphenyl claim 1 , 4-iso-propoxyphenyl claim 1 , 2-cyanophenyl claim 1 , 3-cyanophenyl claim 1 , and 4-cyanophenyl.6. The method according to claim 1 , wherein Rand Rare taken together to form a pyrrolidin-1-yl ring.9. The method according to claim 1 , wherein R is substituted or unsubstituted heteroaryl.10. The method according to claim 1 , wherein R is a unit chosen from pyridin-2-yl claim 1 , pyridin-3-yl claim 1 , pyridin-4-yl claim 1 , pyrimidin-2-yl claim 1 , pyrimidin-4-yl claim 1 , pyrimidin-5-yl claim 1 , isoquinolin-1-yl claim 1 , isoquinolin-3-yl claim 1 , and isoquinolin-4-yl.11. The method according to claim 1 , wherein R is a unit chosen from thiazol-2-yl claim 1 , thiazol-4-yl claim 1 , 1 claim 1 ,2 claim 1 ,3 claim 1 ,4-tetrazol-5-yl claim 1 , [1 claim 1 ,2 claim 1 ,4]triazol-5-yl claim 1 , imidazol-2-yl claim 1 , furan-2-yl claim 1 , furan-3-yl claim 1 , thiophene-2-yl claim 1 , and thiophene-3-yl.12. The method according to claim 1 , wherein Ris —OH.13. The method according to claim 1 , wherein Ris —OCH.14. The method according to claim 1 , wherein Ris —NRR; Rand Rare each independently hydrogen claim 1 , methyl claim 1 , or ethyl.15. The method according to claim 1 , wherein Ris chosen from:{'sub': '2', 'i) —NH;'}{'sub': '3', 'ii) —NHCH; or'}{'sub': 3', '2, 'iii) —N(CH).'}16. The method according to claim 1 , wherein Ris hydrogen.17. The method according to claim 1 , wherein L has the formula chosen from:{'sub': 2', '2, 'i) —CHCH—; or'}{'sub': 3', '2, 'ii) —C(CH)—.'}18. The method according to claim 1 , wherein L has the formula —CH—.21. The method according to claim 20 , wherein Ris —OH.22. The method according to claim 20 , wherein Ris —OCHor —OCHCH.23. The method according to claim 20 , wherein Ris chosen from —NH claim 20 , —NHCH claim 20 , or —N(CH).24. The method according to claim 20 , wherein Rand Rare both hydrogen.26. The method according to claim 25 , wherein Ris —OH.27. The method according to claim 25 , wherein Ris —OCHor —OCHCH.28. The method according to claim 25 , wherein Ris chosen from —NH claim 25 , —NHCH claim 25 , or —N(CH).29. The method according to claim 25 , wherein Rand Rare both hydrogen.31. The method according to claim 30 , wherein Ris —OH.32. The method according to claim 30 , wherein Ris —OCHor —OCHCH.33. The method according to claim 30 , wherein Ris chosen from —NH claim 30 , —NHCH claim 30 , or —N(CH).34. The method according to claim 30 , wherein Rand Rare both hydrogen.36. The method according to claim 35 , wherein Ris —OH.37. The method according to claim 35 , wherein Ris —OCHor —OCHCH.38. The method according to claim 35 , wherein Ris chosen from —NH claim 35 , —NHCH claim 35 , or —N(CH).39. The method according to claim 35 , wherein Rand Rare both hydrogen.40. A method for treating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more compounds chosen from:{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(2-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Fluoro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;{[3-Hydroxy-5-(4-isopropyl-phenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Ethyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[3-Hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(3-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(3-Carbamoyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;({5-[3-(Cyclopropanecarbonyl-amino)-phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid methyl ester[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid methyl ester;[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(4-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(2-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;[(3-Hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]-acetic acid;{[5-(4-Ethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[3-Hydroxy-5-(4-isopropylphenyl)pyridine-2-carbonyl]amino}-acetic acid;{[3-Hydroxy-5-(3-trifluoromethylphenyl)pyridine-2-carbonyl]amino}-acetic acid;{[5-(4-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(3-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(5-Chloro-2-methylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[3-Hydroxy-5-(4-isopropoxyphenyl)pyridine-2-carbonyl]amino}-acetic acid;({5-[3-(Cyclopropanecarbonylamino)phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-acetic acid;({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)phenyl]-pyridine-2-carbonyl}amino)-acetic acid;({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)phenyl]-pyridine-2-carbonyl}-amino)-acetic acid;[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid;[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid;[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid;[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid;[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid;{[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid;5-(3-Chlorophenyl)-N-(2-amino-2-oxo-1,1-dimethylethyl)-3-hydroxylpyridin-2-yl amide;5-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;5-(3-Chlorophenyl)-N-(2-amino-2-oxo-1-methylethyl)-3-hydroxylpyridin-2-yl amide;5-(4-Methylphenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;2-{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester;2-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid3[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester;3[(3-Hydroxy-5-(3-chlorophenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester;3-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-propionic acid;3[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid;5-(3-Chlorophenyl)-N-(3-amino-3-oxo-1,1-dimethylpropyl)-3-hydroxylpyridin-2-yl amide; and5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; ora pharmaceutically acceptable salt thereof.43. The method according to claim 41 , wherein Ris —OH.44. The method according to claim 41 , wherein Ris —OCHor —OCHCH.45. The method according to claim 41 , wherein Ris chosen from —NH claim 41 , —NHCH claim 41 , or —N(CH).46. The method according to claim 41 , wherein Rand Rare both hydrogen.47. A method for promoting wound healing comprising administering to a human or mammal in need of treatment an effective amount of one or more compounds chosen from:{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(2-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Fluoro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;{[3-Hydroxy-5-(4-isopropyl-phenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Ethyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[3-Hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(4-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(3-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;{[5-(3-Carbamoyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;({5-[3-(Cyclopropanecarbonyl-amino)-phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid methyl ester[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid methyl ester;[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(4-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(2-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;[(3-Hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]-acetic acid;{[5-(4-Ethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[3-Hydroxy-5-(4-isopropylphenyl)pyridine-2-carbonyl]amino}-acetic acid;{[3-Hydroxy-5-(3-trifluoromethylphenyl)pyridine-2-carbonyl]amino}-acetic acid;{[5-(4-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(3-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[5-(5-Chloro-2-methylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;{[3-Hydroxy-5-(4-isopropoxyphenyl)pyridine-2-carbonyl]amino}-acetic acid;({5-[3-(Cyclopropanecarbonylamino)phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-acetic acid;({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)phenyl]-pyridine-2-carbonyl}amino)-acetic acid;({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)phenyl]-pyridine-2-carbonyl}-amino)-acetic acid;[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid;[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid;[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid;[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid;[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid;{[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid;5-(3-Chlorophenyl)-N-(2-amino-2-oxo-1,1-dimethylethyl)-3-hydroxylpyridin-2-yl amide;5-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;5-(3-Chlorophenyl)-N-(2-amino-2-oxo-1-methylethyl)-3-hydroxylpyridin-2-yl amide;5-(4-Methylphenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;2-{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester;2-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid3[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester;3[(3-Hydroxy-5-(3-chlorophenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester;3-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-propionic acid;3[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid;5-(3-Chlorophenyl)-N-(3-amino-3-oxo-1,1-dimethylpropyl)-3-hydroxylpyridin-2-yl amide; and5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; ora pharmaceutically acceptable salt thereof.