Claims for Patent: 8,343,952

Summary for Patent: 8,343,952

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):	Shengde Wu, Namal C. Warshakoon, Artem G. Evdokimov, Kenneth D. Greis, Angelique Sun Boyer, Richard Masaru Kawamoto
Assignee:	Akebia Therapeutics Inc
Application Number:	US12/860,073
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,343,952
Patent Claims:	1. A compound having the formula: wherein R2 is chosen from: i) —OR6; or ii) —NR7aR7b; R6 is hydrogen, methyl, or ethyl; R7a and R7b are each independently: i) hydrogen; or ii) methyl; R3 is hydrogen or methyl; R8a and R8b are each independently hydrogen, methyl, or ethyl; R10 represents from 1 to 5 substitutions for hydrogen, said substitutions independently chosen from: i) fluoro; ii) chloro; iii) trifluoromethyl; iv) methyl; or v) two adjacent R10 units can be taken together to form a 6-member ring having one or two oxygen atoms, provided no two oxygen atoms are adjacent to one another in the ring; and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, having the formula: 3. The compound according to claim 2, wherein R2 is —OH. 4. The compound according to claim 2, wherein R2 is —OCH3 or —OCH2CH3. 5. The compound according to claim 2, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 6. The compound according to claim 2, wherein R8a and R8b are both hydrogen. 7. The compound according to claim 1, having the formula: 8. The compound according to claim 7, wherein R2 is —OH. 9. The compound according to claim 7, wherein R2 is —OCH3 or —OCH2CH3. 10. The compound according to claim 7, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 11. The compound according to claim 7, wherein R8a and R8b are both hydrogen. 12. The compound according to claim 1, having the formula: 13. The compound according to claim 12, wherein R2 is —OH. 14. The compound according to claim 12, wherein R2 is —OCH3 or —OCH2CH3. 15. The compound according to claim 12, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 16. The compound according to claim 12, wherein R8a and R8b are both hydrogen. 17. The compound according to claim 1, having the formula: 18. The compound according to claim 17, wherein R2 is —OH. 19. The compound according to claim 17, wherein R2 is —OCH3 or —OCH2CH3. 20. The compound according to claim 17, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 21. The compound according to claim 17, wherein R8a and R8b are both hydrogen. 22. The compound according to claim 1, having the formula: 23. The compound according to claim 22, wherein R2 is —OH. 24. The compound according to claim 22, wherein R2 is —OCH3 or —OCH2CH3. 25. The compound according to claim 22, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 26. The compound according to claim 22, wherein R8a and R8b are both hydrogen. 27. A compound chosen from: {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid ethyl ester; 5-(3-Chlorophenyl)-N-(1-methyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1-methyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1-methyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid methyl ester; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid ethyl ester; 5-(3-Chlorophenyl)-N-(1,1-dimethyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1,1-dimethyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1,1-dimethyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(4-Fluorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Fluorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid ethyl ester; 5-(4-Fluorophenyl)-N-(1-methyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1-methyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1-methyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid methyl ester; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid ethyl ester; 5-(4-Fluorophenyl)-N-(1,1-dimethyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1,1-dimethyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1,1-dimethyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(3-Trifluoromethylphenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid ethyl ester; 5-(3-Trifluoromethylphenyl)-N-(1-methyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(1-methyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(1-methyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid methyl ester; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid ethyl ester; 5-(3-Trifluoromethylphenyl)-N-(1,1-dimethyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(1,1-dimethyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(1,1-dimethyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(3-Chloro-6-methyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chloro-6-methyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chloro-6-methyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid ethyl ester; 5-(3-Chloro-6-methyl)-N-(1-methyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chloro-6-methyl)-N-(1-methyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chloro-6-methyl)-N-(1-methyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid methyl ester; {[5-(3-Chloro-6-methyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid ethyl ester; 5-(3-Chloro-6-methyl)-N-(1,1-dimethyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chloro-6-methyl)-N-(1,1-dimethyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; and 5-(3-Chloro-6-methyl)-N-(1,1-dimethyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(2,3-dihydrobenzo [1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(2,3-dihydrobenzo [1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(2,3-dihydrobenzo [1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid ethyl ester; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(1-methyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(1-methyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(1-methyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(2,3-dihydrobenzo [1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid; {[5-(2,3-dihydrobenzo [1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid methyl ester; {[5-(2,3-dihydrobenzo [1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid ethyl ester; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(1,1-dimethyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(1,1-dimethyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; and 5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-N-(1,1-dimethyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; or a pharmaceutically acceptable salt thereof 28. A composition for treating anemia, comprising: A) One or more compounds having the formula: wherein R2 is chosen from: i) —OR6; or ii) —NR7aR7b; R6 is hydrogen, methyl, or ethyl; R7a and R7b are each independently: i) hydrogen; or ii) methyl; R3 is hydrogen or methyl; R8a and R8b are each independently hydrogen, methyl, or ethyl; R10 represents from 1 to 5 substitutions for hydrogen, said substitutions independently chosen from: i) fluoro; ii) chloro; iii) trifluoromethyl; iv) methyl; or v) two adjacent R10 units can be taken together to form a 6-member ring having one or two oxygen atoms, provided no two oxygen atoms are adjacent to one another in the ring; and pharmaceutically acceptable salts thereof; and B) one or more pharmaceutically acceptable excipients. 29. The composition according to claim 28, wherein the compound is chosen from {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, {[5-(4-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, {[5-(3-trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, and {[5-(3-chloro-6-methylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. 30. A composition for treating wounds, comprising: A) One or more compounds having the formula: wherein R2 is chosen from: i) —OR6; or ii) —NR7aR7b; R6 is hydrogen, methyl, or ethyl; R7a and R7b are each independently: i) hydrogen; or ii) methyl; R3 is hydrogen or methyl; R8a and R8b are each independently hydrogen, methyl, or ethyl; R10 represents from 1 to 5 substitutions for hydrogen, said substitutions independently chosen from: i) fluoro; ii) chloro; iii) trifluoromethyl; iv) methyl; or v) two adjacent R10 units can be taken together to form a 6-member ring having one or two oxygen atoms, provided no two oxygen atoms are adjacent to one another in the ring; and pharmaceutically acceptable salts thereof; and B) one or more pharmaceutically acceptable excipients. 31. The composition according to claim 30, wherein the compound is {[5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. 32. The compound {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]-amino}acetic acid.