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):	Shengde Wu, Namal C. Warshakoon, Artem G. Evdokimov, Kenneth D. Greis, Angelique Sun Boyer, Richard Masaru Kawamoto
Assignee:	Akebia Therapeutics Inc
Application Number:	US12/860,136
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,323,671
Patent Claims:	1. A method for treating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more compounds having the formula: wherein R is a unit chosen from: i) substituted or unsubstituted phenyl; or ii) substituted or unsubstituted heteroaryl; said substitutions chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; v) —CN; vi) —NHC(O)R4 vii) —C(O)NR5aR5b; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms; R4 is C1-C4 linear, branched, or cyclic alkyl; R5a and R5b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring having from 3 to 7 atoms; R2 is chosen from: i) —OR6; or ii) —NR7aR7b; R6 is hydrogen or C1-C4 linear, branched, or cyclic alkyl; R7a and R7b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R7a and R7b can be taken together to form a ring having from 3 to 7 ring atoms; R3 is hydrogen, methyl, or ethyl; L is a linking unit having the formula: —[C(R8aR8b)]n— R8a and R8b are each independently hydrogen, methyl, or ethyl; the index n is from 1 to 3; R9 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof. 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, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, and 4-chlorophenyl. 4. The method according to claim 1, wherein R is chosen from 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-iso-propoxyphenyl, 3-iso-propoxyphenyl, 4-iso-propoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, and 4-cyanophenyl. 5. The method according to claim 1, wherein R is a unit having the formula: wherein R10 has the formula —C(O)NR5aR5b; R5a and R5b are each hydrogen or R5a and R5b are taken together to form a ring having 5 or 6 atoms. 6. The method according to claim 1, wherein R5a and R5b are taken together to form a pyrrolidin-1-yl ring. 7. The method according to claim 1, wherein R is a unit having the formula: wherein R10 has the formula —NHC(O)R4; R4 is a unit chosen from methyl, ethyl, n-propyl, iso-propyl, and cyclopropyl. 8. The method according to claim 1, wherein R is a unit having the formula: wherein R10 is a heteroaryl unit chosen from 1,2,3,4-tetrazol-5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, and thiophene-3-yl. 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, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl. 11. The method according to claim 1, wherein R is a unit chosen from thiazol-2-yl, thiazol-4-yl, 1,2,3,4-tetrazol-5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, and thiophene-3-yl. 12. The method according to claim 1, wherein R2 is —OH. 13. The method according to claim 1, wherein R2 is —OCH3. 14. The method according to claim 1, wherein R2 is —NR7aR7b; R7a and R7b are each independently hydrogen, methyl, or ethyl. 15. The method according to claim 1, wherein R2 is chosen from: i) —NH2; ii) —NHCH3; or iii) —N(CH3)2. 16. The method according to claim 1, wherein R3 is hydrogen. 17. The method according to claim 1, wherein L has the formula chosen from: i) —CH2CH2—; or ii) —C(CH3)2—. 18. The method according to claim 1, wherein L has the formula —CH2—. 19. The method according to claim 1, wherein the compound has 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. 20. The method according to claim 19, wherein the compound has the formula: 21. The method according to claim 20, wherein R2 is —OH. 22. The method according to claim 20, wherein R2 is —OCH3 or —OCH2CH3. 23. The method according to claim 20, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 24. The method according to claim 20, wherein R8a and R8b are both hydrogen. 25. The method according to claim 19, wherein the compound has the formula: 26. The method according to claim 25, wherein R2 is —OH. 27. The method according to claim 25, wherein R2 is —OCH3 or —OCH2CH3. 28. The method according to claim 25, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 29. The method according to claim 25, wherein R8a and R8b are both hydrogen. 30. The method according to claim 19, wherein the compound has the formula: 31. The method according to claim 30, wherein R2 is —OH. 32. The method according to claim 30, wherein R2 is —OCH3 or —OCH2CH3. 33. The method according to claim 30, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 34. The method according to claim 30, wherein R8a and R8b are both hydrogen. 35. The method according to claim 19, wherein the compound has the formula: 36. The method according to claim 35, wherein R2 is —OH. 37. The method according to claim 35, wherein R2 is —OCH3 or —OCH2CH3. 38. The method according to claim 35, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 39. The method according to claim 35, wherein R8a and R8b are 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 acid 3[(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; and 5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; or a pharmaceutically acceptable salt thereof. 41. 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 having the formula: wherein R is a unit chosen from: i) substituted or unsubstituted phenyl; or ii) substituted or unsubstituted heteroaryl; said substitutions chosen from: i) C1-C4 linear, branched, or cyclic alkyl; ii) C1-C4 linear, branched, or cyclic alkoxy; iii) C1-C4 linear, branched, or cyclic haloalkyl; iv) halogen; v) —CN; vi) —NHC(O)R4 vii) —C(O)NR5aR5b; viii) heteroaryl; or ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms; R4 is C1-C4 linear, branched, or cyclic alkyl; R5a and R5b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring having from 3 to 7 atoms; R2 is chosen from: i) —OR6; or ii) —NR7aR7b; R6 is hydrogen or C1-C4 linear, branched, or cyclic alkyl; R7a and R7b are each independently: i) hydrogen; ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R7a and R7b can be taken together to form a ring having from 3 to 7 ring atoms; R3 is hydrogen, methyl, or ethyl; L is a linking unit having the formula: —[C(R8aR8b)]n— R8a and R8b are each independently hydrogen, methyl, or ethyl; the index n is from 1 to 3; R9 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof. 42. The method according to claim 41, wherein the compound has the formula: 43. The method according to claim 41, wherein R2 is —OH. 44. The method according to claim 41, wherein R2 is —OCH3 or —OCH2CH3. 45. The method according to claim 41, wherein R2 is chosen from —NH2, —NHCH3, or —N(CH3)2. 46. The method according to claim 41, wherein R8a and R8b are 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 acid 3[(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; and 5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; or a pharmaceutically acceptable salt thereof.