Claims for Patent: 7,811,595

Summary for Patent: 7,811,595

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):	Richard Masaru Kawamoto, Shengde Wu, Namal C. Warshakoon, Artem G. Evdokimov, Kenneth D. Greis, Angelique Sun Boyer
Assignee:	Akebia Therapeutics Inc
Application Number:	US11/821,936
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,811,595
Patent Claims:	1. A compound having the formula: wherein R and R1 are each independently: i) hydrogen; ii) substituted or unsubstituted phenyl; or iii) substituted or unsubstituted heteroaryl; said substitutions being: 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; or viii) heteroaryl; or ix) two substitutions are 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 are taken together to form a ring having from 3 to 7 atoms; R2 is: i) —OR6; or ii) —NR7aR7b; R6 is hydrogen or C1-C4 linear, branched, or cyclic alkyl; R7a and R7b are each independently: i) hydrogen; or ii) C1-C4 linear, branched, or cyclic alkyl; or iii) R7a and R7b are 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; and R9 is hydrogen or methyl; or a pharmaceutically acceptable salt thereof; provided R and R1 are not both hydrogen. 2. A compound according to claim 1, wherein R is substituted or unsubstituted phenyl. 3. A compound according to claim 1, wherein R is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, and 4-chlorophenyl. 4. A compound 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. A compound according to claim 1, wherein R1 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. 6. A compound 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 from a ring having 5 or 6 atoms. 7. A compound according to claim 1, wherein R5a and R5b are taken together to form a pyrrolidin-1-yl ring. 8. A compound 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. 9. A compound 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. 10. A compound according to claim 1, wherein R is substituted or unsubstituted heteroaryl. 11. A compound 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. 12. A compound 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. 13. A compound according to claim 1, wherein R2 is —OR6; R6 is hydrogen or methyl. 14. A compound according to claim 1, wherein R6 is hydrogen. 15. A compound according to claim 1, wherein R6 is methyl. 16. A compound according to claim 1, wherein R2 is —NR7aR7b; R7a and R7b are each independently hydrogen, methyl, or ethyl. 17. A compound according to claim 1, wherein R2 is chosen from: i) —NH2; ii) —NHCH3; or iii) —N(CH3)2. 18. A compound according to claim 1, wherein R3 is methyl. 19. A compound according to claim 1, wherein R3 is hydrogen. 20. A compound according to claim 1, wherein L has the formula chosen from: i) —CH2—; ii) —CH2CH2—; or iii) —C(CH3)2—. 21. A compound according to claim 1, wherein L has the formula —CH2—. 22. A compound according to claim 1, having the formula: wherein R is substituted or unsubstituted phenyl; said substitutions are 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. 23. A compound according to claim 1, having the formula: wherein R is a heteroaryl 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, thiophene-3-yl, 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. 24. A compound according to claim 1, having the formula: wherein R is substituted or unsubstituted phenyl; said substitutions are 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. 25. A compound according to claim 1, having the formula: wherein R is a heteroaryl 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, thiophene-3-yl, 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. 26. A compound 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-(Chlorophenyl)-N-(2-amino-2-oxo-1,1-dimethylethyl)-3-hydroxylpyridin-2-yl amide; 5-(Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(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-(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. 27. A composition comprising: A) one or more compounds according to claim 1; and B) one or more excipients or carriers. 28. A compound according to claim 1, wherein the compound is a pharmaceutically acceptable salt of either basic groups or acid groups. 29. A compound according to claim 1, wherein the compounds are salts comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate. 30. A compound according to claim 1, wherein the compounds are salts comprising cations chosen from sodium, lithium, potassium, calcium, magnesium, and bismuth. 31. A compound according to claim 1, having the formula: wherein R is substituted or unsubstituted phenyl; said substitutions are 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. 32. A compound according to claim 1, having the formula: wherein R is a heteroaryl 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, thiophene-3-yl, 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.