Granted Patent B2

US 10,092,558 · App. 15/133,104 · Granted Oct 9, 2018

Inventors: Michael P. Arend (Foster City, CA); Lee A. Flippin (Woodside, CA); Volkmar Guenzler-Pukall (San Leandro, CA); Wen-Bin Ho (Los Altos, CA); Eric D. Turtle (Belmont, CA); Xiaohui Du (Foster City, CA)

Assignee: FibroGen, Inc.

A61K31/472A61K31/473A61K31/4725A61K38/1816C07D217/26C07D221/08C07D401/04C07D401/06C07D401/12C07D403/12C07D217/24

Abstract

Claims (215)

1. A method of treating a condition mediated at least in part by hypoxia inducible factor (HIF) and/or erythropoietin (EPO), wherein said condition is anemia associated with myelodysplastic syndrome, comprising administering to a mammalian patient in need thereof a therapeutically effective amount of a compound of formula ID:

wherein

q is zero or one;

R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl or, when X is —NR 7 —, then R 7 and R 6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;

R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O) n —N(R 6 )—R 6 where n is 0, 1, or 2, —NR 6 C(O)NR 6 R 6 , and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, each R 6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that when X is —S— or —SO 2 —, then R 6 is not hydrogen, and R 7 is selected from the group consisting of hydrogen, alkyl, and aryl, or R 2 and R 3 together with the carbon atoms pendent thereto, form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R 4 and R 5 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl or, when X is —NR 7 —, then R 7 and R 6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;

R″ is selected from the group consisting of hydrogen, alkyl and substituted alkyl; and

R′″ is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, and —S(O) n —R 10 wherein R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl and n is zero, one or two;

or a pharmaceutically acceptable salt, ester, or amide derived from an amine of the formula HNR 20 R 21 where R 20 and R 21 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, thereof;

with the proviso that when R″ is hydrogen and q is zero, then at least one of the following occurs:

1) R 1 is fluoro, bromo, iodo, alkyl, substituted alkyl, alkoxy, aminoacyl, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl; or

2) R 2 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl provided that:

a) when R 2 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) alkyl and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:

—O—[CH 2 ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or

3) R 3 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromo, iodo, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl provided that:

a) when R 3 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) alkyl and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:

—O—[CH 2 ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or

4) R 4 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl provided that:

a) when R 4 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:

—O—[CH 2 ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or

5) R 5 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7 is hydrogen, alkyl or aryl provided that:

a) when R 5 is substituted alkyl such a substituent does not include trifluoromethyl;

b) —XR 6 is not alkoxy; and

c) when —XR 6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:

—O—[CH 2 ] x —C f H (2f+1−g) F g

where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1);

and with the further following proviso:

that when R 1 , R 3 , R 4 , and R 5 are hydrogen, then R 2 is not bromo and the compound is not N-((6-benzyloxy-1-chloro-4-hydroxy-isoquinolin-3-yl)-carbonyl-amino)-acetic acid or N-((7-benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino)-acetic acid.

2. The method of claim 1 , wherein the compound is administered in a pharmaceutical composition which further comprises a pharmaceutically acceptable excipient.

3. The method of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, halo, alkoxy, aryloxy, substituted aryloxy, substituted aryl, alkylthio, aminoacyl, aryl, substituted amino, heteroaryl, heteroaryloxy, —S(O) n -aryl, —S(O) n — substituted aryl, —S(O) n -heteroaryl, and —S(O) n -substituted heteroaryl, where n is zero, one or two.

4. The method of claim 1 , wherein R 1 is selected from the group consisting of (4-methoxy)phenylsulfonylamino, 2,6-dimethylphenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy, 3-chloro-4-fluorophenoxy, 3-methoxy-4-fluorophenoxy, 3-methoxy-5-fluorophenoxy, 4-(methylsulfonamido)phenoxy, 4-(phenylsulfonamido)phenoxy, 4-CF 3 —O-phenoxy, 4-CF 3 -phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, 4-(4-fluorophenoxy)phenoxy, 4-methoxyphenoxy, 4-nitrophenoxy, benzyloxy, bromo, butoxy, CF 3 , chloro, cyclohexyloxy, cyclohexylsulfanyl, cyclohexylsulfonyl, fluoro, hydrogen, iodo, isopropoxy, methyl, phenoxy, phenyl, phenylsulfanyl, phenylsulfinyl, phenylsulfonyl, phenylurea, pyridin-1-ylsulfanyl, pyridin-3-yloxy, and pyridin-4-ylsulfanyl.

5. The method of claim 1 , wherein R 2 is selected from the group consisting of substituted amino, aryloxy, substituted aryloxy, alkoxy, substituted alkoxy, halo, hydrogen, alkyl, substituted alkyl, aryl, —S(O) n -aryl, —S(O) n -substituted aryl, —S(O) n -cycloalkyl, where n is zero, one or two, aminocarbonylamino, heteroaryloxy, and cycloalkyloxy.

6. The method of claim 1 , wherein R 2 is selected from the group consisting of (4-methoxy)phenylsulfonylamino, 2,6-dimethylphenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy, 3-chloro-4-fluorophenoxy, 3-methoxy-4-fluorophenoxy, 3-methoxy-5-fluorophenoxy, 4-(methylsulfonamido)phenoxy, 4-(phenylsulfonamido)phenoxy, 4-CF 3 —O-phenoxy, 4-CF 3 -phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, 4-(4-fluorophenoxy)phenoxy, 4-methoxyphenoxy, 4-nitrophenoxy, benzyloxy, bromo, butoxy, CF 3 , chloro, cyclohexyloxy, cyclohexylsulfanyl, cyclohexylsulfonyl, fluoro, hydrogen, iodo, isopropoxy, methyl, phenoxy, phenyl, phenylsulfanyl, phenylsulfinyl, phenylsulfonyl, phenylurea, pyridin-1-ylsulfanyl, pyridin-3-yloxy, and pyridin-4-ylsulfanyl.

7. The method of claim 1 , wherein R 3 is selected from the group consisting of substituted aryloxy, substituted alkoxy, alkoxy, substituted alkyl, alkyl, amino, cycloalkyloxy, hydrogen, halo, aryl, aminocarbonylamino, heteroaryloxy, —S(O) n -aryl, —S(O) n -substituted aryl, —S(O) n -heteroaryl, and —S(O) n -substituted heteroaryl, where n is zero, one or two.

8. The method of claim 1 , wherein R 3 is selected from the group consisting of amino, (4-methyl)phenylsulfonylaminophenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy, 3-fluoro-5-methoxy-phenoxy, 3-chloro-4-fluorophenoxy, 4-CF 3 —O-phenoxy, 4-CF 3 -phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, 4-(4-fluorophenoxy)phenoxy, 4-methoxyphenoxy, benzyloxy, bromo, butoxy, CF 3 , chloro, cyclohexyloxy, hydrogen, iodo, isopropoxy, phenoxy, phenyl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl, phenylurea, pyridin-1-ylsulfanyl, pyridin-3-yloxy, and pyridin-4-ylsulfanyl.

9. The method of claim 1 , wherein R 2 and R 3 , combined with the carbon atoms pendent thereto, join to form an aryl group.

10. The method of claim 1 , wherein the aryl group is phenyl.

11. The method of claim 1 , wherein R 4 is selected from the group consisting of substituted arylthio, halo, hydrogen, substituted alkyl and aryl.

12. The method of claim 1 , wherein R 4 is selected from the group consisting of 4-chlorophenyl sulfanyl, chloro, hydrogen, methoxymethyl, and phenyl.

13. The method of claim 1 , wherein R 5 is hydrogen or aryl.

14. The method of claim 1 , wherein R 5 is phenyl.

15. The method of claim 1 , wherein R″ is hydrogen.

16. The method of claim 1 , wherein R′″ is selected from the group consisting of hydrogen, hydroxy, alkoxy, substituted alkoxy, thiol, acyloxy and aryl.

17. The method of claim 1 , wherein R′″ is selected from the group consisting of hydroxy, benzyloxy, ethoxy, hydrogen, thiol, methoxy, methylcarbonyloxy, and phenyl.

18. A method of treating a condition mediated at least in part by hypoxia inducible factor (HIF) and/or erythropoietin (EPO), wherein said condition is anemia associated with myelodysplastic syndrome, comprising administering to a mammalian patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

{[4-Hydroxy-1-(naphthalen-2-yloxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(pyridin-3-yloxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(3-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-(3-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-(4-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-(2-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(2-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-(4-Acetylamino-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(4-methanesulfonylamino-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(4-Hydroxy-1-phenylamino-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[4-Hydroxy-6-(pyridin-3-yloxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(pyridin-3-yloxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(1-Chloro-4-methoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-ethoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-methoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Ethoxy-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Acetoxy-1-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Ethoxy-4-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-methyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-methoxymethyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Dimethylcarbamoyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-methyl-6-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Ethoxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Dimethylcarbamoyl-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-p-tolyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[7-(4-Fluoro-phenoxy)-4-hydroxy-1-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Chloro-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Chloro-4-hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Chloro-4-hydroxy-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Chloro-4-hydroxy-6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Chloro-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[7-(4-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Chloro-6-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[6-(4-Fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(pyridin-4-ylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-6-(pyridin-4-ylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(7-Benzenesulfinyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(7-Benzenesulfonyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(6-Benzenesulfinyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(6-Benzenesulfonyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(6-Amino-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[4-Hydroxy-7-(4-methoxy-benzenesulfonylamino)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-6-(3-phenyl-ureido)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(4-Hydroxy-1-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[1-(4-Chloro-phenylsulfanyl)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(4-Hydroxy-1-p-tolylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[4-Hydroxy-1-(pyridin-2-ylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(3-methoxy-phenylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(2-methoxy-phenylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-1-(naphthalen-2-ylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(1-Benzenesulfinyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Benzenesulfonyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[4-Hydroxy-7-(pyridin-2-ylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-6-(pyridin-2-ylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(1-Chloro-4-hydroxy-6,7-diphenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-6,7-diphenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

({4-Hydroxy-7-[4-(toluene-4-sulfonylamino)-phenoxy]-isoquinoline-3-carbonyl}-amino)-acetic acid;

{[4-Hydroxy-7-(4-nitro-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(4-Mercapto-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Mercapto-7-trifluoromethyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[7-(4-Benzenesulfonylamino-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(4-methanesulfonylamino-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[7-(4-Chloro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[6-(4-Chloro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[6-(3-Fluoro-5-methoxy-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[7-(3-Fluoro-5-methoxy-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[7-(3,4-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[6-(3,4-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(4-trifluoromethoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-6-(4-trifluoromethoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(4-Hydroxy-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-6-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-6-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-6-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-6-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[7-(2,6-Dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Chloro-7-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[1-Bromo-7-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(1-Bromo-7-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-6-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-7-trifluoromethyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-6-trifluoromethyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1,7-dibromo-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(7-Bromo-1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(6-Bromo-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-7-fluoro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(7-Fluoro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-7-fluoro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-benzo[g]isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-6-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-7-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-6-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-7-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-6-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-7-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-5-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-8-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-5-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-8-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-5-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-8-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Ethylsulfanyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[4-Hydroxy-1-(4-methoxy-phenylsulfanyl)-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(1-Chloro-4-hydroxy-7-iodo-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Chloro-4-hydroxy-6-iodo-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-7-iodo-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-4-hydroxy-7-methyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-7-butoxy-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Bromo-6-butoxy-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(6-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-methyl-amino]-acetic acid;

[(1-Chloro-4-hydroxy-isoquinoline-3-carbonyl)-methyl-amino]-acetic acid;

[(1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carbonyl)-methyl-amino]-acetic acid;

[(1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carbonyl)-methyl-amino]-acetic acid;

[Carboxymethyl-(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[Carboxymethyl-(1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

{[7-(3,5-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[6-(3,5-Difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

({7-[4-(4-Fluoro-phenoxy)-phenoxy]-4-hydroxy-isoquinoline-3-carbonyl}-amino)-acetic acid;

({6-[4-(4-Fluoro-phenoxy)-phenoxy]-4-hydroxy-isoquinoline-3-carbonyl}-amino)-acetic acid;

{[7-(3-Chloro-4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[6-(3-Chloro-4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[7-(4-Chloro-phenoxy)-4-hydroxy-1-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[6-(4-Chloro-phenoxy)-4-hydroxy-1-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[7-(3,5-Difluoro-phenoxy)-4-hydroxy-1-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-7-(4-methoxy-phenoxy)-1-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid;

{[4-Hydroxy-6-(4-methoxy-phenoxy)-1-methyl-isoquinoline-3-carbonyl]-amino}-acetic acid;

[(6-Cyclohexyloxy-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(7-Cyclohexyloxy-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(7-Cyclohexyloxy-4-hydroxy-1-methyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(7-Cyclohexylsulfanyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(7-Cyclohexanesulfonyl-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-isobutyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-pyridin-2-yl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Ethyl-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(1-Dimethylaminomethyl-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid;

[(4-Hydroxy-1-methyl-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-acetic acid; and

{[4-Hydroxy-1-methyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-acetic acid;

or a pharmaceutically acceptable salt, ester or amide derived from an amine of the formula HNR 20 R 21 where R 20 and R 21 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, thereof.

19. The method of claim 18 , wherein the compound is [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid or a pharmaceutically acceptable salt, ester or amide derived from an amine of the formula HNR 20 R 21 where R 20 and R 21 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, thereof.

20. The method of claim 18 , wherein the compound is [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid.

Assignments (3)

Continuity (11)