US 10,092,558 B2Granted

Nitrogen-containing heteroaryl compounds and methods of use thereof

AssigneeFibroGen, Inc.

InventorsMichael P. Arend, Lee A. Flippin, Volkmar Guenzler-Pukall, Wen-Bin Ho, Eric D. Turtle, Xiaohui Du

Life of this patent

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Abstract

The present invention relates to compounds suitable for use in mediating hypoxia inducible factor and for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo.

Claims20

Dependent claims

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;
R1 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 —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl or, when X is —NR7—, then R7 and R6, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;
R2 and R3 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(R6)—R6 where n is 0, 1, or 2, —NR6C(O)NR6R6, and —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, each R6 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 —SO2—, then R6 is not hydrogen, and R7 is selected from the group consisting of hydrogen, alkyl, and aryl, or R2 and R3 together with the carbon atoms pendent thereto, form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R4 and R5 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl or, when X is —NR7—, then R7 and R6, 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—R10 wherein R10 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 HNR20R21 where R20 and R21 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) R1 is fluoro, bromo, iodo, alkyl, substituted alkyl, alkoxy, aminoacyl, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl;
or
2) R2 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R2 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C1-C5) alkyl and (C1-C5) alkoxy or does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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) R3 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromo, iodo, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R3 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C1-C5) alkyl and (C1-C5) alkoxy or does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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) R4 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R4 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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) R5 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R5 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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 R1, R3, R4, and R5 are hydrogen, then R2 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.

50 more elements

{[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 HNR20R21 where R20 and R21 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl, thereof.

157 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/133,104Filed 19 Apr 2016 · continuation
Priority: 6 Jun 2003
Published: US 2017/0035747 A19 Feb 2017
Granted: 9 Oct 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification32 codes

A61K 31/472
Quinolines; Isoquinolines: non-condensed isoquinolines, e.g. papaverine
A61K 31/4725
Non-condensed isoquinolines, e.g. papaverine: containing further heterocyclic rings
A61K 31/473
Quinolines; Isoquinolines: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
A61K 38/1816
Growth factors; Growth regulators: erythropoietin [EPO]

Family

Application60/476,811Us provisional application · filed 6 Jun 2003
Application60/476,420Us provisional application · filed 6 Jun 2003
Application60/476,633Us provisional application · filed 6 Jun 2003
Application60/476,519Us provisional application · filed 6 Jun 2003
Application10/861,082Parent of this division · filed 4 Jun 2004
Application12/015,275Parent of this continuation · filed 16 Jan 2008
Application13/186,351Parent of this continuation · filed 19 Jul 2011
Application13/599,161Parent of this continuation · filed 30 Aug 2012
Application13/912,483Parent of this continuation · filed 7 Jun 2013
Application14/284,325Parent of this continuation · filed 21 May 2014
US 2017/0035747 A1Pre-grant publication · published 9 Feb 2017
US 9,339,527 B2Parent of this continuation
US 8,765,956 B2Parent of this continuation
US 8,916,585 B2Parent of this continuation
US 8,278,325 B2Parent of this continuation
US 8,017,625 B2Parent of this continuation
US 7,323,475 B2Parent of this division
Application12/015,275Parent of this division
US 2004/0254215 A1Published application
US 2008/0293763 A1Published application
US 2012/0029011 A1Published application
US 2013/0178417 A1Published application
US 2013/0310565 A1Published application
US 2014/0343094 A1Published application
US 10,092,558 B2This patent

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Abstract

wherein
q is zero or one;
R1 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 —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl or, when X is —NR7—, then R7 and R6, together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;
R2 and R3 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(R6)—R6 where n is 0, 1, or 2, —NR6C(O)NR6R6, and —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, each R6 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 —SO2—, then R6 is not hydrogen, and R7 is selected from the group consisting of hydrogen, alkyl, and aryl, or R2 and R3 together with the carbon atoms pendent thereto, form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R4 and R5 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl or, when X is —NR7—, then R7 and R6, 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—R10 wherein R10 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 HNR20R21 where R20 and R21 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) R1 is fluoro, bromo, iodo, alkyl, substituted alkyl, alkoxy, aminoacyl, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl;
or
2) R2 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R2 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C1-C5) alkyl and (C1-C5) alkoxy or does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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) R3 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromo, iodo, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R3 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C1-C5) alkyl and (C1-C5) alkoxy or does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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) R4 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R4 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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) R5 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or —XR6 where X is oxygen, —S(O)n— or —NR7— where n is zero, one or two, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R7 is hydrogen, alkyl or aryl provided that:
a) when R5 is substituted alkyl such a substituent does not include trifluoromethyl;
b) —XR6 is not alkoxy;
and
c) when —XR6 is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:
—O—[CH2]x—CfH(2f+1−g)Fg
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 R1, R3, R4, and R5 are hydrogen, then R2 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.

50 more elements

Facts

Application

15/133,104Filed 19 Apr 2016 · continuation

Priority

6 Jun 2003

Published

US 2017/0035747 A19 Feb 2017

Granted

9 Oct 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification32 codes

A61K 31/472
Quinolines; Isoquinolines: non-condensed isoquinolines, e.g. papaverine
A61K 31/4725
Non-condensed isoquinolines, e.g. papaverine: containing further heterocyclic rings
A61K 31/473
Quinolines; Isoquinolines: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
A61K 38/1816
Growth factors; Growth regulators: erythropoietin [EPO]

Family

Application60/476,811Us provisional application · filed 6 Jun 2003

Application60/476,420Us provisional application · filed 6 Jun 2003

Application60/476,633Us provisional application · filed 6 Jun 2003

Application60/476,519Us provisional application · filed 6 Jun 2003

Application10/861,082Parent of this division · filed 4 Jun 2004

Application12/015,275Parent of this continuation · filed 16 Jan 2008

Application13/186,351Parent of this continuation · filed 19 Jul 2011

Application13/599,161Parent of this continuation · filed 30 Aug 2012

Application13/912,483Parent of this continuation · filed 7 Jun 2013

Application14/284,325Parent of this continuation · filed 21 May 2014

US 2017/0035747 A1Pre-grant publication · published 9 Feb 2017

US 9,339,527 B2Parent of this continuation

US 8,765,956 B2Parent of this continuation

US 8,916,585 B2Parent of this continuation

US 8,278,325 B2Parent of this continuation

US 8,017,625 B2Parent of this continuation

US 7,323,475 B2Parent of this division

Application12/015,275Parent of this division

US 2004/0254215 A1Published application

US 2008/0293763 A1Published application

US 2012/0029011 A1Published application

US 2013/0178417 A1Published application

US 2013/0310565 A1Published application

US 2014/0343094 A1Published application

US 10,092,558 B2This patent

From the US filing history. Foreign family members aren’t listed.