Nitrogen-containing heteroaryl compounds and methods of use thereof
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.
1. A compound represented by formula IC:
wherein
q is zero or one;
W is selected from the group consisting of oxygen, —S(O) n — and —NR 9 — where n is zero, one or two, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and R 8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, or when W is —NR 9 — then R 8 and R 9 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or a substituted heterocyclic group, provided that when W is —S(O) n — and n is one or two, then R 8 is not hydrogen;
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 , —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 —SO— or —SO 2 —, then R 6 is not hydrogen, and R 7 is selected from the group consisting of hydrogen, alkyl, aryl, or R 2 , R 3 together with the carbon atom 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, deuterium and methyl;
R′ is selected from the group consisting of alkyl, substituted alkyl and substituted amino; alternatively, R and R′ and the carbon pendent thereto can be joined to form cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group;
R″ is selected from the group consisting of hydrogen and alkyl or R″ together with R′ and the nitrogen pendent thereto can be joined to form a heterocyclic or substituted heterocyclic group;
R′″ is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, —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 and prodrug thereof;
with the following proviso:
that when R 1 , R 3 , R 4 , and R 5 are hydrogen, then R 2 is not bromo.
2. A compound as in 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.
3. A compound as in claim 2 , 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.
4. A compound as in 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.
5. A compound as in claim 4 , 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.
6. A compound as in 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, —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, aminocarbonylamino, and heteroaryloxy.
7. A compound as in claim 6 , 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.
8. A compound as in claim 1 , wherein R 2 and R 3 , combined with the carbon atom pendent thereto, join to form an aryl group.
9. A compound as in claim 8 , wherein said aryl group is phenyl.
10. A compound as in claim 1 , wherein R 4 is selected from the group consisting of substituted arylthio, halo, hydrogen, substituted alkyl and aryl.
11. A compound as in claim 10 , wherein R 4 is selected from the group consisting of:
4-chlorophenyl sulfanyl;
chloro;
hydrogen;
methoxymethyl; and
phenyl.
12. A compound as in claim 1 , wherein R 5 is hydrogen or aryl.
13. A compound as in claim 12 , wherein R 5 phenyl.
14. A compound as in claim 1 , wherein R is selected from the group consisting of hydrogen, deuterium, aryl and alkyl.
15. A compound as in claim 14 , wherein R is selected from the group consisting of phenyl, hydrogen, deuterium and methyl.
16. A compound as in claim 1 , wherein R′ is selected from the group consisting of alkyl, substituted alkyl, and substituted amino.
17. A compound of claim 16 , wherein R′ is selected from the group consisting of:
4-aminobutyl;
4-hydroxybenzyl;
benzyl;
carboxylmethyl;
hydroxymethyl;
imidazol-4-ylmethyl;
isopropyl;
methyl; and
propyl.
18. A compound as in claim 1 , wherein R, R′ and the carbon atom pendent thereto join to form a cycloalkyl.
19. A compound as in claim 18 , wherein said cycloalkyl is cyclopropyl.
20. A compound as in claim 1 , wherein R″ is hydrogen.
21. A compound as in claim 1 , wherein R′, R″ and the carbon atom and nitrogen atom respectively pendent thereto join to form a heterocyclic group.
22. A compound as in claim 21 , wherein said heterocyclic group is pyrrolidinyl.
23. A compound as in claim 1 , wherein R″′ is selected from the group consisting of hydrogen, hydroxy, alkoxy, substituted alkoxy, thiol, acyloxy and aryl.
24. A compound as in claim 23 , wherein R″′ is selected from the group consisting of:
hydroxy;
benzyloxy;
ethoxy;
hydrogen;
thiol;
methoxy;
methylcarbonyloxy; and
phenyl.
25. A compound as in claim 1 , wherein WR 8 is preferably selected from the group consisting of amino, substituted amino, hydroxy, and alkoxy.
26. A compound as in claim 25 , wherein WR 8 is selected from the group consisting of:
amino;
dimethylamino;
hydroxy;
methoxy; and
methylcarbonylamino.
27. A compound as in claim 1 , wherein said compound is represented by formula IIC:
wherein:
q is zero or one;
R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, 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;
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —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;
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;
R is selected from the group consisting of hydrogen and methyl;
R′ is selected from the group consisting of alkyl and substituted alkyl; or R and R′ can be joined to form cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic
R″ is selected from the group consisting of hydrogen and alkyl or R″ together with R′ and the nitrogen pendent thereto forms a heterocyclic or substituted heterocyclic group;
W is selected from the group consisting of oxygen, —S(O) n — and —NR 9 — where n is zero, one or two, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; or
or a pharmaceutically acceptable salt or prodrug thereof.
28. A compound selected from the group consisting of:
1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide;
1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide;
1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
29. A compound represented by formula:
wherein:
R 2 and R 3 are independently selected from hydrogen or alkoxy;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
30. A compound as in claim 29 , wherein R 2 is hydrogen or isopropoxy.
31. A compound as in claim 29 , wherein R 3 is hydrogen or isopropoxy.
32. A compound represented by formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof.
33. A compound represented by formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof.
34. A compound represented by formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof.
35. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
36. A composition comprising the compound of claim 1 or a mixture of compounds of claim 4 in combination with at least one additional therapeutic agent.
37. The composition of claim 36 wherein the additional therapeutic agent is erythropoietin.
38. A method of treating a condition mediated at least in part by hypoxia inducible factor (HIF) and/or erythropoietin (EPO) is provided, said method comprises administering to a mammalian patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 and pharmaceutically acceptable excipient or carrier, wherein said condition is selected from the group consisting of anemic disorders; neurological disorders and/or injuries; cases of stroke, trauma, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, and stroke; peripheral vascular disorders, ulcers, burns, and chronic wounds; pulmonary embolism; and ischemic-reperfusion injury.