Naphthyridine derivatives as inhibitors of hypoxia inducible factor (HIF) hydroxylase

Patent metadata

Field	Value
Publication number	US-9271970-B2
Application number	US-201414581592-A
Country	US
Kind code	B2
Filing date	Dec 23, 2014
Priority date	Feb 2, 2011
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

The present disclosure relates to novel compounds, methods, and compositions capable of inhibiting HIF hydroxylase enzyme activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF).

First claim

What is claimed is:

1. A method of treating, anemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula Ia:

wherein
q is 0 or 1;
R 1 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, alkoxy, amino, acyloxy, aminoacyl, alkyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl;
one of Z 1 or Z 2 is —NR 2 — and the other of Z 1 or Z 2 is —C(O)—;
R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, acyloxy, aminoacyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl;
— is a single or a double bond;
Y is —NR 6 — or —O—;
n is 1, 2, 3, 4, 5, or 6;
R 5 is selected from the group consisting of hydrogen, acyl, sulfonyl, aminoacyl, oxycarbonyl, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; or R 7 and R 8 together with the carbon atom to which they are attached form a cycloalkyl, or heterocycloalkyl;
W is selected from the group consisting of R 9 , —C(O)OR 9 , —C(O)NR 6 R 9 , —NR 6 C(O)R 9 , —NR 6 C(O)OR 9 , —NR 6 C(O)NR 6 R 9 , —NR 6 S(O) 2 R 9 , —S(O) 2 NR 6 R 9 , —NR 6 R 9 and —OR 9 ; and
R 9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; and
further wherein each alkyl, alkoxy, amino, acyloxy, aminoacyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl described above for R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 can be optionally substituted with from 1 to 3 R 10 ,
wherein each R 10 is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, thioxo, carboxyl, carboxyl ester, cycloalkyl, thio, alkylthio, arylthio, cycloalkylthio, heteroarylthio, heterocyclicthio, sulfonyl, heteroaryl, heterocyclic, cycloalkoxy, heteroaryloxy, heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -heterocyclic, —OSO 2 —NR 40 R 40 , —NR 40 S(O) 2 —NR 40 -alkyl, —NR 40 S(O) 2 —NR 40 -aryl, —NR 40 S(O) 2 —NR 40 -heteroaryl, and —NR 40 S(O) 2 —NR 40 -heterocyclic, where each R 40 is independently hydrogen or alkyl; and further wherein each alkyl, alkoxy, aryl, aryloxy, aryloxyaryl, cycloalkyl, alkylthio, arylthio, cycloalkylthio, heteroarylthio, heterocyclicthio, heteroaryl, heterocyclic, cycloalkoxy, heteroaryloxy, or heterocyclyloxy may be additionally substituted with from 1-3 substituents independently alkyl, alkoxy, haloalkyl, haloalkoxy, or halogen;
or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, ester, tautomer or prodrug thereof.

2. The method of claim 1 , wherein the compound is represented by Formula IIa:

wherein
R 1 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, alkoxy, amino, acyloxy, aminoacyl, alkyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl;
R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
— is a single or a double bond;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, acyloxy, aminoacyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl;
Y is —NR 6 — or —O—;
n is 1, 2, 3, 4, 5, or 6;
R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; or R 7 and R 8 together with the carbon atom to which they are attached form a cycloalkyl, or heterocycloalkyl;
W is selected from the group consisting of R 9 , —C(O)OR 9 , —C(O)NR 6 R 9 ,—NR 6 C(O)R 9 , —NR 6 C(O)OR 9 , —NR 6 C(O)NR 6 R 9 ,—NR 6 S(O) 2 R 9 , —S(O) 2 NR 6 R 9 , —NR 6 R 9 and —OR 9 ; and
R 9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
further wherein each alkyl, alkoxy, amino, acyloxy, aminoacyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl described above for R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 can be optionally substituted with from 1 to 3 R 10 ,
wherein each R 10 is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, aryloxy, aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, thioxo, carboxyl, carboxyl ester, cycloalkyl, thio, alkylthio, arylthio, cycloalkylthio, heteroarylthio, heterocyclicthio, sulfonyl, heteroaryl, heterocyclic, cycloalkoxy, heteroaryloxy, heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -heterocyclic, —OSO 2 —NR 40 R 40 ,—NR 40 S(O) 2 —NR -alkyl, —NR 40 S(O) 2 —NR 40 -aryl, —NR 40 S(O) 2 —NR 40 -heteroaryl, and —NR 40 S(O) 2 —NR-heterocyclic, where each R 40 is independently hydrogen or alkyl; and further wherein each alkyl, alkoxy, aryl, aryloxy, aryloxyaryl, cycloalkyl, alkylthio, arylthio, cycloalkylthio, heteroarylthio, heterocyclicthio, heteroaryl, heterocyclic, cycloalkoxy, heteroaryloxy, or heterocyclyloxy may be additionally substituted with from 1-3 substituents independently alkyl, alkoxy, haloalkyl, haloalkoxy, or halogen;
or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, ester, tautomer or prodrug thereof.

3. The method of claim 1 , wherein the compound is represented by Formula IIb:

wherein
R 1 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, alkoxy, amino, acyloxy, aminoacyl, alkyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl;
R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
— is a single or a double bond;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, acyloxy, aminoacyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, heterocycloalkyl, heteroaryloxy, and heteroaryl;
Y is —NR 6 — or —O—;
n is 1, 2, 3, 4, 5, or 6;
R 6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;
R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; or R 7 and R 8 together with the carbon atom to which they are attached form a cycloalkyl, or heterocycloalkyl;
W is selected from the group consist

Assignees

• Fibrogen Inc

Inventors

• Ng Danny
• Arend Michael P
• Flippin Lee A

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• C12Y114/1103

  Hypoxia-inducible factor-asparagine dioxygenase (1.14.11.30) · CPC title