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

摘要

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).;

主权项

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; R1 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 Z1 or Z2 is —NR2— and the other of Z1 or Z2 is —C(O)—; R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; R3 and R4 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 —NR6— or —O—; n is 1, 2, 3, 4, 5, or 6; R5 is selected from the group consisting of hydrogen, acyl, sulfonyl, aminoacyl, oxycarbonyl, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; R7 and R8 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl; or R7 and R8 together with the carbon atom to which they are attached form a cycloalkyl, or heterocycloalkyl; W is selected from the group consisting of R9, —C(O)OR9, —C(O)NR6R9, —NR6C(O)R9, —NR6C(O)OR9, —NR6C(O)NR6R9, —NR6S(O)2R9, —S(O)2NR6R9, —NR6R9 and —OR9; and R9 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 R1, R2, R3, R4, R6, R7, R8 and R9 can be optionally substituted with from 1 to 3 R10, wherein each R10 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, —OSO2—NR40R40, —NR40S(O)2—NR40-alkyl, —NR40S(O)2—NR40-aryl, —NR40S(O)2—NR40-heteroaryl, and —NR40S(O)2—NR40-heterocyclic, where each R40 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.