Isoxazolopyridine derivatives for use in the treatment of hif-mediated conditions
AssigneeFibroGen, Inc.
InventorsMichael P. Arend, Heng Cheng, Lee A. Flippin, Danny Ng, Eric D. Turtle, Min Wu
Life of this patent
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Abstract
The present invention relates to novel compounds capable of modulating the stability and/or activity of hypoxia inducible factor (HIF) by inhibiting the activity of at least one HIF hydroxylase enzyme.
Claims32
A compound of Formula I:
- wherein
- q is 0 or 1;
- X and Z are independently selected from the group consisting of —O—, ═N—, and ═C(R3)—;
- Y is ═C(R5)— or ═N—,
- with the proviso that at least one of the following is present
- a) one of X or Z is —O— and the other is ═N—, and Y is ═C(R5)—;
- or
- b) one of X or Z is —O— and the other is ═C(R3)—, and Y is ═N—;
- R1 is selected from the group consisting of hydrogen, deuterium, alkyl, and substituted alkyl;
- R2 is selected from the group consisting of hydrogen, halo, cyano, nitro, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, amino, substituted amino, aminoacyl, acylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, alkylthio, substituted alkylthio, cycloalkylthio, substituted cycloalkylthio, arylthio, substituted arylthio, heteroarylthio, substituted heteroarylthio, heterocyclicthio, substituted heterocyclicthio, and acyl;
- R3 and R5 are independently selected from the group consisting of hydrogen, hydroxy, cyano, halo, nitro, acyl, amino, substituted amino, acylamino, sulfonyl, substituted sulfonyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, alkylthio, substituted alkylthio, cycloalkylthio, substituted cycloalkylthio, arylthio, substituted arylthio, heteroarylthio, substituted heteroarylthio, heterocyclicthio, substituted heterocyclicthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, and substituted heteroaryloxy;
- R6 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
- R7 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, mercapto, alkylthio, substituted alkylthio, cycloalkylthio, substituted cycloalkylthio, arylthio, substituted arylthio, heteroarylthio, substituted heteroarylthio, heterocyclicthio, substituted heterocyclicthio, amino, substituted amino, and acylamino;
- and
- R8 is selected from the group consisting of hydrogen, deuterium, and methyl;
- or a pharmaceutically acceptable salt, single stereoisomer, mixture of stereoisomers, ester, or prodrug thereof.
A compound selected from the group consisting of [(7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, {[2-(4-fluoro-phenyl)-7-hydroxy-oxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, [(7-hydroxy-4-methyl-2-phenyl-oxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(4-ethyl-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(7-hydroxy-2,4-diphenyl-oxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(7-hydroxy-2-phenyl-4-phenylethynyl-oxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(4-butyl-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, {[4-(4-fluoro-phenyl)-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, [(7-hydroxy-2-phenyl-oxazolo[5,4-c]pyridine-6-carbonyl)-amino]-acetic acid, {[7-hydroxy-4-(3-methoxy-phenyl)-2-phenyl-oxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, [(4-Hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, [(4-hydroxy-7-methyl-3-phenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, [(4-hydroxy-3,7-diphenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, {[3-(4-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(2-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[4-hydroxy-3-(4-methoxy-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(3-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(2-chloro-6-fluoro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(4-fluoro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]amino}-acetic acid, [(7-cyano-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, {[3-(4-chloro-phenyl)-4-hydroxy-7-methyl-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[7-cyano-3-(4-fluoro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]amino}-acetic acid, {[7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(4-chloro-phenyl)-7-cyano-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(4-fluoro-phenyl)-4-hydroxy-7-methyl-isoxazolo[5,4-c]pyridine-5-carbonyl]amino}-acetic acid, {[3-(3-chloro-phenyl)-7-(ethanic acid-2-yl)amino-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(4-chloro-phenyl)-7-ethynyl-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, [(3-biphenyl-4-yl-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, (S)-2-[(4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-propionic acid, (R)-2-[(4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-propionic acid, {[4-hydroxy-3-(3-trifluoromethoxy-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, [(4-hydroxy-3-phenyl-7-pyridin-3-yl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, {[4-hydroxy-3-(4-trifluoromethyl-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[4-hydroxy-3-(2-trifluoromethoxy-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, [(4-hydroxy-3-phenyl-7-pyridin-4-yl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, [(4-hydroxy-3-phenyl-7-pyridin-2-yl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, [(4-hydroxy-3-phenyl-7-trifluoromethyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, {[4-hydroxy-3-(4-trifluoromethoxy-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(4-tert-butyl-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, [(7-bromo-4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, [(7-hydroxy-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, (S)-2-[(7-hydroxy-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-propionic acid, (R)-2-[(7-hydroxy-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-propionic acid, {[3-(4-fluoro-phenyl)-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, {[7-hydroxy-3-(4-methoxy-phenyl)-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, [(7-hydroxy-3-thiophen-2-yl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(7-hydroxy-3-pyridin-4-yl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino}-acetic acid, {[3-(5-bromo-furan-2-yl)-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, [(7-hydroxy-4-methyl-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(4-cyano-7-hydroxy-3-thiophen-2-yl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, {[4-cyano-3-(4-fluoro-phenyl)-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, {[4-cyano-7-hydroxy-3-(4-methoxy-phenyl)-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, {[3-(5-bromo-furan-2-yl)-4-cyano-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, {[7-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, {[7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, [(7-hydroxy-3-phenyl-4-phenylethynyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(4-ethynyl-7-hydroxy-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(4-cyclopropyl-7-hydroxy-3-thiophen-2-yl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, {[7-hydroxy-3-(4-methoxy-phenyl)-4-pyrazol-1-ylmethyl-isoxazolo[4,5-c]pyridine-6-carbonyl]amino}-acetic acid, [(4-acetyl-7-hydroxy-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(4-benzyl-7-hydroxy-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, {[4-(1-benzyl-1H-[1,2,3]triazol-4-yl)-7-hydroxy-3-phenyl-isoxazolo[4,5-c]pyridine-6-carbonyl]-amino}-acetic acid, [(7-hydroxy-3-phenyl-4-trifluoromethyl-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(3-cyclohex-1-enyl-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, [(3-ethyl-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid, {[3-(3-Cyano-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(4-Cyano-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[4-Hydroxy-3-(4-phenoxy-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, [(4-Hydroxy-3-methyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, [(4-Hydroxy-3-methyl-7-phenyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, [(4-Hydroxy-3,7-dimethyl-isoxazolo[5,4-c]pyridine-5-carbonyl)-amino]-acetic acid, {[4-Hydroxy-7-methyl-3-(4-trifluoromethoxy-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[4-Hydroxy-3-(4-methoxy-phenyl)-7-methyl-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, {[3-(2,4-Dichloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid, and {[4-Hydroxy-3-(4-methanesulfonyl-phenyl)-isoxazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid.
Dependencies are inferred from the claim text.