Inhibitors of HIF prolyl hydroxylase

Patent metadata

Field	Value
Publication number	US-10000501-B2
Application number	US-201515513852-A
Country	US
Kind code	B2
Filing date	Sep 23, 2015
Priority date	Sep 28, 2014
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

The present invention concerns a compound of formula I or a pharmaceutically acceptable salt thereof, which inhibit HIF prolyl hydroxylase, their use for enhancing endogenous production of erythropoietin, and for treating conditions associated with reduced endogenous production of erythropoietin such as anemia and like conditions, as well as pharmaceutical compositions comprising such a compound and a pharmaceutical carrier.

First claim

What is claimed is:

1. A compound of formula II or a pharmaceutically acceptable salt thereof:

wherein:
W is CH 2 or NR 5 ;
X is O, or NR 5 ;
Y is CH 2 , O, (C═O), or NR 5 ;
Z is CH 2 or NR 5 ; wherein when W is CH 2 and Z is CH 2 then W and Z optionally combine with another carbon atom to form a bridge;
R 1 is selected from hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, aryl, heterocyclyl, Me-aryl, Me-heterocyclyl, Me-cycloalkyl, said cycloalkyl, aryl and heterocyclyl are optionally substituted with 1, 2, or 3 substituents chosen from: halogen, CHF 2 , OCHF 2 , CF 3 , OCF 3 , CN, C 1-4 alkyl, O(C 1-4 )alkyl, S(O) 2 R b , C(O)N(R b ) 2 , phenyl, wherein said alkyl and phenyl are optionally substituted with 1, 2, or 3 substituents chosen from: OH, CF 3 , OCF 3 , halogen, C(O)N(R b ) 2 , and CN;
R 5 is independently hydrogen, methyl or phenyl; and
R b is independently hydrogen or C 1-4 alkyl.

2. A compound which is:
2-(4-Hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-7-methyl-2,6-dioxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-Cyanobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-1-(4-(trifluoromethoxy)benzyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-(difluoromethoxy)benzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-fluorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-chlorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-(methylsulfonyl)benzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-isopropylbenzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-isopropoxybenzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(benzo[d]thiazol-2-ylmethyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(3,4-difluorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(2,4-difluorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-cyano-2-fluorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-chloro-2-fluorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-ethyl-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(cyclohexylmethyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(naphthalen-2-ylmethyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-methyl-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-1-((5-(trifluoromethyl)pyrimidin-2-yl)methyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-1-(2,4,5-trifluorobenzyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-1-(4-(methylcarbamoyl)benzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-1-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-Cyano-3-methylbenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-Cyano-3-fluorobenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-1-((6-methoxypyridin-3-yl)methyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-1-(thiazol-5-ylmethyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-1-((1-phenyl-1H-pyrazol-3-yl)methyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-1-(4-(2-hydroxypropan-2-yl)benzyl)-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-carbamoylbenzyl)-4-hydroxy-2-oxo-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-1-((2-(trifluoromethyl)thiazol-4-yl)methyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(4-Hydroxy-2-oxo-1-(4-(trifluoromethoxy)phenyl)-2,5,7,8-tetrahydro-1H-pyrano[4,3-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(2,4-difluorobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-isopropylbenzyl)-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-cyanobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-(methylsulfonyl)benzyl)-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-1-(2,4,5-trifluorobenzyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-cyano-2-fluorobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-cyano-3-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-1-((5-(trifluoromethyl)pyrimidin-2-yl)methyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-chloro-2-fluorobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(benzo[d]thiazol-2-ylmethyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-(difluoromethoxy)benzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-2-oxo-1-(4-(trifluoromethoxy)benzyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(4-fluorobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(3,4-difluorobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-(methylcarbamoyl)benzyl)-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(4-hydroxy-1-(4-isopropoxybenzyl)-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(3-cyanobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;
2-(1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyra

Assignees

• Merck Sharp & Dohme
• Msd R&D China Co Ltd

Inventors

• Cai Jiaqiang
• Colandrea Vincent
• Crespo Alejandro
• Debenham John
• Du Xiaoxing
• Guiadeen Deodialsingh
• Liu Ping
• Liu Rongqiang
• Madsen-Duggan Christina B
• Mccoy Joshua G
• Quan Weiguo
• Sinz Christopher
• Wang Liping

Classifications

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D221/22

  Bridged ring systems · CPC title

• C07D491/052 Primary

  the oxygen-containing ring being six-membered · CPC title

• C07D215/56

  with oxygen atoms in position 4 · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title