IP Library › Granted Patent US 10,000,501
Granted Patent B2
US 10,000,501 · App. 15/513,852 · Granted Jun 19, 2018

Inhibitors of HIF prolyl hydroxylase

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Quick Facts
Patent No.
US 10,000,501
App. No.
15/513,852
Granted
Jun 19, 2018
Kind
B2
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.

Claims (106)

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-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(4-hydroxy-2-oxo-1-(pyridin-2-ylmethyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(4-hydroxy-2-oxo-1-(pyridin-4-ylmethyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(1-(4-cyano-3-fluorobenzyl)-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-(thiazol-5-ylmethyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(4-Hydroxy-1-(4-(2-hydroxypropan-2-yl)benzyl)-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(1-(4-Carbamoylbenzyl)-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-((4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(4-hydroxy-2-oxo-1-((4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)methyl)-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(1-((4′-chloro-[1,1′-biphenyl]-4-yl)methyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(1-((4′-carbamoyl-[1,1′-biphenyl]-4-yl)methyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(1-((4′-cyano-[1,1′-biphenyl]-4-yl)methyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxamido)acetic acid;

2-(1-(4-Cyano-2-fluorobenzyl)-4-hydroxy-7-methyl-2,6-dioxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(4-hydroxy-7-methyl-1-(4-(methylsulfonyl)benzyl)-2,6-dioxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(1-(2,4-difluorobenzyl)-4-hydroxy-7-methyl-2,6-dioxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(1-(3-cyanobenzyl)-4-hydroxy-7-methyl-2,6-dioxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(1-(4-cyanobenzyl)-4-hydroxy-7-methyl-2,6-dioxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(1-(4-chlorobenzyl)-4-hydroxy-7-methyl-2,6-dioxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(1-(2-chlorobenzyl)-4-hydroxy-7-methyl-2,6-dioxo-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(4-Hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,6,7,8-hexahydro-1,8-naphthyridine-3-carboxamido)acetic acid;

2-(4-Hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamido)acetic acid;

2-(7-Benzyl-4-hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,6,7,8-hexahydro-1,7-naphthyridine-3-carboxamido)acetic acid;

2-(4-Hydroxy-6-methyl-2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamido)acetic acid;

2-((5S,8R)-1-(benzo[d]thiazol-2-ylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydro-5,8-methanoquinoline-3-carboxamido)acetic acid;

2-(−4-hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,6,7,8-hexahydro-5,8-methanoquinoline-3-carboxamido)acetic acid;

2-(−4-hydroxy-2-oxo-1-((2-phenylthiazol-5-yl)methyl)-1,2,5,6,7,8-hexahydro-5,8-methanoquinoline-3-carboxamido)acetic acid; or

2-(−4-hydroxy-2-oxo-1-((4-phenylthiazol-2-yl)methyl)-1,2,5,6,7,8-hexahydro-5,8-methanoquinoline-3-carboxamido)acetic acid;

or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound of formula II as recited in claim 1 and a pharmaceutically acceptable carrier.

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

wherein:

W is CH 2 or NR 5 ;

X is CH 2 , O, (C═O), or NR 5 ;

Y is 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.

5. A pharmaceutical composition comprising a compound of formula II as recited in claim 4 and a pharmaceutically acceptable carrier.

Assignments (5)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 26, 2017
From: LIU, RONGQIANG
To: MSD R&D (CHINA) CO., LTD.
Reel/Frame 041745/0185 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 26, 2017
From: WUXI APPTEC (SHANGHAI) CO., LTD.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 041745/0194 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 26, 2017
From: CAI, JIAQIANG; DU, XIAOXING; QUAN, WEIGUO
To: WUXI APPTEC (SHANGHAI) CO., LTD.
Reel/Frame 041745/0201 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 26, 2017
From: COLANDREA, VINCENT; CRESPO, ALEJANDRO; DEBENHAM, JOHN; GUIADEEN, DEODIALSINGH; LIU, PING; MADSEN-DUGGAN, CHRISTINA B.; MCCOY, JOSHUA G.; SINZ, CHRISTOPHER; WANG, LIPING
To: MERCK SHARP & DOHME CORP.
Reel/Frame 042093/0702 →