US 2014/0349972 A1Published application

Substituted pyrimidines

AssigneeMerck Sharp & Dohme Corp.

InventorsQun Dang, Changyou Zhou, Wuxin Zou, Yuxia Hua

Life of this patent

Estimating the term…

Abstract

The present invention relates to substituted pyrimidines useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.

Claims20

Dependent claims

A compound of formula I or pharmaceutically acceptable salts thereof:

R1 is a heteroaryl selected from isoxazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyradizinyl, and pyrimidinyl;
R2 and R3 are each independently chosen from hydrogen, hydroxy, —OR, —OCOR, —OCOOR, —OCONHR, and C1-6alkyl;
X is selected from —(C0-3alkyl)PO(R′)OR, —(C0-3 alkyl)PO(OR)2, —(C0-3alkyl)PO(NRR)2, —SO3R,
—(C0-3 alkyl)PO(C1-10alkyl)OR, —(C0-3 alkyl)PO(C3-10cycloalkyl)OR,
(C0-3alkyl)PO(H)OR, —(C0-3alkyl)PO(NHCR′R″COOR)2 and —COOR;
R is independently selected from hydrogen, C1-10 alkyl, —C1-5 alkylaryl, —CR′R′—OCO—C1-10 alkyl, and
—CR′R′—OCO—O—C1-10 alkyl;
R′ and R″ are independently selected from hydrogen and C1-10 alkyl;
L is chosen from a bond, —CONR4—, —NR4CO—, aryl, and heteroaryl;
D is chosen from a bond, aryl, and heteroaryl, provided that when L is a bond then D is aryl or heteroaryl;
R4, R6, and R7 are each independently selected from
hydrogen,
halogen,
carboxyl C0-10 alkyl,
C1-10 alkyl,
C2-10 alkenyl,
C2-10 alkynyl,
C1-10 alkenylamino,
C1-10 alkyl(oxy)0-1 carbonylC1-10 alkyl,
aryl C0-10 alkyl(oxy)0-1 carbonylC1-10 alkyl,
C3-8 cycloalkyl C0-10 alkyl(oxy)0-1carbonyl C1-10 alkyl,
(C3-8)heterocyclyl C0-10 alkyl(oxy)0-1 carbonyl C1-10 alkyl,
(C3-8)heterocycloalkyl C0-10 alkyl(oxy)0-1 carbonyl C1-10 alkyl,
aryl(oxy)0-1C0-10 alkyl,
C3-8 cycloalkyl(oxy)0-1 C0-10 alkyl,
C3-8 heterocyclyl(oxy)0-1 C0-10 alkyl,
C3-8 heterocycloalkyl (oxy)0-1C0-10 alkyl,
C1-10 alkoxyl,
arylC1-10 alkoxyl, and
hydroxyC0-10alkyl;
wherein R1, R2, R3, R4, R6, R7, and D are optionally substituted with 1, 2, or 3 substituent R5 chosen from:
halogen,
(carbonyl)0-1C1-10 alkyl,
(carbonyl)0-1C2-10 alkenyl,
(carbonyl)0-1 C2-10 alkynyl,
C1-10 alkylcarbonyl,
C2-10 alkenylcarbonyl,
C2-10 alkynylcarbonyl,
aryl C0-10 alkyl,
(C3-8)heterocyclyl C0-10 alkyl,
C3-8 cycloalkyl C0-10 alkyl,
(C3-8)heterocycloalkyl C0-10 alkyl,
C1-4acylamino C0-10 alkyl,
C0-10 alkylamino C0-10 alkyl,
arylC0-10 alkylamino C0-10 alkyl,
C3-8 cycloalkyl C0-10 alkylamino C0-10 alkyl,
C3-8 heterocyclyl C0-10 alkylamino C0-10 alkyl,
C3-8 heterocycloalkyl C0-10 alkylamino C0-10 alkyl,
C1-10alkyloxy C0-10alkyl,
(C1-10 alkyl)2aminocarbonyloxy,
hydroxy C0-10alkyl,
C1-10 alkylsulfonyl,
C1-10 alkylsulfonylamino,
aryl C1-10 alkylsulfonylamino,
C3-8 heterocyclyl C1-10 alkylsulfonylamino,
C3-8 heterocycloalkyl C1-10 alkylsulfonylamino,
C3-8 cycloalkyl C1-10 alkylsulfonylamino,
cyano,
nitro,
perfluoroC1-6alkyl, and
perfluoroC1-6alkoxy;
wherein R5 is optionally substituted with 1, 2, or 3 substituents chosen from hydrogen, hydroxy, (C1-6)alkoxyl, halogen, CO2H, CN, O(C═O)C1-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, —O(0-1)(C1-10)perfluoroalkyl, and NH2;
and
provided that when X is —COOR then L is isoxazoldiyl and D is phenyl.

61 more elements

A compound or pharmaceutically aselected from:

diethyl 4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphonate;
4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphonic acid;
(2S,2′S)-diethyl 2,2′-((4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenyl)phosphoryl)bis(azanediyl)dipropanoate;
diethyl 2,2′-((4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenyl)phosphoryl)bis(azanediyl)bis(2-methylpropanoate);
diethyl 2,2′-((4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenyl)phosphoryl)bis(azanediyl)diacetate;
4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphinic acid;
Diethyl 4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido) (phenyl)methyl)phenyl phosphonate;
4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl phosphonic acid;
Ethyl 4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenylphosphonate;
ethyl 4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinate;
4-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinic acid;
diethyl 4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenyl phosphonate;
4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonic acid;
ethyl hydrogen 4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonate;
diethyl (R)-4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenyl phosphonate;
(R)-4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonic acid;
diethyl (S)-4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenyl phosphonate;
(S)-4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonic acid;
(S)-4-(1-(4-hydroxy-2-(pyridazin-3-yl) pyrimidine-5-carboxamido)ethyl)phenylphosphonic acid;
diethyl 5-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido) (phenyl)methyl)pyridin-2-ylphosphonate;
ethyl hydrogen 5-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido) (phenyl)methyl) pyridin-2-ylphosphonate;
3-((4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphonic acid;
diisopropyl (4-hydroxy-2-(pyridin-2-yl) pyrimidine-5-carboxamido) (phenyl) methyl phosphonate;
isopropyl Hydrogen (4-hydroxy-2-(pyridin-2-yl) pyrimidine-5-carboxamido) (phenyl)methylphosphonate;
isopropyl Hydrogen (4-hydroxy-2-(pyridin-2-yl) pyrimidine-5-carboxamido) (phenyl)methylphosphonate;
diethyl 4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidin-5-ylamino)-1-oxopropan-2-yl)phenyl phosphonate;
ethyl 4-(1-(4-hydroxy-2-(pyridin-2-yl)pyrimidin-5-ylamino)-1-oxopropan-2-yl)phenylphosphonate;
diethyl 4-((4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido) (phenyl)methyl)phenylphosphonate;
ethyl hydrogen 4-((4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenylphosphonate;
ethyl 4-((4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido) (phenyl)methyl)phenyl(methyl)phosphinate;
4-((4-Hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinic acid;
diethyl 4-((4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenylphosphonate;
4-((4-Hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphinic acid;
4-((4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphinic acid;
diethyl (4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methylphosphonate;
diethyl 4-(1-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidin-5-ylamino)-1-oxopropan-2-yl)phenylphosphonate;
diethyl 4-(1-(4-hydroxy-2-(1H-pyrazol-1-yl) pyrimidin-5-ylamino)-2-methyl-1-oxopropan-2-yl)phenylphosphonate;
diethyl 4-(1-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidin-5-ylamino)-3-methyl-1-oxobutan-2-yl)phenylphosphonate;
diethyl 4-(2-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidin-5-ylamino)-2-oxo-1-phenylethyl)phenylphosphonate;
diethyl 4-(2-(4-hydroxy-2-(pyridazin-3-yl)pyrimidin-5-ylamino)-2-oxo-1-phenylethyl)phenylphosphonate;
4-(1-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonic acid;
(R)-4-(1-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)ethyl)phenyl phosphonic acid;
(S)-4-(1-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)ethyl)phenylphosphonic acid;
4-((4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(propyl)phosphinic acid;
4-((4-fluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinic acid;
4-((R)-(4-fluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinic acid;
4-((S)-(4-fluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinic acid;
4-((R)-(2,4-difluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinic acid;
4-((S)-(2,4-difluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinic acid;
4-((S)-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinic acid;
4-((R)-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido) (phenyl)methyl)phenyl(methyl)phosphinic acid;
3-((R)-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinic acid;
3-((S)-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)(phenyl)methyl)phenyl(methyl)phosphinic acid;
4-((R)-cyclohexyl(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinic acid;
4-((S)-cyclohexyl(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinic acid;
4-((S)-(2-(4-fluoro-1H-pyrazol-1-yl)-4-hydroxypyrimidine-5-carboxamido)(4-fluorophenyl)methyl)phenyl(methyl)phosphinic acid;
4-((R)-(2-(4-fluoro-1H-pyrazol-1-yl)-4-hydroxypyrimidine-5-carboxamido)(4-fluorophenyl)methyl)phenyl(methyl)phosphinic acid;
(4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(phenyl)methylphosphonic acid;
(4-Hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl) methyl phosphonic acid;
(4-Hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(naphthalen-2-yl)methyl phosphonic acid;
diethyl 2,2′-((4-((4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenyl)phosphoryl)bis(azanediyl)diacetate;
(2S,2′S)-Diethyl 2,2′-((4-((4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenyl)phosphoryl)bis(azanediyl)dipropanoate;
4-((4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)benzylphosphonic acid;
4-(5-(2-(4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)propan-2-yl) pyridine-2-yl)phenylphosphonic acid;
3-((4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl)methyl)phenylphosphonic acid;
3-(2-(4-hydroxy-2-(pyridazin-3-yl)pyrimidin-5-ylamino)-2-oxoethyl)phenyl phosphonic acid;
(4-Hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamido)(4-methoxyphenyl) methyl phosphonic acid;
4-(5-(4-Hydroxy-2-(pyridin-2-yl)pyrimidin-5-yl)isoxazol-3-yl)benzoic acid;
and
4-(5-(4-hydroxy-2-(pyridin-2-yl)pyrimidin-5-yl)isoxazol-3-yl)phenyl(methyl)phosphinic acid;
or pharmaceutically acceptable salts, thereof.

68 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/346,513Filed 19 Sep 2012
Priority: 23 Sep 2011
Published: 27 Nov 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…
C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
C07F 9/65031
Five-membered rings: having the nitrogen atoms in the positions 1 and 2
C07F 9/6521
Having three nitrogen atoms as the only ring hetero atoms: six-membered rings

Family

Application61/555,693Us provisional application · filed 4 Nov 2011
Application14/346,513Continuation
US 9,079,930 B2Related patent
US 2014/0349972 A1This patent

From the US filing history. Foreign family members aren’t listed.

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A compound of formula I or pharmaceutically acceptable salts thereof:

R1 is a heteroaryl selected from isoxazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyradizinyl, and pyrimidinyl;
R2 and R3 are each independently chosen from hydrogen, hydroxy, —OR, —OCOR, —OCOOR, —OCONHR, and C1-6alkyl;
X is selected from —(C0-3alkyl)PO(R′)OR, —(C0-3 alkyl)PO(OR)2, —(C0-3alkyl)PO(NRR)2, —SO3R,
—(C0-3 alkyl)PO(C1-10alkyl)OR, —(C0-3 alkyl)PO(C3-10cycloalkyl)OR,
(C0-3alkyl)PO(H)OR, —(C0-3alkyl)PO(NHCR′R″COOR)2 and —COOR;
R is independently selected from hydrogen, C1-10 alkyl, —C1-5 alkylaryl, —CR′R′—OCO—C1-10 alkyl, and
—CR′R′—OCO—O—C1-10 alkyl;
R′ and R″ are independently selected from hydrogen and C1-10 alkyl;
L is chosen from a bond, —CONR4—, —NR4CO—, aryl, and heteroaryl;
D is chosen from a bond, aryl, and heteroaryl, provided that when L is a bond then D is aryl or heteroaryl;
R4, R6, and R7 are each independently selected from
hydrogen,
halogen,
carboxyl C0-10 alkyl,
C1-10 alkyl,
C2-10 alkenyl,
C2-10 alkynyl,
C1-10 alkenylamino,
C1-10 alkyl(oxy)0-1 carbonylC1-10 alkyl,
aryl C0-10 alkyl(oxy)0-1 carbonylC1-10 alkyl,
C3-8 cycloalkyl C0-10 alkyl(oxy)0-1carbonyl C1-10 alkyl,
(C3-8)heterocyclyl C0-10 alkyl(oxy)0-1 carbonyl C1-10 alkyl,
(C3-8)heterocycloalkyl C0-10 alkyl(oxy)0-1 carbonyl C1-10 alkyl,
aryl(oxy)0-1C0-10 alkyl,
C3-8 cycloalkyl(oxy)0-1 C0-10 alkyl,
C3-8 heterocyclyl(oxy)0-1 C0-10 alkyl,
C3-8 heterocycloalkyl (oxy)0-1C0-10 alkyl,
C1-10 alkoxyl,
arylC1-10 alkoxyl, and
hydroxyC0-10alkyl;
wherein R1, R2, R3, R4, R6, R7, and D are optionally substituted with 1, 2, or 3 substituent R5 chosen from:
halogen,
(carbonyl)0-1C1-10 alkyl,
(carbonyl)0-1C2-10 alkenyl,
(carbonyl)0-1 C2-10 alkynyl,
C1-10 alkylcarbonyl,
C2-10 alkenylcarbonyl,
C2-10 alkynylcarbonyl,
aryl C0-10 alkyl,
(C3-8)heterocyclyl C0-10 alkyl,
C3-8 cycloalkyl C0-10 alkyl,
(C3-8)heterocycloalkyl C0-10 alkyl,
C1-4acylamino C0-10 alkyl,
C0-10 alkylamino C0-10 alkyl,
arylC0-10 alkylamino C0-10 alkyl,
C3-8 cycloalkyl C0-10 alkylamino C0-10 alkyl,
C3-8 heterocyclyl C0-10 alkylamino C0-10 alkyl,
C3-8 heterocycloalkyl C0-10 alkylamino C0-10 alkyl,
C1-10alkyloxy C0-10alkyl,
(C1-10 alkyl)2aminocarbonyloxy,
hydroxy C0-10alkyl,
C1-10 alkylsulfonyl,
C1-10 alkylsulfonylamino,
aryl C1-10 alkylsulfonylamino,
C3-8 heterocyclyl C1-10 alkylsulfonylamino,
C3-8 heterocycloalkyl C1-10 alkylsulfonylamino,
C3-8 cycloalkyl C1-10 alkylsulfonylamino,
cyano,
nitro,
perfluoroC1-6alkyl, and
perfluoroC1-6alkoxy;
wherein R5 is optionally substituted with 1, 2, or 3 substituents chosen from hydrogen, hydroxy, (C1-6)alkoxyl, halogen, CO2H, CN, O(C═O)C1-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, —O(0-1)(C1-10)perfluoroalkyl, and NH2;
and
provided that when X is —COOR then L is isoxazoldiyl and D is phenyl.

61 more elements

Facts

Application

14/346,513Filed 19 Sep 2012

Priority

23 Sep 2011

Published

27 Nov 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…
C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
C07F 9/65031
Five-membered rings: having the nitrogen atoms in the positions 1 and 2
C07F 9/6521
Having three nitrogen atoms as the only ring hetero atoms: six-membered rings