US 2014/0275020 A1Published application

Inhibitors of the renal outer medullary potassium channel

AssigneeMerck Sharp & Dohme Corp.

InventorsShawn P. Walsh, Alexander Pasternak, Zhi-Cai Shi, Brian Cato

Life of this patent

Estimating the term…

Abstract

This invention relates to compounds of Formula I having the following general structure: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

Claims18

Dependent claims

A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:
—X—R—(CH2)n2- is
and where R represents a 4-6-membered heterocyclic ring of the following structure:
with the proviso that R—I is not a para-substituted 6-membered ring;
a is CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2OCH2— or absent;
wherein the CH2— is optionally substituted with 1-2 of —F, and wherein the —CH2CH2—, —CH2CH2CH2—, or —CH2OCH2— is optionally substituted with 1-3 of —F;
and wherein a forms a bridge between two non-adjacent carbons;
R5 is —H, —F with the proviso that —F is not attached to a carbon also bonded to nitrogen, —CH3, —CF3, —CHF2, —CH2F, or —CH2OH, or R5 represents di-substitution on a single carbon with two of —F with the proviso that the two —F are not attached to a carbon also bonded to nitrogen, or two of —CH3;
R6 and R7 are individually either H, C1-3 alkyl optionally substituted with 1-3 of —F, or R6 and R7 can be taken together with the carbon atom to which they are attached to form C3 cycloalkyl optionally substituted with 1-3 of —F;
R8 is H, —F, —CH3, —CF3, —CHF2, —CH2F, or —CH2OH, or phenyl optionally substituted with 1-3 of —F or C1-3 alkyl;
n1 and n2 can be individually either 0 or 1;
Z1 is:
one of W1 and W2 is N and the other is CH;
R1 and R2 are each independently —H, —F, —Cl, —Br, cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3alkyl optionally substituted with 1-3 of —F;
one of R3a and R3b is —CN, tetrazolyl, or S(O)2C1-3alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3 alkyl optionally substituted with 1-3 of —F;
one of R4a and R4b is —CN, tetrazolyl, or S(O)2C1-3alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3 alkyl optionally substituted with 1-3 of —F;
Ra, Raa, Rb and Rbb are each independently —H, —F, Cl, —C1-3alkyl optionally substituted with 1 to 3 of —F, or —OC1-3alkyl optionally substituted with 1 to 3 of —F;
Re and Rd are each independently H, —F, Cl, —C1-3 alkyl optionally substituted with 1 to 3 of —F, or —OC1-3 alkyl optionally substituted with 1 to 3 of —F;
X is absent or C1 alkyl having 2 substituents independently H, or —C1-3 alkyl optionally substituted with 1 to 3 of —F, wherein two —C1-3 alkyl substituents can be taken together with the C1 alkyl to which they are attached to form a C3-6 cycloalkyl;
and
one of Y1 or Y2 is CH(OH)—;
and the other is CH(OH)—;
S(O)2—;
S(O)2CH2—;
—CH2— wherein —CH2— is optionally substituted with —C1-3 alkyl optionally substituted with OH, —OC1-3alkyl, or −1-3 of —F, or absent;
provided that where Y1 or Y2 is S(O)2— or S(O)2CH2—, then the adjacent n1 or n2, respectively, is 0;
and provided further that where Y1 or Y2 is CH(OH)—, then the adjacent n1 or n2, respectively, is 1.

24 more elements

A compound selected from:

5-{(1R)-1-Hydroxy-2-[(3R)-3-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-Hydroxy-2-[3-(1-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}cyclobutyl)pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-Hydroxy-2-[2-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-Hydroxy-2-[2-({[2-hydroxy-1-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-Hydroxy-2-[2-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)piperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-Hydroxy-2-[2-({[2-hydroxy-1-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)piperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-Hydroxy-2-[3-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)-3-methylpyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1 (3H)-one;
5-{(1R)-1-Hydroxy-2-[3-({[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}methyl)-3-methylpiperidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
6-{1-Hydroxy-2-[({1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]pyrrolidin-2-yl}methyl)amino]ethyl}pyridine-3-carbonitrile;
6-(1-Hydroxy-2-((R)-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-ylamino)ethyl)nicotinonitrile;
6-(1-Hydroxy-2-((S)-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-ylamino)ethyl)nicotinonitrile;
6-(1-Hydroxy-2-((R)-3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethylamino)pyrrolidin-1-yl)ethyl)nicotinonitrile;
6-{1-Hydroxy-2-[({1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperidin-2-yl}methyl)amino]ethyl}pyridine-3-carbonitrile;
(R)-4-Cyano-N-((1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)azetidin-3-yl)methyl)benzenesulfonamide;
4-Cyano-N—((R)-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)benzenesulfonamide;
(R)-1-(4-Cyanophenyl)-N-((1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)azetidin-3-yl)methyl)methanesulfonamide;
5-{(1R)-1-Hydroxy-2-[(1S,4S)-6-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}-2-azabicyclo[2.2.1]hept-2-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
6-((1-(R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-2-yl)methylamino)nicotinonitrile;
N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-2-yl)methyl)-4-(1H-tetrazol-1-yl)benzenesulfonamide;
6-(3-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethylamino)piperidin-1-yl)nicotinonitrile;
6-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methylpyrrolidin-3-yl)methylamino)nicotinonitrile;
6-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-phenylpyrrolidin-3-yl)methylamino)nicotinonitrile;
5-((1R)-2-(3-(1-([1,2,4]Triazolo[4,3-a]pyrazin-8-ylamino)cyclobutyl)pyrrolidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one and
5-((1R)-2-(3-(([1,2,4]Triazolo[4,3-c]pyrazin-8-ylamino)methyl)-3-phenylpyrrolidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one;
or a pharmaceutically acceptable salt thereof.

22 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/353,817Filed 25 Oct 2012
Priority: 31 Oct 2011
Published: 18 Sep 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 405/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
C07D 471/08
In which the condensed system contains two hetero rings: bridged systems
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems

Family

Application61/553,358Us provisional application · filed 31 Oct 2011
US 9,108,947 B2Related patent
US 2014/0275020 A1This patent

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

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Abstract

A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:
—X—R—(CH2)n2- is
and where R represents a 4-6-membered heterocyclic ring of the following structure:
with the proviso that R—I is not a para-substituted 6-membered ring;
a is CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2OCH2— or absent;
wherein the CH2— is optionally substituted with 1-2 of —F, and wherein the —CH2CH2—, —CH2CH2CH2—, or —CH2OCH2— is optionally substituted with 1-3 of —F;
and wherein a forms a bridge between two non-adjacent carbons;
R5 is —H, —F with the proviso that —F is not attached to a carbon also bonded to nitrogen, —CH3, —CF3, —CHF2, —CH2F, or —CH2OH, or R5 represents di-substitution on a single carbon with two of —F with the proviso that the two —F are not attached to a carbon also bonded to nitrogen, or two of —CH3;
R6 and R7 are individually either H, C1-3 alkyl optionally substituted with 1-3 of —F, or R6 and R7 can be taken together with the carbon atom to which they are attached to form C3 cycloalkyl optionally substituted with 1-3 of —F;
R8 is H, —F, —CH3, —CF3, —CHF2, —CH2F, or —CH2OH, or phenyl optionally substituted with 1-3 of —F or C1-3 alkyl;
n1 and n2 can be individually either 0 or 1;
Z1 is:
one of W1 and W2 is N and the other is CH;
R1 and R2 are each independently —H, —F, —Cl, —Br, cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3alkyl optionally substituted with 1-3 of —F;
one of R3a and R3b is —CN, tetrazolyl, or S(O)2C1-3alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3 alkyl optionally substituted with 1-3 of —F;
one of R4a and R4b is —CN, tetrazolyl, or S(O)2C1-3alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3 alkyl optionally substituted with 1-3 of —F;
Ra, Raa, Rb and Rbb are each independently —H, —F, Cl, —C1-3alkyl optionally substituted with 1 to 3 of —F, or —OC1-3alkyl optionally substituted with 1 to 3 of —F;
Re and Rd are each independently H, —F, Cl, —C1-3 alkyl optionally substituted with 1 to 3 of —F, or —OC1-3 alkyl optionally substituted with 1 to 3 of —F;
X is absent or C1 alkyl having 2 substituents independently H, or —C1-3 alkyl optionally substituted with 1 to 3 of —F, wherein two —C1-3 alkyl substituents can be taken together with the C1 alkyl to which they are attached to form a C3-6 cycloalkyl;
and
one of Y1 or Y2 is CH(OH)—;
and the other is CH(OH)—;
S(O)2—;
S(O)2CH2—;
—CH2— wherein —CH2— is optionally substituted with —C1-3 alkyl optionally substituted with OH, —OC1-3alkyl, or −1-3 of —F, or absent;
provided that where Y1 or Y2 is S(O)2— or S(O)2CH2—, then the adjacent n1 or n2, respectively, is 0;
and provided further that where Y1 or Y2 is CH(OH)—, then the adjacent n1 or n2, respectively, is 1.

24 more elements

Facts

Application

14/353,817Filed 25 Oct 2012

Priority

31 Oct 2011

Published

18 Sep 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 405/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
C07D 471/08
In which the condensed system contains two hetero rings: bridged systems
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems