US 9,850,245 B2Granted

Inhibitors of the renal outer medullary potassium channel

AssigneeMerck Sharp & Dohme Corp.

InventorsAlexander Pasternak, Fa-Xiang Ding, Shuzhi Dong, Jinlong Jiang, Haifeng Tang, Xin Gu, Reynalda K. DeJesus, Jessica Frie, Qinghong Fu, Takao Suzuki, Zhifa Pu

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Abstract

The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.

Claims20

Dependent claims

A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:
R1 is —H, —F, —OH, —C1-3alkyl or —OC1-3alkyl;
R2 is —H, or C1-4alkyl;
R3 is —H, or —C1-3alkyl optionally substituted with —OH, —OCH3 or 1 to 3 of —F;
R4 is —H, or —C1-3alkyl optionally substituted with —OH, —OCH3 or 1 to 3 of —F;
or R3 and R4 are joined together to form —CH2—CH2—;
n is 1 or 2;
R5 is —H, halo, —C3-6cycloalkyl or —C1-3alkyl;
X1 is —C(O)—, —CH2—, —CR6R7C(O)—, —CH2CR6R7—, or —CR6R7CH2—;
X2 is —O—, —OCH2— or —N(R);
X3 is —C(O)—, —CH2—, —CR6R7C(O)—, —CH2CR6R7—, or —CR6R7CH2—;
wherein the ring bearing X1, X2 and X3 is a 5-7 membered ring which results in a (i) 11-13-membered spirocyclic core where n is 1, or a (ii) 12-14-membered spirocyclic core where n is 2;
each R6 and R7 is independently —H, halo, —OH, —OC1-3alkyl, or —C1-3alkyl optionally substituted with —OH, —OCH3 or 1 to 3 of —F;
R8 is —H or —C1-3alkyl;
Z is
Y1, Y2, Y3 and Y4 are each independently selected from C(R9) or N;
provided that at most two of Y1, Y2, Y3 and Y4 are N;
each R9 is independently —H, halo, C1-4alkyl optionally substituted with 1-3 of —F, or OC1-4alkyl;
R10 is —H, halo, or C1-4alkyl optionally substituted with 1-3 of —F;
R11 is —H, C1-4alkyl optionally substituted with 1-3 of —F, or halo;
and
R12 is —H or C1-4alkyl.

19 more elements

A compound which is:

9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one dihydrochloride;
9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
9-(2-(4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
(R)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(S)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-(2-(4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.6]dodecan-5-one;
(R)-8-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;
8-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;
9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
(R)-5-(1-hydroxy-2-(4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)-4-methylisobenzofuran-1(3H)-one;
4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
(R)-5-(2-(4-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one;
(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-chlorofuran-2(5H)-one;
3-chloro-4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;
9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;
(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-cyclopropylfuran-2(5H)-one;
(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-cyclopropylfuran-2(5H)-one;
3-cyclopropyl-4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
4-(9-(2-hydroxy-2-(2-methyl-4-(1H-tetrazol-1-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
4-(9-(2-hydroxy-2-(2-methyl-4-(1H-tetrazol-1-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
4-(9-(2-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
4-(9-(2-hydroxy-2-(2-methoxy-4-(1H-tetrazol-1-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
(R)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-1-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
(1R,2′R,5S)-8-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4′-(5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;
(R)-3-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-11-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-7-oxa-3,11-diazaspiro[5.6]dodecan-12-one;
3-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-11-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-7-oxa-3,11-diazaspiro[5.6]dodecan-12-one;
9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
4-(3-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-7-oxa-3,10-diazaspiro[5.6]dodecan-10-yl)-3-methylfuran-2(5H)-one;
(R)-5-(1-hydroxy-2-(10-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-7-oxa-3,10-diazaspiro[5.6]dodecan-3-yl)ethyl)-4-methylisobenzofuran-1(3H)-one;
(1R,2′R,5S)-8-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;
9-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(1R,2′r,5S)-8-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;
9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-(2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(1R,2′R,5S)-8-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;
4-(9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
9-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(1R,2′r,5S)-8-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)ethyl)-4′-(5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-fluoroethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-fluoroethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-9-(2-fluoro-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(S)-9-(2-fluoro-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;
9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;
or a pharmaceutically acceptable salt thereof.

67 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/505,277Filed 26 Oct 2015
Priority: WO PCT/CN2014/08999831 Oct 2014
Published: US 2017/0275283 A128 Sep 2017
Granted: 26 Dec 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 471/10
In which the condensed system contains two hetero rings: spiro-condensed systems
A61K 31/401
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: proline; Derivatives…
A61K 31/41
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with two or more ring hetero atoms, at least…
A61K 31/4178
1,3-Diazoles: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin