US 10,208,064 B2Granted

Inhibitors of the renal outer medullary potassium channel

AssigneeMerck Sharp & Dohme Corp.

InventorsAlexander Pasternak, Ian Davies, Fa-Xiang Ding, Jinlong Jiang, Shuzhi Dong, Xin Gu, Takao Suzuki, Joseph P. Vacca, Zhifa Pu, Shouning Xu

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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.

Claims9

Dependent claims

A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:
Z is
X is C(R4);
R1 is —H, halo, —OH, or —OC1-3alkyl;
R2 is —H, ═O, —OH, —C1-3alkyl or —OC1-3alkyl;
R3a is —H, —C3-4cycloalkyl or —C1-3alkyl optionally substituted with —OCH3 or 1 to 3 of —F;
R3b is —H or —C1-3alkyl, or R3b is absent when the dashed bond is a double bond;
or R3a and R3b are joined together with the carbon to which they are both attached to form cyclopropyl or cyclobutyl;
R4 is —H, halo, —CN, —C3-6cycloalkyl, —C(O)OC1-4alkyl, —OC1-4alkyl, or —C1-4alkyl optionally substituted with OH or 1-3 of —F;
R5 is —H, halo, or —C1-3alkyl optionally substituted with —O—C1-3alkyl;
R6 is —H or —C1-3alkyl;
R7 is —H or —C1-3alkyl optionally substituted with —OH, —OCH3 or 1 to 3 of —F, or R7 is absent when n is zero;
R8 is —H or —C1-3alkyl, or R8 is absent when n is zero;
or R7 and R8 are joined together with the carbon to which they are both attached to form cyclopropyl or cyclobutyl;
R9 is —H, halo, —OH, —C1-3alkyl, —OC1-3alkyl or —CH2OH;
R10 is —H, or —C1-3alkyl optionally substituted with —OH, —OCH3, or 1 to 3 of —F;
R11 is —H, or —C1-3alkyl optionally substituted with —OH, —OCH3, or 1 to 3 of —F;
R12 and R13 are each independently —H, halo, —CN, —C3-6cycloalkyl, —C(O)OC1-4alkyl, —OC1-4alkyl, or C1-4alkyl optionally substituted with —OH or 1-3 of —F;
m is zero where R3b is absent, or one where R3b is present;
the partially dashed double bond (“”) represents a single or double bond wherein:
(i) when m is one, then the dashed bond is a single bond;
and
(ii) when m is zero and R2 is not ═O, then the dashed bond is a double bond;
and
n is zero or one.

22 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/323,989Filed 9 Jul 2015
Priority: WO PCT/CN2014/08211914 Jul 2014
Published: US 2017/0197989 A113 Jul 2017
Granted: 19 Feb 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification21 codes

C07D 519/00
Heterocyclic compounds containing more than one system of two or more relevant
A61K 31/435
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having six-membered rings with one nitrogen as the only ring hetero atom
A61K 31/4375
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring…
A61K 31/4745
Ortho- or peri-condensed with heterocyclic ring systems: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines