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Substituted bicyclic heterocyclic compounds

A technology of compounds and heterocyclic groups, applied in the fields of drug combination, organic chemistry, medical preparations containing active ingredients, etc., can solve problems such as reducing the incidence of hypokalemia

Active Publication Date: 2019-02-05
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

Taken together, these data suggest that inhibition of ROMK produces comparable or better diuretic potency than existing loop diuretics and may reduce the incidence of hypokalemia

Method used

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  • Substituted bicyclic heterocyclic compounds
  • Substituted bicyclic heterocyclic compounds
  • Substituted bicyclic heterocyclic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-I and 1-II

[0438] 1-(6-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indole-4-carbonitrile (enantiomers-I and II)

[0439]

[0440] Intermediate 1A: 1-(6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1H-indole-4-carbonitrile

[0441]

[0442] K 2 CO 3 (0.798g, 5.78mmol) and XANTPHOS (0.223g, 0.385mmol). The resulting reaction mixture was degassed with nitrogen for 5 min before adding Pd 2 (dba) 3 (0.176 g, 0.193 mmol) and the reaction mixture was degassed with nitrogen for another 5 minutes. The reaction mixture was heated in a sealed tube at 100 °C for 16 hours, cooled and concentrated under reduced pressure. The residue was diluted with EtOAc and filtered through celite. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was washed with diethyl ether (50 mL) to afford Intermediate 1A (0.600 g, 81.1%) as a light yellow solid. ...

Embodiment 1-I

[0446] Example 1-I: (Enantiomer-I)

[0447] Intermediate 1B (0.0950 g, 0.345 mmol) and Intermediate I-1-I (0.0980 g, 0.518 mmol) were dissolved in ethanol (15 mL) and heated to reflux for 48 hours. The resulting reaction mixture was evaporated to dryness under reduced pressure. By preparative HPLC [Sunfire (250x30ID) 5 microns, mobile phase A: 0.1% HCOOH / water, mobile phase B: ACN, gradient: 10-45% B over 7 minutes, flow rate: 25 mL / min, retention time 12.05, UV 254 nm] to obtain Example 1-I (Enantiomer-I) (0.0800 g, 48.3%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δppm 2.33(s, 3H), 2.66-2.77(m, 2H), 3.00(t, J=5.2Hz, 4H), 3.84(q, J=8.4Hz, 2H), 5.22(t, J=4.4Hz , 1H), 5.40(d, J=2.8Hz, 3H), 5.44(d, J=4.0Hz, 1H), 6.91(dd, J=0.4Hz, J=3.2Hz, 1H), 7.49(t, J =8.0Hz, 1H), 7.70(t, J=8.0Hz, 1H), 7.74(d, J=3.2Hz, 1H), 8.50(d, J=3.6Hz, 1H), 8.64(s, 1H), 9.06 (d, J=8.4Hz, 1H). LCMS (Method-E): Retention time 2.85, [M+H] 466.2. HPLC (Method-N): Retention time 6.71 min, purity 9...

Embodiment 1-II

[0448] Example 1-II: (Enantiomer-II)

[0449] Example 1-II (enantiomer-II) (0.010 g, 6.28%), which is an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δppm 2.33(s, 3H), 2.66-2.77(m, 2H), 3.00(t, J=5.2Hz, 4H), 3.84(q, J=8.4Hz, 2H), 5.22(t, J=4.4Hz , 1H), 5.40(d, J=2.8Hz, 3H), 5.44(d, J=4.0Hz, 1H), 6.91(dd, J=0.4Hz, J=3.2Hz, 1H), 7.49(t, J =8.0Hz, 1H), 7.70(t, J=8.0Hz, 1H), 7.74(d, J=3.2Hz, 1H), 8.50(d, J=3.6Hz, 1H), 8.64(s, 1H), 9.06 (d, J=8.4Hz, 1H). LCMS / HPLC (Method A): retention time 2.18, [M+1] 466.1, purity: 96.3%. (Method B): retention time 1.39, [M+1] 466.1, purity: 94.5%. Chiral purity (Method XVI): retention time 11.37 min, 98.4% ee.

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Abstract

Disclosed are compounds of Formula (I), or a salt thereof, wherein: X is CR4 or N; Y is CR4 or N, provided that Y is N only if X is N; R1 is Formulae (A) or (B); each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, R3, R4, L1, R1a, R1b, R1c, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprisingsuch compounds. These compounds are useful in treating cardiovascular diseases.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 62 / 325,255, filed April 20, 2016, which is hereby incorporated in its entirety. technical field [0003] The present invention generally relates to substituted bicyclic heterocyclic compounds useful as inhibitors of ROMK channel activity. The application provides substituted bicyclic heterocyclic compounds, compositions comprising these compounds, and methods of use thereof. The present invention also relates to pharmaceutical compositions containing at least one compound of the present invention, which are useful for the treatment of disorders associated with ROMK channel activity, including cardiovascular diseases. Background technique [0004] Extrarenal medullary potassium (ROMK, Kirl.1) channels are weakly inwardly rectifying K + channel, in the kidney K + Play a key role in circulation and secretion (Ho et al., Nature, 1993, 362, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D271/04A61K31/4725A61K31/519A61P9/00
CPCC07D271/04C07D471/04C07D407/04C07D407/06C07D413/14C07D487/04C07D519/00A61P13/12A61P43/00A61P7/10A61P9/00A61P9/04A61P9/12A61K31/4725A61K31/519
Inventor P·格纳加J·里希特N·D·亚达夫M·潘达S·哥德斯
Owner BRISTOL MYERS SQUIBB CO
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