4-methylsulfonyl-substituted piperidine urea compounds
Inventors
Oslob, Johan • Aubele, Danielle • Kim, Jae • McDowell, Robert • Song, Yonghong • Sran, Arvinder • Zhong, Min
Assignees
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Publication Number
US-10758525-B2
Publication Date
2020-09-01
Expiration Date
Abstract
The present invention provides novel 4-methylsulphone-substituted piperidine urea compounds that are useful for the treatment of dilated cardiomyopathy (DCM) and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the compounds is described, as well as methods for treating DCM and other forms of heart disease.
Core Innovation
The invention relates to compounds having a specified formula, or pharmaceutically acceptable salts thereof, for use in treating heart failure with reduced ejection fraction (HFrEF) and dilated cardiomyopathy. The compound structure is defined by Ar1, Ar2, R1, R2, and R3 substitution and optional ring-forming relationships, with Ar1 selected from pyridyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-thiadiazolyl, isothiazolyl, and thiazolyl, and Ar2 selected from phenyl, pyridyl, pyrazolyl, and pyrazolo[1,5-a]pyridyl.
The structural definition includes R1 and R2 selected from H, F, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 haloalkyl, with an optional option to combine R1 and R2 to form a C3- to C5 carbocyclic ring optionally substituted with one or two F. R3 is selected from H, F, OH, and C1-C4 alkyl, and Ra and Rb are defined by halo, CN, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, sulfonyl, and amidino options, including optional formation of 4- to 6-membered or 5- or 6-membered rings having 0, 1 or 2 ring members selected from O, N and S.
The examples describe substituted piperidine-1-carboxamide and piperidine urea scaffolds with sulfonyl-linked heteroaryl or aryl groups, including pyridazinyl, pyrazolyl, isoxazolyl, and related fluorinated substituent patterns. The document also reports characterization data for multiple specific compounds and stereoisomers, including LC-MS, 1H NMR, 19F NMR, optical rotation, and salt formation for selected piperidine derivatives.
Claims Coverage
Two independent claims are present, each directed to a method of treating a specific cardiac condition by administering an effective amount of a compound having the defined structural formula or a pharmaceutically acceptable salt. Across the claims, the inventive coverage is anchored by the same constrained aromatic ring selections, R1/R2 substitution and optional ring-formation logic, and the defined options for R3 and the Ra/Rb substituent sets.
Treatment of heart failure with reduced ejection fraction using a defined compound formula
Administering to a subject in need thereof an effective amount of a compound having the formula, or a pharmaceutically acceptable salt, wherein Ar1 is selected from pyridyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-thiadiazolyl, isothiazolyl, and thiazolyl; Ar2 is selected from phenyl, pyridyl, pyrazolyl, and pyrazolo[1,5-a]pyridyl; R1 and R2 are each independently selected from H, F, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 haloalkyl or optionally combined to form a C3-C5 carbocyclic ring optionally substituted with one or two F; R3 is selected from H, F, OH and C1-C4 alkyl; and Ra and Rb are selected from the defined substituent and ring-forming options.
Treatment of dilated cardiomyopathy using a defined compound formula
Administering to a subject in need thereof an effective amount of a compound having the formula, or a pharmaceutically acceptable salt, wherein Ar1 is selected from pyridyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-thiadiazolyl, isothiazolyl, and thiazolyl; Ar2 is selected from phenyl, pyridyl, pyrazolyl, and pyrazolo[1,5-a]pyridyl; R1 and R2 are each independently selected from H, F, C1-C4 alkyl, C1-C4 deuteroalkyl, and C1-C4 haloalkyl or optionally combined to form a C3-C5 carbocyclic ring optionally substituted with one or two F; R3 is selected from H, F, OH and C1-C4 alkyl; and Ra and Rb are selected from the defined substituent and ring-forming options.
Across both independent claims, coverage is directed to administering an effective amount of a compound of a specified structural formula for HFrEF or dilated cardiomyopathy, with the core limitations centered on Ar1/Ar2 selections and defined substituent frameworks including R1/R2 and R3 and specified Ra/Rb options.
Stated Advantages
Enhances contractility.
Increases phosphate release from myosin.
Does not prolong systole.
Does not shorten diastole.
Documented Applications
Synthesis and analytical characterization of specific substituted piperidine-1-carboxamide and sulfonamide compounds, including numbered examples and stereochemical variants, with reported 1H NMR and LC-MS m/z data.
Treatment of heart failure with reduced ejection fraction (HFrEF).
Treatment of dilated cardiomyopathy.
Treating cardiac conditions characterized by left and/or right ventricular systolic dysfunction or reduced systolic reserve.
Treatment of heart failure phenotypes including HFrEF and HFpEF.
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