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EP-4493546-B1 - IMIDAZOLE DERIVATIVES AS POTASSIUM CHANNEL INHIBITORS

EP4493546B1EP 4493546 B1EP4493546 B1EP 4493546B1EP-4493546-B1

Inventors

  • METE, ANTONIO
  • SØRENSEN, Ulrik

Dates

Publication Date
20260506
Application Date
20230313

Claims (15)

  1. A compound of formula (I) Wherein R1 is selected from hydrogen and C 1-6 alkyl; R2-R3 are independently a group selected from hydrogen and C 1-6 alkyl; or R2 and R3 taken together with the carbon atom to which they are linked form a C 3-4 cycloalkyl; R4-R6 are independently a group selected from hydrogen, halogen, and C 1-4 alkyl; R7 is selected from the group consisting of hydrogen and C 1-4 alkyl, R8 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with one OH, and C 1-6 alkyl substituted with one OC 1-3 alkyl, or R7 and R8 taken together with the carbon atom to which they are linked form a C3-4 cycloalkyl; R9-R13 are independently a group selected from hydrogen, halogen, C 1-6 alkyl substituted with at least one halogen, C 1-6 alkoxy, C 1-6 alkoxy substituted with at least one halogen, C 1-6 alkylthio, and cyano; R14 is selected from H, C 1-6 alkyl, or C 1-6 alkoxy; R15 is selected from H, C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, C 1-6 alkoxy, C 1-6 alkoxy substituted with at least one a halogen, or C 3-4 cycloalkyl; or R14 and R15 taken together with the nitrogen atom to which they are linked form a 4-6 membered non-aromatic heterocycle containing 1-2 nitrogen atoms, optionally 1 oxygen atom, and optionally 1 sulphur atom, optionally substituted with at least one group selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, C 1-6 alkoxy, C 1-6 alkoxy substituted with at least one halogen; or a pharmaceutically acceptable salt thereof.
  2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen (H) and methyl, such as H.
  3. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R2-R3 are independently a group selected from H and C 1-3 alkyl, such as H and Methyl.
  4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R2-R3 are both H.
  5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R4-R6 are independently a group selected from H, F, and methyl.
  6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R7 is a group selected from H and C 1-3 alkyl, such as methyl and ethyl.
  7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R8 is a group selected from C 1-4 alkyl substituted with one OH, and C 1-4 alkyl substituted with one OC 1-3 alkyl, such as CH 2 OH, CH 2 CH 2 OH, CH 2 OCH 3 , and CH 2 CH 2 O- CH 3 .
  8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R9-R13 are independently a group selected from H, halogen, C 1-6 alkyl substituted with at least one halogen, and C 1-6 alkoxy substituted with at least one halogen.
  9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R9, R12 and R13 are all H, and R10-R11 are independently a group selected from H, halogen, C 1-6 alkyl substituted with at least one halogen, and C 1-6 alkoxy substituted with at least one halogen; provided that R10 and R11 are not both H.
  10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R14 is selected from H and C 1-6 alkyl, such as H, methyl and ethyl.
  11. The compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R15 is selected from H, C 1-6 alkyl, C 1-6 alkyl substituted with at least one halogen, C 1-6 alkoxy, C 1-6 alkoxy substituted with at least one halogen, or C 3-4 cycloalkyl, such as methyl, ethyl, methoxy, cyclopropyl, CH 2 CH 2 CF 3 , or CH 2 CH 2 OCF 3 .
  12. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R14 and R15 taken together with the nitrogen atom to which they are linked form a 4-6 membered non-aromatic heterocycle containing 1 nitrogen atom and optionally 1 oxygen atom, optionally substituted with at least one halogen, such as azetidinyl, piperidinyl, morpholinyl, and isoxazolidinyl, optionally substituted with at least one F.
  13. The compound of claim 1 selected from any one of: 1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, 3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-1, 1-dimethylurea, (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1, 1-dimethylurea, (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-1, 1-dimethylurea, 1-((2-((1-methoxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-3-methylurea, (+)-1-((2-((1-methoxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol -4-yl) methyl)-3-methylurea, (-)-1-((2-((1-methoxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol -4-yl) methyl)-3-methylurea, 1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl|propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}-3-methoxy-3-methylurea, (+)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea, (-)-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-1-methoxy-1-methylurea, 1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-1-methylurea, (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino) -1H-benzo[d] imidazol-4-yl) methyl)-1-methylurea, (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino) -1H-benzo [d] imidazol-4-yl) methyl)-1-methylurea, 3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-1, 1-dimethylurea, (+)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1, 1-dimethylurea, (-)-3-((5-fluoro-2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1, 1-dimethylurea, 1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl) urea, (-)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl)propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl)methyl)urea, (+)-1-cyclopropyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl) urea, N-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl) azetidine-1-carboxamide, (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl) azetidine-1-carboxamide, (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl) azetidine-1-carboxamide, 3-ethyl-1-{[2-({1-hydroxy-2-[3-(trifluoromethyl)phenyl]propan-2-yl}amino)-1H-1,3-benzodiazol-4-yl]methyl}urea, (+)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl) urea, (-)-1-ethyl-3-((2-((1-hydroxy-2-(3-(trifluoromethyl)phenyl) propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)urea, 1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) butan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) butan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) butan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1-methoxy-1-methylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d] imidazol-4-yl)methyl)-1-methoxy-1-methylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d] imidazol-4-yl)methyl)-1-methoxy-1-methylurea, 1-[[2-[[1-(3-chloro-4-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl] amino]-1H-benzimidazol-4-yl] methyl]-3-methyl-urea, (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (H)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-hydroxypropan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-1, 1-dimethylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1, 1-dimethylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1, 1-dimethylurea, 1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-3-(3, 3, 3-trifluoropropyl) urea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-3-(3, 3, 3-trifluoropropyl) urea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-3-(3, 3, 3-trifluoropropyl) urea, N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl) azetidine-1-carboxamide, (-)-(N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl) azetidine-1-carboxamide, (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo [d]imidazol-4-yl) methyl) azetidine-1-carboxamide, 1-((2-((1-hydroxy-2-(3-(trifluoromethoxy)phenyl)propan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (-)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, (+)-1-((2-((1-hydroxy-2-(3-(trifluoromethoxy) phenyl) propan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, 1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl) amino)-1H-benzo [d]imidazol-4-yl) methyl)-3-methylurea, (+)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, (-)-1-((2-((2-(3-chloro-4-fluorophenyl)-1-methoxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-3-methylurea, 3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo [d]imidazol-4-yl) methyl)-1-ethyl-1-methylurea, (-)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1-ethyl-1-methylurea, (+)-3-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-4-yl) methyl)-1-ethyl-1-methylurea, N-[[2-[[1-(3-chlorophenyl)-2-hydroxy-1-methyl-ethyl] amino]-3H-benzimidazol-4-yl] methyl] isoxazolidine-2-carboxamide, (-)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol -7-yl) methyl) isoxazolidine-2-carboxamide, (+)-N-((2-((2-(3-chlorophenyl)-1-hydroxypropan-2-yl) amino)-1H-benzo[d] imidazol-7-yl) methyl) isoxazolidine-2-carboxamide, 1-((2-((4-hydroxy-2-(3-(trifluoromethyl) phenyl) butan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl)-3-methylurea, (-)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, (+)-1-((2-((4-hydroxy-2-(3-(trifluoromethyl)phenyl)butan-2-yl)amino)-1H-benzo[d]imidazol-4-yl)methyl)-3-methylurea, N-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl) morpholine-4-carboxamide, (+)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl) morpholine-4-carboxamide, and (-)-N-((2-((1-hydroxy-2-(3-(trifluoromethyl) phenyl) propan-2-yl) amino)-1H-benzo[d]imidazol-4-yl) methyl) morpholine-4-carboxamide; or a pharmaceutically acceptable salt thereof.
  14. A pharmaceutical composition comprising the compound of any one of the previous claims and optionally a pharmaceutically acceptable additive, such as carrier or excipient.
  15. The compound of any one of the claims 1-14 for use in a method for treating a cardiac disease, disorder or condition in a mammal, wherein the disease, disorder or condition is associated with an abnormal rhythm of the heart or variant and exercise induced angina or wherein the disease, disorder or condition is selected from the group consisting of cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmias, and an abnormal rhythm arising after cardiac surgery or a cardiac ablation procedure.

Description

Technical field The present invention relates to novel compounds, the use of said compounds as medicament and for the manufacture of a medicament for the treatment of a cardiac disease, disorder or condition in mammals. The invention also relates to pharmaceutical compositions comprising said novel compounds. Background Art The heart is a muscle, which pumps the blood in the circulation by contracting 1-3 times per second. The heartbeat is caused by simultaneous contraction of the individual cardiac muscle cells (cardiac myocytes). The synchronization of the cellular contraction is governed by the electrical cardiac impulse (the cardiac action potential), which is generated in the pacemaker cells of the sine node and spreads rapidly over the heart through a specific conduction system. Disturbances in the generation of the impulse and the conduction of impulse may occur either as a consequence of a disease, a drug treatment, or electrolyte imbalances. Such disturbances in the impulse are called arrhythmia or dysrythmia and they may lead to unease, emboli, syncope or sudden death. In its simplest form, an arrhythmia covers everything different from a normal cardiac sinus rhythm. Disturbances can cover anything from simple palpitations to devastating ventricular fibrillation including bradycardia and tachycardia. At a molecular level a group of proteins called ion channels underlie the electrical events in the heart since they are able to conduct electrical currents across the cell membrane. Different types of ion channels are thus instrumental in the generation and conduction of the cardiac action potential, in the regulation of the heart rate by the autonomic nervous system, and in the contractile process in the individual heart cells. The different types of ion channels are therefore evident targets for anti-arrhythmic cardiac drugs, and many anti-arrhythmic drugs on the market do exert their effect by interacting with ion channels. Anti-arrhythmic drugs are usually divided into four main classes according to the so-called Singh Vaughan Williams classification: Class I compounds all inhibit the cardiac voltage-dependent sodium channel. Some Class I compounds do have additional effects influencing the cardiac action potential being the basis for a further subdivision into three subclasses: Class IA compounds are sodium channel inhibitors such as Quinidine, Procainamide or Disopyramid, which prolong the action potential;Class IB compounds are sodium channel inhibitors such as Lidocaine, Mexiletine, Tocainide or Phenytoine, which shorten the action potential; andClass IC compounds are sodium channel inhibitors such as Flecainide, Moricizine or Propafenone, which do not change the action potential duration.Class I compounds interact with the sodium channel during its open or inactivated state and are dissociated from the channels during its closed state (during diastole). The rate of dissociation determines whether they show a frequencydependent channel inhibition. Some of the class I compounds also inhibit subtypes of potassium or calcium permeable channels in addition to their sodium channel inhibiting effect.Class II compounds are β-adrenoceptor inhibitors and include drugs like Atenolol, Metoprolol, Timolol or Propranolol. β-adrenoceptor inhibitors can be selective for cardiac β1-receptors or have affinity for β1- as well as β2-receptors. Some of the compounds also have an intrinsic β-stimulating effect.Class III compounds are potassium channel inhibitors such as Amiodarone, Dronedarone, Sotalol, Ibutilide and Dofetilide, which prolong the action potential.Class IV compounds are inhibitors of L-type calcium channels such as Verapamil. Small-conductance calcium-activated potassium (SK) channels belongs to the family of Ca2+-activated K+ channels. Three SK channel subtypes have been cloned: SK1, SK2 and SK3 (corresponding to KCNN1-3 using the genomic nomenclature). The activity of these channels is determined by the concentration of free intracellular calcium ([Ca2+]i) via calmodulin that is constitutively bound to the channels. SK channels are tightly regulated by [Ca2+]i in the physiological range being closed at [Ca2+]i up to around 0.1 µM but fully activated at a [Ca2+]i of 1 µM. Being selective for potassium, open or active SK channels have a hyperpolarizing influence on the membrane potential of the cell. SK channels are widely expressed in the central nervous system (CNS) and in peripheral tissue, including the heart. The hyperpolarizing action of active SK channels plays an important role in the control of firing pattern and excitability of excitable cells. SK channel inhibitors such as apamin and N-methyl bicuculline, have been demonstrated to increase excitability, whereas the SK channel opener 1-EBIO is able to reduce electrical activity. In non-excitable cells, where the amount of Ca2+ influx via voltageindependent pathways is highly sensitive to the membrane potential, an activation of SK channel