Aminoalkylated benzoxy compounds for use in the treatment of cardiac disorders

Abstract

Novel aminoalkylated benzoxy compounds with potassium channel blocking activity, pharmaceutical compositions comprising the novel compounds, novel aminoalkylated benzoxy compounds with potassium channel blocking activity for use in therapy, in particular in the prevention or treatment of a cardiac disorder or disease and methods for the tretment of a dis- order or disease, in particular a cardiac disorder or disease are provided.

Description

[0001] Aminoalkylated benzoxy compounds for use in the treatment of cardiac disorders FIELD OF THE INVENTION Novel aminoalkylated benzoxy compounds with potassium channel blocking activity, phar- maceutical compositions comprising the novel compounds, novel aminoalkylated benzoxy compounds with potassium channel blocking activity for use in therapy, in particular in the prevention or treatment of a cardiac disorder or disease and methods for the tretment of a dis- order or disease, in particular a cardiac disorder or disease are provided. In particular, a novel aminoalkylated benzoxy compound for use in the treatment of atrial fibrillation is provided. BACKGROUND OF THE INVENTION Cardiovascular diseases including sudden cardiac death and stroke are among the leading ca- uses of mortality in industrialized countries. The most serious ventricular arrhythmia – ventri- cular fibrillation (VF) – causes more than 300000 deaths in the USA annually. Atrial fibril- lation (AF) is one of the most common arrhythmia entities with 2-5 % incidence in the elderly (60-65 years) population. In addition, AF often elicits dangerous or life-threatening ventricu- lar arrhythmias including VF and contributes to the pathogenesis of stroke. At present the pharmacological treatment of arrhythmias including AF is not satisfactory, since the available drugs either do not control arrhythmias properly or have serious side effects. Therefore, there is an increasing demand for safe and effective new drugs to treat AF and arrhythmias – inc- luding VF – in general. The available Class III antiarrhythmic drugs like dofetilide, ibutilide or sotalol and Class Ic drugs like flecainide or propafenone drugs used in the field have substantial proarrhythmic potential as shown in the CAST, CASH and SWORD studies (Echt et al, (1991). "Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo". New England Journal of Medicine. 324 (12): 781–788. Kuck et al, Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation. 2000 Aug 15;102(7):748-54.), which greatly limits their use. Unfortunately, the proarrhythmic and antiarrhythmic mechanisms are closely related to each other i.e., in the case of Class III effect to the reverse rate dependent repolari- zation lengthening and in the case of Class Ic effect to the slow kinetical recovery type sodi- um channel blocking property. To avoid this problem, in recent years new compounds like XEN D103 or W were developed to selectively inhibit certain type of potassium channels (Kv1.5 and SK2) that are not or weakly expressed in the ventricular muscle but are abundant in the atria. These drugs seem to have no or less proarrhythmic side effects, but serious questions emerged regarding their the- rapeutical effectiveness. Mexiletine is indicated for the treatment of ventricular arrhythmias but – like other class IB drugs – exerts no beneficial effect in atrial fibrillation (Augmenting Maintanace of Sinus Rhythm in the Control of Atrial Fibrillation by Antiarrhythmic Drug Combinations. Bramah N. Singh, Journal of Cardiovascular Pharmacology and Therapeutics, 2010, 15: 31S-35S). Also, the use of mexiletine is accompanied by severe adverse gastrointestinal side effects. Amiodarone (AMIO) application is the most effective pharmacological treatment to combat AF and ventricular arrhythmias. Amiodarone has less proarrhythmic risk than other currently used antiarrhythmics (Shinagawa et al. Effects of antiarrhythmic drugs on fibrillation in the remodelled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circu- lation.107:1440-6; 2003., Ravens U: Antiarrhythmic therapy in atrial fibrillation. Pharmacol. & Ther. 128: 129-145, 2010.). Amiodarone, which has a very complex mode of action (inhi- biting cardiac sodium, calcium, potassium currents and beta adrenoceptors) also exerts serious extracardiac adverse effects like pulmonary fibrosis, hepatotoxicity, photodermatosis, cornea deposits etc., which greatly limits its clinical use (Tisdale et al: Risk factors for the develop- ment of specific noncardiovascular adverse effects associated with amiodarone. J. Clin. Pharmacol. 35: 351-356, 1995.). The toxic effect of amiodarone is enhanced by its slow eli- mination (half time 40-80 days!) resulting drug accumulation in different tissues of the body. New chemical entities exhibiting an advantageous multi-component cellular antiarrhythmic profile and which are free from the unfavourable pharmacokinetical properties and side ef- fects of the currently available drugs, e.g. AMIO, are much needed. BRIEF DESCRIPTION OF THE INVENTION Preferably the compound is for use in therapy, more preferably in the treatment or prevention of a cardiovascular disorder or disease, more preferably in the treatment or prevention, prefe- rably treatment of cardiac arrythymia, preferably ventricular arrythymia, highly preferably atrial arrythymia. In an aspect compounds having a general formula (I) and pharmaceutically acceptable salts, stereoisomers or mixture of stereoisomers thereof for use in therapy are provided, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, C1-7alkyl-S(O)2-NH-, -COX group, wherein X is -OH, C1-7alkyl-O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2 or C1-3alkyl- ; R2, R3, R4and R5are selected form hydrogen and iodine; R6and R7are independently C1-7alkyl-; and n is 1, 2 or 3; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hydrogen; and if R4is iodine then R2and R5are hydrogen. Preferably in (I) R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl- O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2or C1-3alkyl- ; R2, R3, R4and R5are selected form hydrogen and iodine; R6and R7are independently C1-7alkyl-; and n is 1, 2 or 3; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hydrogen; and if R4is iodine then R2and R5are hydrogen. In another aspect compounds having a general formula (I) and pharmaceutically acceptable salts, stereoisomers or mixture of stereoisomers thereof are provided, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl- O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2 or C1-3alkyl- ; R2, R3, R4and R5are selected form hydrogen and iodine; R6and R7are independently C1-7alkyl-; and n is 1, 2 or 3; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hy- drogen; and if R4is iodine then R2and R5are hydrogen; and when R2, R5, R6and R7are hydrogen, R3and R4are iodine and n is 1, then R1is selected from the group consisting of C1­7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl-O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2 or C1-3alkyl-. In a preferred embodiment the compound has general formula (II) or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1­7alkyl­O-, -NH2, C1-7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H or -NH-N(C1-7alkyl)2; and R2, R3, R4and R5are selected form hydrogen and iodine; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hy- drogen; and if R4is iodine then R2and R5are hydrogen; and when R2and R5are hydrogen, R3and R4are iodine, then R1is selected from the group consisting of C1­7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl-O-, - NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2or C1-3alkyl-. In another preferred embodiment the compound has general formula (II) or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1­7alkyl­O-, -NH2, C1-7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H or -NH-N(C1-7alkyl)2; and R2, R3, R4and R5are selected form hydrogen and iodine; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hy- drogen; and if R4is iodine then R2and R5are hydrogen and R1and R3are not hydrogen at the same time; and when R2and R5are hydrogen, R3and R4are iodine, then R1is selected from the group consisting of C1­7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl-O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2or C1-3alkyl-. In a preferred embodiment said compound is selected from 1-(2-iodophenoxy)propan-2-amine, (S)-1-(2-iodophenoxy)propan-2-amine, 4-(2-aminopropoxy)-3,5-diiodobenzonitrile, 1-(3,5-diiodophenoxy)propan-2-amine, 1-(2,6-diiodo-4-(trifluoromethyl)phenoxy)propan-2-amine, 4-(2-aminopropoxy)-3,5-diiodobenzamide, 1-((3,5-diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-amine, 1-(2,6-diiodo-4-methylphenoxy)propan-2-amine and 1-(2,6-diiodo-4-nitrophenoxy)propan-2-amine, and pharmaceutically acceptable salts thereof. In a more preferred embodiment said compound is selected from 4-(2-aminopropoxy)-3,5-diiodobenzonitrile, 1-(3,5-diiodophenoxy)propan-2-amine, 1-(2,6-diiodo-4-(trifluoromethyl)phenoxy)propan-2-amine, 4-(2-aminopropoxy)-3,5-diiodobenzamide, 1-((3,5-diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-amine, 1-(2,6-diiodo-4-methylphenoxy)propan-2-amine and 1-(2,6-diiodo-4-nitrophenoxy)propan-2-amine, and pharmaceutically acceptable salts thereof. 6. In a particularly preferred embodiment said compound is selected from 4-(2-aminopropoxy)-3,5-diiodobenzonitrile and 1-(3,5-diiodophenoxy)propan-2-amine, and pharmaceutically acceptable salts thereof. In a particularly preferred embodiment said compound is 4-(2-aminopropoxy)-3,5- diiodobenzonitrile or pharmaceutically acceptable salts thereof. In a preferred embodiment said compound is selected from 1-(2-iodophenoxy)propan-2-amine hydrochloride (compound 1), (S)-1-(2-iodophenoxy)propan-2-amine hydrochloride (compound 2), 4-(2-aminopropoxy)-3,5-diiodobenzonitrile hydrochloride (compound 3), 1-(3,5-diiodophenoxy)propan-2-amine hydrochloride (compound 5), 1-(2,6-diiodo-4-(trifluoromethyl)phenoxy)propan-2-amine hydrochloride (compound 6), 4-(2-aminopropoxy)-3,5-diiodobenzamide hydrochloride (compound 7), 1-((3,5-diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-amine hydrochloride (compound 8), 1-(2,6-diiodo-4-methylphenoxy)propan-2-amine hydrochloride (compound 9) and 1-(2,6-diiodo-4-nitrophenoxy)propan-2-amine hydrochloride (compound 10). In a more preferred embodiment said compound is selected from 4-(2-aminopropoxy)-3,5-diiodobenzonitrile hydrochloride (compound 3), 1-(3,5-diiodophenoxy)propan-2-amine hydrochloride (compound 5), 1-(2,6-diiodo-4-(trifluoromethyl)phenoxy)propan-2-amine hydrochloride (compound 6), 4-(2-aminopropoxy)-3,5-diiodobenzamide hydrochloride (compound 7), 1-((3,5-diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-amine hydrochloride (compound 8), 1-(2,6-diiodo-4-methylphenoxy)propan-2-amine hydrochloride (compound 9) and 1-(2,6-diiodo-4-nitrophenoxy)propan-2-amine hydrochloride (compound 10). In a particularly preferred embodiment said compound is selected from 4-(2-aminopropoxy)-3,5-diiodobenzonitrile hydrochloride (compound 3) and 1-(3,5-diiodophenoxy)propan-2-amine hydrochloride (compound 5). In the most preferred embodiment said compound is 4-(2-aminopropoxy)-3,5- diiodobenzonitrile hydrochloride (compound 3). Preferably the compound is for use in therapy. Preferably the compound for use in therapy is for use in the treatment or prevention of a car- diovascular disorder or disease. A pharmaceutical composition comprising the compound or the compound for use in therapy and a pharmaecutically acceptable excipient is provided. A method for the treatment of a disorder or disease is provided, the method comprising admi- nistering a therapeutically effective amount of the compound or the compound for use in the- rapy or a pharmaceutical composition comprising a compound the compound or the com- pound for use in therapy to a subject in need thereof. Preferably the disorder or disease is a cardiac disorder or disease. Preferably the cardiovascular disorder or disease is cardiac arrythymia. Preferably the cardiac arrythymia is ventricular arrythymia, preferably ventricular fibrillation or atrial arrythymia, preferably atrial fibrillation. Preferably the cardiac arrythymia is ventricular arrythymia, preferably ventricular fibrillation and the compound of formula (I) is 1-(2-iodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, (2S)-1-(2- iodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, 4-(2-aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof), 1-(2,4,6- triiodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixtu- re of stereoisomers thereof or 1-(3,5-diiodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, preferably 4-(2- aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, 1-(2,4,6-triiodophenoxy)propan-2-amine or a pharmaceuti- cally acceptable salt, stereoisomer or mixture of stereoisomers thereof or 1-(3,5- diiodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, more preferably 4-(2-aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof. Preferably the cardiac arrythymia is atrial arrythymia, preferably atrial fibrillation and the compound of formula (I) is 1-(2-iodophenoxy)propan-2-amine or a pharmaceutically accep- table salt, stereoisomer or mixture of stereoisomers thereof, (2S)-1-(2-iodophenoxy)propan-2- amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof or 4-(2-aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoi- somer or mixture of stereoisomers thereof, more preferably 4-(2-aminopropoxy)-3,5- diiodobenzonitrile or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoi- somers thereof. In another aspect a method is provided for the preparation of compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer or mixtures of stereoisomers thereof, wherein R1is selected from the group consisting of C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, and -CONH2; R2and R5are hydrogen and R3is iodine; wherein the method comprises the following steps: a) reacting a compound of formula (IIa) i) with KI and I2 in water at room temperature in the presence of NH4OH added dropwise to the reaction mixture to obtain a compound of formula (IIb) ii) with I2 and H2O2 in water to obtain a compound of formula (IIb) (IIb), wherein R1is -CHlg3 or ­NO2; or iii) with KI and N-chlorobenzenesulfonamide-sodium in NaOH solution at a temperature of 80°C to obtain a compound of formula (IIb) (IIb), wherein R1is C6­10aryl-; b) reacting the compound of formula (IIb) with K2CO3 and 1-chloropropan-2-one in organic solvent, preferably CH3CN or DMF under reflux, then cooling the reaction mixture to room temperature and isolating a compound of formula (IIc) by filtration and optionally extraction (IIc); c) reacting the compound of formula (IIc) with NH4OAc in organic solvent, preferably meth- anol or ethanol in the presence of NaBH3CN at room temperature, and isolating the compound of formula (II) by extraction with organic solvent, preferably CHCl3 or DCM. The conversion of compound of formula (II) to its pharmaceutically acceptable salt is known by a person skilled in the art. Further, a method is provided for the preparation of compound of formula (III) wherein the method comprises the following steps: a) reacting 2-iodophenol with propylene oxide in the presence of K2CO3in an organic solvent, preferably acetone at a temperature of 75°C to obtain a compound of formula (IIIa) (IIIa); b) reacting the compond of formula (IIIa) with phtalimide in an organic solvent, preferably THF under inert atmosphere to obtain a suspension; c) cooling the suspension followed by addition of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to obtain a compound of formula (IIIb) (IIIb); d) reacting the compound of (IIIb) with hydrazine hydrate in the presence of AcOH in an or- ganic solvent, preferably methanol, then isolating the compound of formula (III) by filtering and extraction. The conversion of compound of formula (III) to its pharmaceutically acceptable salt is known by a person skilled in the art. Further, a method is provided for the preparation of compound of formula (IV) wherein the method comprises the following steps: a) reacting 2-iodophenol with (+)-(2R)-propylene oxide in the presence of K2CO3 in an organ- ic solvent, preferably acetone by heating the reaction mixture to obtain a compound of formu- la (IVa) b) reacting the compond of formula (IVa) with phtalimide in an organic solvent, preferably THF under inert atmosphere to obtain a suspension; c) cooling the suspension followed by addition of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to obtain a compound of formula (IVb); d) reacting the compound of (IVb) with hydrazine hydrate in the presence of AcOH in an or- ganic solvent, preferably methanol, then isolating the compound of formula (IV) by filtering and extraction. The conversion of compound of formula (IV) to its pharmaceutically acceptable salt is known by a person skilled in the art. Further, a method is provided for the preparation of compound of formula (V) wherein the method comprises the following steps: a) reacting 2,4,6-triiodophenol with 1-chloroacetone in the presence of anhydrous potassium carbonate in an organic solvent, preferably DMF at a temperature of 27°C to obtain a com- pound of formula (Va) b) reacting the compound of formula (Va) with NH4OAc in an organic solvent, preferably methanol in the presence of NaBH3CN at room temperature, then isolating the compound of formula (V) by extraction with organic solvent, preferably CHCl3.The conversion of compound of formula (V) to its pharmaceutically acceptable salt is known by a person skilled in the art. Further, a method is provided for the preparation of compound of formula (VI) wherein the method comprises the following steps: a) reacting 3,5-diiodoaniline with NaNO2 under diazotization conditions and boiling the solu- tion to obtain a compound of formula (VIa) b) reacting the compound of formula (VIa) with 1-chloropropan-2-one in the presence of K2CO3 in an organic solvent, preferably CH3CN under reflux, then cooling the reaction mix- ture and isolating a compound of formula (VIb) by filtering and extraction with alkaline aqueous solution, preferably NaOH solution c) reacting the compound of formula (VIb) with NH4OAc in the presence of NaBH3CN in an organic solvent, preferably methanol at room temperature, then isolating a compound of for- mula (VI) by extraction with organic solvent, preferably CHCl3. The conversion of compound of formula (VI) to its pharmaceutically acceptable salt is known by a person skilled in the art. BRIEF DESCRIPTION OF THE FIGURES Figure 1. Effects of SZV-2598 on GIRK (left) and on hERG (right) currents in HEK cell li- nes. Figure 2. Effects of 2 on GIRK (left) and on hERG (right) currents in HEK cell lines. Figure 3. Effects of 3 on GIRK (left) and on hERG (right) currents in HEK cell lines. Figure 4. Effects of 4 on GIRK (left) and on hERG (right) currents in HEK cell lines. Figure 5. Effects of 5 on GIRK (left) and on hERG (right) currents in HEK cell lines. Figure 6. Incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) between groups; n=9-14, *p<0.05 as analyzed by Chi-square test with Yate’s correction, pairwise compared to Vehicle (VEH, Vehicle; MEX, mexiletine; DOFE, dofetilide) Figure 7. Cycle length dependent effect of 3 on Vmax in dog right ventricular muscle prepara- tions. Figure 8. Effect of 3 on recovery of Vmax in dog right ventricular muscle preparations. Figure 9. The onset kinetics of Vmax block in the presence of 3 in dog right ventricular muscle preparations. Figure 10. Effects of compound 3 on heart rate Figure 11 Effect of compound 4 on right ventricular muscle; all significant except for points 2-5 of 2.5 µM Figure 12 Effect of compound 5 on right ventricular muscle; *p<0.05 DETAILED DESCRIPTION OF THE INVENTION Compounds of general formula (I) are provided. Table 1: Examples of the compounds according to general formula (I) Compound Structure Name 1 1-(2-iodophenoxy)propan-2-amine (SZV-2598) hydrochloride) 2 (S)-1-(2-iodophenoxy)propan-2-amine (SZV-2615) hydrochloride 3 4-(2-aminopropoxy)-3,5- (SZV-2649) diiodobenzonitrile hydrochloride 4 1-(2,4,6-triiodophenoxy)propan-2- (SZV-2765) amine hydrochloride Compound Structure Name 5 1-(3,5-diiodophenoxy)propan-2-amine (SZV-2766) hydrochloride 6 1-(2,6-diiodo-4- (trifluoromethyl)phenoxy)propan-2- amine hydrochloride 7 4-(2-aminopropoxy)-3,5- diiodobenzamide hydrochloride 8 1-((3,5-diiodo-[1,1'-biphenyl]-4- yl)oxy)propan-2-amine hydrochloride 9 1-(2,6-diiodo-4- methylphenoxy)propan-2-amine hy- drochloride 10 1-(2,6-diiodo-4-nitrophenoxy)propan- 2-amine hydrochloride The term “alkyl” as used herein refers to an optionally substituted straight chain, or optionally substituted branched chain saturated alkyl hydrocarbon radical having from one to seven car- bon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl radicals and the like. The term “alkoxy” as used herein refers to the alkyl-O- groups, wherein the alkyl term is defi- ned as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy groups and the like. The term “aryl” as used herein refers to an aryl group having six to ten carbon atoms in the cyclic backbone, for example phenyl and naphthyl. The term “arylalkyl” as used herein refers to an alkyl radical, in which at least one hydrogen is replaced with an aryl radical defined above, for example benzyl, 2-phenyl-ethyl and the like. The term “halogen” as used herein refers to fluoro, chloro, bromo, and iodo. Some compounds provided herein may contain one or more chiral centres and therefore may exist in enantiomeric or diastereoisomeric forms. The scope covered by the present invention is intended to include all isomers per se, and the mixture of the cis and trans isomers, the mix- ture of enantiomers or diastereoisomers and the racemic mixture of enantiomers (optical isomers), too. In addition it is possible to use well known techniques for the separation of the different forms, and the compounds provided herein may include the purified or enriched forms of a given enantiomer or diastereomer. The “therapeutically / pharmaceutically suitable salt” may be prepared from any compound having salt-forming, for example basic or acidic functionality. Pharmaceutically suitable salt may be prepared with organic or inorganic acids or bases. The compounds which have one or more basic functional group (for example amino, alkyl-amino) can form pharmaceutically suitable salt with pharmaceutically suitable organic or inorganic salts. These salts can be pre- pared in situ in the course of the final isolation or purification of the compounds, or by sepa- rately reacting the purified compounds provided herein in the form of free base with suitable organic or inorganic acids, and by separating the salt generated this way. Suitable salts may be for example: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulphate, butyrate, citrate, camphorate, camphorsulphonate, cyclopentanepropionate, digluconate, do- decylsulphate, ethanesulphonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulphonate, lactate, maleate, malonate, methanesulphonate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenyl-propionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulphate, tartrate, thiocyanate, tosylate, and undecanoate. Other acids, like for example the oxalic acid, which in themselves are pharmaceutically unsuitable, can be used as intermediates in the course of the preparation of suitable salts for the preparation of pharmaceutically suitable compounds or their acid addi- tion salts. The compounds which have one or more acidic functional group can form pharma- ceutically suitable salt with pharmaceutically suitable bases. In this case the term “pharma­ ceutically suitable salt” relates to the base addition salts, formed with relatively non-toxic inorganic and organic bases. These salts can similarly be prepared in situ in the course of the final isolation or purification of the compounds, or by separately reacting the purified com- pounds in the form of free acid with suitable organic or inorganic base, for example with pharmaceutically suitable metal-cation hydroxide, carbonate or bicarbonate, with ammonia or pharmaceutically suitable organic primary, secondary or tertiary amine. The pharmaceutically suitable cations include the alkali or alkaline earth metal salts, like for example the lithium, sodium, calcium, magnesium, aluminium and zinc salts and the like. Illustrative examples for some suitable base are the sodium hydroxide, potassium hydroxide, choline hydroxide, sodi- um carbonate, tetrabutylammonium hydroxide and the like. The representative organic amines which are useful in the preparation of base addition salts are the ethylamine, methylamine, ethylene diamine, ethanolamine, diethanolamine, piperazine and the like. The quaternization of any kind of nitrogen containing groups of the compounds presented here is also anticipated. Product soluble in water or in oil can be obtained with such quaternization (see for example: Berge et al. "Pharmaceutical Salts", J. Pharm. Sci.1977, 66:1-19). It is obvious that the reference to a salt includes its solvent containing or crystalline forms, especially the solvates and the polymorphs. The solvates contain solvent in stoichiometric or non-stoichiometric amount, and are often formed in the course of the crystallization with such, therapeutically suitable solvents as the water, ethanol and the like. Hydrates form when the solvent is water, or alcoholates form when the solvent is ethanol. The polymorphs include the different crystalline arrangement of a compound with the same elemental composition. Polymorphs usually have different X-ray diffraction pattern, infrared spectrum, melting point, specific gravity, hardness, crystalline form, optical and electric properties, stability and so- lubility. Different factors like the recrystallization solvent, rate of crystallization, and storage temperature may give rise the dominance of a single crystalline form. Compounds of general formula (I) have proven to possess antiarrhythmic effects, in particular antiarrhythmic effects characteristic of Class IB antiarrhythmic drugs. Suprisingly, the com- pounds also showed lengthening of both ventricular and atrial repolarization and inhibition of the acethylcholin dependent potassium channels. The compounds do not affect the repolari- zation of Purkinje fibers, thus lack the proarrhythmic torsadogenic effect of Class III antiarr- hythmic drugs, such as dofetilide and sotalol. The antiarrhytmic and cardiac electrophysiological effects of the compounds of formula (I) were first studied in vitro in mammalian HEK cell line in which the HERG channel (the pore forming unit of the native IKr cardiac potassium channel) and the the GIRK transmembrane ion channel were stably expressed. Inhibition or decrease of HERG channel is expected to lengthen the repolarization both in the atria and in the ventricle. Inhibition or decrease of the GIRK channel is expected to decrease the acetylcholine dependent potassium current which plays important role in the pathogenesis of AF. The compounds exerted very potent inhibition both on the GIRK and hERG channels, with EC50 values in the submicromolar range (Figures 3-5). The cellular cardiac electrophysiological effects of the compounds of formula (I) were further investigated with the standard microelectrode technique in isolated dog cardiac preparations. As Table 2-3 show compounds 4 and 5 significantly decreased the maximal rate of depolari- zation (Vmax) This indicates the Class I antiarrhythmic property of these compounds. Table 2. The effect of compound 4 on the major action potential parameters in ventricular muscle Ventricular muscle (n=7) CL=1000 ms Parameters Control 4 4 4 2.5 µM) 5 µM 10 µM RP (mV)-86.3 ^ 2.1 -85.3 ^ 2.0 -83.7 ^ 1.9 -84.7 ^ 1.5 APA (mV) 119.0 ^ 2.2 118.5 ^ 2.3 115.7 ^ 1.9 114.8 ^ 2.1 Vmax (V / s) 233.6 ^ 18.6 214.5 ^ 198.6 ^ 20. 184.8 ^ 24.5 6 20.7 APD50 (ms) 199.7 ^ 6.9 202.0 ^ 6.3 204.8 ^ 4.7 204.9 ^ 5.7 APD90 (ms) 233.9 ^ 5.4 236.2 ^ 5.1 238.3 ^ 4.8 239.1 ^ 6.0 P < 0.05 versus Control CL stimulation cycle length, RP resting membrane potential, APA action potential amplitude, Vmax maximum upstroke velocity, APD50 and APD90 action potential duration measured at 50% and 90% of repolarization. Table 3. The effect of compound 5 on the major action potential parameters in ventricular muscle Ventricular muscle (n=6) CL=1000 ms Parameters Control 5 5 5 2.5 µM) 5 µM 10 µM RP (mV)-84.2 ^ 1.1 -84.2 ^ 1.1 -83.0 ^ 1.5 -83.1 ^ 1.4 APA (mV)123.0 ^ 2.2 122.2 ^ 2.3 121.5 ^ 1.9 119.5 ^ 1.7 Vmax (V / s) 226.7 ^ 20.2 215.6 ^ 183.4 ^ 23.7 203.2 ^ 20.4 14.1 APD50 (ms) 212.5 ^ 3.7 209.7 ^ 3.7 207.4 ^ 4.2 205.4 ^ 5.3 APD90 (ms) 246.0 ^ 4.3 243.4 ^ 4.2 241.6 ^ 4.6 240.5 ^ 5.0 P < 0.05 versus Control CL stimulation cycle length, RP resting membrane potential, APA action potential amplitude, Vmax maximum upstroke velocity, APD50 and APD90 action potential duration measured at 50% and 90% of repolarization. The effects of compound 3 were studied in dog ventricular, atrial and Purkinje fiber prepara- tions. Results at physiologic stimulation frequency (60 beat / minutes = 1Hz) are shown in Ta- bles 4-6. As shown in the tables, compound 3 decreases Vmax and lengthen APD90 in ven- tricular muscle, Purkinje and atrial preparations indicating Class I antiarrhythmic property. In addition, compound 3 in ventricular and atrial muscle preparations significantly lengthened APD90 indicating Class III antiarrhythmic property. Table 4. The effect of compound 3 on the major action potential parameters in ventricular muscle Ventricular muscle (n=8) CL=1000 ms Parameters Control 3 3 3 2.5 µM) 5 µM 10 µM RP (mV)-86.4 ^ 1.1 -84.6 ^ 1.3 -84.5 ^ 2.0 -86.1 ^ 2.0 APA (mV)118.0 ^ 2.6 116.8 ^ 2.7 118.3 ^ 1.9 117.1 ^ 2.1 Vmax(V / s)240.2 ^ 21.3228.3 ^ 203.2 ^ 23.5 227.4 ^ 24.2 24.3 APD50 (ms)190.2 ^ 3.2 204.2 ^ 4.5 212.2 ^ 5.7 213.4 ^ 5.8 APD90 (ms) 227.1 ^ 3.3 240.0 ^ 3.5 251.6 ^ 4.0 252.8 ^ 5.0 P < 0.05 versus Control CL stimulation cycle length, RP resting membrane potential, APA action potential amplitude, Vmax maximum upstroke velocity, APD50 and APD90 action potential duration measured at 50% and 90% of repolarization Table 5. The effect of compound 3 on the major action potential parameters in atrial muscle Atrial muscle (n=11) CL=1000 ms Parameters Control 3 3 5 µM 10 µM RP (mV)-87.7 ^ 1.5 -88.2 ^ 1.8 -85.1 ^ 1.7 APA (mV)109.4 ^ 2.1 108.8 ^ 1.9 102.6 ^ 3.2 Vmax(V / s)205.8 ^ 17.0195.3 ^ 22.0 145.9 ^ 12.1 APD50(ms)75.6 ^ 7.3 73.3 ^ 6.2 70.1 ^ 6.2 APD90(ms)160.8 ^ 9.1168.9 ^ 8.8 176.8 ^ 8.5 P < 0.05 versus Control CL stimulation cycle length, RP resting membrane potential, APA action potential amplitude, Vmaxmaximum upstroke velocity, APD50and APD90action potential duration measured at 50% and 90% of repolarization. Table 6. The effect of compound 3 on the major action potential parameters in Purkinje fiber Purkinje fiber (n=10) CL=500 ms Parameters Control 3 3 3 2.5 µM) 5 µM 10 µM RP (mV) -89.2 ^ 2.1 -89.3 ^ 2.0 -84.7 ^ 1.7 -86.0 ^ 1.1 APA (mV) 127.4 ^ 2.2 128.8 ^ 1.5 123.8 ^ 2.3 119.2 ^ 3.3 Vmax (V / s) 633.4 ^ 37.3 581.1 ^ 507.4 ^ 53.4 415.0 ^ 39.0 28.9 APD50 (ms) 144.8 ^ 4.2 128.9 ^ 6.0 113.6 ^ 5.6 112.4^ 7.9 APD90 (ms) 216.3 ^ 5.0 219.4 ^ 3.7 217.4 ^ 5.1 223.4 ^ 5.6 P < 0.05 versus Control CL stimulation cycle length, RP resting membrane potential, APA action potential amplitude, Vmax maximum upstroke velocity, APD50 and APD90 action potential duration measured at 50% and 90% of repolarization. Different frequency dependent protocols (Figures 7, 8 and 9) showed that compound 3 has a Class I / B antiarrhythmic property. Effects of the compounds of formula (I) on ventricular arrhythmias were shown in anesthe- tized rats after coronary ligation (Figure 6). Compound 3 proved to have an increased effect compared to reference drug mexiletine. Compound 3 of formula (I), in similar to the reference compound propafenone shows a pro- tective effect in the carbachol infusion and electrical stimulation induced atrial fibrillation model in anesthetized dogs. Table 7. Effect of compound 3 on atrial fibrillation induced by carbachol infusion and electri- cal stimulation in anesthetized dogs. Carbachol 50 Control µg iv bolus + Propafenone burst Propafenone Experiment 100 µg / h 0.5 mg / kg iv 800 / min 0.5 mg / kg iv maintenance for 10 s infusion + burst AF AF AF Propafenone group AF inducibilty conversion to inducibility reinducibility SR Dog 1 N (-) Y (+) Y (+) N (-) Dog 2 N (-) Y (+) Y (+) N (-) Dog 3 N (-) Y (+) Y (+) Y (+) Dog 4 N (-) Y (+) Y (+) Y (+) Dog 5 N (-) Y (+) Y (+) N (-) SZV-2649 (compound 3) SZV-2649 SZV-2649 10 group 10 mg / kg iv. mg / kg iv. Dog 6 Y(+) N (-) Y (+) N (-) Dog 7 N (-) Y (+) Y (+) N (-) Dog 8 Y(+) N (-) Y (+) N (-) Dog 9 N (-) Y (+) Y (+) N (-) Dog 10v N (-) Y (+) Y (+) Y (+) Dog 11 N (-) Y (+) Y (+) N (-) Pharmaceutical compositions comprising a compound provided herein and at least one phar- maceutically acceptable excipient are also provided. The term “pharmaceutically suitable ex- cipient” as used herein refers to a pharmaceutically accepted substance, composition or carri- er, like for example liquid or solid filler, diluent, adjuvant, solvent, encapsulating material which is taking part in carrying or transportation of said agent from one organ or body part to another organ or body part. Each carrier should be “acceptable” in a sense, that it is compati- ble with the other components of the formulation, and it is not harmful for the patient. Some examples of the substances, without the intention of limitation, which can serve as pharma- ceutically suitable carriers: sugars, like for example lactose, glucose and saccharose; starches, like for example the corn starch and potato starch; cellulose and derivatives thereof, like for example sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder, malt, gelatine, talc, excipients, like for example the cocoa butter and suppository waxes, oils, like for example the peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, like propylene glycol, polyols, like for example glycerine, sorbitol, mannitol and polyethylene glycol; esters like the ethyl oleate and ethyl laurate; agar; buffer substances, like for example magnesium hydroxide and aluminium hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solution, and other non-toxic substances, used in the pharmaceutical compositions, compatible with the pharmaceutical composition. The term “excipient” relates to a neutral substance, which is added to the pharmaceutical preparation, to facilitate the application of a compound. Some examples for the excipients, without the intention of limitation, calcium carbonate, calcium phosphate, different kind of sugars and starch, cellulose derivatives, gelatine, vegetable oils and polyethylene glycols. The term “therapeutically effective amount” relates to a quantity, which is capable of eliciting a therapeutic and / or a prophylactic effect. Of course, the specified dose of the compound to achieve therapeutic and / or prophylactic effect will be determined by the particular circum- stances specific to each case, including for examplePélda the administration of the specified compound, the route of administration, the pathophysiological condition treated, and the treated patient. A typical daily dose (in a single or in divided dose) extends from about 0.01 mg / kg to 50-100 mg / kg, and ideally extends from about 0.1 mg / kg to 10 mg / kg. The factors like the clearance rate, half-life and maximum tolerated dose (MTD) have not been deter- mined yet, but these can be defined by a person with a general expertise, using standard pro- cedures. The pharmaceutical compositions may be administered orally, parenterally, with spray inhala- tion, locally, rectally, nasally, buccally, vaginally, or with an implanted dispenser intrathecally and intracerebrally. The term “parenteral” as used herein relates to the subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intra- cranial injection or infusion techniques. The pharmaceutical compositions may be used orally, in any orally acceptable dosage form, including, without the intention of limitation, capsules, tablets, aqueous suspensions and solu- tions. In case of orally applicable tablets frequently used carriers include lactose and corn starch. Lubricants such as magnesium stearate, are also typically added. Lactose and dried corn starch are useful diluents for the orally applicable capsule form. When aqueous suspen- sions and solutions and propylene glycol are administered orally, the active ingredient is combined with emulsifying and suspending agents. Certain sweeteners and / or flavouring and / or colouring agents may also be added if necessary. The compositions may be prepared with methods known per se in relation to the preparation of the pharmaceutical preparation, by mixing the active ingredient and the suitable carriers and / or excipients. The compositions generally contain 0.5-99.5% active compound. EXAMPLES Materials and methods Animals All experiments were carried out in compliance with the Guide for the Care and Use of Labo- ratory Animals (USA NIH publication NO 85-23, revised 1996) and conformed to the Di- rective 2010 / 63 / EU of the European Parliament. The protocols have been approved by the Ethical Committee for the Protection of Animals in Research of the University of Szeged, Szeged, Hungary (approval number: I-74-5-2012) and by the Department of Animal Health and Food Control of the Ministry of Agriculture and Rural Development (authority approval number XIII / 1211 / 2012). Acute dog AF method Beagle dogs of either sex weighing 12–14 kg are used for the experiments (least 5-6 dogs for control and test groups, respectively) Following 0.5 μg / kg sufentanyl premedication and 150 mg / kg i.v. pentobarbital anaesthesia induction, left thoracotomy is performed on all animals. Dogs are endotracheally intubated and mechanically ventilated (UGO Basile, respirator; Bio- logical Research Apparatus, Italy) Physiological parameters (non-invasive blood pressure, SpO2, ECG) are continuously monitored during surgery and experiments (InnoCare-VET Patient Care Monitor; Budapest, Hungary). The ECGs are recorded using precordial leads and was digitized and stored on a computer for off-line analysis using National Instruments data acquisition hardware (National Instruments, Austin, Texas, USA) and SPEL Advanced Ha- emosys software (version 3.2, MDE Heidelberg GmbH, Germany). Under pentobarbital ana- esthesia 2 pacemaker electrodes (Biotronik Solia S 60; Biotronik Ltd., Hungary) are positi- oned epicardially into the left atrial appendage and apex of the left ventricle, respectively, and electrodes are connected to pacemakers (Effecta D; Biotronik Hungary Ltd., Hungary). Pace- makers are programmed in VVI mode using Biotronik IC: 4808A-Renamic programmer to prevent the potentially bradycardizing effect of carbachol leading to hemodynamic instability. Atrial and ventricular threshold are measured before AF induction in all animals. Ventricular and atrial pacing were set to three times the measured threshold. AF inducibility are tested in both groups using a control set (25 times) of 10-second-long rapid atrial bursts (800 beats / min, at threefold threshold). Following 25 atrial burst stimulus, 2x2mcg / kg loading dose of intravenous carbachol is administered followed by 8 mcg / kg / h maintenance dose. Atrial fibrillation is induced using 10-second-long atrial burst stimulus in the presence of carbachol in both groups of dogs. If atrial fibrillation is not converted spontaneously to sinus rhythm, control dogs receive 0.5 mg / kg propafenone intravenously in 5 min (as a positive control), while the test group dogs receive the test drug (SZV2649, compound 3) and the reference drug (propafenone) in the investigated concentration in 5 min. After conversion to sinus rhythm, inducibility of AF is repeatedly tested using 10-second-long atrial burst stimulus in the presence of carbachol and propafenone (control group) and in the presence of carbachol and test drug. In the experiments, we investigate whether AF is converted to SR under the effect of the test drug(s). All intravenous infusions are performed using a programmable infu- sion pump (Terufusion TE-3; Terumo Europe, Leuven, Belgium). The effect of compound 3 was investigated in carbachol infused and programmed electrical stimulation induced atrial fibrillation model in anesthetized dogs. In these experiments pro- pafenone was used as reference compound for comparison. Results are shown in Table 1. The results shown in Table 1 indicate that in the control group charbacol and electrical stimulation evoked atrial fibrillation in 100 % (5 / 5) of the animals, while compound 3 similarly to pro- pafenone had substantial protective effect (100 % and 66.7 %, respectively) in this model. Coronary ligation and reperfusion induced ventricular arrhythmias in rat The surgical procedure is based on a modified method described in detail in Gömöri et al (Gömöri et al. Cardioprotective Effect of Novel Matrix Metalloproteinase Inhibitors. Int J Mol Sci. 2020 Sep 23;21(19):6990.). Pentobarbital-anesthetized rats are mechanically venti- lated and subjected to thoracic surgery to perform a 6-min coronary artery occlusion and 5- min of reperfusion for the development of ischemia-induced ventricular arrhythmias. The right jugular vein is cannulated for the administration of test compounds (SZV-2649 (com- pound 3), SZV-2765 (compound 4) and SZV-2766 (compound 5)), and the right carotid artery is used to measure blood pressure. Three-lead electrocardiogram and body temperature is con- tinuously registered. Ten to twelve rats per group are administered vehicle (dimethyl sul- foxide, 200 µL / kg) or test drugs, as well as 3 mg / kg mexiletine or 300 µg / kg dofetilide as positive and negative controls, respectively, 2 min before the onset of ischemia as a slow i.v. bolus injection through the right jugular vein. At the end of 5-min reperfusion, hearts are isolated, mounted onto Langendorff perfusion system, and after re-occluding the coronary artery, perfused with 5-mL of 70% ethanol via the ascending aorta to delineate the ischemic zone. Then, the left ventricle is cut along the demarcation lines of denatured area, and the sections are weighed to determine the area of risk to normalize the extent of the ischaemic insult. We evaluate the occurrence of severe ventricular arrhythmias based on the recom- mendations of the modified Lambeth Conventions published by Curtis et al (The Lambeth Conventions (II): guidelines for the study of animal and human ventricular and supraventricu- lar arrhythmias. Pharmacol Ther.2013 Aug;139(2):213-48.). Compounds 3, 4 and 5 were investigated in athe cute ischemia induced ventricular arrhythmia model in anesthetized rats. Mexiletine and dofetilide were used as reference compounds for comparison. As Figure 6 shows in the control group in 100 % of the animals ventricular fibril- lation developed which was decreased by different degree by the applied compounds. The most effective compound was 3 which decreased the incidence of ventricular fibrillation to 20 %. The effects of the other compounds were less in magnitude. (Compound 4: 36.3 %, com- pound 535.7 %, mexiletine 38.5 % and dofetilide 77.8 %.) Conventional Microelectrode Technique Action potentials were recorded in ventricular trabeculae and papillary muscle preparations obtained from the right ventricles of rabbit or from undiseased human donor hearts using con- ventional microelectrode techniques. New Zealand rabbits of either sex weighing 2–3 kg were sacrificed by cervical dislocation after an intravenous injection of 400 U / kg heparin. Then the chest was opened, and the heart was rapidly removed. The heart was immediately rinsed in oxygenated modified Locke’s solution containing (in mM): NaCl 128.3, KCl 4, CaCl2 1.8, MgCl20.42, NaHCO321.4, and glucose 10. The pH of this solution was set between 7.35 and 7.4 when gassed with the mixture of 95% O2 and 5% CO2 at 37°C. In case of human donor hearts, after explantation, each heart was perfused with cardioplegic solution and kept cold (4–6°C) for 2-4 h before dissection. Isolated muscle preparations obtained from the right ventricle were individually mounted in a tissue chamber with the volume of 50 ml. Each preparation was initially stimulated through a pair of platinum electrodes in contact with the preparation using rectangular current pulses of 2 ms duration. These stimuli were delivered at a constant cycle length of 1000 ms for at least 60 min allowing the preparation to equilibrate before the measurements were initiated. Transmembrane potentials were recorded using conventional glass microelectrodes, filled with 3 M KCl and having tip resistances of 5–20 MΩ, connected to the input of a high impe­ dance electrometer (Experimetria, type 309, Budapest, Hungary) which was coupled to a dual beam oscilloscope. The resting potential (RP), action potential amplitude (APA), maximum upstroke velocity (Vmax), and APD measured at 50% and 90% of repolarization (APD50 and APD90, respectively) were off-line determined using a home-made software (APES) running on a computer equipped with an ADA 3300 analog-to-digital data acquisition board (Real Time Devices, Inc., State College, Pennsylvania) having a maximum sampling frequency of 40 kHz. Stimulation with a constant cycle length of 1000 ms was applied in the course of all experiments. Attempts were made to maintain the same impalement throughout each experi- ment. In case an impalement became dislodged, adjustment was attempted, and if the action potential characteristics of the re-established impalement deviated by less than 5% from the previous measurement, the experiment continued (Jost et al, 2005. Restricting excessive car- diac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation, 112(10): 1392–1399.; Kristóf et al. (2012). Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve. PloS one. 7. e53255. 10.1371 / journal.pone.0053255.; Lengyel et al.2001. Pharmacological block of the slow com- ponent of the outward delayed rectifier current I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration. Br. J. Pharmacol., 132(1): 101–110.). All meas- urements were carried out at 37°C. The effects of compound 3 were studied in dog ventricular, atrial and Purkinje fiber preparati- ons. Results at physiologic stimulation frequency (60 beat / minutes = 1Hz) are shown in Tab- les 4-6. As shown in the tables, compound 3 decreases Vmax and lengthen APD90 in ventri- cular muscle, Purkinje and atrial preparations indicating Class I antiarrhythmic property. In addition, compound 3 in ventricular and atrial muscle preparations significantly lengthened APD90 indicating Class III antiarrhythmic property. The Class I property of compound 3 was further studied with different frequency dependent protocols. When different steady-state stimulation cycle lengths were applied – like amio- darone – compound 3 decreased Vmax at cycle lengths shorter than 1500 ms (Figure 7). Also, the recovery of Vmax was measured (offset kinetics of Vmax block) with premature stimu- lation with gradually increasing diastolic intervals from 1 Hz basic frequency the recovery time constant was 590 ms (Figure 8) very similar to that observed after chronic amiodarone application. The onset kinetic of Vmax block i.e., the development of Vmax inhibition after 1 minute rest at stimulation cycle length of 400 ms was relatively fast (3.1) similar to that of amiodarone (Figure 9). Based on these frequency dependent Vmax behavior the effect of compound 3 – like amiodarone – can be characterized with Class I / B antiarrhythmic property. Automated Planar Patch-clamp Measurements The hERG channel current was measured by using planar patch-clamp technology in the who- le-cell configuration with a 4 channel medium-throughput fully automated patch-clamp plat- form (Patchliner Quattro, Nanion Technologies GmbH, Munich, Germany) with integrated temperature control. Data acquisition and online analysis were performed with an EPC-10 Quadro patch-clamp amplifier (HEKA Elektronik Dr Schulze GmbH, Lambrecht / Pfalz, Ger- many), using PatchMaster 2.65 software (HEKA Elektronik Dr. Schulze GmbH). The pipet- ting protocols were controlled by PatchControlHT 1.09.30 software (Nanion Technologies GmbH). Experiments were carried out at room or physiological (37°C) temperature, on HEK293 (hu- man embryonic kidney) cells stably expressing the hERG (Kv11.1) potassium channel. The cell line originated from Cell Culture Service GmbH (Hamburg, Germany). Cells were cultu- red at 37°C, in 5% CO2 in IMDM medium (PAA Laboratories GmbH, Pasching, Austria) supplemented with 10% FBS (PAA Laboratories GmbH), 2 mM L-glutamine (Life Technolo- gies Corporation, Carlsbad, California), 1 mM Na-piruvate (PAA Laboratories GmbH), and 500 µg / ml G418 (PAA Laboratories GmbH). Suspension of cells was used for measurements from running cell culture. Cells were washed twice with PBS (Life Technologies Corporation) and then detached with trypsin-EDTA (PAA Laboratories GmbH) for 30–60 s before the measurement. Trypsin was blocked with the serum-containing medium. The cell suspension was next centrifuged (2 min, 100 × g), resuspended in IMDM medium at a final density of 1 × 106–5× 106cells / ml, and kept in the cell hotel of the Patchliner. Cells were recovered after 15–30 min and remained suitable for automated patch-clamp recordings for up to 4 h. The following solutions were used during patch-clamp recording (compositions in mM): in- ternal solution: KCl 50, NaCl 10, KF 60, EGTA 20, HEPES 10, pH 7.2 (KOH); external so- lution: NaCl 140, KCl 4, glucose-monohydrate 5, MgCl2 1, CaCl2 3, HEPES 10, pH 7.4 (NaOH). All solutions were sterile filtered. Aliquots were stored at −20°C and warmed up to room temperature before use. The voltage protocol for hERG ion channel started with a short (100 ms) −40 mV step to establish the baseline region. A depolarizing step was applied to the test potential of 20 mV for 3 s, and then the cell was repolarized to −40 mV to evoke outward tail current. Holding potential was −80 mV. The pulse frequency was approximately 0.1 Hz. Currents were low-pass filtered at 2.9 kHz using the internal Bessel filter of the EPC-10 Quadro patch-clamp amplifier (HEKA Elektronik Dr. Schulze GmbH) and digitized at 10 kHz. The peak tail current was corrected the leak current defined during the first period to −40 mV. Recording started in external solution. After this control period, 6 increasing concentrati- ons of the test compound were applied, each for approximately 3 min (in case of dofetilide 6 min) to record a complete concentration-response curve. Amitriptyline (10 µM) was applied as a reference inhibitor then a wash-out step terminated the protocol. Statistics All data are expressed as means ± SEM. The “n” number refers to the number of experiments (i.e., the number of cells in case of patch-clamp and the number of ventricular muscle prepa- rations—papillary or trabecular muscle—in case of action potential measurements) except native IKr measurements when it refers to the number of experiments regarding 1 data point of the concentration-response curve and the means ± SEM values were calculated according­ ly. Statistical analysis was performed with Student’s t test for paired data or one-way analysis of variance (ANOVA). The results were considered statistically significant when p was <.05. Preparation of the compounds provided herein The compounds according to general formula (I) may be prepared by using classical tech- niques (Tetrahedron.2013, 69, 1255-1278). As an example, the compounds may be prepared with the procedures presented on Reaction Schemes 1, 2 and 3. Reaction Scheme 1

[0002] Reaction Scheme 2 Reaction Scheme 3 As it may be realized by a skilled practitioner, these processes are not the only possible methods of production (see e.g. R. R. Tidwell et al. J. Med. Chem.1975, 5, 477–481; C. Piantadosi et al. J. Med. Chem.1973, 9, 970–975; J. Tae et al. Tetrahedron Lett. 1985, 17, 2043–2046; C. Ra- minelli et al. J. Braz. Chem. Soc., 2010, 21, 770-774; C. Raminelli et al. Synthesis 2017, 5, 1093–1102; F. Haipeng et al. Patent, CN106675574, 2017; M. Chen et al. Tetrahedron, 2013, 69, 642–646; D. R. M. Moreire et al. J. Med. Chem.2012, 55, 10918–10936; A. B. Reitz et al. Organic Reactions Vol.59. edited by L. E. Overman et al.2002, Chapter 1) with which the dis- cussed and claimed compounds may be prepared. Additional methods will also be obvious for people skilled in the art. Preferably, these compounds can be readily prepared from starting materials commercially available. Otherwise preparation of the compounds is feasible on the basis of the technical liter- atures cited, or as described herein. The compounds were characterized with1H and13C NMR data (on 400 MHz or 500 MHz for1H and 100 MHz or 125 MHz for13C Bruker spectrophotometer, recorded in deuterated sol- vent), and / or with the melting point values. EXAMPLE 1 1-(2-iodophenoxy)-2-propanol See e.g. US9181298, Hoveyda et al, Optimization of the Potency and Pharmacokinetic Prop- erties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP- 101) from Hit to Clinic, Journal of Medicinal Chemistry (2011), 54(24), 8305 – 8320. 2-[1-(2-iodophenoxy)propan-2-yl]-1H-isoindole-1,3(2H)-dione 1-(2-Iodophenoxy)-2-propanol (5.39 g, 19.38 mmol) was dissolved in dry THF (50 mL) under inert atmosphere and phtalimide (3.14 g, 21.36 mmol) was added. The suspension was cooled by ice-bath followed by addition of triphenylphosphine (5.60 g, 21.37 mmol), respectively DIAD (4.20 mL, d = 1.03 g / mL, 21.37 mmol). The solution was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by column chromatography (hexane:EtOAc 3:1) to give the product: 6.63 g yellow solid, yield: 84%, Mp: 76-79 °C.1H (400 MHz, CDCl3), ^ (ppm): 1.59 (d, J = 7.2 Hz, 3H), 4.24 (dd, J = 8.8 Hz, J = 6.0 Hz, 1H), 4.52 (t, J = 9.2 Hz,1H), 4.83-4.95 (m, 1H), 6.63-6.72 (m, 1H), 6.79 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H), 7.31-7.21 (m, 2H), 7.62-7.72 (m, 2H), 7.80-7.89 (m, 2H),13C (100 MHz, CDCl3), ^ (ppm): 15.11, 45.98, 68.77, 86.48, 112.19, 122.88, 123.18, 129.39, 132.13, 133.90, 139.36, 156.75, 168.34. 1-(2-iodophenoxy)propan-2-amine To a solution of 2-[1-(2-iodophenoxy)propan-2-yl]-1H-isoindole-1,3(2H)-dione (4.48 g, 11.00 mmol) in MeOH (50 ml), glacial AcOH (1.26 mL, d = 1.05 g / mL, 22.00 mmol) and hydrazine hydrate (1.07 mL, d = 1.03 g / mL, 22.00 mmol) were added and the mixture was kept under reflux for 5 h, respectively cooled overnight. The solid residue was filtered off and washed twice with EtOAc (2x10 mL). After evaporation of the filtrate, the residue was taken up in EtOAc (50 mL) and extracted with 2N HCl (4x25 mL). The aqueous phase was treated with 2N NaOH (pH = 9-10) and extracted several times with EtOAc (5x25 mL). The combined organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the product: 3.00 g yellow oil, yield: 98%.1H (400 MHz, CDCl3), ^ (ppm): 1.50 (d, J = 6.8 Hz, 3H), 3.68-3.78 (m, 1H), 4.04-4.11 (m, 1H), 4.13-4.20 (m, 1H), 6.69-6.77 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 7.20 (s, 2H), 7.23-7.30 (m, 1H), 7.73 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H),13C (100 MHz, CDCl3), ^ (ppm): 16.54, 47.25, 70.95, 86.86, 112.93, 123.54, 129.62, 136.42, 156.34. 1-(2-iodophenoxy)propan-2-amine hydrochloride (compound 1) The 1-(2-iodophenoxy)propan-2-amine (2.99 g, 10.80 mmol) was dissolved in abs. EtOH (30 mL) and cooled by ice-bath. 37% HCl (5.00 mL, d = 1.19 g / mL, 60 mmol) was added in small proportions and stirred overnight at room temperature. After concentration in vacuo, the oily residue was triturated with hexane:Et2O 2:1 (15 mL), filtered and dried to give the prod- uct: 2.38 g light yellow solid, yield: 70%, Mp: 116-120 °C.1H (400 MHz, DMSO), ^ (ppm): 1.38 (d, J = 6.8 Hz, 3H), 3.57 (s, 1H), 4.09-4.23 (m, 2H), 6.76-6.84 (m, 1H), 7.05 (d, J = 7.2 Hz, 1H), 7.33-7.42 (m, 1H), 7.79 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H), 8.42 (brs, 3H),13C (100 MHz, DMSO), ^ (ppm): 15.69, 46.05, 69.99, 87.17, 113.67, 123.75, 130.08, 139.33, 156.61. EXAMPLE 2 (2R)-1-(2-iodophenoxy)propan-2-ol To a solution of 2-iodophenol (2.50 g, 11.36 mmol) in abs. acetone (25 mL) were added under stirring: dry K2CO3(1.88 g, 13.62 mmol) and (+)-(2R)-propylene oxide (4.00 mL, d = 0.83 g / mL, 57.17 mmol). The suspension was heated (Toil = 90°C), stirred for 16 h and then the reac- tion mixture was left to cool at room temperature. The inorganic solid was filtered off and the filtrate was evaporated under vacuum. The crude product was dissolved in Et2O (50 mL) and wased with 1M NaOH (2x25 mL), respectively brine (2x20 mL). The organic phase was dried (MgSO4), filtered and concentrated under vacuum to give the product: 3.06 g light yellow oil, yield: 97%, [α]20D = −30° (c = 1g / 100 mL CHCl3).1H (400 MHz, CDCl3),^ (ppm): 1.32 (d, J=6.4 Hz, 3H), 2.61 (s, 1H), 3.81 (dd, J = 7.6 Hz, J = 9.2 Hz, 1H), 4.02 (dd, J = 3.2 Hz, J = 8.8 Hz, 1H), 4.19-4.29 (m, 1H), 6.74 (t, J = 6.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.26-7.33 (m, 1H), 7.77 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H),13C (100 MHz, CDCl3), ^ (ppm): 18.59, 66.11, 74.52, 86.85, 112.47, 123.03, 129.55, 139.29, 156.79. 2-[(2S)-1-(2-iodophenoxy)propan-2-yl]-1H-isoindole-1,3(2H)-dione (2R)-1-(2-Iodophenoxy)-2-propanol (2.78 g, 0.01 mmol) was dissolved in abs. THF (25 mL) under inert atmosphere and phtalimide (1.62 g, 0.01 mmol) was added. The suspension was cooled by ice-bath followed by addition of triphenylphosphine (2.88 g, 0.01 mmol), respec- tively DIAD (2.16 mL, d = 1.03 g / mL, 0.01 mmol). The solution was stirred at room tempera- ture overnight and concentrated in vacuo. The residue was purified by column chromatog- raphy with gradient elution (hexane followed by hexane:EtOAc 2:1) to give the product: 3.04 g light yellow oil, yield: 75%, [α]20D = −32° (c = 1g / 100 mL CHCl3).1H (400 MHz, CDCl3), ^ (ppm): 1.59 (d, J = 7.2 Hz, 3H), 4.20-4.29 (m, 1H), 4.52 (t, J = 9.2 Hz, 1H), 4.83-4.96 (m, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 7.21-7.31 (m, 1H), 7.63-7.74 (m, 3H), 7.80-7.88 (m, 2H),13C (100 MHz, CDCl3), ^ (ppm): 15.08, 45.93, 68.69, 86.43, 112.12, 122.84, 123.16, 129.38, 132.07, 133.89, 139.32, 156.68, 168.34. (2S)-1-(2-iodophenoxy)propan-2-amine To a solution of 2-[(2S)-1-(2-iodophenoxy)propan-2-yl]-1H-isoindole-1,3(2H)-dione (2.44 g, 6.00 mmol) in MeOH (30 mL), glacial AcOH (0.69 mL, d = 1.05 g / mL, 12.00 mmol) and hy- drazine hydrate (0.58 mL, d = 1.03 g / mL, 12.00 mmol) were added and the mixture was kept under reflux for 6 h, respectively cooled overnight. The solid residue was filtered off and washed twice with EtOAc (2x10 mL). After evaporation of the filtrate, the residue was taken up in EtOAc (50 mL) and extracted with 2N HCl (4x15 mL). The aqueous phase was treated with 2N NaOH (pH = 10-11) and extracted several times with EtOAc (4x25 mL). The combined organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the product: 1.50 g light yellow oil, yield: 90%, [α]20D= +19° (c = 1g / 100 mL CHCl3), respectively [α]20D= +15° (c = 1g / 100 mL abs. MeOH).1H (400 MHz, CDCl3), ^ (ppm): 1.22 (d, J = 6.8Hz, 3H), 3.37-3.47 (m, 1H), 3.68-3.76 (m, 1H), 3.95 (dd, J = 4.0 Hz, J = 8.8 Hz, 1H), 6.67-6.77 (m, 1H), 6.75-6.83 (m, 1H), 7.26-7.34 (m, 1H), 7.72-7.79 (m, 1H),13C (100 MHz, CDCl3), ^ (ppm): 19.60, 46.30, 75.35, 86.65, 112.07, 122.63, 129.46, 139.27, 157.04. (2S)-1-(2-iodophenoxy)propan-2-amine hydrochloride (compound 2) The (2S)-1-(2-iodophenoxy)propan-2-amine (1.11 g, 4.00 mmol) was dissolved in abs. EtOH (20 mL) and cooled by ice-bath.37% HCl (2.20 mL, d = 1.19 g / mL, 26.40 mmol) was added in small proportions and stirred overnight at room temperature. After concentration in vacuo, the oily residue was triturated with Et2O:hexane 3:1 (12 mL), filtered and dried to give the product: 1.10 g white solid, yield: 88%, Mp: 126-129 °C, [α]20D = +10° (c = 1g / 100 mL abs. MeOH).1H (400 MHz, DMSO), ^ (ppm): 1.39 (d, J = 6.4 Hz, 3H), 3.58 (s, 1H), 4.09-4.18 (m, 1H), 4.16-4.24 (m, 1H), 6.77-6.85 (m, 1H), 7.06 (d, J = 7.2 Hz, 1H), 7.34-7.42 (m, 1H), 7.79 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H), 8.42 (brs, 3H),13C (100 MHz, DMSO), ^ (ppm):15.63, 46.03, 70.00, 87.13, 113.68, 123.72, 130.04, 139.30, 156.59. EXAMPLE 3 4-Hydroxy-3,5-diiodobenzonitrile To a solution of 4-hydroxybenzonitrile (2.00 g, 16.79 mmol) in water (400 mL), KI (4.00 g, 24.10 mmol) and I2 (8.80 g, 34.40 mmol) were added and the mixture was kept at room temper- ature. Over a reaction time of 16 h, 1 mL of 1N NH4OH was added dropwise, every half an hour. The reaction was monitored by TLC (n-hexane:EtOAc 4:1). After the reaction was com- plete, Na2S2O5was added to the system to reduce unreacted I2. The aqueous phase was extract- ed, using DCM (2 x 50 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized using EtOAc (15 mL): 5.70 g white crystal, yield: 92 %. The compound has been characterized in various literature, e.g.. Patrick et al. Syn- thesis and antiprotozoal activities of benzyl phenyl ether diamidine derivatives, European Jour- nal of Medicinal Chemistry (2013), 67, 310 – 324., CN101328139. 3,5-diiodo-4-(2-oxopropoxy)benzonitrile To a solution of 4-hydroxy-3,5-diiodobenzonitrile (5.00 g, 15.00 mmol) in abs. CH3CN (50 mL), dry K2CO3(10.35 g, 75.00 mmol) and 1-chloropropan-2-one (1.80 mL, d = 1.16 g / mL, 22.60 mmol) were added and the mixture was kept under reflux for 22 h, respectively cooled to room temperature. The inorganic solid was filtered off and washed twice with acetone (2x15 mL). After evaporation of the filtrate, the residue was taken up in EtOAc (150 mL) and extracted with 2N NaOH (4x50 mL). The combined organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was recrystalyzed from CH3CN (50 mL) to give the product: 2.82 g yellow solid, yield: 44%, Mp: 165-167 °C.1H (400 MHz, CDCl3), ^ (ppm): 2.46 (s, 3H), 4.54 (s, 2H), 8.07 (s, 2H),13C (100 MHz, CDCl3), ^ (ppm): 27.23, 76.05, 90.59, 112.34, 115.01, 143.17, (143.27), 160.54, 203.14. 4-(2-aminopropoxy)-3,5-diiodobenzonitrile To a cooled solution of 3,5-diiodo-4-(2-oxopropoxy)benzonitrile (2.77 g, 6.50 mmol) in abs. MeOH (30 mL), NH4OAc (5.00 g, 65.00 mmol) and NaBH3CN (2.05 g, 32.50 mmol) were added and the mixture was stirred 42 h at room temperature. The received suspension was cooled by ice-bath, diluted with H2O and the excess of reagent quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extracted with CHCl3(3x50 mL). The combined organic layer was dried (MgSO4), filtered and concentrated in vac- uo to give the product: 2.68 g light yellow solid, yield: 96%, Mp: 110-115 °C.1H (400 MHz, CDCl3), ^ (ppm): 1.22 (d, J = 6.5 Hz, 3H), 1.29-1.52 (m, 2H), 3.46-3.58 (m, 1H), 3.80-3.92 (m, 2H), 8.02-8.08 (m, 2H),13C (100 MHz, CDCl3), ^ (ppm): 19.56, 47.17, 79.25, 91.06, 111.52, 115.25, 143.15, 161.47. 4-(2-aminopropoxy)-3,5-diiodobenzonitrile hydrochloride (compound 3) The 4-(2-aminopropoxy)-3,5-diiodobenzonitrile (1.25 g, 2.92 mmol) was dissolved in abs. EtOH (20 mL) and cooled by ice-bath.37% HCl (2.00 mL, d = 1.19 g / mL, 24.00 mmol) was added in small proportions and stirred overnight at room temperature. After concentration in vacuo, the oily residue was triturated with Et2O (10 mL), filtered and dried to give the prod- uct: 1.13 g white solid, yield: 83%, Mp: 216-219 °C1H (400 MHz, DMSO), ^ (ppm): 1.42 (d, J = 6.8 Hz, 3H), 3.64-3.76 (m, 1H), 3.98-4.06 (m, 1H), 4.06-4.15 (m, 1H), 8.32 (s, 2H), 8.42 (s, 1H), 8.43 (s, 1H),13C (100 MHz, DMSO), ^ (ppm): 15.50, 46.74, 72.96, 92.89, 111.26, 115.67, 143.26, 160.64. EXAMPLE 4 1-(2,4,6-triiodophenoxy)propan-2-one synthesized according to literature: See e.g. Hunter and Weutney; A Catalytic Decomposition of Certain Phenol Silver Salts. VI. Intermediate Stages, Journal of American Chemical Society (1932), 54, 1167-1173. WO 2009012998. 1-(2,4,6-triiodophenoxy)propan-2-amine To a cooled solution of 1-(2,4,6-triiodophenoxy)propan-2-one (4.23 g, 8.00 mmol) in abs. MeOH (50 mL), NH4OAc (6.16 g, 80.00 mmol) and NaBH3CN (2.52 g, 40.00 mmol) were added and the mixture was stirred 42 h at room temperature. The received suspension was cooled by ice-bath, diluted with H2O and the excess of reagent quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extracted with CHCl3 (4x50 mL). The combined organic layer was dried (MgSO4), filtered and concentrated in vac- uo to give the product: 4.10 g yellow oil, yield: 97%.1H (400 MHz, CDCl3), ^ (ppm): 1.20 (d, J = 6.4 Hz, 3H), 1.30-1.35 (m, 1H), 1.69 (s, 2H), 3.44-3.52 (m, 1H), 3.72-3.86 (m, 2H), 8.04 (s, 2H),13C (100 MHz, CDCl3), ^ (ppm): 19.69, 47.18, 79.11, 89.22, 92.09, 147.33, 157.48. 1-(2,4,6-triiodophenoxy)propan-2-amine hydrochloride (compound 4) The 1-(2,4,6-triiodophenoxy)propan-2-amine (1.59 g, 3.00 mmol) was dissolved in a mixture of abs. EtOH (15 mL), respectively EtOAc (10 mL) and cooled by ice-bath.37% HCl (5.00 mL, d = 1.19 g / mL, 36.00 mmol) was added in small proportions and stirred overnight at room tem- perature. After concentration in vacuo, the oily residue was triturated with hexane:Et2O 2:1 (9 mL), filtered and dried to give the product: 1.20 g white solid, yield: 71%, Mp: 221-226 °C.1H (400 MHz, DMSO), ^ (ppm): 1.41 (d, J = 6.8 Hz, 3H), 3.60-3.68 (m, 1H), 3.91-4.18 (m, 2H), 8.17 (t, J = 1.2 Hz, 2H), 8.36 (brs, 3H),13C (100 MHz, DMSO), ^ (ppm): 15.47, 46.74, 72.76, 92.28, 93.75, 146.77, 156.61. EXAMPLE 5 3,5-diiodophenol synthesized according to literature: See e.g. Höger et al. Synthesis, Aggregation, and Adsorption Phenomena of Shape-Persistent Macrocycles with Extraannular Polyalkyl Substituents, J. Am. Chem. Soc.(2001), 123, 5651- 5659. Yu Feng et al; A Pronounced Halogen Effect on the Organogelation Properties of Pe- ripherally Halogen Functionalized Poly(benzyl ether) Dendrons, Chem. Eur. J. (2016), 22, 4980 – 4990 1-(3,5-diiodophenoxy)propan-2-one To a solution of 3,5-diiodophenol (5.88 g, 17.00 mmol) in abs. CH3CN (70 ml), dry K2CO3 (11.73 g, 85.00 mmol), 1-chloropropan-2-one (2.03 mL, d = 1.16 g / mL, 25.50 mmol) were added and the mixture was kept under reflux for 22 h, respectively cooled. The inorganic solid was filtered off and washed twice with acetone (2x25 mL). After evaporation of the filtrate, the residue was taken up in EtOAc (150 mL) and extracted with 2N NaOH (4x50 mL). The combined organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography with CHCl3as eluent to give the product: 4.14 g yellow solid, yield: 61%, Mp: 104-107 °C.1H (400 MHz, CDCl3), ^ (ppm): 2.27 (s, 3H), 4.51 (s, 2H), 7.18 (s, 1H), 7.20 (s, 1H), 7.68 (s, 1H),13C (100 MHz, CDCl3), ^ (ppm): 26.63, 72.83, 94.71, 123.43, 138.68, 158.22, 203.88. 1-(3,5-diiodophenoxy)propan-2-amine To a cooled solution of 1-(3,5-diiodophenoxy)propan-2-one (3.62 g, 9.00 mmol) in abs. MeOH (70 mL), NH4OAc (6.93 g, 90.00 mmol), NaBH3CN (2.84 g, 45.00 mmol) were added and the mixture was stirred 21 h at room temperature. The received solution was cooled by ice-bath, diluted with H2O and the excess of reagent quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extracted with CHCl3(4x50 mL). The combined organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the product: 3.43 g yellow oil, yield: 94%.1H (400 MHz, CDCl3), ^ (ppm): 1.18 (d, J = 7.6 Hz, 3H), 2.09 (s, 2H), 3.15-3.33 (m, 1H), 3.45-3.68 (m, 1H), 3.72-3.85 (m, 1H), 7.15-7.25 (m, 2H), 7.64 (s, 1H),13C (100 MHz, CDCl3), ^ (ppm): 19.55, 46.10, 74.61, 94.59, 123.40, 137.60, 139.47. 1-(3,5-diiodophenoxy)propan-2-amine hydrochloride (compound 5) The 1-(3,5-diiodophenoxy)propan-2-amine (1.41 g, 3.50 mmol) was dissolved in abs. EtOH (25 mL) and cooled by ice-bath.37% HCl (2.00 mL, d = 1.19 g / mL, 24.00 mmol) was added in small proportions and stirred overnight at room temperature. After concentration in vacuo, the oily residue was triturated with Et2O (15 mL), filtered and dried to give the product: 1.26 g white solid, yield: 82%, Mp: 284-286 °C.1H (400 MHz, DMSO), ^ (ppm): 1.26 (d, J = 6.8 Hz, 3H), 3.53 (s, 1H), 4.00 (dd, J = 7.6 Hz, J = 10.4 Hz, 1H), 4.16 (dd, J = 3.6 Hz, J = 10.0 Hz, 1H), 7.38 (s, 1H), 7.39 (s, 1H), 7.68 (s, 1H), 8.32 (brs, 3H),13C (100 MHz, DMSO), ^ (ppm):14.82, 45.92, 69.20, 96.24, 123.31, 137.17, 158.88. EXAMPLE 6 2,6-Diiodo-4-(trifluoromethyl)phenol To a solution of 4-(trifluoromethyl)phenol (1.00 g, 6.17 mmol) in water (10 mL) ), I2(1.74 g, 6.86 mmol) and H2O2 (0.5 mL, 35 %) was added. The reaction mixture was agitated for 16 h, while additional H2O2(1 mL) was added dropwise hourly. The remaining I2was reduced by adding Na2S2O5in small quantities to prevent violent decomposition of H2O2by in situ gener- ated NaI. The aqueous phase was extracted, using DCM (2 x 15 mL) and the combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized us- ing n-hexane (5 mL). The crystals were filtered and washed with hexane (2 x 10 mL): 1.06 g, beige crystals, yield: 41 %, Mp.: 103-105 °C.1H (500 MHz, DMSO), ^ (ppm): 8.04 (2H s), 10.03 (2H, brs);13C (125 MHz, DMSO) 87.0, 124.2, 124.5, 136.4, 136.4, 159.7. 1-(2,6-Diiodo-4-(trifluoromethyl)phenoxy)propan-2-one To a solution of 2,6-diiodo-4-(trifluoromethyl)phenol (0.15 g, 0.69 mmol) in abs. DMF (1 mL), dry K2CO3 (0.09 g, 0.64 mmol), 1-chloropropan-2-one (0.09 mL, d = 1.16 g / ml, 1.14 mmol) were added and the mixture was kept under reflux for 22 h, respectively cooled. After completition 1 mL of H2O was added and the unsoluble solid was filtered off and washed with EtOAc (2 x 10 mL): 0.19 g white cystal, yield: 60%. Mp.: 105-106 °C.1H (500 MHz, CDCl3), ^ (ppm): 2.41 (s, 3H), 4.53 (s, 2H), 8.02 (s, 2H);13C (125 MHz, CDCl3), ^ (ppm): 27.3, 29.7, 76.2, 90.3, 130.2, 130.4, 137.1, 137.2, 159.5, 203.7. 1-(2,6-Diiodo-4-(trifluoromethyl)phenoxy)propan-2-amine To the solution of 1-(2,6-diiodo-4-(trifluoromethyl)phenoxy)propan-2-one (0.10 g, 0.21 mmol) in abs. EtOH (4 mL), NH4OAc (0.16 g, 2.10 mmol) was added and the reaction was stirred for 1 h at room temperature. In 10 min intervals NaBH3CN (in total: 0.03 g, 0.48 mmol) was added in small quantities. After completition the excess of reagent was quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extract- ed with DCM (2 x 5 mL). The combined organic layer was dried (Na2SO4), filtered, concen- trated in vacuo and crystallized from Et2O (5 ml): 0.06 g yellow oil, yield: 64 %.1H (500 MHz, DMSO), ^ (ppm):1.18 (d, J = 6.7, 3H), 3.53 (m, 1H), 3.75-3.82 (m, 2H), 8.18 (s, 2H);13C (125 MHz, DMSO), ^ (ppm): 20.2, 47.2, 79.2, 93.0, 128.3, 128.5, 137.0, 137.0, 161.3. 1-(2,6-Diiodo-4-(trifluoromethyl)phenoxy)propan-2-amine hydrochloride (compound 6) 1-(2,6-Diiodo-4-(trifluoromethyl)phenoxy)propan-2-one (0,03 g, 0,06 mmol) was dissolved in Et2O (1 mL) and cooled by ice-bath. 22% HCl / EtOH was added in small proportions until reaching pH = 1-2. The precipitated product was filtered and washed with Et2O (2 x 1 mL): 0.03 g white crystal, yield: 93 %, Mp.: decomposition over 170 °C.1H (500 MHz, DMSO), ^ (ppm): 1.24 (d, J = 6.6 Hz, 3H), 3.54 (ddd, J = 4.2 Hz, J = 4.2 Hz, J = 4.3 Hz, 1H), 3.82-3.92 (m, 2H), 8.02 (s, 2H);13C (125 MHz, DMSO), ^ (ppm): 19.6, 47.3, 79.2, 79.2, 90.7, 120.6, 122.8, 129.5, 129.7, 137.1, 137.1, 160.4. EXAMPLE 7 4-hydroxy-3,5-diiodobenzamide To a solution of 4-hydroxybenzamide (0.50 g, 3.65 mmol) in water (50 mL), KI (1.00 g, 6.02 mmol) and I2(2.2 g, 8.66 mmol) were added and the mixture was kept at room temperature. Over a reaction time of 16 h, 1 mL of 1N NH4OH was added dropwise, every half an hour. The reaction was monitored by TLC (n-hexane:EtOAc 4:1). After the reaction was complete, Na2S2O5 was added to the system to reduce unreacted I2. The aqueous phase was extracted, us- ing DCM (3 x 25 mL). The combined organic phase was dried (Na2SO4), filtered and concen- trated in vacuo. The residue was crystallized using EtOAc (10 mL): 1.10 g beige crystal, yield: 77 %. Mp.: 250–252 °C.1H (500 MHz, DMSO), ^ (ppm): 7.30 (1H, brs), 7.92 (1H, brs), 8.24 (2H, s), 10.02 (1H, brs);13C (125 MHz, DMSO), ^ (ppm): 86.4, 130.0, 139.1, 158.4, 165.2. 3,5-diiodo-4-(2-oxopropoxy)benzamide To a solution of 4-hydroxy-3,5-diiodobenzamide (0.15 g, 0.38 mmol) in abs. DMF (1 mL), dry K2CO3(0.05 g, 0.30 mmol), 1-chloropropan-2-one (0.05 mL, d = 1.16 g / ml, 0.63 mmol) were added and the mixture was kept under reflux for 22 h, respectively cooled. After com- pletition 1 mL of H2O was added and the unsoluble solid was filtered off and washed with EtOAc (2 x 10 mL): 0.11 g white cystal, yield: 64%. Mp.: 186-188 °C.1H (500 MHz, DMSO), ^ (ppm): 2.29 (3H, s), 4.59 (2H, s), 7.49 (1H, brs), 9.07 (1H, brs), 8.31 (2H, s);13C (125 MHz, DMSO), ^ (ppm): 27.1, 76.6, 91.8, 134.3, 139.4, 159.2, 164.9, 203.0. 4-(2-aminopropoxy)-3,5-diiodobenzamide To the solution of 3,5-diiodo-4-(2-oxopropoxy)benzamide (0.10 g, 0.26 mmol) in abs. EtOH (4 mL), NH4OAc (0.17 g, 2.21 mmol) was added and the reaction was stirred for 1 h at room temperature. In 10 min intervals NaBH3CN (in total: 0.03 g, 0.48 mmol) was added in small quantities. After completition the excess of reagent was quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extracted with DCM (2 x 5 mL). The combined organic layer was dried (Na2SO4), filtered, concentrated in vacuo and crystal- lized from Et2O (5 ml): 0.26 g yellowish white crystals, yield: 23 %, Mp.: 98-100 °C.1H (500 MHz, DMSO), ^ (ppm): 1.16 (d, J=6,5 Hz, 3H), 3.30-3.41 (m, 1H), 3.71-3.78 (m, 2H); 7.47 (brs, 1H), 8.05 (brs, 1H), 8,31 (s, 2H),13C (125 MHz, DMSO), ^ (ppm): 20.4, 47.2, 79.3, 92.0, 133.8, 139.5, 160.0, 165.0. 4-(2-aminopropoxy)-3,5-diiodobenzamide hydrochloride (compound 7) The 4-(2-aminopropoxy)-3,5-diiodobenzamide (0,02 g, 0,05 mmol) was dissolved in Et2O (1 mL) and cooled by ice-bath. 22% HCl / EtOH was added in small proportions until reaching pH = 1-2. The precipitated product was filtered and washed with Et2O (2 x 1 mL): 0.02 g white crystal, yield: 92 %, Mp.: decomposition over 180 °C.1H (500 MHz, DMSO), ^ (ppm): 1.40 (d, J=6.7 Hz, 3H), 3.66-3.75 (m, 1H), 3.97-4.09 (m, 2H) 7.52 (brs, 1H), 8.08 (brs, 1H), 8.14 (brs, 2H), 8.34 (s, 2H);13C (125 MHz, DMSO), ^ (ppm): 15.9, 47.4, 73.3, 91.9, 134.4, 139.6, 159.0, 164.8. EXAMPLE 8 3,5-Diiodo-[1,1'-biphenyl]-4-ol To a solution of [1,1'-biphenyl]-4-ol (2.00 g, 11.76 mmol) in 5N NaOH (40 mL) KI (3.32 g, 20.00 mmol) and N-chlorobenzenesulfonamide-sodium (5.62 g, 26.31 mmol) was added. The reaction was let stir for 16 h at 80 °C. After completition of the reaction cc. HCl was added until reaching pH = 1-2 and the aqueous phase was extracted by DCM (3 x 40 mL). The combined organic phases were dried, filtered, concentrated in vacuo and crystallized using n-hexane (10 mL). The filtered crystals were washed with n-hexane (2 x 5 mL): 1.10 g beige crystal, yield: 77 %. Mp.: 155–157 °C.1H (500 MHz, DMSO), ^ (ppm): 7.23 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.56 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.86 (s, 1H);13C (125 MHz, DMSO), ^ (ppm): 93.6, 126.3, 126.3, 129.1, 129.2, 129.3, 135.1, 140.4, 161.6. 1-((3,5-Diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-one To a solution of 3,5-diiodo-[1,1'-biphenyl]-4-ol (0.30 g, 0.71 mmol) in abs. DMF (3 mL) K2CO3(0.10 g, 1.37 mmol) and 1-chloropropan-2-one (0.10 ml, d = 1.16 g / ml, 1.26 mmol) were aded and the mixture was agitated for 6 h at 50 °C. The reaction was monitored by TLC and after completition 3 mL of H2O was added and the unsoluble solid was filtered off and washed with EtOAc (2 x 10 mL): 0.25 g qhite crystal, yield: 74 %. Mp.: 108-110 °C1H (500 MHz, CDCl3), ^ (ppm):2.49 (s, 3H), 4.54 (s, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.98 (s, 2H);13C (125 MHz, CDCl3), ^ (ppm): 27.4, 76.5, 90.5, 127.0, 128.3, 129.0, 137,4.138.6, 141.8, 155.8. 1-((3,5-Diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-amine To a solution of 1-((3,5-diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-one (0.20 g, 0.42 mmol) in abs. EtOH (2 ml) NH4OAc-ot (0.32 g, 4.20 mmol) was added and the reaction was stirred for 1 h at room temperature. In 10 min intervals NaBH3CN (in total: 0.05 g, 0.84 mmol) was add- ed in small quantities. After completition the excess of reagent was quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extracted with DCM (2 x 3 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo: 0.19 g pale yellow oil, yield: 94 %.1H (500 MHz, CDCl3), ^ (ppm): 1.24 (d, J = 6.6 Hz, 3H), 3,53 (ddd, J = 4.0 Hz, J = 4.0 Hz, J = 4.3 Hz, 1H), 3.81-3.93 (m, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.98 (s, 2H);13C (125 MHz, CDCl3), ^ (ppm): 1-((3,5-Diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-amine hydrochloride (compound 8) To a solution of 1-((3,5-diiodo-[1,1'-biphenyl]-4-yl)oxy)propan-2-amine (0.18 g, 0.38 mmol) in Et2O (5 ml) cooled by ice-bath 22% HCl / EtOH was added in small proportions until reach- ing pH = 1-2. The precipitated product was filtered and washed with Et2O (2 x 5 mL): 0.18 g white crystal, yield: 92 %. Mp.: decomposition over 183 °C.1H (500 MHz, DMSO), ^ (ppm): 1.42 (d, J=6.7 Hz, 3H), 3.66-3.76 (m, 1H), 3.98-4.10 (m, 2H) 7.40 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.66 (d, J = 7.8 Hz, 2H), 8.13 (s, 2H);13C (125 MHz, DMSO), ^ (ppm): 15.9, 47.4, 73.3, 92.7, 127.4, 128.7, 129.5, 137.0, 138.3, 141.1, 156.2. EXAMPLE 9 2,6-diiodo-4-methylphenol To a suspension of 4-methylphenol (0.50 g, 4.63 mmol) in water (50 mL), KI (1.00 g, 6.02 mmol) and I2(2.20 g, 8.66 mmol) was added and the reaction mixture was agitated for 16 h, while 0.25 mL 1N NH4OH was added dropwise every 30 min. The remaining I2 was reduced by adding Na2S2O5. The aqueous phase was extracted by DCM (3 x 25 mL) and the combined organic phase was dried (Na2SO4) and evaporated under vacuo. The residue was crystallized using EtOAc (10 mL) and washed with EtOAc (2 x 5 mL): 1.53 g beige crystal, yield: 92%. Mp.: 51–53°C.1H (500 MHz, CDCl3), ^ (ppm): 2.22 (s, 3H), 5.57 (s, 1H), 7.49 (s, 2H);13C (125 MHz, CDCl3), ^ (ppm): 81.9, 133.9, 139.6, 151.4. 1-(2,6-diiodo-4-methylphenoxy)propan-2-one To a solution of 2,6-diiodo-4-methylphenol (0.50 g, 1.39 mmol) in abs. DMF (5 ml), dry K2CO3(0.19 g, 1.37 mmol), 1-chloropropan-2-one (0.13 mL, d = 1.16 g / mL, 1.67 mmol) were added and the mixture was kept under reflux for 22 h, respectively cooled. After com- pletition 5 mL of H2O was added and the unsoluble solid was filtered off and washed with EtOAc (2 x 10mL): 0.43 g white crystal, yield: 74 %. Mp.: 104-106 °C.1H (500 MHz, CDCl3), ^ (ppm): 2.25 (s, 3H), 2.46 (s, 3H), 4.46 (s, 2H), 7.59 (s, 2H);13C (125 MHz, CDCl3), ^ (ppm): 19.7, 27.4, 76.5, 89.8, 138.6, 140.4, 154.4, 204.9. 1-(2,6-diiodo-4-methylphenoxy)propan-2-amine To the solution of 1-(2,6-diiodo-4-methylphenoxy)propan-2-one (0.40 g, 0.96 mmol) in abs. EtOH (2 mL), NH4OAc (0.74 g, 9.60 mmol) was added and the reaction was stirred for 1 h at room temperature. In 10 min intervals NaBH3CN (in total: 0.12 g, 1.91 mmol) was added in small quantities. After completition the excess of reagent was quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extracted with DCM (2 x 5 mL). The combined organic layer was dried (MgSO4), filtered and concentrated in vac- uo: 0.34 g pale yellow oil, yield: 85 %.1H (500 MHz, CDCl3), ^ (ppm): 1,22 (d, J=6,6 Hz, 3H), 2.24 (s, 3H), 3,46-3.54 (m, 1H), 3.74-3.87 (m, 2H), 7.58 (s, 2H),13C (125 MHz, CDCl3), ^ (ppm): 19.52, 19.6, 47.3, 78.8, 90.4, 137.8, 140.4, 155.0. 1-(2,6-diiodo-4-methylphenoxy)propan-2-amine hydrochloride (compound 9) The 1-(2,6-diiodo-4-methylphenoxy)propan-2-amine (0.30 g, 0.72 mmol) was dissolved in Et2O (5 mL) and cooled by ice-bath. 22% HCl / EtOH was added in small proportions until reaching pH = 1-2. The precipitated product was filtered and washed with Et2O (2 x 5 mL): 0.32 g white crystal, yield: 98 %. Mp.: decomposition over 222 °C.1H (500 MHz, DMSO), ^ (ppm): 1.39 (d, J = 6.7 Hz, 3H), 2.22 (s, 3H), 3.66 (brs, 1H), 3.99-4.02 (m, 2H) 7.71 (s, 2H), 8.12 (brs, 3H);13C (125 MHz, DMSO), ^ (ppm): 15.9, 19.4, 47.3, 73.2, 91.6, 139.2, 140.6, 154.5. EXAMPLE 10 2,6-diiodo-4-nitrophenol To a suspension of 4-nitrophenol (0.25 g, 1.80 mmol) in water (2.5 mL), I2(0.66 g, 2.60 mmol) and H2O2 (0.2 mL, 35 %) was added. The reaction mixture was agitated for 16 h, while additional H2O2 (0.3 mL) was added dropwise hourly. The remaining I2 was reduced by add- ing Na2S2O5in small quantities to prevent violent decomposition of H2O2by in situ generated NaI. The aqueous phase was extracted, using DCM (2 x 15 mL) and the combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized us- ing n-hexane (5 mL). The crystals were filtered and washed with n-hexane (2 x 10 mL): 0.08 g, beige crystals, yield: 12 %, Mp.: 103-105 °C.1H (500 MHz, CDCl3), ^ (ppm): 2.22 (s, 3H), 5.57 (s, 1H), 7.49 (s, 2H);13C (125 MHz, CDCl3), ^ (ppm): 81.9, 133.9, 139.6, 151.4. 1-(2,6-diiodo-4-nitrophenoxy)propan-2-one To a solution of 2,6-diiodo-4-nitrophenol (0.05 g, 0.13 mmol) in abs. DMF (1 ml), dry K2CO3 (0.02 g, 0.13 mmol), 1-chloropropan-2-one (0.01 mL, d = 1.16 g / mL, 0.16 mmol) were added and the mixture was kept under reflux for 22 h, respectively cooled. After completition 5 mL of H2O was added and the unsoluble solid was filtered off and washed with EtOAc (2 x 10mL): 0.03 g white crystal, yield: 58 %. Mp.: 104-106 °C.1H (500 MHz, CDCl3), ^ (ppm): 2.25 (s, 3H), 2.46 (s, 3H), 4.46 (s, 2H), 7.59 (s, 2H);13C (125 MHz, CDCl3), ^ (ppm): 19.7, 27.4, 76.5, 89.8, 138.6, 140.4, 154.4, 204.9. 1-(2,6-diiodo-4-nitrophenoxy)propan-2-amine To the solution of 1-(2,6-diiodo-4-nitrophenoxy)propan-2-one (0.03 g, 0.07 mmol) in abs. EtOH (1 mL), NH4OAc (0.05 g, 0.70 mmol) and NaBH3CN (0.01 g, 0.16 mmol) was added and the reaction was stirred for 1 h at room temperature. After completition the excess of rea- gent was quenched by 37% HCl (pH = 1-2). After adding 4M NaOH (pH = 12-13), the aqueos phase was extracted with DCM (2 x 5 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated in vacuo: 0.34 g pale yellow oil, yield: 85 %.1H (500 MHz, CDCl3), ^ (ppm): 1,22 (d, J=6,6 Hz, 3H), 2.24 (s, 3H), 3,46-3.54 (m, 1H), 3.74-3.87 (m, 2H), 7.58 (s, 2H),13C (125 MHz, CDCl3), ^ (ppm): 19.52, 19.6, 47.3, 78.8, 90.4, 137.8, 140.4, 155.0. 1-(2,6-diiodo-4-nitrophenoxy)propan-2-amine hydrochloride (compound 10) The 1-(2,6-diiodo-4-nitrophenoxy)propan-2-amine (0.30 g, 0.72 mmol) was dissolved in Et2O (5 mL) and cooled by ice-bath.22% HCl / EtOH was added in small proportions until reaching pH = 1-2. The precipitated product was filtered and washed with Et2O (2 x 5 mL): 0.32 g white crystal, yield: 98 %. Mp.: decomposition over 222 °C.1H (500 MHz, DMSO), ^ (ppm): 1.39 (d, J = 6.7 Hz, 3H), 2.22 (s, 3H), 3.66 (brs, 1H), 3.99-4.02 (m, 2H) 7.71 (s, 2H), 8.12 (brs, 3H);13C (125 MHz, DMSO), ^ (ppm): 15.9, 19.4, 47.3, 73.2, 91.6, 139.2, 140.6, 154.5.

Claims

CLAIMS 1. Compound for use in therapy, the compound having general formula (I)or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, C1-7alkyl-S(O)2-NH-, -COX group, wherein X is -OH, C1-7alkyl-O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2or C1-3alkyl- ; R2, R3, R4and R5are selected form hydrogen and iodine; R6and R7are independently C1-7alkyl-; and n is 1, 2 or 3; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hydrogen; and if R4is iodine then R2and R5are hydrogen.

2. The compound for use according to claim 1, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl- O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2or C1-3alkyl- ; R2, R3, R4and R5are selected form hydrogen and iodine; R6and R7are independently C1-7alkyl-; and n is 1, 2 or 3; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hydrogen; and if R4is iodine then R2and R5are hydrogen.

3. The compound for use according to claim 1 or 2, wherein the compound is for use in the treatment of a cardiac disorder.

4. The compound for use according to claim 3, wherein the cardiac disorder is cardiac arrythymia.

5. The compound for use according to claim 4, wherein the cardiac arrythymia is ventricular arrythymia.

6. The compound for use according to claim 4, wherein the cardiac arrythymia is atrial arrythymia.

7. The compound for use according to claim 5, wherein the compound is 1-(2-iodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, (2S)-1-(2-iodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, 4-(2-aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoiso- mer or mixture of stereoisomers thereof), 1-(2,4,6-triiodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof or 1-(3,5-diiodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

8. The compound for use according to claim 7, wherein the compound is 4-(2-aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoiso- mer or mixture of stereoisomers thereof, 1-(2,4,6-triiodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof or 1-(3,5-diiodophenoxy)propan-2-amine or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

9. The compound for use according to claim 8, wherein the compound is 4-(2-aminopropoxy)- 3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

10. The compound for use according to claim 4, wherein the atrial arrythymia is atrial fibril- lation.

11. The compound for use according to claim 4 or 10, wherein the compound is 4-(2- aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

12. Pharmaceutical composition comprising a compound as defined in any one of claims 1, 2, 8 and 11 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12, wherein the compound is a com- pound defined in claim 8.

14. The pharmaceutical composition according to claim 13, wherein the compound is 4-(2- aminopropoxy)-3,5-diiodobenzonitrile or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof.

15. A compound having general formula (I)or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl- O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2 or C1-3alkyl- ; R2, R3, R4and R5are selected form hydrogen and iodine; R6and R7are independently C1-7alkyl-; and n is 1, 2 or 3; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hy- drogen; and if R4is iodine then R2and R5are hydrogen; and when R2, R5, R6and R7are hydrogen, R3and R4are iodine and n is 1, then R1is selected from the group consisting of C1­7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, whereinX is -OH, C1-7alkyl-O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2 or C1-3alkyl-.

16. The compound according to claim 15, wherein the compound has general formula (II)or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1­7alkyl­O-, -NH2, C1-7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H or -NH-N(C1-7alkyl)2; and R2, R3, R4and R5are selected form hydrogen and iodine; with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hy- drogen; and if R4is iodine then R2and R5are hydrogen; and when R2and R5are hydrogen, R3and R4are iodine, then R1is selected from the group consisting of C1­7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1-7alkyl-O-, - NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H, ­NH­N(C1­7alkyl)2or C1-3alkyl-.

17. The compound according to claim 16, wherein the compound has general formula (II)or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein R1is selected from the group consisting of hydrogen, iodine, C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, -COX group, wherein X is -OH, C1­7alkyl­O-, -NH2, C1-7alkyl-NH-, -NH-NH2, -NH-N(C1-7alkyl)H or -NH-N(C1-7alkyl)2; and R2, R3, R4and R5are selected form hydrogen and iodine;with the provisio that if R4is hydrogen then R2and R5are iodine and R1and R3are hydrogen; and if R4is iodine then R2and R5are hydrogen and R1and R3are not hydrogen at the same time; and when R2and R5are hydrogen, R3and R4are iodine, then R1is selected from the group consisting of C1­7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, - COX group, wherein X is -OH, C1-7alkyl-O-, -NH2, C1­7alkyl-NH-, -NH-NH2, -NH-N(C1- 7alkyl)H, ­NH­N(C1­7alkyl)2 or C1-3alkyl-.

18. The compound according to any one of claims 15-17, for use in therapy.

19. The compound for use according to claim 18, wherein the compound is for use in the tre- atment of a cardiac disorder.

20. The compound for use according to claim 19, wherein the cardiac disorder is cardiac arrythymia.

21. The compound for use according to claim 20, wherein the cardiac arrythymia is ventricu- lar arrythymia.

22. The compound for use according to claim 20, wherein the cardiac arrythymia is atrial arrythymia.

23. Method for the preparation of compound of formula (II)or a pharmaceutically acceptable salt, stereoisomer or mixtures of stereoisomers thereof, wherein R1is selected from the group consisting of C1-7alkyl-, C6­10aryl-, ­NO2, -CN, -CHlg3, wherein Hlg is F, Cl, Br or I, and -CONH2; R2and R5are hydrogen and R3is iodine; wherein the method comprises the following steps: a) reacting a compound of formula (IIa)i) with KI and I2in water at room temperature in the presence of NH4OH added dropwise to the reaction mixture to obtain a compound of formula (IIb)wherein R1is C1-7alkyl-, -CN or -CONH2;or ii) with I2and H2O2in water to obtain a compound of formula (IIb)wherein R1is -CHlg3 or ­NO2; or iii) with KI and N-chlorobenzenesulfonamide-sodium in NaOH solution at a temperature of 80°C to obtain a compound of formula (IIb)(IIb), wherein R1is C6­10aryl-; b) reacting the compound of formula (IIb) with K2CO3and 1-chloropropan-2-one in organic solvent, preferably CH3CN or DMF under reflux, then cooling the reaction mixture to room temperature and isolating a compound of formula (IIc) by filtration and optionally extractionc) reacting the compound of formula (IIc) with NH4OAc in organic solvent, preferably meth- anol or ethanol in the presence of NaBH3CN at room temperature, and isolating the compound of formula (II) by extraction with organic solvent, preferably CHCl3or DCM.

24. Method for the preparation of compound of formula (III)wherein the method comprises the following steps: a) reacting 2-iodophenol with propylene oxide in the presence of K2CO3 in an organic solvent, preferably acetone at a temperature of 75°C to obtain a compound of formula (IIIa)(IIIa); b) reacting the compond of formula (IIIa) with phtalimide in an organic solvent, preferably THF under inert atmosphere to obtain a suspension; c) cooling the suspension followed by addition of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to obtain a compound of formula (IIIb)(IIIb); d) reacting the compound of (IIIb) with hydrazine hydrate in the presence of AcOH in an or- ganic solvent, preferably methanol, then isolating the compound of formula (III) by filtering and extraction. The conversion of compound of formula (III) to its pharmaceutically acceptable salt is known by a person skilled in the art.

25. Method for the preparation of compound of formula (IV)wherein the method comprises the following steps: a) reacting 2-iodophenol with (+)-(2R)-propylene oxide in the presence of K2CO3 in an organ- ic solvent, preferably acetone by heating the reaction mixture to obtain a compound of formu- la (IVa)b) reacting the compond of formula (IVa) with phtalimide in an organic solvent, preferably THF under inert atmosphere to obtain a suspension; c) cooling the suspension followed by addition of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) to obtain a compound of formula (IVb);d) reacting the compound of (IVb) with hydrazine hydrate in the presence of AcOH in an or- ganic solvent, preferably methanol, then isolating the compound of formula (IV) by filtering and extraction. The conversion of compound of formula (IV) to its pharmaceutically acceptable salt is known by a person skilled in the art.

26. Method for the preparation of compound of formula (V)wherein the method comprises the following steps: a) reacting 2,4,6-triiodophenol with 1-chloroacetone in the presence of anhydrous potassium carbonate in an organic solvent, preferably DMF at a temperature of 27°C to obtain a com- pound of formula (Va)b) reacting the compound of formula (Va) with NH4OAc in an organic solvent, preferably methanol in the presence of NaBH3CN at room temperature, then isolating the compound of formula (V) by extraction with organic solvent, preferably CHCl3.The conversion of compound of formula (V) to its pharmaceutically acceptable salt is known by a person skilled in the art.

27. Method for the preparation of compound of formula (VI)wherein the method comprises the following steps: a) reacting 3,5-diiodoaniline with NaNO2 under diazotization conditions and boiling the solu- tion to obtain a compound of formula (VIa)b) reacting the compound of formula (VIa) with 1-chloropropan-2-one in the presence of K2CO3 in an organic solvent, preferably CH3CN under reflux, then cooling the reaction mix- ture and isolating a compound of formula (VIb) by filtering and extraction with alkaline aqueous solution, preferably NaOH solutionc) reacting the compound of formula (VIb) with NH4OAc in the presence of NaBH3CN in an organic solvent, preferably methanol at room temperature, then isolating a compound of for- mula (VI) by extraction with organic solvent, preferably CHCl3.

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