CHANNEL MODULATORS

TECHNICAL FIELD

This invention relates to novel benzimidazolyl-acetamide derivatives and their use as modulators of small-conductance calcium-activated potassium channels (SK channels). Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels.

BACKGROUND ART

Three subtypes of small-conductance calcium-activated potassium channels (SK channels) have been cloned: SK1 , SK2 and SK3 (corresponding to KCNN1 -3 using the genomic nomenclature). The activity of these channels is determined by the concentration of free intracellular calcium ([Ca ²⁺ ],) via

calmodulin that is constitutively bound to the channels. SK channels are tightly regulated by [Ca ²⁺ ], in the physiological range being closed at [Ca ²⁺ ], up to around 0.1 μΜ but fully activated at a [Ca ²⁺ ], of 1 μΜ. Being selective for potassium, open or active SK channels have a hyperpolarizing influence on the membrane potential of the cell. SK channels are widely expressed in the central nervous system (CNS) and in peripheral tissue.

The distribution of the SK1 and SK2 subtypes in the CNS show a high degree of overlap and display the highest levels of expression in neocortical, limbic and hippocampal areas in the mouse brain. In contrast, the SK3 channels show high levels of expression in the basal ganglia, thalamus and the brain stem monoaminergic neurons e.g. dorsal raphe, locus coeruleus and the ventral tegmental area. The SK channels are also present in several peripheral cells including heart, skeletal muscle, certain gland cells, and liver cells.

The hyperpolarizing action of active SK channels plays an important role in the control of firing pattern and excitability of excitable cells. SK channel blockers such as apamin and /V-methyl bicuculline have been demonstrated to increase excitability whereas the SK channel activator 1 -EBIO is able to reduce electrical activity. In non-excitable cells where the amount of Ca ²⁺ influx via voltage-independent pathways is highly sensitive to the membrane potential an activation of SK channels will increase the driving force whereas a blocker of SK channels will have a depolarising effect and thus diminish the driving force for calcium.

Based on the important role of SK channels in linking [Ca ²⁺ ], and membrane potential, SK channels are interesting targets for developing novel therapeutic agents, and the potential of inhibitors of small-conductance calcium- activated potassium channels (SK channels) for use in anti-arrhythmic treatment has recently been established, see e.g. Nattel S; J. Physiol. 2009 587 1385-1386; and Diness JG, S0rensen US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS; Circ. Arrhythm. Electrophvsiol. 2010 3 380-90.

Most known modulators of SK channels suffer from being large, often positively charged, molecules or peptides (like the blockers apamin, scyllatoxin, tubocurarine, dequalinium chloride and UCL1684), or from having low potency (e.g. the activators 1 -EBIO and riluzole). Thus, there is a continued need for compounds with an optimized pharmacological profile.

S0rensen et al. (S0rensen, Ulrik S.; Stwbask, Dorte; Christophersen, Palle; Hougaard, Charlotte; Jensen, Marianne L; Nielsen, Elsebet 0.; Peters, Dan; Teuber, Lene; Journal of Medicinal Chemistry 2008 51 (23) 7625-7634) describe synthesis and structure-activity relationship studies of certain 2-(N- substituted)-aminobenzimidazoles useful as potent negative gating modulators of small conductance Ca ²⁺ -activated K ⁺ channels.

WO 2006/099379 describes certain benzazole derivatives useful as beta-secretase inhibitors.

However, the benzimidazolyl-acetamide derivatives of the present invention are not reported. SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel benzimidazolyl- acetamide derivatives capable of modulating SK channels, or subtypes of SK channels.

In one aspect, the present invention provides benzimidazolyl-acetamide derivatives represented by Formula I

a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein R', R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined below.

In another aspect, the invention provides pharmaceutical compositions comprising an effective amount of a benzimidazolyl-acetamide derivative of the invention.

In further aspects the invention relates to use of a benzimidazolyl- acetamide derivative of the invention for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, and to method of treatment or alleviation of disorders or conditions responsive to modulation of potassium channels.

Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples. DETAILED DISCLOSURE OF THE INVENTION

In one aspect, the present invention provides a benzimidazolyl- acetamide derivative represented by Formula I

(I)

a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein

R' represents Ci-3-alkyl;

R represents hydrogen or Ci-3-alkyl;

R ¹ -R ⁵ , independently of each other, represent hydrogen, Ci-3-alkyl, halogen or trifluoromethyl; and

R ⁶ represents hydrogen or Ci-3-alkyl; or

R ⁶ together with R ⁵ , and together with the carbon atoms and the phenyl ring to which they are attached, form a tetrahydronaphthalene group, wherein R ¹ - R ⁵ are as defined above, see Formula II (II)

In a preferred embodiment the benzimidazolyl-acetamide derivative of the invention is a compound of Formula I or of Formula II, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein R' represents Ci-3-alkyl.

In another preferred embodiment R' represents methyl.

In a third preferred embodiment R' represents ethyl.

In a fourth preferred embodiment R' represents isopropyl, and in particular n-propyl or isopropyl.

In a fifth preferred embodiment the benzimidazolyl-acetamide derivative of the invention is a compound of Formula I or of Formula II, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein R represents hydrogen or Ci-3-alkyl;

In a sixth preferred embodiment R represents hydrogen.

In a seventh preferred embodiment R represents Ci-3-alkyl, and in particular methyl.

In an eight preferred embodiment the benzimidazolyl-acetamide derivative of the invention is a compound of Formula I, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein R ¹ -R ⁵ , independently of each other, represent hydrogen, Ci-3-alkyl, halogen or trifluoromethyl.

In a ninth preferred embodiment R ¹ -R ⁵ , independently of each other, represent hydrogen, methyl, fluoro, chloro or trifluoromethyl.

In a tenth preferred embodiment R ¹ -R ⁵ represents Ci-3-alkyl, halogen or trifluoromethyl; and the remaining of R ¹ -R ⁵ , all represent hydrogen.

In an eleventh preferred embodiment one of R ² -R ⁴ represents Ci-3-alkyl, halogen or trifluoromethyl; and R ¹ and R ⁵ , and the others of R ² -R ⁴ , all represent hydrogen.

In a twelfth preferred embodiment one of R ¹ -R ⁵ represents halogen; and another one of R ¹ -R ⁵ represents trifluoromethyl; and the remaining of R ¹ -R ⁵ represent hydrogen. In a thirteenth preferred embodiment one of R ² -R ⁴ represents halogen, and in particular fluoro or chloro; and another one of R ² -R ⁴ represents

trifluoromethyl; and R ¹ and R ⁵ , and the remaining of R ² -R ⁴ represent hydrogen.

In a fourteenth preferred embodiment two of R ¹ -R ⁵ represent halogen, and in particular fluoro or chloro; or two of R ¹ -R ⁵ represent trifluoromethyl; and the remaining of R ¹ -R ⁵ represent hydrogen.

In a fifteenth preferred embodiment two of R ² -R ⁴ represent halogen, and in particular fluoro or chloro; or two of R ² -R ⁴ represent trifluoromethyl; and R ¹ and R ⁵ , and the remaining of R ¹ -R ⁵ , all represent hydrogen.

In a sixteenth preferred embodiment the benzimidazolyl-acetamide derivative of the invention is a compound of Formula I, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein R ⁶ represents hydrogen or Ci-3-alkyl.

In a seventeenth preferred embodiment R ⁶ represents hydrogen.

In an eighteenth preferred embodiment R ⁶ represents Ci-3-alkyl.

In a nineteenth preferred embodiment R ⁶ represents methyl.

In a twentieth preferred embodiment R ⁶ represents ethyl.

In a twenty-first preferred embodiment R ⁶ represents n-propyl or isopropyl.

In a twenty-second preferred embodiment the benzimidazolyl- acetamide derivative of the invention is a compound of Formula II, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein R', R and R ¹ -R ⁴ are as defined above.

In a twenty-third preferred embodiment one or two of R ¹ -R ⁴ represent halo or trifluoromethyl, and the remaining of R ¹ -R ⁴ represent hydrogen.

In a twenty-fourth preferred embodiment two of R ¹ -R ⁴ represent halo and in particular fluoro or chloro, and the remaining two of R ¹ -R ⁴ represent hydrogen.

In a twenty-fifth preferred embodiment one of R ¹ -R ⁴ represents halo or trifluoromethyl, and the remaining three of R ¹ -R ⁴ represent hydrogen.

In a twenty-sixth preferred embodiment all of R ¹ -R ⁴ represent hydrogen In a more preferred embodiment the benzimidazolyl-acetamide derivative of the invention is /V-[2-[1 -[3-(trifluoromethyl)phenyl]ethylamino]-1 H-benzimidazol-4- yl]acetamide;

/V-[2-[(3,4-difluorophenyl)methylamino]-1 /-/-benzimidazol-4- yl]acetamide;

/V-[2-[1 -[3-(trifluoromethyl)phenyl]ethylamino]-1 H-benzimidazol-4- yl]propanamide;

/V-[2-[1 -[3-(trifluoromethyl)phenyl]propylamino]-1 H-benzimidazol-4- yl]acetamide;

A/-[2-[1 -(3,4-dichlorophenyl)ethylamino]-1 H-benzimidazol-4- yl]acetamide;

/V-[2-[1 -[3,5-bis(trifluoromethyl)phenyl]ethylamino]-1 H-benzimidazol-4- yl]acetamide;

/V-[2-[(3-chlorophenyl)methylamino]-1 H-benzimidazol-4-yl]acetamide;

2-methyl-/V-[2-[1 -[3-(trifluoromethyl)phenyl]ethylamino]-1 H- benzimidazol-4-yl]propanannide;

/V-[2-[[2-methyl-1 -[3-(trifluoromethyl)phenyl]propyl]amino]-1 /-/- benzimidazol-4-yl]acetannide;

/V-[2-[1 -[3-(trifluoromethyl)phenyl]butylamino]-1 /-/-benzimidazol-4- yl]acetamide;

/V-[2-[1 -[3-fluoro-5-(trifluoromethyl)phenyl]ethylamino]-1 H-benzimidazol- 4-yl]acetamide;

A/-{2-[(1 ,2,3,4-tetrahydronaphthalen-1 -yl)amino]-1 H-1 ,3-benzimidazol-4- yl}acetamide;

A/-(2-{[(1 R)-1 ,2,3,4-tetrahydronaphthalen-1 -yl]amino}-1 H-1 ,3- benzimidazol-4-yl)acetannide;

A/-{2-[(7-Chloro-1 ,2,3,4-tetrahydronaphthalen-1 -yl)amino]-1 H-1 ,3- benzimidazol-4-yl}acetannide;

A/-{2-[(6,7-Dichloro-1 ,2,3,4-tetrahydronaphthalen-1 -yl)amino]-1 H-1 ,3- benzimidazol-4-yl}acetannide;

A/-(2-{[7-(Trifluoronnethyl)-1 ,2,3,4-tetrahydronaphthalen-1 -yl]amino}-1 H- 1 ,3-benzimidazol-4-yl)acetannide;

A/-{2-[(7-Fluoro-1 ,2,3,4-tetrahydronaphthalen-1 -yl)amino]-1 H-1 ,3- benzimidazol-4-yl}acetannide; or A/-{2-[(6,7-Difluoro-1 ,2,3,4-tetrahydronaphthalen-l -yl)amino]-1 H-1 ,3- benzimidazol-4-yl}acetannide;

a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof.

In another more preferred embodiment the benzimidazolyl-acetamide derivative of the invention is

A/-[2-[[(1 S)-1 -[3-(trifluoromethyl)phenyl]ethyl]amino]-1 H-benzimidazol-4- yl]acetamide;

A/-[2-[[(1 R)-1 -[3-(trifluoromethyl)phenyl]ethyl]amino]-1 H-benzimidazol-4- yl]acetamide;

A/-[2-[[(1 R)-1 -[4-fluoro-3-(trifluoromethyl)phenyl]ethyl]amino]-1 H- benzimidazol-4-yl]acetamide;

A/-[2-[[(1 S)-1 -[4-fluoro-3-(trifluoromethyl)phenyl]ethyl]amino]-1 H- benzimidazol-4-yl]acetamide;

A/-[2-[[(1 S)-1 -[3-fluoro-5-(trifluoromethyl)phenyl]ethyl]amino]-1 H- benzimidazol-4-yl]acetamide;

A/-[2-[[(1 R)-1 -[3-fluoro-5-(trifluoromethyl)phenyl]ethyl]amino]-1 H- benzimidazol-4-yl]acetamide;

A/-(2-{methyl[(1 R)-1 -[3-(trifluoromethyl)phenyl]ethyl]amino}-1 H-1 ,3- benzodiazol-4-yl)acetamide;

A/-[2-[[(1 R)-1 -(m-tolyl)ethyl]amino]-1 H-benzimidazol-4-yl]acetamide;

A/-[2-[[(1 S)-1 -(m-tolyl)ethyl]amino]-1 H-benzimidazol-4-yl]acetamide;

A/-(2-{[(1 S)-7-(trifluoromethyl)-1 ,2,3,4-tetrahydronaphthalen-1 -yl]amino}- 1 H-1 ,3-benzimidazol-4-yl)acetamide;

A/-(2-{[(1 R)-7-(trifluoromethyl)-1 ,2,3,4-tetrahydronaphthalen-1 -yl]amino}- 1 H-1 ,3-benzimidazol-4-yl)acetamide;

A/-(2-{[(1 R)-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1 -yl]amino}-1 H-1 ,3- benzimidazol-4-yl)acetamide; or

A/-(2-{[(1 S)-7-fluoro-1 ,2,3,4-tetrahydronaphthalen-1 -yl]amino}-1 H-1 ,3- benzimidazol-4-yl)acetamide;

or a pharmaceutically acceptable addition salt thereof. Definition of Terms

As used throughout the present specification and appended claims, the following terms have the indicated meaning:

The term "Ci-3-alkyl" as used herein means a saturated, branched or straight hydrocarbon group having from 1 -3 carbon atoms, and may be substituted for methyl, ethyl and propyl (incl. prop-1 -yl, prop-2-yl or /so-propyl).

The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine.

Certain of the defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

The term "treatment" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular a human being.

The terms "disease", "condition" and "disorder" as used herein are used interchangeably to specify a state of a patient which is not the normal physiological state of man.

The term "medicament" as used herein means a pharmaceutical composition suitable for administration of the pharmaceutically active compound to a patient.

The term "pharmaceutically acceptable" as used herein means suited for normal pharmaceutical applications, i.e. giving rise to no adverse events in patients etc.

The term "effective amount" as used herein means a dosage which is sufficient in order for the treatment of the patient to be effective compared with no treatment.

The term "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by

constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.

Steric isomers

It will be appreciated by those skilled in the art that the benzimidazolyl- acetamide derivatives of the present invention may exist in different stereoisomeric forms. The invention includes all such stereoisomers and any mixtures thereof including racemic mixtures.

Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of separating the diastereomenc salts is by use of an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example.

The benzimidazolyl-acetamide derivatives of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the benzimidazolyl-acetamide derivatives of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of

diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known in the art. Such methods include those described by Jaques J, Collet A, & Wilen S in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981 ). Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the chemical compound of the invention.

As used herein the term "pharmaceutically acceptable salt" refers to salts of a compound of the present invention which are substantially non-toxic to living organisms. Such salts and common methodology for preparing them are well known in the art. See e.g. Stahl P et al: Handbook of Pharmaceutical Salts:

Properties Selection and Use; VCHA/Wiley-VCH, 2002; and Berge S M, Bighley L D, Monkhouse D C: Pharmaceutical salts; J. Pharm. Sci. 1977 66 (1 ) 1 -19.

Methods of Preparation

The benzimidazolyl-acetamide derivatives of the invention may be prepared by conventional methods of chemical synthesis, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.

The end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.

Biological Activity

The benzimidazolyl-acetamide derivatives of the invention are found to modulate potassium channels, and have in particular been shown to potently inhibit the SK channels (i.e. small-conductance Ca ²⁺ -activated K ⁺ channels, SK channels, K _Ca 2). The ionic current through small-conductance Ca ²⁺ -activated K ⁺ channels (SK channels, K _Ca 2) have been recorded using the whole-cell configuration of the patch-clamp technique in a classic set-up as described in e.g. WO 2006/100212.

The benzimidazolyl-acetamide derivatives tested showed a biological activity determined as described herein in the micromolar and sub-micromolar range, i.e. of from below 1 to above 100 μΜ e.g. from below 0.1 to about 10 μΜ. The benzimidazolyl-acetamide derivative of the invention therefore may find utility as a medicament, and in particular for use as a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of SK channels.

In a preferred embodiment the disease, disorder or condition responsive to modulation of SK channels is any disease, disorder or condition associated with an abnormal rhythm of the heart.

In another preferred embodiment the disease, disorder or condition is cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmias, or any other abnormal rhythm, e.g. caused by myocardial ischaemia, myocardial infarction, cardiac hypertrophy, cardiomyopathy or a genetic disease.

In a third preferred embodiment a cardiac disease, disorder or condition is cardiac ishemia, ishcemic heart disease, hypertrophic heart, cardiomyopathia or failing heart.

In a fourth preferred embodiment a cardiac disease, disorder or condition of the invention is cardiac arrhythmia, atrial fibrillation and/or ventricular tachyarrhythmia.

In a fifth preferred embodiment a cardiac disease, disorder or condition of the invention is atrial fibrillation.

Pharmaceutical Compositions

In yet another aspect the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the benzimidazolyl- acetamide derivatives of the invention.

While a compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers and/or diluents. The compound of the present invention is preferably formulated as a pharmaceutical composition which may be administered by a variety of routes. Most preferably, such composition is for oral administration, and the active ingredient may be administered in one or several doses per day. Such

pharmaceutical compositions and processes for preparing same are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (A,

Gennaro, et al., eds., 19 ^th ed., Mack Publishing Co., 1995).

The actual dosage depends on the nature and severity of the disease being treated and the route of administration, and is within the discretion of the physician, and may be varied by titration of the dosage to the particular

circumstances of this invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, e.g. from about 1 to about 100 mg, e.g. from about 1 to about 10 mg, are suitable for therapeutic treatments.

Methods of Therapy

In another aspect the invention provides a method for the prevention, treatment or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to modulation of small-conductance Ca ²⁺ -activated K ⁺ channels, SK channels, and which method comprises comprising administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound of the invention.

The indications contemplated according to the invention are those stated above.

In a preferred embodiment the disease or disorder or condition is a disease, disorder or condition associated with an abnormal rhythm of the heart.

In a preferred embodiment the disease or disorder or condition is atrial fibrillation.

It is at present contemplated that suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, or 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge. EXAMPLES

The invention is further illustrated with reference to the following examples, which are not intended to be in any way limiting to the scope of the invention as claimed.

General: The procedures represent generic procedures used to prepare the benzimidazolyl-acetamide derivatives of the invention. Abbreviations used are as follows:

Ac: acetyl

Eq: equivalent

Et: ethyl

h: hour

Me: Methyl

MW: microwave

NMP: 1 -methyl-2-pyrrolidinone

rt: room temperature

THF: tetrahydrofuran

Procedure A

Step A: Commercially available 3-nitrobenzene-1 ,2-diamine is dissolved in THF, cooled to 0°C, W,/V-carbonyldiimidazole (3 eq) is added, and the mixture stirred at rt until complete conversion of the starting material. The reaction mixture is concentrated to dryness and the residue is diluted with ice-cold water. The yellow precipitate is isolated by filtration, washed with EtOAc and dried under vacuum to give crude 4-nitro-1 ,3-dihydrobenzimidazol-2-one for use in Step B.

Step B: A suspension of 4-nitro-1 ,3-dihydrobenzimidazol-2-one in distilled phosphorus oxychloride is refluxed at 120°C until complete conversion of the starting material. The reaction mixture is cooled to rt and concentrated in vacuo to remove excess POCI3. The remaining crude product is diluted with ice- cold water. The precipitated solid is filtered off and washed with petroleum ether and dried under vacuum to give 2-chloro-4-nitro-1 H-benzimidazole to be used without further purification in the next reaction step.

Step C: To a pre-cooled (0°C) solution of stannous chloride (3 eq) in concentrated hydrochloric acid is portion-wise added 2-chloro-4-nitro-1 H-benzimidazole at 0 °C.

The reaction mixture is slowly warmed to rt and stirred for 2 h. The mixture is neutralised with solid sodium bicarbonate and diluted with methanol and filtered.

The filtrate is concentrated to afford crude 2-chloro-1 H-benzimidazol-4-amine as a yellowish solid. The crude product is purified by column chromatography using 2% methanol in chloroform to afford crude 2-chloro-1 H-benzimidazol-4-amine

(MS(ES ⁺ ) m/z 168 ([M+1 ]\ 100)).

.Alternatively, Step C is performed using iron as reducing agent in the following procedure: Iron powder (5 eq) suspended in a mixture of EtOH and concentrated HCI is heated to 65°C for 2 h. The temperature is decreased to 50 °C and ammonium chloride and 2-chloro-4-nitro-1 H-benzimidazole are added. The reaction mixture is stirred at 65°C for 6 hours and subsequently cooled to rt, filtered through a bed of celite and washed with EtOH. The filtrate is concentrated and diluted with water and basified with sodium bicarbonate to pH 7. The aqueous layer is extracted with 10% MeOH in dichloromethane. The organic layer is concentrated in vacuo, and the crude product is purified by column

chromatography to give 2-chloro-1 H-benzimidazol-4-amine.

Step D: To a solution of 2-chloro-1 H-benzimidazol-4-amine in acetonitrile at 0°C under nitrogen atmosphere is added the required acyl chloride (1 .5 eq) and the mixture slowly warmed to rt. After 1 .5 h at rt, or until conversion of the starting material, the reaction mixture is concentrated in vacuo to remove the solvent. The remaining crude product is purified by column chromatography using EtOAc/hexane as eluent to give the pure A/-(2-chloro-1 H-benzimidazol-4- yl)acylamide.

Step E: A suspension of the A/-(2-chloro-1 H-benzimidazol-4- yl)acylamide and the required amine derivative (either commercially available or prepared from known procedures such as reductive amination of the

corresponding ketone intermediate, as described in e.g. Journal of Medicinal Chemistry 1982, 25, p 850-854) in acetonitrile is heated at 170-185°C by MW heating until conversion of starting material. The reaction mixture is cooled to rt and evaporated to dryness. The remaining crude product is purified by column chromatography to afford the desired product as solid. Alternatively, the reaction can be performed in a similar way using as solvent 1 -methyl-2-pyrrolidinone (NMP) and heating of the reaction mixture to 150°C by conventional heating or MW.

An example of Procedure A, the preparation of A/-(2-{[1 -[3-fluoro-5- (trifluoromethyl)phenyl]ethyl]amino}-1 H-benzimidazol-4-yl)acetamide (see also Example 12) is shown in Scheme 1 below.

Following Step E, when starting from a racemic benzylamine or 1 ,2,3,4- tetrahydro-1 -naphtylamine derivative, the corresponding pure enantiomers can subsequently be isolated upon separation by chiral chromatography. In addition, a pure enantiomeric product can be obtained directly when in Step E using as reagent the stereochemically pure benzylamine or 1 ,2,3,4-tetrahydro-1 - naphtylamine derivative.

Scheme 1

Step A Step B Step C

chiral separation

5 Example 1

/V-[2-({1 -[3-(Trifluoromethyl)phenvnethyl)a

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide (MS(ES ⁺ ) m/z 210 ([M+1 ] ⁺ , 100)) and commercially

10 available 1 -[3-(trifluoromethyl)phenyl]ethanamine) by column chromatography as the parent compound. HR-MS: 363.1447 ([M+1 ] ⁺ , Ci ₈ Hi ₈ N ₄ OF ₃ ; calc. 363.14327). Subsequently, the two enantiomers of the title compound can be isolated by separation of the above racemate by preparative chiral chromatography.

Enantiomer A: HR-MS: 363.14383 ([M+1 ] ⁺ , Ci ₈ Hi ₈ N ₄ OF ₃ ; calc.

15 363.142725. Enantiomer B: HR-MS: 363.14382 ([M+1 ] ⁺ , Ci ₈ Hi ₈ N ₄ OF ₃ ; calc.

363.142725.

Example 2

/V-(2-{[(3^-Difluorophenyl)methyl1amino)-1 H-benzimidazol-4-yl)acetam

The title compound is prepared in five steps as described in Procedure A and isolated after Step E (starting from A/-(2-chloro-1 H-benzimidazol-4- yl)acetamide and commercially available 3,4-difluorobenzylamine) by column chromatography as the parent compound.

HR-MS: 317.1212 ([M+1 ] ⁺ , Ci ₆ Hi ₅ N ₄ OF ₂ ; calc. 317.121392).

Example 3

A/-[2-({1 -[3-(Trifluoromethyl)phenyl1ethyl)amino)-1 /-/-benzimidazol-4- yllpropanamide

The title compound is prepared in five steps as described in Procedure

A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)propanamide (MS(ES ⁺ ) m/z 224 ([M+1 ] ⁺ , 100)) and

commercially available 1 -[3-(trifluoromethyl)phenyl]ethanamine) by column chromatography as the parent compound.

HR-MS: 377.15897 ([M+1 ]\ Ci9H ₂ oN ₄ OF ₃ ; calc. 377.158375).

Example 4

A/-[2-({1 -[3-(Trifluoromethyl)phenyllpropyl)amino)-1 /-/-benzimidazol-4-yl1acetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 1 -[3- (trifluoromethyl)phenyl]propanamine) by column chromatography as the parent compound.

HR-MS: 377.15987 ([M+1 ]\ Ci9H ₂ oN ₄ OF ₃ ; calc. 377.158375).

Example 5

A/-(2-{[1 -(3,4-Dichlorophenyl)ethyl1amino)-1 /-/-benzimidazol-4-yl)acetamide The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 1 -(3,4- dichlorophenyl)ethan-1 -amine) by column chromatography as the parent compound.

HR-MS: 363.07764 ([M+1 ]\ Ci ₇ Hi ₇ N ₄ OCI ₂ ; calc. 363.077397). Example 6

A/-[2-({1 -[3,5-Bis(trifluoromethyl)phenyl1ethyl)amino)-1 /-/-benzimidazol-4- yllacetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 1 -[3,5- bis(trifluoromethyl)phenyl]ethylamine) by column chromatography as the parent compound.

HR-MS: 431 .1304 ([M+1 ]\ Ci ₉ Hi ₇ N ₄ OF ₆ ; calc. 431 .130109). Example 7

A/-(2-{[(3-Chlorophenyl)methyl1amino)-1 /-/-benzimidazol-4-yl)acetamide

The title compound is prepared in five steps as described in Procedure

A and isolated after Step E (starting from A/-(2-chloro-1 H-benzimidazol-4- yl)acetamide and commercially available 3-chlorobenzylamine) by column chromatography as the parent compound.

HR-MS: 315.10124 ([M+1 ]\ Ci ₆ Hi ₆ N ₄ OCI; calc. 315.100719).

Example 8

2-Methyl-/V-r2-({1 -r3-(thfluoromethyl)phenyl1ethyl)amino)-1 /-/-benzimidazol-4- yllpropanamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)-2-methylpropanamide (MS(ES ⁺ ) m/z 238 ([M+1 ] ⁺ , 100)) and commercially available 1 -[3-(trifluoromethyl)phenyl]ethanamine) by column chromatography as the parent compound. HR-MS: 391 .17493 ([M+1 ] ⁺ , C ₂ oH22N ₄ OF ₃ ; calc. 391 .174025). Example 9

/V-[2-({2-Methyl-1 -[3-(trifluoro

yllacetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 2-methyl-1 -[3- (trifluoromethyl)phenyl]propan-1 -amine) by column chromatography as the parent compound.

HR-MS: 391 .17418 ([M+1 ] ⁺ , C ₂ oH22N ₄ OF ₃ ; calc. 391 .174025). Example 10

A/-[2-({1 -[3-(Trifluoromethyl)phenyl1butyl)amino)-1 /-/-benzimidazol-4-yl1acetamide

The title compound is prepared in five steps as described in Procedure

A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 1 -[3- (trifluoromethyl)phenyl]butan-1 -amine) by column chromatography as the parent compound.

HR-MS: 391 .17397 ([M+1 ] ⁺ , C ₂ oH22N ₄ OF ₃ ; calc. 391 .174025).

Example 11

A/-[2-({1 -[4-Fluoro-3-(trifluoromethyl)phenyl1ethyl)amino)-1 /-/-benzimidazol-4- yllacetamide

The title compound is prepared in five steps as described in Procedure

A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and 1 -[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine, the latter prepared from commercially available 4'-fluoro-3'-(trifluoromethyl)- acetophenone by reductive amination using ammonium acetate and sodium cyanoborohydride as described in Journal of Medicinal Chemistry 1982, 25, p 850- 854) by column chromatography as the parent compound. Subsequently, the two enantiomers of the title compound are isolated by separation of the above racemate by preparative chiral chromatography. Enantiomer A: HR-MS: 381 .1345 ([M+1 ] ⁺ , Ci ₈ Hi ₇ N ₄ OF ₄ ; calc. 381 .133303.

Enantiomer B: HR-MS: 381 .13467 ([M+1 ] ⁺ , Ci ₈ Hi ₇ N ₄ OF ₄ ; calc.

381 .133303).

5

Example 12

/V-[2-({1 -[3-Fluoro-5-(trifluorom

yllacetamide

The title compound is prepared in five steps as described in Procedure 10 A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and 1 -[3-fluoro-5-(trifluoromethyl)phenyl]ethanamine, the latter prepared from commercially available 3'-fluoro-5'-(trifluoromethyl)- acetophenone by reductive amination using ammonium acetate and sodium cyanoborohydride as described in Journal of Medicinal Chemistry 1982, 25, p 850- 15 854) by column chromatography as the parent compound. HR-MS: 381 .13423 ([M+1 ] ⁺ , Ci ₈ Hi ₇ N ₄ OF ₄ ; calc. 381 .133303). Subsequently, the two enantiomers of the title compound can be isolated by separation of the above racemate by preparative chiral chromatography.

Enantiomer A: HR-MS: 381 .13389 ([M+1 ] ⁺ , Ci ₈ Hi ₇ N ₄ OF ₄ ; calc.

20 381 .133303.

Enantiomer B: HR-MS: 381 .13416 ([M+1 ] ⁺ , Ci ₈ Hi ₇ N ₄ OF ₄ ; calc.

381 .133303).

Example 13

25 A/-(2-{[1 -(3-Methyl phenyl )ethvHamino)-1 H-benzimidazol-4-yl)acetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available l -(m-tolyl)ethanamine) by column chromatography as the parent compound. Subsequently, the two

30 enantiomers of the title compound are isolated by separation of the above

racemate by preparative chiral chromatography.

Enantiomer A: HR-MS: 309.17166 ([M+1 ] ⁺ , Ci ₈ H ₂ iN ₄ O; calc.

309.170991 . Enantiomer B: HR-MS: 309.17173 ([M+1 ] ⁺ , Ci ₈ H ₂ iN ₄ O; calc.

309.170991 .

Example 14

A/-(2-(methyir(1 ff)-1 -r3-(trifluorom

vDacetamide

The title compound is prepared in five steps as described in Procedure A and isolated as the pure stereoisomer after Step E (starting from A/-(2-chloro- 1 H-benzimidazol-4-yl)acetamide and methyl[(1 R)-1 -[3- (trifluoromethyl)phenyl]ethyl]amine, the latter prepared in two steps using the following procedure: to a solution (1 R)-1 -[3-(trifluomethyl)phenylethylamine in THF is added di-terf-butyl dicarbonate (1 .1 eq) and stirred at 70°C for 10 hours. The reaction mixture is concentrated under reduced pressure, the obtained residue is diluted with water and extracted with dichloromethane. The combined organic layer is dried over anhydrous sodium sulphate, filtered and concentrated to afford terf-butyl A/-[(1 R)-1 -[3-(trifluoromethyl)phenyl]ethyl]carbamate as a white solid. In the second step, terf-butyl A/-[(1 R)-1 -[3-(trifluoromethyl)phenyl]ethyl]carbamate is added to a suspension of lithium aluminium hydride in dry THF under nitrogen atmosphere and the reaction mixture is heated to 70 °C and stirred for 3.5 hours. The mixture is then cooled to 0°C and quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl[(1 R)-1 -[3-(trifluoromethyl)- phenyl]ethyl]amine as a liquid, (MS(ES ⁺ ) m/z 168 ([M+1 ] ⁺ , 100)), by column chromatography as the parent compound.

HR-MS: 377.15972 ([M+1 ] ⁺ , Ci9H ₂ oN ₄ OF ₃ ; calc. 377.158375.

Example 15

A/-{2-[(1 ,2,3,4-tetrahydronaphthalen-1 -yl)amino1-1 /-/-1 ,3-benzimidazol-4- vDacetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 1 ,2,3,4-tetrahydro-l - naphtylamine) by column chromatography as the parent compound.

In addition, the title compound is prepared in five steps as the stereochemical^ pure (R)-enantiomer as described in Procedure A. After Step E (starting from A/-(2-chloro-1 /-/-benzimidazol-4-yl)acetamide and commercially available (1 R)-1 ,2,3,4-tetrahydro-1 -naphtylamine) the desired product was isolated by column chromatography as the parent compound.

HR-MS: 321 .17205 ([M+1 ] ⁺ , Ci ₉ H ₂ i N ₄ O; calc. 321 .170991 . Example 16

A/-{2-r(7-Chloro-1 ,2,3,4-tetrahvdronaphthalen-1 -yl)amino1-1 H-1 ,3-benzimidazol-4- vDacetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 7-chloro-1 ,2,3,4- tetrahydro-1 -naphtylamine) by column chromatography as the parent compound.

HR-MS: 355.13176 ([M+1 ] ⁺ , Ci ₉ H ₂₀ N ₄ OCI; calc. 355.132019).

Example 17

A/-{2-r(6,7-Dichloro-1 ,2,3,4-tetrahvdronaphthalen-1 -yl)amino1-1 H-1 ,3-benzimidazol- 4-yl)acetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and commercially available 6,7-dichloro-1 ,2,3,4- tetrahydro-1 -naphtylamine) by column chromatography as the parent compound.

HR-MS: 389.09307 ([M+1 ] ⁺ , Ci ₉ Hi ₉ N ₄ OCI ₂ ; calc. 389.093047).

Example 18

N-(2-{r7-(Trifluoromethyl)-1 ,2,3,4-tetrahvdronaphthalen-1 -yllaminoH H-1 ,3- benzimidazol-4-yl)acetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and 7-(trifluoromethyl)-1 ,2,3,4-tetrahydro-1 - naphtylamine, the latter prepared from commercially available 7-(trifluoromethyl)- 1 -tetralone by reductive amination using ammonium acetate and sodium

cyanoborohydride as described in Journal of Medicinal Chemistry 1982, 25, p 850- 854) by column chromatography as the parent compound. HR-MS: 389.15951 ([M+1 ] ⁺ , C ₂ oH ₂ oN ₄ OF ₃ ; calc. 389.158375). Subsequently, the two enantiomers of the title compound can be isolated by separation of the above racemate by preparative chiral chromatography.

Enantiomer A: HR-MS: 389.15918 ([M+1 ] ⁺ , C ₂ oH ₂ oN ₄ OF ₃ ; calc. 389.158375.

Enantiomer B: HR-MS: 389.15871 ([M+1 ] ⁺ , C ₂₀ H ₂₀ N ₄ OF ₃ ; calc.

389.158375.

Example 19

A/-{2-[(7-Fluoro-1 ,2,3,4-tetrahvdronaphthalen-1 -yl)amino1-1 H-1 ,3-benzimidazol-4- vDacetamide

The title compound is prepared in five steps as described in Procedure A and isolated as a racemate after Step E (starting from A/-(2-chloro-1 H- benzimidazol-4-yl)acetamide and 7-fluoro-1 ,2, 3,4-tetrahydro-1 -naphtylamine, the latter prepared from commercially available 7-fluoro-1 -tetralone by reductive amination using ammonium acetate and sodium cyanoborohydride as described in Journal of Medicinal Chemistry 1982, 25, p 850-854) by column chromatography as the parent compound. HR-MS: 339.16295 ([M+1 ] ⁺ , Ci ₉ H ₂₀ N ₄ OF; calc.

339.161569). Subsequently, the two enantiomers of the title compound can be isolated by separation of the above racemate by preparative chiral

chromatography.

Enantiomer A: HR-MS: 339.16290 ([M+1 ] ⁺ , C ₂ oH ₂₀ N ₄ OF ₃ ; calc. 339.161569.

Enantiomer B: HR-MS: 339.16293 ([M+1 ] ⁺ , C ₂₀ H ₂₀ N ₄ OF ₃ ; calc. 339.161569.

Example 20

Ν-(2-(Γ(1 f?)-6.7-Difluoro-1 ,2,3.4-tetrahvdronaphthalen-1 -yllamino)-1 H-1 ,3- benzimidazol-4-yl)acetamide The title compound is prepared in five steps as described in Procedure A and isolated after Step E (starting from A/-(2-chloro-1 H-benzimidazol-4- yl)acetamide and commercially available (1 R)-6,7-difluoro-1 ,2,3,4-tetrahydro-1 - naphtylamine) by column chromatography as the parent compound.

HR-MS: 357.15259 ([M+1 ]\ Ci ₉ Hi ₉ N ₄ OF ₂ ; calc. 357.152147).

Example 21

Biological Activity

This example demonstrates the biological activity of the benzimidazolyl- acetamide derivatives of the invention. The ionic current through small-conductance Ca ²⁺ -activated K ⁺ channels (SK channels, subtype 1 ) is recorded using the whole- cell configuration of the patch-clamp technique in a classic patch-clamp set-up using HEK293 tissue culture cells expressing hSK1 channels as described in e.g. WO 2006/100212.

For inhibitors a K _d value, defined as the concentration required for decreasing the baseline current to 50% of the initial current, is estimated.

+ indicates K _d > 3.0 μΜ

++ indicates 3.0 μΜ > K _d > 1 .0 μΜ

+++ indicates 1 .0 μΜ > K _d > 0.1 μΜ

++++ indicates K _d < 0.1 μΜ

Example K _d (μΜ)

1 +++

2 +a)

3 + + +

4 + +

5 +

6 + +

7 + +

8 + + + 9 +++

10 +++

1 1 ++++

12 +++

13 ++

14 +++

15 +++

16 ++++

17 +++

18 ++++

19 +++

20 n.d.

Determined on the SK3 subtype