EP1794150A1 - Benzimidazole derivatives and their use as cannabinoid receptor ligands I - Google Patents

Abstract

Compounds of Formula I, or pharmaceutically acceptable salts thereof: (I) wherein R1, R2, R3, R4, and R5 are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

Benz imidazole derivatives and their use as cannabinoid receptor ligands I

BACKGROUND OF THE INVENTION 1. Field of the invention

The invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof. Particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders.

2. Discussion of Relevant Technology

Pain management has been studied for many years. It is known that cannabinoid receptor (e.g., CB₁ receptor, CB₂ receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CB₁ and/or CB₂ receptors. Generally, CB₁ receptors are located predominately in the central nervous system, whereas CB₂ receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.

While CB₁ receptor agonists, such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and anadamide, are useful in anti-nociception models in animals, they tend to exert undesired CNS side-effects, e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc. These undesired side effects are known to be mediated by the CB₁ receptors located in CNS. There are lines of evidence, however, suggesting that CB₁ agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CB₁ receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side-effects.

DESCRIPTION OF THE EMBODIMENTS The present invention provides CB₁ receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.

The term "C_m-n" or "C_m-n group" used alone or as a prefix, refers to any group having m to n carbon atoms.

The term "alkyl" used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms. Illustrative examples of alkyls include, but are not limited to, C_1-4alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2-methyl-2- propyl, butyl, isobutyl, t-butyl.

The term "cycloalkyl," used alone or as suffix or prefix, refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms. Examples of cycloaljkyls include, but are not limited to, C_3-7cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes. A cycloalkyl can be unsubstituted or substituted by one or two suitable substituents. Preferably, the cycloalkyl is a monocyclic ring or bicyclic ring.

The term "alkoxy" used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is an alkyl. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and isobutoxy.

Halogen includes fluorine, chlorine, bromine and iodine.

"RT" or "rt" means room temperature.

In one aspect, an embodiment of the invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:

wherein R¹ and R² are independently selected from -H, hydroxy, C_1-4alkyl, C_3- βcycloalkyl, C_1-4alkoxy, and hydroxy-C_1-4alkyl; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

In another embodiment, the compounds are those of formula I, wherein R¹ and R² are independently selected from -H, hydroxy, C_1-4alkyl, C_1-4alkoxy, and hydroxy-C_1-4alkyl; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

Another embodiment of the invention provides a compound of formula I, wherein R¹ and R² are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R¹ and R² being different groups; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

A further embodiment of the invention provides a compound of formula I, wherein R and R are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R¹ and R² being different groups; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl with R³, R⁴ and R⁵ b beeiinngg t thhee s saammee..

An even further embodiment of the invention provides a compound of formula I, wherein

R¹ and R^z are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R¹ and R² not being -H at the same time; and R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

In a further embodiment, R¹ and R² are independently selected from -H and C_3-6cylcoalkyl.

In an even further embodiment, R³, R⁴ and R⁵ are independently selected from fluoro and methyl with R³, R⁴ and R⁵ being the same. In another embodiment, R¹ and R² are independently selected from -H, hydroxy, methyl, ethyl, 2-hydroxylethyl, methoxy and t-butyl with R¹ and R² being different groups. In another embodiment, R¹ and R² are independently selected from -H, hydroxy, methyl, ethyl, cyclopropyl, cyclobutyl, 2-hydroxylethyl, methoxy and t- butyl with R¹ and R² being different groups.

A further embodiment of the invention provides a compound selected from

, and pharmaceutically acceptable salts thereof. It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter. It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the Formula I.

It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the Formula I. Within the scope of the invention are also salts of the compounds of the

Formula I. Generally, pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.

In one embodiment, the compound of Formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or j?-toluenesulphonate.

We have now found that the compounds of the invention have activity as pharmaceuticals, in particular as modulators or ligands such as agonists, partial agonists, inverse agonist or antagonists Of CB₁ receptors. More particularly, the compounds of the invention exhibit selective activity as agonist of the CB₁ receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction Of CB₁ receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders. Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.

Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.

Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids. Also within the scope of the invention is the use of any of the compounds according to the Formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above. A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I above, is administered to a patient in need of such treatment. Thus, the invention provides a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes

"prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and "therapeutically" should be contrued accordingly. The term "therapy" within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.

The compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.

In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, transdermally, mtracerebroventricularly and by injection into the joints.

In one embodiment of the invention, the route of administration may be oral, intravenous or intramuscular.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid and liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.

A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art. Within the scope of the invention is the use of any compound of Formula I as defined above for the manufacture of a medicament.

Also within the scope of the invention is the use of any compound of Formula I for the manufacture of a medicament for the therapy of pain. Additionally provided is the use of any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.

A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I above, is administered to a patient in need of such therapy.

Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

Particularly, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain. Further, there is provided a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above. In a further aspect, the present invention provides a method of preparing the compounds of the present invention.

In one embodiment, the invention provides a process for preparing a compound of Formula I, comprising:

reacting a compound of Formula II with a compound of formula III,

HI wherein R , 1 , τ R>2 , τ R) 3 , τ R>4 and R are as defined above. In another embodiment, the invention provides a process for preparing a compound of Formula I, comprising

I reacting a compound of Formula IV with triphosgene and an amine R₁(R₂)NH,

IV wherein R¹, R², R³, R⁴ and R⁵ are as defined above. Compounds of the present invention may also be prepared according to the synthetic routes as depicted in Schemes 1-3.

Scheme 1

H₂, Pd

heating, 50-150⁰C base, e.g. DMAP solvent, e.g. CH₂CI₂ reducing agent when Y=OH e.g. AIH₃ base, e.g. DMAP solvent, THF solvent, e.g. DMF coupling reagent, e.g. HATU

3) solvent, e.g. AcOH acid, e.g. AcOH microwave oven heating, 100-19O⁰C

R¹, R², R³, R⁴ and R⁵ are as defined above.

Scheme 2

Reduction reaction

H₂ catalyst, e.g. 10% Pd/C

Solvent, EtOAc

R¹, R², R³, R⁴ and R⁵ are as defined above. Scheme 3

Biological Evaluation hCB^ and I1CB2 receptor binding

Human CB₁ receptor from Receptor Biology (!1CB₁) or human CB₂ receptor from BioSignal (hCB₂) membranes are thawed at 37 ⁰C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates. The IC₅₀ of the compounds of the invention at JiCB₁ and hCB₂ are evaluated from 10-point dose-response curves done with ³H-CP55,940 at 20000 to 25000 dpm per well (0.17- 0.21 nM) in a final volume of 300 μl. The total and non-specific binding are determined in the absence and presence of 0.2 μM of HU210 respectively. The plates are vortexed and incubated for 60 minutes at room temperature, filtered through

Unifilters GF/B (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl₂, 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 ⁰C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid.

JiCB₁ and hCB? GTPγS binding

Human CB₁ receptor from Receptor Biology (!1CB₁) or human CB₂ receptor membranes (BioSignal) are thawed at 37 ⁰C₃ passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPγS binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl₂, pH 7.4, 0.1% BSA). The EC₅₀ and E_max of the compounds of the invention are evaluated from 10-point dose- response curves done in 300μl with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg³⁵S per well (0.11 -0.14 nM). The basal and maximal stimulated binding is determined in absence and presence of 1 μM (hCB₂) or 10 μM (hCBi) Win 55,212-2 respectively. The membranes are pre-incubated for 5 minutes with 56.25 μM (hCB2) or 112.5 μM (hCBO GDP prior to distribution in plates (15 μM (hCB₂) or 30 μM (!1CB₁) GDP final). The plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifϊlters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl₂, 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid. Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist. Based on the above assays, the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation:

Ki = IC₅₀/(l+[rad]/Kd),

Wherein IC₅₀ is the concentration of the compound of the invention at which 50% displacement has been observed;

[rad] is a standard or reference radioactive ligand concentration at that moment; and Kd is the dissociation constant of the radioactive ligand towards the particular receptor.

Using the above-mentioned assays, the Ki towards human CB₁ receptors for certain compounds of the invention are in the range of between 5 nM and 52 nM. EC₅₀ for these compounds are in the range of between 10 nM and 202 nM. Emax for these compounds are in the range of between 70% and 151%.

EXAMPLES

The invention will further be described in more detail by the following

Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention.

Example 1

4-[(Aminocarbonyl)amino]-iV-[2-terf-butyl-l-(tetrahydro-2Jϊ-pyran-4-ylmethyl)- ljH-benzimidazol-5-yl]-iV-methylbenzenesuIfonainide

Step A. 4-[(Aminocarbonyl)amino]-iV-[2-ter?-butyl-l-(tetrahydro-2fi-pyran-4- yImethyl)-lJϊ-benzimidazol-5-yl]-iV-methylbenzenesulfonamide

2-tert-Butyl-N-methyl- 1 -(tetrahydro-2H-pyran-4-yhnethyl)- lH-benzimidazol-5-amine (see following Steps B, C, D, E and F for preparation) (30 mg, 0.0995 mmol) and 4- ureido-benzenesulfonyl chloride (28 nag, 0.119 mmol) were stirred in 3 mL of DMF containing a catalytic amount of DMAP at rt for 4h. The solvent was evaporated. The product was purified by reversed-phase HPLC using 10-70% CH₃CN/H₂O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 24 mg (39%); ¹H NMR (400 MHz, METHANOL-D₄): δ 1.50 - 1.55 (m, 2 H), 1.56 - 1.63 (m, 2 H), 1.67 (s, 9 H), 2.32 - 2.40 (m, 1 H), 3.23 (s, 3 H), 3.34 (dt, J=I 1.42, 2.34 Hz, 2 H), 3.92 (d, J=3.12 Hz, 1 H), 3.95 (d, J=3.12 Hz, 1 H), 4.51 (d, J=7.42 Hz, 2 H), 7.32 (ddd, J=9.03, 2.00, 0.88 Hz, 1 H), 7.38 (d, J=8.20 Hz, 2 H), 7.49 - 7.54 (m, 3 H), 7.88 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)⁺: 500.0; Anal. Calcd for C₂₅H₃₃N₅O₄S + 1.7 TFA + 0.6 H₂O: C, 48.43; H, 5.14; N, 9.94. Found: C, 48.44; H, 5.04; N, 10.04.

Step B: Methyl (4-fluoro-3-nitrophenyl)carbamate

Methyl chloroformate (13.2 mL, 170.2 mmol) was added dropwise to a cold (0°C) dichloromethane (200 mL) solution of 4-fluoro-3-nitro aniline (24.15 g, 154.7 mmol) and DIPEA (35 mL, 201 mmol). The reaction mixture was stirred at rt overnight. The solution was then diluted with 200 mL of dichloromethane and washed with 2M HCl, brine and dried over anhydrous MgSO₄. The solvent was concentrated and the product was directly used for next step without further purification. Yield: 35.5 g (99%); ¹H NMR (400 MHz, CHLOROFORM-D): δ 3.81 (s, 3H), 7.02 (s, IH), 7.23 (m, IH), 7.72 (d, J = 8.59Hz, IH), 8.17 (dd, J = 6.35, 2.64Hz, IH).

Step C. Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl}carbamate

Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75⁰C for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO₄, saturated aqueous NaHCO₃ solution, brine and dried over anhydrous MgSO₄. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53 g (88%); ¹H NMR (400 MHz, CHLOROFORM-D): δ 1.42 (ddd, J=25.24, 12.06, 4.49 Hz, 2 H), 1.73 (d, J=I.76 Hz, 1 H), 1.76 (d, J=I.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (td, J=11.86, 2.05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H).

Step D. Methyl {3-amino-4-[(tetrahydro-2J3-pyran-4- ylmethyl)amino]phenyl}carbamate

Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4-yhnethyl)amino]phenyl} carbamate (2.53 g, 8.18 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H₂ atmosphere (40 psi) using a Parr hydrogenation apparatus overnight at rt. The solution was filtered through Celite and the solvent was evaporated. Yield: 2.29 g (99%); ¹H NMR (400 MHz,

CHLOROFORM-D): δ 1.40 (ddd, J=25.09, 12.01, 4.49 Hz, 2 H), 1.70 - 1.74 (m, 1 H), 1.74 - 1.77 (m, 1 H), 1.81 - 1.92 (m, 1 H), 2.99 (d, J=6.64 Hz, 2 H), 3.34 (br.s, 2 H), 3.41 (dt, J=I 1.81, 2.15 Hz, 2 H), 3.74 (s, 3 H), 3.99 (d, J=3.51 Hz, 1 H), 4.02 (d, J=3.51 Hz, 1 H), 6.38 (br.s, 1 H), 6.55 - 6.60 (m, 1 H), 6.62 - 6.68 (m, 1 H), 6.95 (br.s, 1 H).

Step E. Methyl [2-tert-butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-yl] carbamate

Methyl {3-amino-4-[(tetrahydro-2H^'-pyran-4-ylmetliyl)amino]phenyl}carbamate (2.29 g, 8.20 mmol) and DMAP (0.20 g, 1.64 mmol) were dissolved in 75 mL of DCM. Trimethylacetyl chloride (1.10 mL, 9.02 mmol) was added dropwise and the solution was stirred at rt for 2h. The solution was washed with aqueous NaHCO₃ solution, brine and dried over anhydrous MgSO₄. The residue was dissolved in 25 mL of AcOH and was heated at 125⁰C for Ih using a Personal Chemistry microwave apparatus. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO₃ solution, brine and dried over anhydrous MgSO₄. The crude product was purified by silica gel flash chromatography using 4:3 / hexanes : acetone as eluent Yield: 1.81 g (64%); ¹H NMR (400 MHz, CHLOROFORM-D): δ 1.48 - 1.54 (m, 4 H) 1.56 (s, 9 H) 2.23 - 2.35 (m, 1 H) 3.27 - 3.35 (m, 2 H) 3.78 (s, 3 H) 3.96 (t, J=2.93 Hz, 1 H) 3.99 (t, J=3.03 Hz, 1 H) 4.18 (d, J=7.42 Hz, 2 H) 6.63 (br.s, 1 H) 7.24 - 7.28 (m, 1 H) 7.41 (br.s, 1 H) 7.61 (d, J=I.95 Hz, 1 H).

Step F: 2-tert-Butyl-N-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- benzimidazol-5-amine

Methyl [2-tert-butyl-l-(tetrahydro-2H-pyran-4-yhnethyl)-lH-benzimidazol-5- yljcarbamate (1.8Og, 5.21 mmol) was dissolved in 75 mL of THF at 0°C. IM

HCl/ether (7.3 mL, 7.29 mmol) was added dropwise and the solution was stirred at 0°C for 15 min. LiAlH₄ (988 mg, 26.1 mmol) was added slowly and the solution was stirred at rt overnight. The reaction was quenched at 0°C by the addition of MeOH (5 mL) followed by water (10 mL) and the solution was left to stir at rt for 30 min. Anhydrous Na₂SO₄ (10 g) was added and the solution was stirred at rt for another 30 min. The solution was filtered and the solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO₃ solution, brine and dried over anhydrous MgSO₄. The solvent was evaporated. Yield: 1.54g (98%); ¹H NMR (400 MHz, CHLOROFORM-D): δ 1.49 - 1.53 (m, 4 H), 1.53 - 1.57 (m, 9 H), 2.22 - 2.32 (m, 1 H), 2.87 (s, 3 H), 3.26 - 3.35 (m, 2 H), 3.95 (t, J=3.03 Hz, 1 H), 3.97 - 4.00 (m, 1 H), 4.13 (d, J=7.42 Hz, 2 H), 6.61 (dd, J=8.59, 2.15 Hz, 1 H), 6.99 (d, J=1.95 Hz, 1 H), 7.11 (d, J=8.59 Hz, I H).

Example 2

4-[(Aminocarbonyl)amino]-iV-methyI-iV-[l-(tetrahydro-2H-pyran-4-ylmethyl)-2- (trifluoromethyl)-li3-benziinidazol-5-yl]benzenesulfonamide

Step A. 4-[(Aminocarbonyl)amino]-iV-inethyl-iV-[l-(tetrahydro-2Jϊ-pyran-4- ylmethyl)-2-(trifluoromethyl)-li3-benzimidazol-5-yl]benzenesulfonamide

A solution of N-methyl-l-(terrahydro-2H-pyran-4-yhnethyl)-2-(trifluoromethyl)-lH^r- benzimidazol-5-amine hydrochloride (76.1 mg, 0.2 mmol) (for preparation, see the steps B, C, D, E, F and G), DMAP (97.7 mg, 0.8 mmol) and 4- [(aminocarbonyl)amino]benzenesulfonyl chloride (94.0 mg, 0.4 mmol) in MeCN (6 mL) was stirred overnight at room temperature. The reaction mixture was quenched with H₂O (6 mL). Upon evaporation, the crude product was purified by reversed- phase HPLC using 20-50% CH₃CN/H₂O and then lyophilized affording the title compound as the corresponding TFA salt. Yield: 42.9 mg (42%). ¹HNMR (400 MHz, CD₃OD): δ 1.40 - 1.52 (m, 4 H), 2.15 - 2.34 (m, 1 H), 3.23 (s, 3 H), 3.31 - 3.40 (m, 2 H), 3.87 - 3.98 (m, 2 H), 4.32 (d, J=7.81 Hz, 2 H), 7.32 (dd, J=8.88, 2.05 Hz, 1 H), 7.37 - 7.43 (m, 3 H), 7.48 - 7.56 (m, 2 H), 7.72 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H)⁺ = 512.0. Anal. Calcd for C₂₂H₂₄F₃N₅O₄S+ 0.3 TFA (545.73): C, 49.74, H, 4.49, N, 12.83; Found: C, 49.84; H, 4.55; N, 12.78.

Step B. iV-(4-fluoro-3-nitrophenyl)acetamide

4-Fluoro-3-nitro-aniline (45.0 g, 0.288 mol) was added in portions to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the title compound (42.0 g, 70%). ¹HNMR (400 MHz, CDCl₃): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6.44, 2.73 Hz, 1 H).

Step C. iV-(4-fluoro-3-nitrophenyl)-iV-methylacetamide

Sodium hydride (2.40 g, 60 mmol) was added in portions to a solution of iV-(4-ftuoro- 3-nitrophenyl)acetamide (7.93 g, 40 mmol) in THF (120 mL) at 0 ⁰C. Stirring for 20 min, iodomethane (17.0 g, 120 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with saturaed NaHCO₃ (30 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with saturated NaCl (2x30 mL). After filtration and concentration, 8.73 g (100%) of the title compound was obtained as a brown solid. ¹H NMR (400 MHz, CDCl₃): δ 1.92 (s, 3 H), 3.30 (s, 3 H), 7.38 (s, 1 H), 7.52 (s, 1 H), 7.95 (s, 1 H).

Step D. iV-methyl-iV-{3-nitro-4-[(tetrahydro-2fr-pyran-4- ylmethyl) amino] phenyl} acetamide

4-Aminomethylpyran (2.50 g, 21.7 mmol ) was added to a mixture of N-(4-fluoro-3- nitrophenyl)-N-methylacetamide (4.61 g, 21.27 mmol) and sodium carbonate (5.10 g, 47.7 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 ⁰C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H₂O (3x50 mL), saturated NaCl (3x50 mL), and dried over Na₂SO₄. After iϊltation and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red solid. ¹H NMR (400 MHz, CDC1₃)_: δ 1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - 3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J-9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)⁺ = 309.12.

Step E. iV-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-A^r- methylacetamide

iV-methyl-iV-{3-mtro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (5.39 g, 16.7 mmol) was hydrogenated in ethyl acetate (200 mL) catalyzed by 10% Pd/C (0.2 g) at 30-40 psi H₂ in Parr shaker for 18 h at room temperature. After filtration through celite and concentration, 6.0 g (100%) of a purple solid was obtained as HCl salt, which was used in the next step without purification. ¹H NMR (400 MHz, CD₃OD): δ 1.32 - 1.46 (m, 2 H), 1.78 - 1.84 (m, 2 H), 1.85 (s, 3 H), 1.91 - 2.06 (m, 1 H), 3.16 (d, J=6.83 Hz, 2 H), 3.20 (s, 3 H), 3.39 - 3.51 (m, 2 H), 3.94 - 4.03 (m, 2 H), 7.01 (d, J=8.59 Hz, 1 H), 7.12 (d, J=2.15 Hz₃ 1 H), 7.17 (dd, J=8.49, 4.39 Hz, 1 H). MS (ESI) (M+H)⁺ = 278.7

Step F. iV-methyl-iV-ll-Ctetrahydro^Jϊ-pyran^-ylmethylJ^-Ctrifluoromethyl)- lH-benzimidazol-S-ylJacetamide

A solution of iV-{3-ammo-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-N- methylacetamide hydrochoride (395.1 mg, 1.42 mmol) in trifluoroacetic acid (10 mL) was heated to reflux for 20 h. After evaporation of the solvent, the crude product was used directly for next step without purification. MS (ESI) (M+H)⁺: 356.02.

Step G. iV-methyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-lJ3- benzimidazol-5-amine

The crude JV-methyl-iV-[ 1 -(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- IH- benzimidazol-5-yl]acetamide (-500 mg, 1.42 mmol) was dissolved in 10 mL of EtOΗ-27VΗCl (3:2), and then heated at 12O⁰C in a Personal Chemistry SmithSynthesizer microwave instrument for 4 h. After concentration and dried in vacuo, 539 mg (100%) of a grey white solid was obtained as the title product, which was used directly for Step A. MS (ESI) (M+H)⁺ = 314.20.

Example 3

7V-Methyl-4-nitro-iV-[l-(tetrahydro-2iϊ-pyran-4-ylmethyl)-2-(trifluoromethyl)- lJ3-benzimidazol-5-yl]benzenesulfonamide

Following the procedure for Step A in Example 2, using iV-methyl-1 -(tetrahydro-2i7- pyran-4-ylmethyl)-2-(trifluoromethyl)-lJi^'-benzirnidazol-5-amine hydrochloride (387.0 mg, 1.0 mmol) (for preparation, see the steps B, C, D, E, F and G in Example 81), DMAP (488.7 mg, 4.0 mmol) and 4-nitrobenzenesulfonyl chloride (443.2 mg, 2.0 mmol) in MeCN (10 mL), the crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 295.0 mg (59%) of a yellow solid as the title compound. ¹FfNMR (400 MHz, CD₃OD): δ 1.39 - 1.54 (m, 4 H), 2.14 - 2.34 (m, 1 H), 3.32 (s, 3 H), 3.33 - 3.40 (m, 2 H), 3.86 - 4.01 (m, 2 H), 4.32 (d, J=7.42 Hz, 2 H), 7.31 (dd, J=8.88, 2.05 Hz, 1 H), 7.45 (d, J=2.15 Hz, 1 H)₃ 7.74 (d, J=8.98 Hz, 1 H), 7.76 - 7.82 (m, 2 H), 8.27 - 8.42 (m, 2 H). MS (ESI) (M+H)⁺ = 499.0. Anal. Calcd for C₂₁H₂₁F₃N₄O₅S+ 0.50 TFA+0.20 H₂O (559.10): C, 47.26; H, 3.95; N, 10.02; Found: C, 47.24; H, 3.80; N, 10.20.

Example 4

4-Amino-Λ^/-methyl-iV-[l-(tetrahydro-2_JBr-pyran-4-ylmethyl)-2-(trifluoromethyl)- liϊ-benzimidazol-5-yl]benzenesuIfonamide

iV-methyl-4-nitro-iV-[ 1 -(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- IH- benzimidazol-5-yl]benzenesulfonamide (235.6 mg, 0.47 mmol) (for preparation, see the Example 3) was hydrogenated in ethyl acetate (20 mL) catalyzed by 10% Pd/C (90 mg) at 30-40 psi H₂ in Parr shaker for 5 h at room temperature. After filtration through celite and concentration, 229.8 mg (100%) of a white solid was obtained. Small amounts of the crude product was purified by reversed-phase HPLC using 20- 70% CH₃CN/H₂O and then lyophilized affording the title compound as the corresponding TFA salt. ¹HNMR ^OO MHZ₅ CD₃OD): δ 1.38 - 1.55 (m, 4 H), 2.15 - 2.35 (m, 1 H), 3.18 (s, 3 H), 3.33 - 3.40 (m, 2 H), 3.82 - 4.02 (m, 2 H), 4.32 (d, J=7.62 Hz, 2 H), 6.58 - 6.69 (m, 2 H), 7.15 - 7.23 (m, 2 H), 7.35 (dd, J=8.98, 1.95 Hz, 1 H), 7.40 (d, J=I.56 Hz, 1 H), 7.71 (d, J=8.79 Hz, 1 H). MS (ESI) (M+H)⁺ = 469.0. Anal. Calcd for C₂₁H₂₃F₃N₄O₃S+ 0.40 TFA (514.11): C, 50.93; H, 4.59; N, 10.90; Found: C, 51.00; H, 4.72; N, 10.54.

Example 5

4-{[(Isopropylamino)carbonyl]amino}-Λ^/-methyl-iV-[l-(tetrahydro-2H^r-pyran-4- ylmethy^-l-^rifluoromethy^-lH-benzimidazol-S-yybenzenesuIfonamide

4-Amino-N-me1liyl-N-[l-(terrahydro-2H-pyran-4-ylme1iiyl)-2-(trifluoromethyl)-li-^/'- benzimidazol-5-yl]benzenesulfonamide (31.3 mg, 0.067 mmol) (for preparation, see the Example 4) and 2-isocyanatopropane (0.5 mL) in DCE (5 mL) was heated overnight at 80⁰C. After evaporation, the crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 17.2 mg (46%) of a white solid as the title compound. ¹HNMR (400 MHz, CD₃OD): δ 1.17 (d, J=6.44 Hz, 6 H), 1.41 - 1.53 (m, 4 H), 2.18 - 2.33 (m, 1 H), 3.23 (s, 3 H), 3.31 - 3.39 (m, 2 H), 3.83 - 3.90 (m, 1 H), 3.90 - 3.96 (m, 2 H), 4.32 (d, J=7.42 Hz, 2 H), 7.32 (dd, J=8.88, 2.05 Hz, 1 H), 7.36 - 7.40 (m, 2 H), 7.40 (d, J=I.56 Hz, 1 H), 7.46 - 7.52 (m, 2 H), 7.72 (d, J=8.59 Hz, 1 H). MS (ESI) (M+H)⁺ = 554.0. Anal. Calcd for C₂₅H₃₀F₃N₅O₄S+ 0.70 TFA+0.20 H₂O +0.5CH₃OH (653.06): C, 49.48; H, 5.11; N, 10.72; Found: C, 49.50; H, 5.16; N, 10.71. Example 6

4-{[(ter^Butylamino)carbonyl]amino}r/V-methyl-iV-[l-(tetrahydro-2jH^r-pyran-4- ylmethy^-Z-^rifluoromethy^-ljH-benzimidazol-S-yllbenzenesulfonamide

Step A. 4-{[(terf-Butylamino)carbonyl]amino}-iV-methyl-iV-[l-(tetrahydro-2JΪ- pyran-4-yImethyl)-2-(trifluoromethyl)-liϊ-benzimidazol-5- yl] b enzenesulf onamide

A solution of 4-isocyanato-iV-methyl-iV-[l -(tetrahydro-2H^*-pyran-4-ylmethyl)-2- (trifluoromethyl)-lH-benzimidazol-5-yl]benzenesulfonamide (see following step B for preparation) in TΗF (3.5 mL, 0.14 mmol) was added to a solution of t-butylamine (18 uL, 12.5 mg, 0.17 mmol) in TΗF (2 mL) at room temeprature. The reaction mixture was stirred overnight, diluted with EtOAc (50 mL), washed with H₂O (10 mL), brine (10 mL) and dried over Na₂SO₄. After evaporation, the crude product was purified by reversed-phase HPLC using 20-70% CH₃CN/H₂O and then lyophilized affording the title compound as the corresponding TFA salt. Yield: 44.6 mg (56%). ¹HNMR (600 MHz, METHANOL-D₄): δ 1.45 (s, 9 H), 1.50 - 1.63 (m, 4 H), 2.27 - 2.41 (m, 1 H), 3.31 (s, 3 H), 3.40 - 3.49 (m, 2 H), 3.95 - 4.07 (m, 2 H)₃ 4.41 (dd, J=7.42 Hz, 2 H), 7.40 (dd, J=8.96, 2.05 Hz, 1 H), 7.43 - 7.48 (m, 2 H), 7.49 (d, J=I .79 Hz, 1 H), 7.51 - 7.57 (m, 2 H), 7.80 (d, J=8.70 Hz, 1 H). MS (ESI) (M+H)⁺ = 568.0. Anal. Calcd for C₂₆H₃₂F₃N₅O₄S+0.50 TFA+0.10 H₂O (626.45): C, 51.77; H, 5.26; N₅ 11.18; Found: C, 51.72; H₃ 5.21; N, 11.28.

Step B. 4-Isocyanato-iV-methyl-iV-[l-(tetrahydro-2_JH-pyran-4-ylmethyl)-2- (trifluoromethyl)-lJΪ-benzimidazol-5-yl]benzenesulfonamide

A solution of 4-amino-N-methyl-iV- [ 1 -(tetrahydro-2H-pyran-4-ylmethyi)-2- (trifluoromethyl)-lH-benzimidazol-5-yl]benzenesulfonamide (1.32 g, 2.82 mmol) (for preparation, see the Example 4) and DIPEA (1.1 mL, 0.82 g, 6.35 mmol) in TΗF (30 mL) was added to a solution of triphosgene (0.31 g, 1.04 mmol) in TΗF (4OmL) at 0 ⁰C during 20 min. The reaction mixture was stirred for 30 min. at 0 ⁰C, 1 h at room temperature and then directly used at the next step.

Example 7

4-({[(2-Ηydroxyethyl)amino]carbonyl}amino)-iV-methyl-iV-[l-(tetrahydro-2Jϊ- pyran-4-ylmethyl)-2-(trifluoromethyl)-ljH-benzimidazol-5- yl]benzenesulfonamide

Following the procedure for Step A in example 6, using a solution of 4-isocyanato-N- methyl-N-[ 1 -(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)- lH-benzimidazol- 5-yl]benzenesulfonamide (see Step B in example 6 for preparation) (0.14 mmol) in 3.5 mL of TΗF and ethanolamine (11 uL, 11.1 mg, 0.18 mmol) in TΗF (2 mL). The crude product was purified by reversed-phase ΗPLC using 20-50% CΗ₃CN/Η₂O and then lyophilized affording the title compound as the corresponding TFA salt. Yield: 41.0 mg (53%). ¹HNMR (OOO MHZ₅ METHANOL-D₄): δ 1.48 - 1.63 (m, 4 H), 2.27 - 2.43 (m, 1 H), 3.32 (s, 3 H), 3.40 - 3.47 (m, 4 H), 3.71 (t, J=5.63 Hz, 2 H), 3.97 - 4.07 (m, 2 H), 4.41 (d, J=7.68 Hz, 2 H), 7.41 (dd, J=8.96, 2.05 Hz, 1 H), 7.45 - 7.49 (m, 2 H), 7.50 (d, J=I.79 Hz, 1 H), 7.57 - 7.64 (m, 2 H), 7.81 (d, J=8.70 Hz, 1 H). MS (ESI) (M+H)⁺ = 556.0. Anal. Calcd for C₂₄H₂₈F₃N₅O₅S+0.60 TFA+0.30 H₂O (629.40): C, 48.09; H, 4.68; N, 11.13; Found: C, 48.08; H, 4.60; N, 11.23.

Example 8 4-{[(Hydroxyamino)carbonyl]amino}-iV-methyl-iV-[l-(tetrahydro-2jKr-pyran-4- ylmethyl)-2-(trifluoromethyl)-LH-benzimidazol-5-yl]benzenesulfonamide

Following the procedure for step A in example 6, using a solution of 4-isocyanato-iV- methyl-iV- [ 1 -(tetrahy dro-2H-pyran-4-yhnethyl)-2-(trifluoromethyl)- lH-benzimidazol- 5-yl]benzenesulfonamide (see Step B in example 6 for preparation) (0.14 mmol) in 3.5 mL of THF in THF (0.14 mmol), hydroxylamine hydrochloride (11.8 mg, 0.17 mmol) and DIPEA (0.1 mL) in THF (2 mL). The crude product was purified by reversed-phase HPLC using 20-50% CH₃CNZH₂O and then lyophilized affording the title compound as the corresponding TFA salt. Yield: 34.8 mg (47%). ¹HNMR (600 MHz, METHANOL-D₄): δ 1.35 (s, 4 H), 2.04 - 2.17 (m, 1 H), 3.16 (s, 3 H), 3.18 - 3.24 (m, 2 H), 3.76 - 3.86 (m, 2 H), 4.28 (d, J=7.17 Hz, 2 H), 7.23 (d, J=8.96 Hz, 1 H), 7.36 (d, J=8.70 Hz, 2 H), 7.45 (s, 1 H), 7.81 (d, J=8.70 Hz, 2 H), 7.84 (d, J=8.70 Hz, 1 H), 9.07 (s, 1 H), 9.14 (s, 1 H), 9.27 (s, 1 H), 9.28 (s, 1 H). MS (ESI) (M+H)⁺ = 528.0. Anal. Calcd for C₂₂H₂₄F₃N₅O₅S+0.30 TFA+0.30 H₂O (567.14): C, 47.86; H, 4.43 N, 12.35; Found: C, 47.88; H, 4.28; N, 12.44.

Example 9

4-({[Methoxy(methyl)amino]carbonyl}amino)-iV-methyl-Λ'-[l-(tetrahydro-2_J9^r- pyran-4-ylmethyl)-2-(trifluoromethyl)-lH-benzimidazol-5- yl]benzenesulfonamide

Following the procedure for step A in example 6, using a solution of 4-isocyanato-iV- methyl-N-[l-(tetxahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-lH-benzimidazol- 5-yl]benzenesulfonamide (see Step B in example 6 for preparation) (0.14 mmol) in 3.5 mL of THF, N,O-dimethylhydroxylamine hydrochloride 27.3 mg, 0.28 mmol) and DBPEA (0.1 mL) in THF (2 mL). The crude product was purified by reversed-phase HPLC using 20-50% CH₃CN/H₂O and then lyophilized affording the title compound as the corresponding TFA salt. Yield: 35.9 mg (46%). ¹HNMR (600 MHz, METHANOL-D₄): δ 1.51 - 1.62 (m, 4 H), 2.26 - 2.42 (m, 1 H), 3.25 (s, 3 H), 3.33 (s, 3 H), 3.40 - 3.48 (m, 2 H), 3.84 (s, 3 H), 3.98 - 4.06 (m, 2 H), 4.41 (d, J=7.68 Hz, 2 H), 7.41 (dd, J=8.83, 1.92 Hz, 1 H), 7.48 - 7.57 (m, 3 H), 7.77 - 7.85 (m, 3 H). MS (ESI) (M+H)⁺ = 556.0. Anal. Calcd for C₂₄H₂₈F₃N₅O₅SmIO TFA+0.50 H₂O +0.20 MeOH(582.4): C, 50.32; H, 5.17; N, 12.03; Found: C, 50.33; H, 5.12; N, 12.05.

Example 10 iV-[2-tert-Butyl-l-(tetrahydro-2i3-pyran-4-ylmethyl)-lfi-benzimidazol-5-yl]-4- {[(ethylamino)carbonyl]amino}-iV-metliylbenzenesulfonamide

Step A. iV-[2-terf-Butyl-l-(tetrahydro-2iϊ-pyran-4-ylmethyl)-lJϊ-benzimidazol-5- yl]-4-{[(ethylamino)carbonyl]amino}-iV-methylbenzenesulfonamide

A solution of N-[2-tert-butyl- 1 -(tetrahydro-2H^"-pyran-4-ylmethyl)- lϋT-benzimidazol- 5-yl]-4-isocyanato-iV-methylbenzenesulfonamide in THF (10 mL, 0.22 mmol) (see following steps B, C, D, E, F, G, H, and I for preparation) was added to a solution of ethylamine (0.26 mmol) in THF (5 mL) at room temeprature. The reaction mixture was stirred overnight, diluted with EtOAc (50 mL), washed with H₂O (10 mL), brine (10 mL) and dried over Na₂SO₄. After evaporation, the crude product was purified by MPLC using EtOAc on silica gel to give 111.8 mg (96%) of a white solid as the title compound. ¹HNMR (OOO MHZ₅ METHANOL-D₄): δ 1.17 (t, J=7.30 Hz, 3 H), 1.52 - 1.65 (m, 4 H), 1.70 (s, 9 H), 2.31 - 2.46 (m, 1 H), 3.21 - 3.27 (q, J =7.4 Hz, 2 H), 3.26 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.97 (m, 2 H), 4.54 (d, J=7.94 Hz, 2 H), 7.35 (dd, J=8.96, 2.05 Hz, 1 H), 7.37 - 7.43 (m, 2 H), 7.50 - 7.56 (m, 3 H), 7.90 (d, J=9.22 Hz, 1 H). MS (ESI) (M+H)⁺ = 528.0. Step B . Λ/-[2-tert-butyl-l-(tetrahydro-2Jϊ-pyran-4-ylmethyl)-ljH^r-benziniidazol-5- yl]-iV-methylacetamide

Trimethylacetyl chloride (3.3 mL, 3.20 g, 26.5 mmol) was dropwise added to a solution of N- {3-amino-4-[(tetrahydro-2H^"-pyran-4-ylmethyl)amino]phenyl} -N- methylacetamide (7.01 g, 25.3 mmol) (for preparation, see steps B to E in example 2) and DIPEA (5.3 mL, 3.92 g, 30.4 mmol) in dichloromethane (170 mL) at 0 ⁰C. The resulting mixture was stirred for 4h at room temperature. After evaporation of the solvent, the residue was dissolved in acetic acid (75 mL) and then divided to 15 sealed test tubes. The mixture was heated at 150°C in a Personal Chemistry

SmithSynthesizer microwave instrument for 2.5 h. The combined reaction mixture was evaporated and then dissolved in EtOAc (400 mL), washed with 2 NNaOH aqueous solution (2x20 mL), brine (2x20 mL) and dried over Na₂SO₄.. After filtration and evaporation, the residue was purified by MPLC using EtOAc/MeOH (10:1) as an eluent on silica gel to give the title compound as a white solid (7.31 g, 84%). MS (ESI) (M+H)⁺ = 344.15

Step C. 2-ter^-Butyl-iV-methyl-l-(tetrahydro-2i?-pyran-4-ylmethyl)-lH- benzimidazol-5-amine

Λ/-[2-ter^Butyl-l-(tetrahydro-2H-pyran-4-yhnethyl)-lH-benzimidazol-5-yl]-N- methylacetamide (4.57g, 13.3 mmol) was dissolved in hydrochloric acid (37%, 100 mL) and then heated overnight at 90-100 ⁰C. Upon concentration, the residue was dissolved in EtOAc and washed with 2NNaOH solution, brine and dried over anhydrous MgSO₄. The solvent was evaporated to give a crude product which was used directly at the next step. Yield: 4.01 g (100%). ¹H NMR (400 MHz, CHLOROFORM-D): δ 1.46 - 1.54 (m, 4 H)₃ 1.54 (s, 9 H), 2.16 - 2.37 (m, 1 H), 2.87 (s, 3 H), 3.23 - 3.38 (m, 2 H), 3.91 - 4.02 (m, 2 H), 4.13 (d, J=7.42 Hz, 2 H), 6.61 (dd, J=8.59, 2.15 Hz, 1 H), 6.99 (d, J=2.15 Hz, 1 H), 7.11 (d, J=8.59 Hz, 1 H); MS (ESI) (M+H)⁺ = 302.06.

Step D. iV-[2-ter^butyl-l-(tetrahydro-2jδ^r-pyran-4-ylmethyl)-liϊ-benzimidazol-5- yl]-iV-methyl-4-nitrobenzenesulfonainide

4-Nitrobenzenesulfonyl chloride (1.06 g, 4.8 mmol) was added to a solution of 2-tert- butyl-N-methyl-l-(te1xahydro-2H-pyran-4-ylmethyl)-lH^'-benzimidazol-5-arnine (1.21 g, 4.0 mmol), DIPEA (0.98 mL, 0.72 g, 5.6 mmol) and DMAP (0.10 g, 0.8 mmmol) in 20 mL of DCM. The mixture was stirred overnight at rt, washed with saturated aqueous NaHCO₃ solution, brine and dried over anhydrous MgSO₄. The crude product was purified by silica gel flash chromatography using Hex/EtOAc (1:1) as eluent. Yield: 1.91 g (98%). ¹H NMR (400 MHz, CHLOROFORM-D): δ 1.51 - 1.57 (m, 13 H), 2.24 - 2.34 (m, 1 H), 3.27 (s, 3 H), 3.30 - 3.38 (m, 2 H), 3.99 (t, J=2.93 Hz, 1 H), 4.02 (t, J=3.03 Hz, 1 H), 4.20 (d, J=7.42 Hz, 2 H), 7.19 - 7.23 (m, 2 H), 7.29 - 7.33 (m, 1 H), 7.77 (d, J=8.98 Hz, 2 H), 8.30 (d, J=8.79 Hz, 2 H).

Step E. 4-Amino-iV-[2-te^-butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-l_JH^r- benzimidazol-5-yl]-7V-methylbenzenesulfonamide

N-[2-ter^Butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl]-N- methyl-4-nitrobenzenesulfonamide (1.91 g, 3.93 mmol) was dissolved in 200 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H₂ atmosphere (40 psi) using a Parr hydrogenation apparatus overnight at rt. The solution was filtered through celite and the solvent evaporated to give a crude product which was used directly at the next step. Yield: 1.80 g (100%). MS (ESI) (JVRH)⁺ = 457.01.

Step F. iV-tl-ter^-butyl-l-^etrahydro-lJϊ-pyran^-ylmethy^-lJΪ-benzimidazol-S- yl]-4-isocyanato-iV-methylbenzenesulfonamide

A solution of 4-amino-JV-[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- IH- benzimidazol-5-yl]-N-methylbenzenesulfonamide (301 mg, 0.66 mmol) and DIPEA (256 uL,193 mg, 1.49 mmol) in TΗF (15 mL) was added to a solution of triphosgene (73 mg, 0.24 mmol) in TΗF (15 mL) at 0 ⁰C during 20 min.. The reaction mixture was stirred for 30 min. at 0 ⁰C, 1 h at room temperature and then directly used at next step

Example 11 iV-[2-ter^Butyl-l-(tetrahydro-2i?-pyran-4-ylmethyl)-lJΪ-benzimidazol-5-yl]-4- { [(hydroxyamino)carbonyl] amino}-iV-methylbenzenesulfonamide

Following the procedure for step A in example 10, using a solution of iV-[2-tert-butyl- l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazol-5-yl]-4-isocyanato-N- methylbenzenesulfonamide (0.22 mmol) in 10 mL of TΗF (see example 10 for preparation), hydroxylamine hydrochloride (30.6 mg, 0.44 mmol) and DIPEA (92 uL, 68.6 mg, 0.53 mmol) in TΗF (5 mL). The crude product was purified by MPLC using EtOAc eluted on silica gel to give 43.0 mg (38%) of a white solid as the title compound. ¹HNMR (600 MHz₅ DMSO-D₆): δ 1.39 - 1.53 (m, 4 H), 1.59 (s, 9 H), 2.15 - 2.26 (m, 1 H), 3.19 (s, 3 H), 3.20 - 3.24 (m, 2 H), 3.47 (s, 1 H), 3.75 - 3.93 (m, 2 H), 4.44 (d, J=6.40 Hz, 2 H)₃ 7.19 (d, J=8.45 Hz, 1 H), 7.40 (d, J=8.71 Hz, 2 H), 7.49 (s, 1 H), 7.84 (d, J-7.68 Hz, 2 H), 7.96 (s, 1 H), 9.19 (s, 1 H), 9.36 (s, 1 H). MS (ESI) (M+H)⁺ = 516.0. Anal. Calcd for C₂₅H₃₃N₅O₅S+ 1.60 HCl+0.30 MeOH (583.59): C₅ 52.07; H, 6.18; N, 12.00; Found: C, 52.14; H₅ 6.10; N, 11.83.

Example 12 iV-[2--'ert-Butyl-l-(tetrahydro-2iϊ-pyran-4-ylmethyl)-lJϊ-benzimidazol-5-yl]-4-

({[methoxy(methyl)amino]carbonyl}amino)-iV-methylbenzenesulfonamide

Following the procedure for step A in example 10, using a solution of iV-[2-tert-butyl- l-(tetrahydro-2H-pyran-4-ylmethyl)-lJi^'-berizimidazol-5-yl]-4-isocyanato-N- methylbenzenesulfonamide (0.22 mmol) in 10 mL of THF (see example 10 for preparation), N,O-dimethylhydroxylamine hydrochloride (42.9 mg, 0.44 mmol) and DIPEA (92 uL, 68.6 mg, 0.53 mmol) in THF (5 mL). The crude product was purified by reversed-phase HPLC using 20-50% CH₃CN/H₂O and then lyophilized affording the title compound as the corresponding TFA salt. Yield: 82.7mg (69%). ¹HNMR (600 MHz, METHANOL-D₄): δ 1.50 - 1.65 (m, 4 H), 1.70 (s, 9 H)₃ 2.32 - 2.45 (m, 1 H), 3.18 (s, 3 H), 3.28 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.77 (s, 3 H), 3.92 - 4.02 (m, 2 H), 4.54 (d, J=7.42 Hz, 2 H), 7.34 (dd, J=8.96, 2.05 Hz, 1 H), 7.41 - 7.49 (m, 2 H), 7.55 (d, J=2.05 Hz, 1 H), 7.68 - 7.76 (m, 2 H), 7.90 (d, J=8.96 Hz, 1 H). MS (ESI) (M+H)⁺ = 544.0. Anal. Calcd for C₂₇H₃₇N₅O₅S+1.70 TFA+0.50 H₂O (746.54): C, 48.91; H, 5.36; N, 9.38; Found: C, 48.93; H, 5.31; N, 9.37.

Example 13

Λ^r-[2-terf-Butyl-l-(tetrahydro-2iϊ-pyran-4-ylmethyl)-liϊ-benzimidazol-5-yl]-4- {[(cyclobutylamino)carbonyl]amino}-iV-niethylbenzenesulfonamide

Following the procedure for step A in example 10, using a solution of iV-β-tert-butyl- l-^eiiahydro^H-pvran^-ylmemy^-lH-beiiziπ^ methylbenzenesulfonamide (0.14 mmol) in 10 mL of THF (see example 10 for preparation) and cyclobutylamine (19.4 mg, 0.27mmol) in THF (2 mL). The crude product was purified by MPLC using EtOAc eluted on silica gel to give 74.1 mg (99%) of a white solid as the title compound. ¹HNMR (600 MHz, METHANOL-D₄): δ 1.50 - 1.66 (m, 4 H), 1.70 (s, 9 H), 1.72 - 1.80 (m, 2 H), 1.89 - 2.01 (m, 2 H), 2.26 - 2.37 (m, 2 H), 2.36 - 2.46 (m, 1 H), 3.26 (s, 3 H)₃ 3.33 - 3.45 (m, 2 H), 3.90 - 4.03 (m, 2 H), 4.16 - 4.29 (m, 1 H), 4.55 (d, J=7.42 Hz, 2 H), 7.35 (dd, J=8.96, 1.79 Hz, 1 H), 7.40 (d, J=8.70 Hz, 2 H), 7.51 (d, J=8.96 Hz, 2 H), 7.55 (d, J=1.54 Hz, 1 H), 7.91 (d, 1=8.96 Hz, 1 H). MS (ESI) (M+H)⁺ = 554.0. Anal. Calcd for C₂₉H₃₉N₅O₄S+!.60 HCl+ 0.10 CH₃OH(615.27): C, 56.81; H, 6.72; N, 11.38; Found: C, 56.80; H, 6.74; N, 11.32.

Example 14 iV-[2-tert-Butyl-l-(tetrahydro-2jEr-pyran-4-ylmethyl)-liϊ-benzimidazoI-5-yl]-4-

{[(cyclopropylamino)carbonyl]amino}-iV-methylbenzenesulfonamide

Following the procedure for step A in example 10, using a solution of iV-[2-tert-butyl- l-(tetrahydro-2H-pyran-4-ylmethyl)-lH^'-benzimidazol-5-yl]-4-isocyanato-N- methylbenzenesulfonamide (0.14 mmol) in 10 mL of THF (see example 10 for preparation) and cyclopropylamine (15.5 mg, 0.27mmol) in THF (2 mL). The crude product was purified by MPLC using EtOAc eluted on silica gel to give 70.7 mg (98%) of a white solid as the title compound. ¹HNMR (600 MHz, METHANOL-D₄): δ 0.48 - 0.55 (m, 2 H), 0.70 - 0.81 (m, 2 H), 1.53 - 1.66 (m, 4 H), 1.71 (s, 9 H), 2.34 - 2.45 (m, 1 H), 2.57 - 2.64 (m, 1 H), 3.26 (s, 3 H), 3.35 - 3.42 (m, 2 H), 3.96 - 3.98 (m, 2 H), 4.56 (d, J=7.68 Hz, 2 H), 7.36 (dd, J=9.22, 2.05 Hz, 1 H), 7.39 - 7.45 (m, J=8.96 Hz, 2 H), 7.52 - 7.60 (m, 3 H), 7.92 (d, J=8.96 Hz, 1 H). MS (ESI) (M+H)⁺ = 540.0. Anal. Calcd for C₂₈H₃₇N₅O₄S+1.00 HCl+ 0.80 H₂CH-1.30 EtOAc(708.26): C, 56.26; H, 7.13; N, 9.88; Found: C, 56.30; H, 7.10; N, 9.92.

Claims

What is claimed is:

1. A compound of formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:

I wherein

R¹ and R² are independently selected from -H, hydroxy, C_1-4alkyl, C_1-4alkoxy, and hydroxy-C_1-4alkyl; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

2. A compound as claimed in claim 1, wherein

R¹ and R² are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R¹ and R² being different groups; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

3. A compound as claimed in claim 1, wherein

R¹ and R² are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R¹ and R² being different groups; and R³, R⁴ and R⁵ are independently selected from fluoro and methyl with R³, R⁴ and R⁵ being the same.

4. A compound as claimed in claim 1, wherein

R¹ and R² are independently selected from -H, hydroxy, methyl, ethyl, 2- hydroxylethyl, methoxy and t-butyl with R¹ and R² not being -H at the same time; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl. . A compound selected from

pharmaceutically acceptable salts thereof.

6. A compound of formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof: I wherein

R¹ and R² are independently selected from -H, hydroxy, C_1-4alkyl, C_{3- 6}cycloalkyl, C_1-4alkoxy, and hydroxy-C_1-4alkyl; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

7. A compound according to any one of claims 1-6 for use as a medicament.

8. The use of a compound according to any one of claims 1-6 in the manufacture of a medicament for the therapy of pain.

9. The use of a compound according to any one of claims 1-6 in the manufacture of a medicament for the treatment of anxiety disorders.

10. The use of a compound according to any one of claims 1-6 in the manufacture of a medicament for the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, gastrointestinal disorders and cardiovascular disorders.

11. A pharmaceutical composition comprising a compound according to any one of claims 1-6 and a pharmaceutically acceptable carrier.

12. A method for the therapy of pain in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-6.

13. A method for preparing a compound of Formula I, comprising:

reacting a compound of Formula II with a compound of formula III,

π_ in wherein

R¹ and R² are independently selected from -H, hydroxy, C_1-4alkyl, C_{3- 6}cycloalkyl, C_1-4alkoxy, and hydroxy-C_1-4alkyl; and

R³, R⁴ and R⁵ are independently selected from fluoro and methyl.

14. A mthod for preparing a compound of Formula I, comprising:

reacting a compound of Formula IV with triphosgene and an amine R₁(R₂)NH,

IV wherein

R¹ and R² are independently selected from -H, hydroxy, C^alkyl, C_{3- 6}cycloalkyl, C_1-4alkoxy, and hydroxy-C_1-4alkyl; and R³, R⁴ and R⁵ are independently selected from fluoro and methyl.