WO2006033630A1 - Compounds, compositions containing them, preparation thereof and uses thereof iii - Google Patents

Compounds, compositions containing them, preparation thereof and uses thereof iii Download PDF

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Publication number
WO2006033630A1
WO2006033630A1 PCT/SE2005/001402 SE2005001402W WO2006033630A1 WO 2006033630 A1 WO2006033630 A1 WO 2006033630A1 SE 2005001402 W SE2005001402 W SE 2005001402W WO 2006033630 A1 WO2006033630 A1 WO 2006033630A1
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Prior art keywords
methyl
butyl
tert
benzimidazol
compound
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PCT/SE2005/001402
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French (fr)
Inventor
Zhong-Yong Wei
Claire Milburn
Helene Desfosses
Daniel PAGÈ
Christopher Walpole
Hua Yang
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Astrazeneca Ab
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Priority claimed from PCT/GB2004/004124 external-priority patent/WO2005030732A1/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP05786563A priority Critical patent/EP1797078A4/en
Priority to BRPI0515890-7A priority patent/BRPI0515890A/en
Priority to MX2007003106A priority patent/MX2007003106A/en
Priority to AU2005287426A priority patent/AU2005287426A1/en
Priority to JP2007533432A priority patent/JP2008514592A/en
Priority to CA002582507A priority patent/CA2582507A1/en
Publication of WO2006033630A1 publication Critical patent/WO2006033630A1/en
Priority to IL181686A priority patent/IL181686A0/en
Priority to ZA200702047A priority patent/ZA200702047B/en
Priority to NO20072091A priority patent/NO20072091L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Compounds of Formula I, or pharmaceutically acceptable salts thereof: I (chemical formula to be inserted here - please see paper copy) wherein R1, R2, R3, R4, R5, R6 and G 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

Benzimidazole derivatives , compositions containing them, preparation thereof and uses thereof Ill
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 "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, C1-4alkyl 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 cycloalkyls include, but are not limited to, C3-7cycloalkyl 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:
Figure imgf000003_0001
wherein
R1 and R2 are each independently — H, C3-6CyClOaIlCyI, and C1-6alkyl, wherein said C3-6cycloalkyl and Ci-6alkyl used in defining R1 and R2 is optionally substituted by C1-6alkoxy, C3-6cycloalkyl, C6-10aryl, -C(=O)-)R7, C(=O)-NHR7, wherein R7 is selected from C1-6alkyl and C3-6cycloalkyl;
G is selected from -CH2-, -0-, -CHF-, and -CF2-;
R6 is selected from -H and methyl and R3, R4 and R5 are independently selected from fluoro and methyl.
In another embodiment, R1 and R2 of formula I are each independently C1- 4alkyl.
In another embodiment, R1 and R2 of formula I are independently selected from -H, methyl, ethyl, 2-methoxylethyl, benzyl, cyclopropylmethyl, isopropyl, butyl, isobutyl and propyl with a proviso that R1 and R2 are not both -H.
In another embodiment, G of formula I is selected from -O-, -CHF-, and -CF2-
In a further embodiment, G of formula I is selected from -CHF- and -CF2-.
In an even further embodiment, the invention provides a compound selected from: N- [2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N, N', N' - trimethylsulfamide ; N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H -benzimidazol-5-yl]-N',N'-diethyl- N- methylsulfamide; N- [2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N',N' - diethyl- N-methylsulfamide; N- [2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N',N' - bis(2-methoxyethyl)- N-methylsulfamide;
N-Butyl-N' -[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]- N,N'-dimethylsulfamide; N-[2-tert-Butyl-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N'- (cyclopropyhnethyl)-N,N'-dimeth ylsulfamide;
N-Benzyl-N'-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-N,N'-dimethylsulfamide; N' -Benzyl-N-[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-benzimidazol-5- yl]-N-methylsulfamide; N -[2-tert-Butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H-berizimidazol-5-yl]-N,N'- dimethylsulfamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N, N', N' - trimethylsulfamide;
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N, N', N' - trimethylsulfamide; N' -[2-tert-Butyl- 1 -(tetrahydro-2H -pyran-4-ylmethyl)- 1H-benzimidazol-5-yl]- N,N- dimethylsulfamide;
Methyl N- { [ {2-tert-butyl- 1 -[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol-5- yl} (methyl)amino]sulfonyl} - N-methylglycinate;
N2-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N 1-ethyl- N2-methylglycinamide; N2- {[ {2-tert-Butyl- 1 -[(4,4-difluorocyclohexyl)methyl]- 1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}- N1-cyclopropyl- N2-methylglycinamide; N- {2-tert-Butyl- 1 - [(4,4-difluorocyclohexyl)methyl] - 1H-benzimidazol-5-yl} - N-ethyl- N-methylsulfamide; N- [ 1 -(cyclohexylmethyl)-2-(l , 1 -difluoroethyl)- 1H-benzimidazol-5-yl]- N-isobutyl- N,N'-dimethylsulfamide; 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/?-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, cardioprotectioή following miocardial infarction, spinal injury and drag 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 construed 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, intracerebroventricularly 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:
Figure imgf000011_0001
reacting a compound of Formula II with a compound of formula III,
Figure imgf000011_0002
alternatively, reacting a compound of formula III with compound IV followed by reacting with TMSOTf and R2(R1)NH. wherein R1, R2, R3, R4, R5, R6 and G are as defined above.
Compounds of the present invention may also be prepared according to the synthetic routes as depicted in Schemes 1-4.
Figure imgf000012_0001
Figure imgf000013_0001
Biological Evaluation hCB1 and hCB2 receptor binding
Human CB1 receptor from Receptor Biology (h CB1) or human CB2 receptor from BioSignal (hCB2) membranes are thawed at 37 °C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 niM 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 hCB1 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 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid.
hCB1 and hCB2 GTPγS binding
Human CB1 receptor from Receptor Biology (hCB1) or human CB2 receptor membranes (BioSignal) are thawed at 37 °C, 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 Emax 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 (hCB1) Win 55,212-2 respectively. The membranes are pre-incubated for 5 minutes with 56.25 μM (hCB2) or 112.5 μM (hCB1) GDP prior to distribution in plates (15 μM (hCB2) or 30 μM ( hCB1) GDP final). The plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters 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/(1+[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 2.98 nM and 495 nM. ECso for these compounds are in the range of between 4.5 nM and 350 nM. Emax for these compounds are in the range of between 73% and 142%.
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 N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N, N', N' - trimethylsulf amide
Figure imgf000015_0001
Step A. N[2-tert-Butyl-1-(cyclohexylmethyl)-1H -benzimidazol-5-yl]-N, N', N' - trimethylsulfamide
Figure imgf000016_0001
2-tert-Butyl- 1 -(cyclohexylmethyl)- N-methyl- 1H-benzimidazol-5 -amine (40 mg, 0.133 mmol) (for preparation, see the following steps B, C, D, E and F) and dimethylsulfamoyl chloride (0.020 mL, 0.173 mmol) were stirred in 3 mL of dichloromethane containing a catalytic amount of DMAP overnight at rt. The solvent was evaporated. The product was purified by reversed-phase HPLC using 20-80% CH3CN/H2O and then lyophilized affording the title compound as the corresponding TFA salt. Yield: 36 mg (52%); 1H NMR (400 MHz, METHANOL-D4) δ 1.22 (m, 5H), 1.62 (m, 2H), 1.65 (s, 9H), 1.67 (m, 1H), 1.75 (m, 2H), 2.10 (m, 1H), 2.81 (s, 6H), 3.29 (s, 3H), 4.44 (d, J = 7.62 Hz, 2H), 7.64 (dd, J = 9.08, 2.05 Hz, 1H), 7.78 (d, J = 1.95 Hz, 1H), 7.90 (d, J = 8.98 Hz, 1H); MS (ESI) (M+H)+ 407.3; Anal. Calcd for C21H34N4O2S + 1.3 TFA + 0.3 H2O: C, 50.60; H, 6.46; N, 10.00. Found: C, 50.64; H, 6.47; N, 10.15.
Step B. Methyl (4-fluoro-3-nitrophenyl)carbamate
Figure imgf000016_0002
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%); 1HNMR (400 MHz, CHLOROFORM-D) δ 3.81 (s, 3H), 7.02 (s, 1H), 7.23 (m, 1H), 7.72 (d, J = 8.59 Hz, 1H), 8.17 (dd, J = 6.35, 2.64 Hz, 1H).
Step C. Methyl {4-[(cyclohexylmethyl)amino]-3-nitrophenyl}carbamate
Figure imgf000017_0001
Methyl (4-fluoro-3-nitrophenyl)carbamate (1.00 g, 4.67 mmol) and cyclohexylmethyl amine (0.730 mL, 5.60 mmol) were stirred in EtOH (20 mL) containing TEA (1.0 mL, 7.00 mmol) at 75°C for 24h. The solvent was concentrated. The residue was dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 4:l/hex:EtOAc on silica gel. Yield: 1.05 g (73%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.04 (ddd, J = 24.02, 12.11, 2.93 Hz, 2H), 1.25 (m, 3H), 1.69 (m, 2H), 1.76 (m, 1H), 1.79 (m, 1H), 1.83 (m, 1H), 1.86 (m, 1H), 3.14 (dd, J = 6.44, 5.66 Hz, 2H), 3.78 (s, 3H), 6.46 (m, 1H), 6.84 (d, J = 9.37 Hz, 1H), 7.63 (m, 1H), 8.05 (d, J = 2.54 Hz, 1H), 8.09 (m, 1H).
Step D. Methyl {3-amino-4-[(cyclohexylmethyl)amino]phenyl}carbamate
Figure imgf000017_0002
Methyl {4-[(cyclohexylmethyl)amino]-3-nitrophenyl} carbamate (1.05 g, 3.42 mmol) was dissolved in 30 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatus under H2 atmosphere (40 psi) at rt overnight. The solution was filtered through Celite and the solvent evaporated. The product was directly used for the next step without further purification. Yield: 950 mg (99%). MS (ESI) (M+H)+ 277.9.
Step E. Methyl [2-tert-butyl-l-(cyclohexylmethyl)-1H -benzimidazol-5- yl] carbamate
Figure imgf000018_0001
Methyl {3-amino-4-[(cyclohexylmethyl)amino]phenyl} carbamate (950 mg, 3.43 mmol) and DMAP (100 mg, 0.858 mmol) were dissolved in 25 mL of dichloromethane. Trimethylacetyl chloride (0.460 mL, 3.77 mmol) was added in dropwise and the solution was stirred at rt for Ih. The solvent was concentrated. The residue was divided in two portions and each of them was dissolved in 3 mL of glacial AcOH in a sealed tube. The solutions were heated at 150°C using a Personal Chemistry Smith Synthesizer microwave instrument for three intervals of 30 min (3 X 30 min). The contents of the two tubes were combined and the solvent was evaporated. The residue was dissolved in EtOAc and washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 3:l/dichloromethane:diethyl ether. Yield: 656 mg (56%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.08 (m, 2H), 1.18 (m, 3H), 1.54 (s, 9H), 1.65 (m, 1H), 1.69 (m, 2H), 1.73 (dd, J = 5.96, 3.22 Hz, 2H), 2.02 (m, 1H), 3.78 (s, 3H), 4.10 (d, J = 7.42 Hz, 2H), 6.64 (m, 1H), 7.25 (d, J = 8.79 Hz, 1H), 7.39 (m, 1H), 7.59 (d, J = 1.76 Hz, 1H).
Step F. 2-tert-Butyl-1-(cyclohexylmethyl)- N-methyl-1H-benzimidazol-5-amine
Figure imgf000018_0002
Methyl [2-tert-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]carbamate (650 mg, 1.89 mmol) was dissolved in 20 mL of THF at 0°C under nitrogen. IM HCl/ether (2.65 mL, 2.65 mmol) was added dropwise and the solution was stirred at 0°C for 15min. LiAlH4 (360 mg, 9.45 mmol) was then slowly added and the solution was stirred at rt overnight. The reaction mixture was quenched at 0°C by addition of MeOH (5 mL) followed by water (10 mL). The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The solvent was evaporated and the product was used directly for Step A without further purification. Yield: 544 mg (96%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.08 (s, 2H), 1.17 (m, 3H), 1.54 (s, 9H), 1.64 (m, 2H), 1.67 (m, 2H), 1.72 (m, 2H), 2.02 (m, 1H), 2.87 (s, 3H), 4.06 (d, J = 7.62 Hz, 2H), 6.60 (dd, J = 8.69, 2.25 Hz, 1H), 7.00 (d, J = 1.76 Hz, 1H), 7.12 (d, J = 8.59 Hz, 1H).
Example 2 N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N',N' -diethyl-N- methylsulfamide
Figure imgf000019_0001
A solution of diethylamine (0.103 mL, 1.00 mmol) in 1 mL dichloromethane and TEA (0.140 mL, 1.00 mmol) were added sequentially to a cold (0°C) solution of SO2Cl2 (0.160 mL, 2.00 mmol) in dichloromethane (1 mL) under a nitrogen atmosphere. The solution was then stirred at rt for 3h. The solution was washed with 5% KHSO4 solution, brine and dried over anhydrous MgSO4. The solvent was concentrated. The residue was then dissolved in 1 mL of dichloromethane, to which a solution of 2-tert-butyl- 1 -(cyclohexylmethyl)-N-methyl- 1H -benzimidazol-5-amine (25 mg, 0.0835 mmol, for preparation, see steps B to F in Example 1) and DMAP (catalytic) in 1 mL of dichloromethane was added dropwise. The solution was stirred at rt for 24h. The product was purified by reversed-phase HPLC using 30-80% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 15 mg (33%); 1H NMR (400 MHz, METHANOL-D4) δ 1.13 (t, J = 7.13Hz, 6H), 1.24 (m, 5H), 1.63 (m, 2H), 1.67 (s, 9H), 1.70 (m, 1H), 1.77 (m, 2H), 2.12 (m, 1H), 3.26 (s, 3H), 3.30 (m, 4H), 4.46 (d, J = 7.62Hz, 2H), 7.61 (dd, J = 8.98, 2.15Hz, 1H), 7.78 (d, J = 1.95 Hz, 1H), 7.89 (d, J = 8.98Hz, 1H); MS (ESI) (M+H)+ 435.2; Anal. Calcd for C23H38N4O2S + 1.2 TFA + 0.8 H2O: C, 52.07; H, 7.02; N, 9.56. Found: C, 52.00; H, 7.01; N, 9.55.
Example 3
N-[2-tert-Butyl-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H-benzimidazol-5-yl]- N',N' -diethyl- N-methylsulfamide
Figure imgf000020_0001
Step A: N-[2-tert-Butyl-1-(tetrahydro-1H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]-N',N' -diethyl- N-methylsulfainide
Figure imgf000020_0002
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-amine (46 mg, 0.153 mmol) (for preparation, see steps B to F) and (tert-butoxycarbonyl){[4- (dimethyliminio)pyridin-1(4H )-yl]sulfonyl}azanide (51 mg, 0.168 mmol) were stirred in 3 mL of DCE at 70°C for Ih. The solution was then passed through a plug of silica gel using EtOAc as eluent. The solvent was evaporated. The residue was dissolved in 3 mL of IM HCl/AcOH and the solution was stirred at rt for Ih. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was dissolved in 3 mL of DMF at 0°C and NaH (60% dispersion in oil) (18 mg, 0.459 mmol) was added. The solution was stirred at 0°C for 10 min. Iodoethane (0.060 mL, 0.765 mmol) was added and the solution was stirred at rt overnight. The reaction was quenched with MeOH at 0°C and the solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 32 mg (38%). 1H NMR (400 MHz, METHANOL-D4) δ 1.14 (t, J=7.13 Hz, 6 H), 1.52 - 1.57 (m, 2 H), 1.58 - 1.66 (m, 2 H), 1.69 (s, 9 H), 2.34 - 2.43 (m, 1 H), 3.26 (s, 3 H), 3.28 - 3.31 (m, 4 H), 3.35 (m, 2 H), 3.93 (d, J=3.12 Hz, 1 H), 3.95 (d, J=3.91 Hz, 1 H), 4.54 (d, J=7.62 Hz, 2 H), 7.64 (dd, J=8.98, 1.95 Hz, 1 H), 7.79 (d, J=I.95 Hz, 1 H), 7.95 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 437.0; Anal. Calcd for C22H36N4O3S + 1.3 TFA + 0.9 H2O: C, 49.16; H, 6.56; N, 9.32. Found: C, 49.05; H, 6.46; N, 9.50.
Step B: Methyl (4-fluoro-3-nitrophenyl)carbamate
Figure imgf000021_0001
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%). 1HNMR (400 MHz, CHLOROFORM-D) δ 3.81 (s, 3H), 7.02 (s, 1H), 7.23 (m, 1H), 7.72 (d, J = 8.59Hz, 1H), 8.17 (dd, J = 6.35, 2.64Hz, 1H).
Step C: Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl}carbamate
Figure imgf000021_0002
Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0g, 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 75°C for 48h. 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: 2.53g (88%). 1H NMR (400 MHz, CHLOROFORM-D) δ1.42 (m, 2 H), 1.73 (d, J=1.76 Hz, 1 H), 1.76 (d, J=1.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (m, 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-2H-pyran-4- ylmethyl)amino]phenyl}carbamate
Figure imgf000022_0001
Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate (2.53g, 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: 2.29g (99%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.40 (m, 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 (m, 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-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-yl] carbamate
Figure imgf000023_0001
Methyl {3-amino-4-[(tetrahydro-2H -pyran-4-ylmethyl)amino]phenyl} carbamate (2.29 g, 8.20 mmol) and DMAP (0.20g, 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 125°C 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: 1.81g (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=1.95 Hz, 1 H).
Step F: 2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H- benzimidazol-5-amine
Figure imgf000023_0002
Methyl [2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5- yl]carbamate (1.80g, 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 (1Og) 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).
Step G: (tert-Butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)- yl] sulfonyl} azanide
Figure imgf000024_0001
Chlorosulfonyl isocyanate (1.2 mL, 13.8 mmol) was added dropwise to a stirring DCM solution (10 mL) of t-butanol (1.3 mL, 13.8 mmol). DMAP (3.45g, 27.6 mmol) was added slowly and the solution was stirred at rt for 2h. The solution was diluted with DCM and washed with water (3X), brine and dried over anhydrous MgSO4. The solvent was evaporated. The product was recrystallized from acetonitrile. Yield (1.68g (40%). 1HNMR (400 MHz, DMSO-D6) δ 1.25 (s, 9 H), 3.21 (s, 6 H), 6.96 (d, J=8.20 Hz, 2 H), 8.45 (d, J=8.01 Hz, 2 H).
Example 4 N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]- N',N' -bis(2-methoxyethyl)- N-methylsulfamide
Figure imgf000024_0002
Following Step A in Example 3 using 2-tert-butyl-N-methyl-1-(tetrahydro-2H-pyran- 4-ylmethyl)-lH-benzimidazol-5-amine (60 mg, 0.199 mmol) and (tert- butoxycarbonyl) {[4-(dimethyliminio)pyridin-1(4H)-yl]sulfonyl}azanide (66 mg, 0.219 mmol) in 3 mL of DCE. 2-Bromoethyl methyl ether (0.056 mL, 0.597 mmol) and NaH (60% dispersion in oil) (25 mg, 0.597 mmol) in 5 mL of DMF were used in the subsequent step. The product was purified by reversed-phase HPLC using 10- 60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 39 mg (32%). 1H NMR (400 MHz, METHANOL-D4) δ 1.51 - 1.58 (m, 2 H), 1.59 - 1.66 (m, 2 H), 1.69 (s, 9 H), 2.35 - 2.43 (m, 1 H), 3.28 (s, 3 H), 3.31 - 3.39 (m, 8 H), 3.43 - 3.48 (m, 4 H), 3.50 - 3.54 (m, 4 H), 3.93 (d, J=3.12 Hz, 1 H), 3.96 (d, J=3.91 Hz, 1 H), 4.55 (d, J=7.42 Hz, 2 H), 7.67 (dd, J=8.98, 1.95 Hz, 1 H), 7.80 (d, J=I.76 Hz, 1 H), 7.97 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 497.0; Anal. Calcd for C24H40N4O5S + 2.2 TFA + 1.1 H2O: C, 44.45; H, 5.83; N, 7.29. Found: C, 44.56; H, 6.02; N, 6.89.
Example 5
N-Butyl-N'-[2-tert-butyl-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H-benzimidazol- 5-yl] -N,N' -dimethylsulfamide
Figure imgf000025_0001
2-tert-Butyl-N-methyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-benzimidazol-5 -amine (75 mg, 0.249 mmol) and (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)- yl]sulfonyl}azanide (82 mg, 0.274 mmol) were stirred in 3 mL of DCE at 70°C for Ih. The solution was then passed through a plug of silica gel using EtOAc as eluent. The solvent was concentrated. The residue was dissolved in 5 mL of DMF at 0°C and NaH (60% dispersion in oil) (15 mg, 0.373 mmol) was added followed by iodomethane (0.031 mL, 0.498 mmol). The solution was stirred at rt for 3h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at 0°C 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 concentrated. The residue was dissolved in 3 mL of IM HCl/AcOH and the solution was stirred at rt for Ih. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was dissolved in 5 mL of DMF at O°C and NaH (60% dispersion in oil) (15 mg, 0.373 mmol) was added. The solution was stirred at 0°C for 10 min. 1-iodobutane (0.085 mL, 0.747 mmol) was added and the solution was stirred at rt for 3h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at 0°C and the solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 58 mg (41%). 1H NMR (400 MHz, METHANOL-D4) δ 0.90 (t, J=7.32 Hz, 3 H), 1.28 (m, 2 H), 1.47 - 1.58 (m, 4 H), 1.58 - 1.67 (m, 2 H), 1.69 (s, 9 H), 2.34 - 2.44 (m, 1 H), 2.84 (s, 3 H), 3.14 - 3.19 (m, 2 H), 3.28 (s, 3 H), 3.35 (m, 2 H), 3.93 (d, J=3.32 Hz, 1 H), 3.96 (d, J=3.71 Hz, 1 H), 4.55 (d, J=7.62 Hz, 2 H), 7.67 (dd, J=9.08, 2.05 Hz, 1 H), 7.80 (d, J=I.76 Hz, 1 H), 7.97 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+451.0; Anal. Calcd for C23H38N4O3S + 1.9 TFA + 0.2 H2O: C, 47.98; H, 6.05; N, 8.35. Found: C, 47.98; H, 5.89; N, 8.62.
Example 6 iV-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-yImethyl)-1H-benzimidazol-5-yl]- N'-
(cyclopropylmethyl)-N,N' -dimethylsulfamide
Figure imgf000026_0001
2-tert-Butyl-N-methyl-1-(tetrahydro-2Η-pyran-4-yhnethyl)-1Η-benzimidazol-5-amine (65 mg, 0.216 mmol) and (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H )- yl]sulfonyl}azanide (71 mg, 0.238 mmol) were stirred in 3 mL of DCE at 70°C for 1h. The solution was then passed through a plug of silica gel using EtOAc as eluent. The solvent was concentrated. The residue was dissolved in 5 mL of DMF at 0°C and NaH (60% dispersion in oil) (13 mg, 0.324 mmol) was added followed by iodomethane (0.025 mL, 0.432 mmol). The solution was stirred at rt for 3h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at 0°C 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 concentrated. The residue was dissolved in 3 mL of IM HCl/ AcOH and the solution was stirred at rt for 1h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was dissolved in 5 mL of DMF at 0°C and NaH (60% dispersion in oil) (13 mg, 0.324 mmol) was added. The solution was stirred at 0°C for 10 min. Bromomethyl cyclopropane (0.031 mL, 0.324 mmol) was added and the solution was stirred at rt overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at 0°C and the solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by reversed-phase HPLC using 10- 60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 36 mg (30%). 1HNMR (400 MHz, METHANOL-D4) δ 0.17 - 0.23 (m, 2 H), 0.49 - 0.56 (m, 2 H), 0.91 - 1.01 (m, 1 H), 1.51 - 1.58 (m, 2 H), 1.59 - 1.66 (m, 2 H), 1.69 (s, 9 H), 2.34 - 2.43 (m, 1 H), 2.93 (s, 3 H), 3.05 (d, J=7.03 Hz, 2 H), 3.27 (s, 3 H), 3.35 (m, 2 H), 3.93 (d, J=3.12 Hz, 1 H), 3.95 (d, J=3.71 Hz, 1 H), 4.54 (d, J=7.42 Hz, 2 H), 7.65 (dd, J=8.98, 1.95 Hz, 1 H), 7.79 (d, J=1.95 Hz, 1 H), 7.95 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 449.0; Anal. Calcd for C23H36N4O3S + 1.3 TFA + 0.8 H2O: C, 50.30; H, 6.41; N, 9.17. Found: C, 50.37; H, 6.45; N, 9.01.
Example 7 iV-Benzyl-N'-[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H -benzimidazol-
5-yl]-N,N' -dimethylsulfamide
Figure imgf000028_0001
2-tert-Butyl-N-methyl- 1 -(tetrahy dro-2H-ρyran-4-ylmethyl)- 1 H-benzimidazol-5-amine (50 mg, 0.116 mmol) and (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)- yl]sulfonyl}azanide (60 mg, 0.199 mmol) were stirred in 3 mL of DCE at 70°C for Ih. The solution was then passed through a plug of silica gel using EtOAc as eluent. The solvent was concentrated. The residue was dissolved in 5 mL of DMF at 0°C and NaH (60% dispersion in oil) (10 mg, 0.249 mmol) was added followed by iodomethane (0.016 mL, 0.249 mmol). The solution was stirred at rt for Ih. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at 0°C 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 concentrated. The residue was dissolved in 3 mL of IM HCl/AcOH and the solution was stirred at rt for Ih. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was dissolved in 5 mL of DMF at 0°C and NaH (60% dispersion in oil) (10 mg, 0.249 mmol) was added. The solution was stirred at 0°C for 10 min. Benzyl bromide (0.030 mL, 0.249 mmol) was added and the solution was stirred at rt overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at 0°C and the solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 45 mg (45%). 1H NMR (400 MHz, METHANOL-D4) δ 1.53 - 1.59 (m, 2 H), 1.59 -. 1.67 (m, 2 H), 1.70 (s, 9 H, 2.36 - 2.44 (m, 1 H), 2.75 (s, 3 H), 3.36 (m, 2 H), 3.34 (s, 3 H), 3.93 (d, J=3.32 Hz, 1 H), 3.96 (d, J=3.71 Hz, 1 H), 4.32 (s, 2 H), 4.56 (d, J=7.42 Hz, 2 H), 7.24 - 7.32 (m, 5 H), 7.71 (dd, J=9.08, 2.05 Hz, 1 H), 7.83 (d, J=1.76 Hz, 1 H), 7.99 (d, J=9.18 Hz, 1 H); MS (ESI) (M+H)+ 485.2; Anal. Calcd for C26H36N4O3S + 1.9 TFA + 0.8 H2O: C, 50.01; H, 5.56; N, 7.83. Found: C, 50.05; H, 5.53; N, 7.86.
Example 8 N'-Benzyl- N-[2-tert-butyl-l-(tetrahydro-2H -pyran-4-ylmethyl)-1H -benzimidazol- 5-yl] -N-methylsulf amide
Figure imgf000029_0001
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-amine (50 mg, 0.166 mmol) and (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)- yl]sulfonyl}azanide (60 mg, 0.199 mmol) were stirred in 3 mL of DCE at 70°C for 1h. The solution was then passed through a plug of silica gel using EtOAc as eluent. The solvent was concentrated. The residue was dissolved in 3 mL of DMF at 0°C and NaH (60% dispersion in oil) (10 mg, 0.249 mmol) was added followed by benzyl bromide (0.030 mL, 0.249 mmol). The solution was stirred at rt overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at O°C 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 concentrated. The residue was dissolved in 3 mL of IM HCl/AcOH and the solution was stirred at rt for Ih. The solvent was evaporated. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 21 mg (22%). 1H NMR (400 MHz, METHANOL-D4) δ1.50 - 1.56 (m, 2 H), 1.57 - 1.62 (m, 2 H), 1.67 (s, 9 H), 2.33 - 2.41 (m, 1 H), 3.22 (s, 3 H), 3.34 (m, 2 H), 3.92 (d, J=3.12 Hz, 1 H), 3.95 (d, J=2.34 Hz, 1 H), 4.16 (s, 2 H), 4.51 (d, J=7.62 Hz, 2 H), 7.22 - 7.26 (m, 1 H), 7.27 (s, 3 H), 7.28 (br.s, 1 H), 7.57 (dd, J=8.98, 2.15 Hz, 1 H), 7.71 (d, J=2.15 Hz, 1 H), 7.87 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 471.0.
Example 9 N-[2-tert-Butyl-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H -benzimi dazol-5-yl]- N,N' -dimethylsulfamide
Figure imgf000030_0001
2-tert-Butyl-N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-amine (40 mg, 0.133 mmol) and (tert-butoxycarbonyl){[4-(dimethyliminio)pyridin-1(4H)- yl]sulfonyl}azanide (48 mg, 0.160 mmol) were stirred in 3 mL of DCE at 70°C for Ih. The solution was then passed through a plug of silica gel using EtOAc as eluent. The solvent was concentrated. The residue was dissolved in 3 mL of DMF at 0°C and NaH (60% dispersion in oil) (8 mg, 0.200 mmol) was added followed by iodomethane (0.012 mL, 0.200 mmol). The solution was stirred at rt for Ih. The reaction was quenched by the addition of saturated aqueous NH4Cl solution at 0°C 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 concentrated. The residue was dissolved in 3 mL of IM HCl/ AcOH and the solution was stirred at rt for Ih. The solvent was evaporated. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 20 mg (30%). 1H NMR (400 MHz, METHANOL-D4) δ 1.50 - 1.55 (m, 2 H), 1.57 - 1.63 (m, 2 H), 1.68 (s, 9 H), 2.34 - 2.41 (m, 1 H), 2.66 (s, 3 H), 3.27 (s, 3 H), 3.34 (m, 2 H), 3.92 (d, J=3.12 Hz, 1 H), 3.95 (d, J=3.71 Hz, 1 H), 4.53 (d, J=7.42 Hz, 2 H), 7.66 (dd, J=8.98, 1.95 Hz, 1 H), 7.78 (d, J=1.76 Hz, 1 H), 7.94 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 395.0; Anal. Calcd for C19H30N4O3S + 1.8 TFA + 0.6 H2O:C, 44.46; H, 5.45; N, 9.18. Found: C, 44.42; H, 5.46; N, 9.31.
Example 10 N-[2-tert-Butyl-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H-benzimidazol-5-yl]- N, N', N' -trimethylsulfamide
Figure imgf000031_0001
2-tert-Butyl-N-methyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- lH-benzimidazol-5-amine (32 mg, 0.106 mmol), DMAP (19 mg, 0.159 mmol) and dimethylsulfamoyl chloride (0.017 mL, 0.159 mmol) were stirred in 2 mL of DCE at 7O°C for 3h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 43 mg (78%). 1H NMR (400 MHz, METHANOL-D4) δ 1.52 - 1.58 (m, 2 H), 1.58 - 1.66 (m, 2 H), 1.69 (s, 9 H), 2.34 - 2.44 (m, 1 H), 2.84 (s, 6 H), 3.30 - 3.32 (s, 3 H), 3.36 (m, 2 H), 3.93 (d, J=2.93 Hz, 1 H), 3.96 (d, J=3.91 Hz, 1 H), 4.55 (d, J=7.62 Hz, 2 H), 7.68 (dd, J=9.08, 2.05 Hz, 1 H), 7.81 (d, J=1.76 Hz, 1 H), 7.97 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 409.0; Anal. Calcd for C20H32N4O3S + 1.4 TFA + 2.1 H2O: C, 45.19; H, 6.25; N3 9.24. Found: C, 45.16; H3 6.19; N3 9.19.
Example 11 N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol-5-yl}- N, N', N' -trimethylsuIfainide
Figure imgf000031_0002
Step A. N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol-5- yl}-N, N', N' -trimethylsulfamide
Figure imgf000032_0001
Methyl (3-amino-4- { [(4,4-difluorocyclohexyl)methyl]araino}phenyl)carbamate (for preparation, see the following steps B, C, D, E and F) (11 mg, 0.0290 mmol) was dissolve in 3 mL of THF at 0°C. IM HCl/ether (0.040 niL, 0.0406 mmol) was added and the solution was stirred at 0°C for 15 min. LiAlH4 (5 mg, 0.145 mmol) was adde and the solution was stirred at rt overnight. The reaction was quenched at 0°C by the addition of MeOH (1 mL) and water (1 mL) and then stirred at rt for 30 min. The solution was extracted with EtOAc (2X). The organic phase was washed with brine and dried over anhydrous MgSO4. The solvent was evaporated. The product was dissolved in 2 mL of DCE and DMAP (5 mg, 0.0435 mmol) followed by dimethylsulfamoyl chloride (0.005 mL, 0.0435 mmol) were added. The solution was stirred at 70°C for 3h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. 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: 5 mg (39%). 1HNMR (400 MHz, METHANOL-D4) δ 1.54 - 1.63 (m, 2 H), 1.68 (s, 9 H), 1.71 - 1.78 (m, 3 H), 1.78 - 1.85 (m, 1 H), 2.02 - 2.12 (m, 2 H), 2.20 - 2.32 (m, 1 H), 2.84 (s, 6 H), 3.31 (s, 3 H), 4.56 (d, J=7.62 Hz, 2 H), 7.67 (dd, J=8.98, 2.15 Hz, 1 H), 7.81 (d, J=I .56 Hz, 1 H), 7.95 (d, J=8.98 Hz, 1 H); (ESI) (M+H)+ 443.0.
Step B. tert-Butyl [(4,4-difluorocyclohexyl)methyl] carbamate
Figure imgf000032_0002
4-N-Boc-aminomethyl cyclohexanone (1.00g, 4.4 mmol) was dissolved in 30 mL of DCM at 0°C. DAST (1.45 mL, 11.0 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 3:1 / hexanes : EtOAc as eluent. Yield: 508mg (46%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.19 - 1.36 (m, 2 H), 1.44 (s, 9 H), 1.51 - 1.56 (m, 1 H), 1.59 - 1.75 (m, 2 H), 1.75 - 1.84 (m, 2 H), 2.01 - 2.16 (m, 2 H), 3.03 (t, J=6,54 Hz, 2 H), 4.62 (br.s, 1 H).
Step C. [(4,4-Difluorocyclohexyl)methyI] amine hydrochloride
Figure imgf000033_0001
tert-Butyl [(4,4-difluorocyclohexyl)methyl]carbamate (505 mg, 2.03 mmol) was stirred in 5 mL of IM HCl/ AcOH at rt for 2h. The solvent was evaporated. The residue was washed with ether, filtered and dried. Yield: 330 mg (88%). 1H NMR (400 MHz, METHANOL-D4) δ 1.28 - 1.40 (m, 2 H), 1.71 - 1.82 (m, 2 H), 1.84 (d, J=3.12 Hz, 2 H), 1.86 - 1.89 (m, 1 H), 2.03 - 2.15 (m, 2 H), 2.85 (d, J=7.03 Hz, 2 H).
Step D. Methyl (4-{[(4,4-difluorocyclohexyl)methyl]amino}-3- nitrophenyl)carbamate
Figure imgf000033_0002
Following the same procedure as in Step C of Example 1 using [(4,4- difluorocyclohexyl)methyl]amine hydrochloride (210 mg, 1.12 mmol), methyl (4- fluoro-3-nitrophenyl)carbamate (200 mg, 0.934 mmol) and TEA (0.390 mL, 2.80 mmol) in 10 mL of EtOH. The crude product was purified by silica gel flash chromatography using 5% ether/DCM as eluent. Yield: 200 mg (62%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.34 - 1.47 (m, 2 H), 1.65 - 1.75 (m, 2 H), 1.78 - 1.85 (m, 1 H), 1.90 - 1.93 (m, 1 H), 1.94 - 1.97 (m, 1 H), 2.10 - 2.21 (m, 2 H), 3.23 (dd, J=6.64, 5.66 Hz, 2 H), 3.78 (s, 3 H), 6.48 (br.s, 1 H), 6.83 (d, J=9.18 Hz, 1 H), 7.66 (br.s, 1 H), 8.05 (br.s, 1 H), 8.07 (d, J=2.54 Hz, 1 H).
Step E. Methyl (3-amino-4-{[(4,4- difluorocyclohexyl)methyl]amino}phenyl)carbamate
Figure imgf000034_0001
Following the same procedure as in Step D of Example 1 using methyl (4- {[(4,4- difluorocyclohexyl)methyl]amino}-3-nitrophenyl)carbamate (200 mg, 0.583 mmol) and a catalytic amount of 10% Pd/C in 20 mL of EtOAc. Yield: 185 mg (99%). MS (ESI) (M+H)+ 314.29.
Step F. Methyl {2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H- benzimidazol-5-yl} carbamate
Figure imgf000034_0002
Methyl (3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)carbamate (185 mg, 0.590 mmol) and DMAP (15 mg, 0.118 mmol) were dissolved in 10 mL of DCM. Trimethylacetyl chloride (0.080 mL, 0.649 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 solvent was concentrated. The residue was dissolved in 4 mL of DCE and P2O5 (catalytic) was added and the solution was heated at 125°C for Ih using a Personal Chemistry microwave apparatus. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 50 to 75% EtOAc / hexanes. Yield: 122 mg (54%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.43 - 1.52 (m, 2 H), 1.55 (s, 9 H), 1.57 - 1.66 (m, 2 H), 1.67 - 1.74 (m, 2 H), 2.08 - 2.18 (m, 3 H), 3.79 (s, 3 H), 4.19 (d, J=7.42 Hz, 2 H), 6.63 (br.s, 1 H), 7.23 (d, J=8.79 Hz, 1 H), 7.37 - 7.46 (m, 1 H), 7.62 (d, J=I.76 Hz, 1 H).
Example 12
Step A: N'-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H -benzim idazol-5- yl] - N,N-dimethylsulf amide
Figure imgf000035_0001
2-tert-Butyl- 1 -(tetrahydro-2H -pyran-4-ylmethyl)- 1H -benzimidazol-5-amine (for preparation see following Steps B, C, D, E and F) (30 mg, 0.104 mmol) and DMAP (13 mg, 0.104 mmol) were dissolved in 2 mL of DCE. Dimethylsulfamoyl chloride (0.035 mL, 0.312 mmol) was added and the solution was stirred at 70°C for 3h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by reversed-phase HPLC using 10-60% CH3CN/H2O and lyophilized affording the title compound as the corresponding TFA salt. Yield: 43 mg (81%); 1H NMR (400 MHz, METHANOL-D4) δ 1.50 - 1.55 (m, 2 H), 1.56 - 1.64 (m, 2 H), 1.66 (s, 9 H), 2.32 - 2.40 (m, 1 H), 2.80 (s, 6 H), 3.34 (m, 2 H), 3.92 (d, J=2.93 Hz, 1 H), 3.94 (d, J=3.91 Hz, 1 H), 4.50 (d, J=7.42 Hz, 2 H), 7.36 (dd, J=8.98, 2.15 Hz, 1 H), 7.68 (d, J=1.76 Hz, 1 H), 7.86 (d, J=9.18 Hz, 1 H); MS (ESI) (M+H)+ 395.0; Anal. Calcd for C19H30N4O3S + 1.7 TFA + 0.6 H2O: C, 44.90; H, 5.53; N, 9.50. Found: C, 44.80; H, 5.30; N, 9.87.
Step B. N-(4-Fluoro-3-nitrophenyI)acetamide
Figure imgf000036_0001
4-Fluoro-3-nitroaniline (5.0g, 32.0 mmol) was dissolved in 50 mL of DCM at 0°C containing TEA (6.7 mL, 48.0 mmol). Acetyl chloride (2.75 mL, 38.4 mmol) was added dropwise and the solution was stirred at rt overnight. The solution was washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was crystallized from DCM. Yield: 5.3g (84%). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.04 (s, 3 H), 7.51 (dd, J=11.23, 9.08 Hz, 1 H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).
Step C. N-{3-Nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} acetamide
Figure imgf000036_0002
N-(4-Fluoro-3-nitrophenyl)acetamide (500 mg, 2.52 mmol) and 4-aminomethyl tetrahydropyran (350 mg, 3.02 mmol) were stirred in 20 mL of EtOH containing TEA (0.525 mL, 3.78 mmol) at 75°C overnight. The solvent was concentrated. 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 EtOAc as eluent. Yield: 611 mg (83%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.42 (m, 2 H),
1.74 (m, 2 H), 1.89 - 2.00 (m, 1H), 2.18 (s, 3 H), 3.22 (dd, J=6.44, 5.66 Hz, 2 H), 3.42 (m, 2 H), 4.02 (m, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br.s, 1 H), 7.81 (dd, J=9.37, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 1 H), 8.10 - 8.12 (m, 1 H).
Step D. N-{3-Amino-4-[(tetrahydro-2H -pyran-4- ylraethyl)amino]phenyl} acetamide
Figure imgf000037_0001
N- {3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]plienyl} acetamide (605mg, 2.06 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: 315mg (58%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.40 (m, 2 H), 1.74 (m, 2 H), 1.82 - 1.91 (m, 1H), 2.13 (s, 3 H), 2.99 (d, J=6.64, 2 H), 3.42 (m, 2 H), 4.02 (m, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br.s, 1 H), 7.81 (dd, J=9.37, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 1 H), 8.10 - 8.12 (m, 1 H).
Step E. N-[2-tert-Butyl-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H -benzi midazol-5- yl] acetamide
Figure imgf000037_0002
N-{3-Amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (315 mg, 1.20 mmol) and DMAP (30 mg, 0.240 mmol) were dissolved in 20 mL of DCM. Trimethylacetyl chloride (0.160 mL, 1.32 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 3 mL of AcOH and was heated at 125°C 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 1:1 / hexanes : acetone as eluent. Yield: 135 mg (34%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.48 - 1.54 (m, 4 H), 1.56 (s, 9 H), 2.20 (s, 3 H), 2.24 - 2.35 (m, 1 H), 3.28 - 3.35 (m, 2 H), 3.96 (t, J= 2.83 Hz, 1 H), 3.99 (t, J= 3.03 Hz, 1 H), 4.19 (d, J=7.42 Hz, 2 H), 7.27 (d, J=8.59 Hz, 1 H), 7.34 (br.s, 1 H), 7.57 (dd, J=8.79, 1.95 Hz, 1 H), 7.67 (d, J=I.95 Hz, I H).
Step F. 2-tert-Butyl-1-(tetrahydro-2H-pyran-4-yImethyl)-1H-benzimidazol-5- amine
Figure imgf000038_0001
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmeth yl)-1H -benzimidazol-5-yl]acetamide (135 mg, 0.409 mmol) was dissolved in 4 mL of 1 : 1 / EtOΗ:2M HCl. The solution was heated at 120°C for 30 min using a Personal Chemistry microwave apparatus.
The solvent was evaporated. The residue was dissolved in EtOAc and washed with
2M NaOH solution, brine and dried over anhydrous MgSO4. The solvent was evaporated. Yield: 117 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.47 - 1.52 (m, 4 H), 1.54 (s, 9 H), 2.23 - 2.31 (m, 1 H), 3.28 - 3.36 (m, 2 H), 3.96 (m, 1
H), 3.97 - 4.00 (m, 1 H), 4.13 (d, J=7.62 Hz, 2 H), 6.66 (dd, J=8.40, 2.15 Hz, 1 H),
7.06 (d, J=2.15 Hz, 1 H), 7.10 (d, J=8.40 Hz, 1 H).
Example 13 Methyl N-{ [{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol-5- yl} (methyl)amino] sulfonyl}- N-methylglycinate
Figure imgf000038_0002
Step A. Methyl N-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H - benzimidazol-5-yl}(methyl)amino]sulfonyl}- N-methylglycinate
Figure imgf000039_0001
Sarcosine methyl ester hydrochloride (100 mg, 0.71 mmol) and Hunig's base (0.3 mL) were added to a solution of l-{[{2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]- 1H-benzimidazol-5-yl}(methyl)amino]sulfonyl}-3-methyl-1H -imidazol-3-ium triflate (crude product from Step B, 0.3 mmol) in MeCN. The reaction mixture was stirred for 12 hr at r.t, and then concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to provide methyl N-{[{2-tert-butyl-1- [(4,4-difluorocyclohexyl)methyl]- 1H-benzimidazol-5-yl} (methyl)amino]sulfonyl} -N- methylglycinate (85 mg, 57 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.56 (m, 2H), 1.67 (s, 9H), 1.75 (m, 4H), 2.04 (m, 2H), 2.26 (m, 1H), 2.93 (s, 3H), 3.29 (s, 3H), 3.71 (s, 3H), 4.01 (s, 2H), 4.55 (d, J = 7.4 Hz, 2H), 7.67 (d, J = 9.0 Hz, 1H), 7.82 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+500.8.
Step B. 1-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-3-methyl-1H -imidazol-3-ium triflate
Figure imgf000040_0001
3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (217 mg; 0.6 mmol) was added into a solution of 2-tert-butyl-1-[(4,4-difluorocycloliexyl)methyl]-iV- methyl-1H-benzimidazol-5-amine (100 mg, 0.3 mmol) (for preparation, see Example 11) in acetonitrile (10 mL). After being stirred at room temperature for 12 hr, the reaction mixture was treated with methyl trifluoromethanesulfonate (98 mg, 0.6 mmol) at r.t for 2 hr. The resulting MeCN solution of 1-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}(m ethyl)amino]sulfonyl}-3- methyl-1H-imidazol-3-ium triflate was then used in the Step A directly.
Example 14 N2-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol-5- yl} (methyl)amino] sulfonyl}-N1-ethyl-N2-methylglycinamide
Figure imgf000040_0002
Step A. N2-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol- 5-yl}(methyl)amino]sulfonyl}- N1-ethyl-N2-methylglycinamide
Figure imgf000041_0001
HATU (150 mg, 0.4 mmol) was added to a solution of N-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]- 1H-benzimidazol-5-yl} (methyl)amino]sulfonyl} -N- methylglycine (50 mg, 0.10 mmol), ethylamine hydrochloride (81 mg, 1.0 mmol) and DIPEA (0.2 mL) in DMF (1.5 mL) at r.t. After 1 hr, the reaction mixture was condensed to give a residue, which was purified by reverse phase HPLC to provide N2- {[ {2-tert-Butyl- 1 -[(4,4-difluorocyclohexyl)methyl]- 1H -benzimidazol-5- yl}(methyl)amino]sulfonyl}-N1-ethyl-N2-methylglycinamide (TFA salt, 48 mg, 75%). 1R NMR (400 MHz, CD3OD, TFA salt) δ 1.09 (t, J=7.4 Hz, 3H), 1.57 (m, 2H), 1.67 (s, 9H), 1.75 (m, 4H), 2.05 (m, 2H), 2.25 (m, 1H), 2.90 (s, 3H), 3.20 (q, J=7.4 Hz, 2H), 3.32 (s, 3H), 3.80 (s, 2H), 4.54 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), .7.85 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+513.7.
Step B: N-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol -5- yl} (methyl)amino] suIfonyl}- N-methylglycine
Figure imgf000041_0002
LiOH (120 mg, 5.0 mmol) was added to a solution of methyl N- {[ {2-tert-butyl-1- [(4,4-difluorocyclohexyl)methyl]- 1H -benzimidazol-5-yl} (methyl)amino]sulfonyl} -N- methylglycinate (80 mg, 0.16 mmol) in MeOH (6 mL) and H2O (2 mL) at r.t. The reaction mixture was stirred overnight, and then was neutralized to pH at 7.0 with hydrochloric acid. After removal of MeOH, the residue was extracted by CH2Cl2, washed with brine, and dried over Na2SO4. Removal of solvents provided N- {[ {2-tert- butyl-1-[(4,4-difluorocyclohexyl)methyl]~1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-iV-methylglycine (65 mg, 84 %), which was used in Step A without further purification.
Example 15 N2-{[{2-tert-ButyI-1-[(4,4-difluorocyclohexyl)methyl]-1H -benzimidazol-5- yl}(methyl)amino]sulfonyl}- N1cyclopropyl- N2-methylglycinainide
Figure imgf000042_0001
HATU (150 mg, 0.4 mmol) was added to a solution of JV-{[{2-tert-butyl-1-[(4,4- difluorocyclohexyl)methyl]- 1H -benzimidazol-5-yl} (methyl)amino]sulfonyl} -N- methylglycine (15 mg, 0.03 mmol), cyclopropylamine (57 mg, 1.0 mmol) and DIPEA (0.2 mL) in DMF (1.0 mL) at r.t. After 1 hr, the reaction mixture was condensed to give a residue, which was purified by reverse phase HPLC to provide N2-{[{2-tert- butyl- 1 - [(4,4-difluorocyclohexyl)methyl]- 1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}-N1-cyclopropyl-N2-methylglycinamide (TFA salt, 6 mg, 31 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 0.46 (m, 2H), 0.70 (m, 2H), 1.59 (m, 2H), 1.67 (s, 9H), 1.75 (m, 4H), 2.05 (m, 2H), 2.25 (m, 1H), 2.64 (m, 1H), 2.89 (s, 3H), 3.32 (s, 3H), 3.80 (s, 2H), 4.54 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.86 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+525.8.
Example 16
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N'- ethyl-N -methylsulfamide
Figure imgf000043_0001
Step A. N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-lH-benzimidazol-5- yl}-N' -ethyl- N-methylsulfamide
Figure imgf000043_0002
N-Ethyl-1,1,1-trimethylsilanamine (from Step B, 1.0 mmol) and Hunig's base (0.3 mL) were added to the solution of 1-{[{2-tert-butyl-1-[(4,4- difiuorocyclohexyl)methyl]- 1H -benzimidazol-5-yl} (methyl)amino] sulfonyl} -3 - methyl- 1H-imidazol-3-ium triflate (64 mg, 0.1 mmol) in MeCN. The reaction mixture was stirred for 12 hr at r.t, and then concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to provide N-{2-tert-butyl- 1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}-N' -ethyl- N- methylsulfamide (4 mg, 7 %). 1H NMR (400 MHz, CD3OD, TFA salt) δ 1.13 (t, J=7.2 Hz, 3H), 1.55 (m, 2H), 1.67 (s, 9H), 1.75 (m, 4H), 2.05 (m, 2H), 2.25 (m, 1H),3.O4 (q, J=7.2 Hz, 2H), 3.33 (s, 3H), 4.55 (d, J = 7.4 Hz, 2H), 7.65 (d, J = 9.0 Hz, 1H), 7.78 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H); MS (ESI) (M+H)+443.0.
Step B: N-Ethyl-1,1,1-trimethylsilanamine
Figure imgf000043_0003
Trimethylsilyl chloride (109 mg, 1.0 mmol) was added to a solution of ethylamine (45 mg, 1.0 mmol) and Hunig's base (0.3 mL) in THF at 0°C. The reaction mixture was stirred for 1 hr at r.t., and was used in Step A directly.

Claims

What is claimed is:
1. A compound of formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000044_0001
wherein
R1 and R2 are each independently -H, C3-6CyClOaIlCyI, and C1-6alkyl, wherein said C3-6cycloalkyl and C1-6alkyl used in defining R1 and R2 is optionally substituted by C1-6alkoxy, C3-6cycloalkyl, C6-10aryl -C(=O)-)R7, C(=O)-NHR7, wherein R7 is selected from C1-6alkyl and C3-6cycloalkyl;
G is selected from -CH2-, -O-, -CHF-, and -CF2-;
R6 is selected from -H and methyl 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 each independently C1-4alkyl.
3. A compound as claimed in claim 1, wherein
R1 and R2 are independently selected from -H, methyl, ethyl, 2-methoxylethyl, benzyl, cyclopropylmethyl, isopropyl, butyl, isobutyl and propyl with a proviso that R1 and R2 are not both -H.
4. A compound as claimed in claim 1, wherein G is selected from -O-, -CHF-, and -CF2-.
5. A compound as claimed in claim 1 , wherein G is selected from -CHF- and -CF2-.
6. A compound selected from:
N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]- N, N', N'- trimethylsulfamide; N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N',N'-diethyl- N- methylsulfamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H -benzimidazol-5-yl]- N',N'- diethyl-N-methylsulfamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N',N' - bis(2-methoxyethyl)-N-methylsulfamide;
N-Butyl-N' -[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]- N',N'-dimethylsulfamide; N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H -benzimidazol-5-yl]- N'-
(cyclopropylmethyl)-N',N'-dimethylsulfamide; N-Benzyl-N' -[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H -benzimidazol-5- yl]-N',N'-dimethylsulfamide; N' -Benzyl-N-[2-tert-butyl- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1H -benzimidazol-5- yl] - N-methylsulfamide;
N-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H -benzimidazol-5-yl]-N',N'- dimethylsulfamide;
N-[2-tert-Butyl-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N',N' - trimethylsulfamide;
N- {2-tert-Butyl- 1 -[(4,4-difluorocyclohexyl)methyl] - 1H -benzimidazol-5-yl} -N, N', N' - trimethylsulfamide; N'-[2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]-N,N- dimethylsulf amide;
Methyl N- { [ {2-tert-butyl- 1 -[(4,4-difluorocyclohexyl)methyl]- 1H-benzimidazol-5- yl} (methyl)amino]sulfonyl} - N-methylglycinate;
N2-{[{2-tert-Butyl-1-[(4,4-difluorocycloliexyl)methyl]-1H-benzimidazol-5- yl} (methyl)amino] sulfonyl} -N1 -ethyl- N2-methylglycinamide; N2-{[{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5- yl}(methyl)amino]sulfonyl}- N'-cyclopropyl-N2-methylglycinamide; N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}- N'-ethyl- N-methylsulfamide; and pharmaceutically acceptable salts thereof.
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:
Figure imgf000046_0001
I reacting a compound of Formula II with a compound of formula III,
Figure imgf000047_0001
alternatively, reacting a compound of formula III with compound IV followed by reacting with TMSOTf and R2(R1)NH. wherein
R and R are each independently -H, C3-6cycloalkyl, and C1-6alkyl, wherein said C3-6cycloalkyl and C1-6alkyl used in defining R1 and R2 is optionally substituted by C1-6alkoxy, C3-6CycloalkyI, C6-10aryl, -C(=O)-)R7, C(=O)-NHR7, wherein R7 is selected from C1-6alkyl and C3-6cycloalkyl; G is selected from -CH2-, -0-, -CHF-, and -CF2-;
R6 is selected from -H and methyl and
R3, R4 and R5 are independently selected from fluoro and methyl..
PCT/SE2005/001402 2004-09-24 2005-09-22 Compounds, compositions containing them, preparation thereof and uses thereof iii WO2006033630A1 (en)

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