WO2020115045A1

WO2020115045A1 - Substituted 1h-benzo[d]imidazole derivatives having multimodal activity against pain and pain related conditions

Info

Publication number: WO2020115045A1
Application number: PCT/EP2019/083499
Authority: WO
Inventors: Carmen ALMANSA-ROSALES; Susana Yenes-Minguez
Original assignee: Esteve Pharmaceuticals, S.A.
Priority date: 2018-12-05
Filing date: 2019-12-03
Publication date: 2020-06-11

Abstract

The present invention relates to new compounds that show pharmacological activity towards the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ- 1 subunit of voltage-gated calcium channels or dual activity towards the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels, and the μ-opiod receptor (MOR or mu-opioid). The invention is also related to the process for the preparation of said compounds as well as to compositions comprising them, and to their use as medicaments.

Description

SUBSTITUTED 1 H-BENZOrD1IMIDAZOLE DERIVATIVES HAVING MULTIMODAL

ACTIVITY AGAINST PAIN AND PAIN RELATED CONDITIONS

FIELD OF THE INVENTION

The present invention relates to new compounds that show pharmacological activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d- 1 subunit of voltage-gated calcium channels or dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage-gated calcium channels, and the m-opiod receptor (MOR or mu-opioid receptor).

More particularly, the present invention relates to substituted substituted 1 H- benzo[c/]imidazole derivatives having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain and pain related conditions.

BACKGROUND OF THE INVENTION

The adequate management of pain constitutes an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved (Turk, D.C., Wilson, H.D., Cahana, A.; 201 1 ; Lancet, 377; 2226- 2235). Pain affects a big portion of the population with an estimated prevalence of 20 % and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which lead to important productivity losses and socio- economical burden (Goldberg, D.S., McGee, S.J.; 201 1 ; BMC Public Health ; 1 1 ; 770). Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.

Voltage-gated calcium channels (VGCC) are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et a/., Pharmacol. Rev. 2015 67:821 -70). The VGCC are assembled through interactions of different subunits, namely oti (Ca_vai), b (Ca_vp) a₂d (Ca_vot₂6) and g (Ca_vy). The oti subunits are the key porous forming units of the channel complex, being responsible for the Ca²⁺ conduction and generation of Ca²⁺ influx. The a,₂d, b, and g subunits are auxiliary, although very important for the regulation of the channel, since they increase the expression of the oti subunits in the plasma membrane as well as modulate their function, resulting in functional diversity in different cell types. Based on their physiological and pharmacological properties, VGCC can be subdivided into low voltage- activated T-type (Ca_v3.1 , Ca_v3.2, and Ca_v3.3), and high voltage-activated L- (Ca_v1 .1 through Ca_v1 .4), N-(Ca_v2.2), P/Q-(Ca_v2.1 ), and R-(Ca_v2.3) types, depending on the channel forming Cava subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1 ) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo, Neurotherapeutics. 2009 6:679-92; Zamponi et al., 2015 supra ; Neumaier etal., Prog. Neurobiol. 2015 129:1 -36.). A large body of data has clearly indicated that VGCC are implicated in mediating various disease states including pain processing. Drugs interacting with the different calcium channel subtypes and subunits have been developed. Current therapeutic agents include drugs targeting L-type Ca_v1 .2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca_v3) channels are the target of ethosuximide, widely used in absence epilepsy. Ziconotide, a peptide blocker of N-type (Ca_v2.2) calcium channels, has been approved as a treatment of intractable pain. (Perret and Luo, 2009, supra, Vink and Alewood, Br J Pharmacol. 2012 167:970-89.).

The Ca_v1 and Ca_v2 subfamilies contain an auxiliary a₂d subunit, which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain. To date, there are four known a₂d subunits, each encoded by a unique gene and all possessing splice variants. Each a₂d protein is encoded by a single messenger RNA and is posttranslationally cleaved and then linked by disulfide bonds. Four genes encoding a₂d subunits have now been cloned. a₂d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution. The a₂d-2 and a₂d-3 subunits were subsequently cloned from brain. The most recently identified subunit, a₂d-4, is largely nonneuronal. The human a₂d-4 protein sequence shares 30, 32 and 61 % identity with the human a₂d-1 , a₂d-2 and a₂d-3 subunits, respectively. The gene structure of all a₂d subunits is similar. All a₂d subunits show several splice variants (Davies et al., Trends Pharmacol Sci. 2007 28:220-8.; Dolphin AC, Nat Rev Neurosci. 2012 13:542-55., Biochim Biophys Acta. 2013 1828:1541 -9.).

The Ca_va₂6-1 subunit may play an important role in neuropathic pain development (Perret and Luo, 2009, supra ; Vink and Alewood, 2012, supra). Biochemical data have indicated a significant Ca_va₂6-1 , but not Ca_va₂6-2, subunit upregulation in the spinal dorsal horn, and DRG (dorsal root ganglia) after nerve injury that correlates with neuropathic pain development. In addition, blocking axonal transport of injury-induced DRG Ca_vot₂5-1 subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Ca_vot₂5-1 subunit contributes to neuropathic allodynia.

The Ca_vot₂5-1 subunit (and the Ca_vot₂5-2, but not Ca_vot₂5-3 and Ca_vot₂5-4, subunits) is the binding site for gabapentin which has anti-allodynic/ hyperalgesic properties in patients and animal models. Because injury-induced Ca_vot₂5-1 expression correlates with neuropathic pain development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability, injury-induced Ca_vot₂5-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn. Intrathecal antisense oligonucleotides against the Ca_vot₂5-1 subunit can block nerve injury-induced Ca_vot₂5-1 upregulation and prevent the onset of allodynia and reserve established allodynia.

As mentioned above, the a,2d subunits of VGCC form the binding site for gabapentin and pregabalin, which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations. The binding of gabapentin and pregabalin to the Ca_vot₂5 subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management. Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009, supra, Vink and Alewood, 2012, supra, Zamponi et al., 2015, supra).

Thus, the present invention relates to compounds with inhibitory effect towards a2d subunits of voltage-gated calcium channels, preferably towards the a2d-1 subunit of voltage-gated calcium channels.

As mentioned before, there are few available therapeutic classes for the treatment of pain, and opioids are among the most effective, especially when addressing severe pain states. They act through three different types of opioid receptors (mu, kappa and gamma) which are transmembrane G-protein coupled receptors (GPCRs). Still, the main analgesic action is attributed to the activation of the m-opioid receptor (MOR). However, the general administration of MOR agonists is limited due to their important side effects, such as constipation, respiratory depression, tolerance, emesis and physical dependence [Meldrum, M.L. (Ed.)· Opioids and Pain Relief: A Historical Perspective. Progress in Pain Research and Management, Vol 25. IASP Press, Seattle, 2003]. Additionally, MOR agonists are not optimal for the treatment of chronic pain as indicated by the diminished effectiveness of morphine against chronic pain conditions. This is especially proven for the chronic pain conditions of neuropathic or inflammatory origin, in comparison to its high potency against acute pain. The finding that chronic pain can lead to MOR down-regulation may offer a molecular basis for the relative lack of efficacy of morphine in long-term treatment settings [Dickenson, A.H., Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur J Pain 9, 1 13-6 (2005)]. Moreover, prolonged treatment with morphine may result in tolerance to its analgesic effects, most likely due to treatment-induced MOR down-regulation, internalization and other regulatory mechanisms. As a consequence, long-term treatment can result in substantial increases in dosing in order to maintain a clinically satisfactory pain relief, but the narrow therapeutic window of MOR agonists finally results in unacceptable side effects and poor patient compliance.

Polypharmacology is a phenomenon in which a drug binds multiple rather than a single target with significant affinity. The effect of polypharmacology on therapy can be positive (effective therapy) and/or negative (side effects). Positive and/or negative effects can be caused by binding to the same or different subsets of targets; binding to some targets may have no effect. Multi-component drugs or multi-targeting drugs can overcome toxicity and other side effects associated with high doses of single drugs by countering biological compensation, allowing reduced dosage of each compound or accessing context-specific multitarget mechanisms. Because multitarget mechanisms require their targets to be available for coordinated action, one would expect synergies to occur in a narrower range of cellular phenotypes given differential expression of the drug targets than would the activities of single agents. In fact, it has been experimentally demonstrated that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities, such selectivity is achieved through differential expression of the drugs’ targets in cell types associated with therapeutic, but not toxic, effects (Lehar et al., Nat Biotechnol 2009; 27: 659-666).

In the case of chronic pain, which is a multifactorial disease, multi-targeting drugs may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive pain. Because they actually make use of biological complexity, multi targeting (or multi-component drugs) approaches are among the most promising avenues toward treating multifactorial diseases such as pain (Gilron et al., Lancet Neurol. 2013 Nov;12(1 1 ):1084-95.). In fact, positive synergistic interaction for several compounds, including analgesics, has been described (Schroder et al., J Pharmacol Exp Ther. 201 1 ; 337:312-20. Erratum in: J Pharmacol Exp Ther. 2012; 342:232; Zhang et al., Cell Death Dis. 2014; 5:e1 138.; Gilron et al., 2013, supra).

Given the significant differences in pharmacokinetics, metabolisms and bioavailability, reformulation of drug combinations (multi-component drugs) is challenging. Further, two drugs that are generally safe when dosed individually cannot be assumed to be safe in combination. In addition to the possibility of adverse drug-drug interactions, if the theory of network pharmacology indicates that an effect on phenotype may derive from hitting multiple targets, then that combined phenotypic perturbation may be efficacious or deleterious. The major challenge to both drug combination strategies is the regulatory requirement for each individual drug to be shown to be safe as an individual agent and in combination (Hopkins, Nat Chem Biol. 2008; 4:682-90.).

An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008, supra).

Thus, the present application further relates to the advantages of having dual activity, for m-receptor and the a,₂d-1 subunit of voltage-gated calcium channels, in the same molecule to treat chronic pain.

In this way, the present invention further relates to compounds having a complementary dual mechanism of action (m-receptor agonist and blocker of the a,₂d subunit, in particular the a,₂d-1 subunit, of voltage-gated calcium channels) which implies a better profile of tolerability than the strong opioids (morphine, oxycodone, fentanyl etc) and/or better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin). Pain is multimodal in nature, since in nearly all pain states several mediators, signaling pathways and molecular mechanisms are implicated. Consequently, monomodal therapies fail to provide complete pain relief. Currently, combining existing therapies is a common clinical practice and many efforts are directed to assess the best combination of available drugs in clinical studies (Mao, J., Gold, M.S., Backonja, M.; 201 1 ; J. Pain; 12; 157-166).

Accordingly, there is still a need to find compounds that have an alternative or improved pharmacological activity in the treatment of pain, being both effective and showing the desired selectivity, and having good“drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion.

Thus, in a preferred embodiment, the compounds of the present invention having affinity for the a2d subunits of voltage-gated calcium channels, preferably towards the a2d-1 subunit of voltage-gated calcium channels, additionally have affinity towards the m- receptor and are, thus, more effective to treat chronic pain.

The inventors have found a serie of compounds that show a primary pharmacological activity towards the a,₂d subunit, in particular the a,₂d-1 subunit, of the voltage-gated calcium channel, and compounds that show dual pharmacological activity towards both the a,₂d subunit, in particular the a,₂d-1 subunit, of the voltage-gated calcium channel and the m-opioid receptor resulting in an innovative, effective, complementary and alternative solution for the treatment of pain.

In view of the existing results of the currently available therapies and clinical practices, the present invention offers a solution by developing compounds binding to a single target or by combining in a single compound binding to two different targets relevant for the treatment of pain. This was mainly achieved by providing the compounds according to the invention that bind to the a,₂d subunit, in particular the a,₂d-1 subunit, of the voltage gated calcium channel, or both to the the m-opioid receptor and to the a,₂d subunit, in particular the a,₂d-1 subunit, of the voltage-gated calcium channel.

SUMMARY OF THE INVENTION

The present invention discloses novel compounds with pharmacological activity to the a2d subunit of voltage-gated calcium channels, more specifically to the a2d-1 subunit, and which in preferred embodiments, have also affinity towards the m-opioid receptor, thus resulting in a dual activity for treating pain and pain related disorders.

The main aspect of the present invention is related to compounds of general formula (I):

A further aspect of the invention refers to the processes for preparation of compounds of formula (I).

A still further aspect of the invention refers to the use of intermediate compounds for the preparation of a compound of formula (I).

It is also an aspect of the invention a pharmaceutical composition comprising a compound of formula (I).

Finally, it is an aspect of the invention a compound of formula (I) for use in therapy and more particularly for the treatment of pain and pain related conditions.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a family of compounds, in particular, to substituted 1 H- benzo[c/]imidazole derivatives which show primary pharmacological activity towards the a,₂d subunit, in particular the a,₂d-1 subunit, of the voltage-gated calcium channel. The invention also refers to compounds having a dual pharmacological activity towards both the a,₂d subunit, in particular the a,₂d-1 subunit, of the voltage-gated calcium channel and the m-opioid receptor and to their use in the treatment of pain and related disorders. The applicant has surprisingly found that the problem of providing a new effective and alternative solution for treating pain and pain related disorders can be solved by using an analgesic approach using compounds binding to the 0,₂6 subunit, in particular the 0,₂6- 1 subunit, of the voltage-gated calcium channel or a multimodal analgesic approach combining two activities in a single drug (i.e., dual ligands which are bifunctional and bind to m-opioid receptor and to 01₂6 subunit, in particular the a₂d-1 subunit, of the voltage gated calcium channel).

As described above, the m-opioid receptor as well as the a2d1 subunit modulate intracellular calcium concentration and the activity of voltage-dependent calcium channels. There is also a robust clinical and pre-clinical evidence linking both targets with the treatment of chronic neuropathic pain. Thus, the present invention, also relates to the advantages of having dual activity, for the a,₂d-1 subunit of voltage-gated calcium channels and the m-opioid receptor, in the same molecule to treat pain. This supports the therapeutic value of a dual agent, whereby the a2d binding component acts as an intrinsic adjuvant of the MOR binding component.

A dual compound that possesses binding to both the m-opioid receptor and to the a2d subunit of the voltage-gated calcium channel shows a highly valuable therapeutic potential by achieving an outstanding analgesia (enhanced in respect to the potency of the opioid component alone) with a reduced side-effect profile (safety margin increased compared to that of the opioid component alone) versus existing opioid therapies.

Advantageously, the dual compounds according to the present invention would in addition show one or more the following functionalities: blockade of the a2d subunit, in particular the a2d-1 subunit, of the voltage-gated calcium channel and m-opioid receptor agonism.

A further advantage of using designed multiple ligands is a lower risk of drug-drug interactions compared to cocktails or multi-component drugs, thus involving simpler pharmacokinetics and less variability among patients. Additionally, this approach may improve patient compliance and broaden the therapeutic application in relation to monomechanistic drugs, by addressing more complex aetiologies.

In a first aspect, the present invention is directed to a compound of formula (I):

wherein

RI is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and a group of the following formula (A):

wherein

Wi is carbon or nitrogen;

R₇ and R_7' are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and Re is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and ORs·, wherein

Re’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

Rr is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₂ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₃ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl; and substituted or unsubstituted heterocyclyl, wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, and substituted or unsubstituted heterocyclyl;

R₄ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₅, R_5’, R_5” and R_5” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C₁-6 alkyl, substituted or unsubstituted C₂-6 alkenyl and substituted or unsubstituted C₂-6 alkynyl; alternatively, R₅ and R₅· and/or R_{5 "} and Rs- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl;

X is selected from the group consisting of a bond, [Chhjp- and NRe; wherein p is 0, 1 or 2; and

R₆ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, and [CH2]_qNR6'R6”; wherein Re· and R_6” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; and

q is 1 , 2 or 3; m is 1 or 2; n is 1 or 2; and wherein when one of Ri or Rr is halogen and the other is hydrogen, m is 1 and n is 1 , then at least one of R_5, Rs·_, Rs- and R₅ is a substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

The compounds of the invention represented by the above described formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds. The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

For the sake of clarity the expression“a compound according to formula (I), wherein Ri, Rr, R2, R3, R4, Rs, Rs’, Rs”, Rs’”, R6, Re·, Re·, R7, Rr, Re, Re’, X, A, n, m, p, q, W and Wi are as defined herein in the detailed description” would (just like the expression “a compound of formula (I) as defined in any one of claims 1 to 7 found in the claims) refer to “a compound according to formula (I)”, wherein the definitions of the respective substituents Ri etc. (also from the cited claims) are applied.

For clarity purposes, all groups and definitions described in the present specification and referring to compounds of formula (I), also apply to all intermediates of synthesis.

In the context of this invention, alkyl is understood as meaning a straight or branched hydrocarbon chain radical containing no unsaturation, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses e.g. -CH3 and -CH2-CH3. In these radicals, C-i-2-alkyl represents C1 - or C2-alkyl, Ci-3-alkyl represents C1 -, C2- or C3-alkyl, Ci-4-alkyl represents C1 -, C2- , C3- or C4-alkyl, Ci-5-alkyl represents C1 -, C2-, C3-, C4-, or C5-alkyl and Ci-₆-alkyl represents C1 -, C2-, C3-, C4-, C5- or C6-alkyl. Examples of alkyl radicals include among others methyl, ethyl, propyl, methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1 - dimethylethyl, pentyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1 -methylpentyl. If substituted by cycloalkyl, it corresponds to a“cycloalkylalkyl” radical, such as cyclopropylmethyl. If substituted by aryl, it corresponds to an "arylalkyl" radical, such as benzyl, benzhydryl or phenethyl. If substituted by heterocyclyl, it corresponds to a“heterocyclylalkyl” radical. Preferably alkyl is understood in the context of this invention Ci-₆-alkyl like methyl, ethyl, propyl, butyl, pentyl, or hexyl; and more preferably is C1-4- alkyl like methyl, ethyl, propyl or butyl.

Alkenyl is understood as meaning straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one unsaturation, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -CH=CH-CH₃. The alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in the context of this invention alkenyl is C2-6-alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C2-4-alkenyl, like ethylene, propylene, or butylenes.

Alkynyl is understood as meaning a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one carbon-carbon triple bond, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -C^C-CHs (1 - propynyl). Preferably alkynyl in the context of this invention is C2-6-alkynyl like ethyne, propyne, butyne, pentyne, or hexyne; or is C2-4-alkynyl like ethyne, propyne or butyne.

In connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl and O-alkyl - unless defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen, -OR’, -SR’, -SOR’, -SO2R’, , -CN, -COR’, -COOR’, -NR’R”, - CONR’R”, haloalkyl, haloalkoxy or -OC1-6 alkyl wherein each of the R’ and R” groups is independently selected from the group consisting of hydrogen, OH, NO2, NH2, SH, CN, halogen, -COH, -C(0)-alkyl, -COOH and C1-6 alkyl.

In a particular embodiment of the invention, the alkyl, alkenyl or alkynyl as defined in Ri- R5 if substituted, is substituted with one or more substituent/s selected from -OR’, halogen, -CN, haloalkyl, haloalkoxy and -NR’R”; wherein R, R’ and R” are independently selected from hydrogen, unsubstituted Ci-₆ alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C2-6 alkynyl;

More than one replacement on the same molecule and also on the same carbon atom is possible with the same or different substituents. This includes for example 3 hydrogens being replaced on the same C atom, as in the case of CF₃, or at different places of the same molecule, as in the case of e.g. -CH(OH)-CH=CH-CHCl2.

In the context of this invention haloalkyl is understood as meaning an alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. -CH2CI, -CH2F, -CHCI2, -CHF2, -CCI3, -CF3 and -CH2-CHCI2. Preferably haloalkyl is understood in the context of this invention as halogen-substituted Ci-4-alkyl representing halogen substituted C1 -, C2-, C3- or C4-alkyl. The halogen- substituted alkyl radicals are thus preferably methyl, ethyl, propyl, and butyl. Preferred examples include -CH₂CI, -CH₂F, -CH₂-CH₂F, -CH₂-CHF₂, -CHCI₂, -CHF₂, and -CF₃.

In the context of this invention haloalkoxy is understood as meaning an -O-alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. -OCH2CI, -OCH2F, -OCHCI2, -OCHF2, -OCCI3, -OCF3 and -OCH2- CHCI2. Preferably haloalkoxy is understood in the context of this invention as halogen- substituted -OCi-4-alkyl representing halogen substituted C1 -, C2-, C3- or C4-alkoxy. The halogen-substituted O-alkyl radicals are thus preferably O-methyl, O-ethyl, O-propyl, and O-butyl. Preferred examples include -OCH2CI, -OCH2F, -OCHCI2, -OCHF2, and - OCF3.

In the context of this invention cycloalkyl is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted. Preferred cycloalkyls are C3-4-cycloalkyl representing C3- or C4-cycloalkyl, C3-5-cycloalkyl representing C3-, C4- or C5-cycloalkyl, C3-6-cycloalkyl representing C3-, C4-, C5- or C6-cycloalkyl, C3-7- cycloalkyl representing C3-, C4-, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl representing C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl representing C4- or C5- cycloalkyl, C4-6-cycloalkyl representing C4-, C5- or C6-cycloalkyl, C4-7-cycloalkyl representing C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl representing C5- or C6- cycloalkyl and C5-7-cycloalkyl representing C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl. Preferably in the context of this invention cycloalkyl is C3-8-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C3-7-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C3-6-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl.

Aryl is understood as meaning 6 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphthyl or anthracenyl, more preferably the aryl is phenyl.

A heterocyclyl radical or group (also called heterocyclyl hereinafter) is understood as meaning 5 to 18 membered mono or polycyclic heterocyclic ring systems, with at least one saturated or unsaturated ring which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. A heterocyclic group can also be substituted once or several times.

Subgroups inside the heterocyclyls as understood herein include heteroaryls and non aromatic heterocyclyls.

the heteroaryl (being equivalent to heteroaromatic radicals or aromatic heterocyclyls) is an aromatic 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more rings of which at least one aromatic ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably it is a 5 to 18 membered mono or polycyclic aromatic heterocyclic ring system of one or two rings of which at least one aromatic ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; more preferably it is selected from furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzothiazole, indole, benzotriazole, carbazole, quinazoline, thiazole, imidazole, pyrazole, oxazole, thiophene and benzimidazole;

the non-aromatic heterocyclyl is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more rings of which at least one ring - with this (or these) ring(s) then not being aromatic - contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two rings of which one or both rings - with this one or two rings then not being aromatic - contain/s one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably it is selected from oxazepam, pyrrolidine, piperidine, piperazine, tetrahydropyran, morpholine, indoline, oxopyrrolidine, benzodioxane, especially is piperazine, benzodioxane, morpholine, tetrahydropyran, piperidine, oxopyrrolidine and pyrrolidine.

Preferably, in the context of this invention heterocyclyl is defined as a 5 to 18 membered mono or polycyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. Preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. More preferably, it is a 5 to 10 membered mono or bicyclic heterocyclyl ring system containing one nitrogen atom and optionally a second heteroatom selected from nitrogen and oxygen. In another preferred embodiment of the invention, said heterocyclyl is a substituted mono or bicyclic heterocyclyl ring system.

Preferred examples of heterocyclyls include oxazepam, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, tetrahydroisoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, especially is pyridine, piperazine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyran, pyrazole, imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane and pyrrolidine. In the context of this invention oxopyrrolidine is understood as meaning pyrrolidin-2-one.

An /V-containing heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains a nitrogen and optionally one or more further heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains a nitrogen and optionally one or more further heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepam, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzimidazole, indazole, benzothiazole, benzodiazole, morpholine, indoline, triazole, isoxazole, pyrazole, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, quinolone, isoquinoline, tetrahydrothienopyridine, phthalazine, benzo-1 ,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, carbazole or thiazole.

In connection with aromatic heterocyclyls (heteroaryls), non-aromatic heterocyclyls, aryls and cycloalkyls, when a ring system falls within two or more of the above cycle definitions simultaneously, then the ring system is defined first as an aromatic heterocyclyl (heteroaryl) if at least one aromatic ring contains a heteroatom. If no aromatic ring contains a heteroatom, then the ring system is defined as a non-aromatic heterocyclyl if at least one non-aromatic ring contains a heteroatom. If no non-aromatic ring contains a heteroatom, then the ring system is defined as an aryl if it contains at least one aryl cycle. If no aryl is present, then the ring system is defined as a cycloalkyl if at least one non aromatic cyclic hydrocarbon is present.

In the context of this invention alkyl-aryl is understood as meaning an aryl group (see above) being connected to another atom through a Ci-₆-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylaryl is understood as meaning an aryl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups. Most preferably alkylaryl is benzyl (i.e. -Chh-phenyl).

In the context of this invention alkylheterocyclyl is understood as meaning an heterocyclyl group being connected to another atom through a Ci-₆-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylheterocyclyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups. Most preferably alkylheterocyclyl is -Chh-pyridine.

In the context of this invention alkylcycloalkyl is understood as meaning an cycloalkyl group being connected to another atom through a Ci-₆-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylcycloalkyl is understood as meaning a cycloalkyl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups. Most preferably alkylcycloalkyl is -CH2- cyclopropyl. Preferably, the aryl is a monocyclic aryl. More preferably the aryl is a 6 or 7 membered monocyclic aryl. Even more preferably the aryl is a 6 membered monocyclic aryl, preferably phenyl.

Preferably, the heteroaryl is a monocyclic heteroaryl. More preferably the heteroaryl is a 5, 6 or 7 membered monocyclic heteroaryl. Even more preferably the heteroaryl is a 5 or 6 membered monocyclic heteroaryl.

Preferably, the non-aromatic heterocyclyl is a monocyclic non-aromatic heterocyclyl. More preferably the non-aromatic heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic heterocyclyl. Even more preferably the non-aromatic heterocyclyl is a 5 or 6 membered monocyclic non-aromatic heterocyclyl. In another preferred embodiment, said non-aromatic heterocyclyl is a bicyclic non-aromatic heterocyclyl.

Preferably, the cycloalkyl is a monocyclic cycloalkyl. More preferably the cycloalkyl is a 3, 4, 5, 6, 7 or 8 membered monocyclic cycloalkyl. Even more preferably the cycloalkyl is a 3, 4, 5 or 6 membered monocyclic cycloalkyl.

In connection with cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl- heterocyclyl), substituted is also understood - unless defined otherwise - as meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl; non-aromatic heterocyclyl or non aromatic alkyl-heterocyclyl with

and/or with =0.

A ring system is a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with“joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings.

The term “leaving group” means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-), mesylate, nosylate or triflate.

The term“salt” is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By salt is also to be understood complexes of the active compound with other molecules and ions, in particular complexes via ionic interactions. The definition particularly includes physiologically acceptable salts, this term must be understood as equivalent to “pharmacologically acceptable salts”.

The term“physiologically acceptable salt” means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially lacking toxicity caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.

These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NhU, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.

Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals. By this it is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

The compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid.

Any compound that is a solvate of a compound according to the invention like a compound according to formula (I) defined above is understood to be also covered by the scope of the invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. The term “solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non- covalent binding another molecule (most likely a polar solvent). Especially preferred examples include hydrates and alcoholates, like methanolates or ethanolates.

Any compound that is a prodrug of a compound according to the invention like a compound according to formula (I) defined above is understood to be also covered by the scope of the invention. The term “prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al.“Textbook of Drug design and Discovery” Taylor & Francis (April 2002).

Any compound that is a N-oxide of a compound according to the invention like a compound according to formula (I) defined above is understood to be also covered by the scope of the invention.

Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C- enriched carbon or of a nitrogen by ¹⁵N-enriched nitrogen are within the scope of this invention.

The compounds of formula (I) as well as their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable pure form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts. This applies also to its solvates or prodrugs.

Unless otherwise defined, all the groups above mentioned that can be substituted or unsubstituted may be substituted at one or more available positions by one or more suitable groups such as OR’, =0, SR’, SOR’, SO2R’, OSO2R’, OSO3R’, NO2, NHR’, N(R’)₂, =N-R’, N(R’)COR’, N(COR’)₂, N(R’)S0₂R’, N(R’)C(=NR’)N(R’)R’, N₃, CN , halogen, COR’, COOR’, OCOR’, OCOOR’, OCONHR’, OCON(R’)₂, CONHR’, CON(R’)₂, CON(R’)OR’, CON(R’)S0₂R’, PO(OR’)₂, PO(OR’)R’, PO(OR’)(N(R’)R’), CM₂ alkyl, C3-10 cycloalkyl, C₂-i₂ alkenyl, C₂-i₂ alkynyl, aryl, and heterocyclic group, wherein each of the R’ groups is independently selected from the group consisting of hydrogen, OH, N0_2, NH₂, SH, CN, halogen, COH, COalkyl, COOH, CM₂ alkyl, C_3-10 cycloalkyl, C₂-i₂ alkenyl, C₂-i₂ alkynyl, aryl and heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list.

In a particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein Ri is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, substituted or unsubstituted C_1-6 alkyl, and a group of the following formula (A):

wherein

Wi is carbon or nitrogen;

R₇ and R_7' are independently selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl; and

Re is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, and ORs·, wherein

Re’ is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a more particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein Ri is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, unsubstituted C_1-6 alkyl, preferably methyl, and a group of the following formula (A):

wherein

Wi is carbon or nitrogen;

R₇ and R_7' are independently selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl, preferably methyl; and

Re is selected from the group consisting of hydrogen, halogen, unsubstituted C_1-6 alkyl, and OR , wherein

Re’ is selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl; preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein Ri is a group of the following formula (A):

wherein

Wi is carbon or nitrogen; R₇ and R_7' are independently selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl, preferably methyl; and

Re’ is selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl; preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a preferred embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein Ri is a group of the following formula (A):

wherein

Wi is carbon or nitrogen;

Re is selected from the group consisting of hydrogen, halogen, and ORs·, wherein

Re’ is selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl; preferably methyl; and

X is selected from the group consisting of a bond, [Chhjp- and NR₆; wherein p is 0, 1 or 2; and

R6 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, and [CH2]_qNR6'R6”; wherein

Re· and R_6” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl; and

q is 1 , 2 or 3;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a more particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein Ri is, halogen, preferably Cl, F or Br; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound of the invention according to formula (I) is a compound, wherein Rr is selected from the group consisting of hydrogen, halogen, preferably Br and F, and substituted or unsubstituted C_1-6 alkyl, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound of the invention according to formula (I) is a compound, wherein Ri and Rr are independently halogen, preferably Br or F; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in Ri and Rr as defined in any of the embodiments of the present invention, the Ci-₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein R₂ is selected from hydrogen and unsubstituted C_1-6 alkyl, preferably C_1-3 alkyl, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a more preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein R₂ is unsubstituted C_1-6 alkyl, preferably C_1-3 alkyl, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₂ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a more preferred embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein R₂ is methyl or ethyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of the invention according to formula (I) is a compound, wherein R₃ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl; and substituted or unsubstituted heterocyclyl, wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, Ci-₆ alkyl, and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a still more particular and prefered embodiment R₃ is selected from hydrogen and unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-3 alkyl, more preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₃ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or

the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or

the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; and/or

the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1 ,2,5- thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, and quinazoline; more preferably is piperazine; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein R₄ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein R₄ is selected from halogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein R₄ is substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a more preferred embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein R₄ is ethyl or propyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₄ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein R₅, Rs’, Rs” and R_5” are independently selected from the group consisting of hydrogen and substituted or unsubstituted C₁-6 alkyl; preferably unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another particular and preferred embodiment, W is N and Rs, Rs’, Rs” and Rs” are independently selected from the group consisting of hydrogen and unsubstituted Ci-₆ alkyl, preferably methyl. More preferably, when R₅ is methyl R₅· is hydrogen and when Rs- is methyl R₅ is hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound of the invention according to formula (I) is a compound, wherein in R₅, Rs’, Rs” and R_5” as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein X is selected from the group consisting of a bond, [CH₂]p- and NRe; wherein p is 0, 1 or 2; and

R₆ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C1-6 alkyl, and [CH2]_qNR6'R6”, wherein

R^and R₆- are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and q is 1 , 2, or 3;

In a preferred embodiment, the compound of the invention according to formula (I) is a compound wherein X is selected from the group consisting of a bond and [Chhjp-, wherein p is 0, 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention the compound according to formula (I) is a compound, wherein in R6, R6’, and R6” as defined in any of the embodiments of the present invention, the Ci-₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein R₇ and R₇ are independently selected from the group consisting of hydrogen and substituted or unsubstituted Ci-₆ alkyl, preferably unsubstituted Ci-₆ alkyl, and even more preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound of the invention according to formula (I) is a compound, wherein in R₇ and R₇· as defined in any of the embodiments of the present invention, the Ci-₆ alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of the invention according to formula (I) is a compound wherein Re is selected from the group consisting of hydrogen, halogen, preferably fluorine, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, and ORs·, wherein

Re· is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl; preferably unsubstituted C_1-6 alkyl, even more preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment the compound of the invention according to formula (I) is a compound, wherein in Re and Re· as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment of the invention m and n are 1 ;

In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein

Ri is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and a group of the following formula (A):

wherein

Wi is carbon or nitrogen; R₇ and R_7' are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; and

Rs is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and ORs·, wherein

Rs’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and/or Rr is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and/or

R₂ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and/or R₃ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl; and substituted or unsubstituted heterocyclyl, wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, and substituted or unsubstituted heterocyclyl; and/or

R₄ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and/or

R₅, R_5’, R_5” and R_5” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C₁-6 alkyl, substituted or unsubstituted C₂-6 alkenyl and substituted or unsubstituted C₂-6 alkynyl; alternatively, R₅ and R₅· and/or R_{5 "} and Rs- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; and/or

R₆ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, and [CH2]_qNR6'R6”; wherein

Re· and R_6” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; and

q is 1 , 2 or 3; m is 1 or 2; n is 1 or 2; and wherein when one of Ri or Rr is halogen and the other is hydrogen, m is 1 and n is 1 , then at least one of R_5, Rs·_, Rs- and Rs is a substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C₂-6 alkenyl or substituted or unsubstituted C₂-6 alkynyl; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein Ri is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, and a group of the following formula (A):

wherein

Wi is carbon or nitrogen;

R₇ and R₇ are independently selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and

Rs is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, and ORs·, wherein Re· is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted Ci- 6 alkyl; and/or

Rr is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and/or

R₂ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and/or

R₃ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, and substituted or unsubstituted heterocyclyl; and/or

R₄ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and/or

R₅, R_5’, R_5” and R_5” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C₁-6 alkyl, preferably unsubstituted C_1-6 alkyl; alternatively, R₅ and R₅· and/or R_{5 "} and Rs- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; and/or

R6 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, and [CH2]_qNR6'R6”; wherein Re· and R_6” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl;

and

q is 1 , 2 or 3; m is 1 or 2; n is 1 or 2; and wherein when one of Ri or Rr is halogen and the other is hydrogen, m is 1 and n is 1 , then at least one of R_5, Rs·_, Rs- and Rs is a substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

wherein Wi is carbon or nitrogen;

R₇ and R_7' are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; and

Re is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and ORs·, wherein

Re· is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and

Rr is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and

R₂ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and

R₃ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl; and substituted or unsubstituted heterocyclyl, wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, and substituted or unsubstituted heterocyclyl; and

R₄ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and Rs, Rs’, Rs” and R_5” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C₁-6 alkyl, substituted or unsubstituted C₂-6 alkenyl and substituted or unsubstituted C₂-6 alkynyl; alternatively, R₅ and Rs· and/or R_{5 "} and Rs- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; and

X is selected from the group consisting of a bond, [Chhjp- and NR6; wherein p is 0, 1 or 2; and

wherein

Wi is carbon or nitrogen;

Rs is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, and ORs·, wherein

Re· is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted Ci-

₆ alkyl; and

Rr is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and

R₂ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and R₃ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, and substituted or unsubstituted heterocyclyl; and

R₄ is selected from the group consisting of halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and

Rs, Rs’, Rs” and R_5” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C₁-6 alkyl, preferably unsubstituted C_1-6 alkyl; alternatively, Rs and Rs· and/or Rs- and Rs- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; and

R₆ is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, and [CH2]_qNR6'R6”; wherein

Re· and R_6” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl;

and

q is 1 , 2 or 3; m is 1 or 2; n is 1 or 2; and wherein when one of Ri or Rr is halogen and the other is hydrogen, m is 1 and n is 1 , then at least one of R_5, Rs·_, Rs- and Rs is a substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a more preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein

Ri is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, and a group of the following formula (A):

wherein

Wi is carbon or nitrogen;

Re is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, and ORs·, wherein

Re’ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, preferably unsubstituted Ci- 6 alkyl; and Rr is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, preferably unsubstituted Ci-₆ alkyl; and

R₂ is substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and

R₃ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, and substituted or unsubstituted heterocyclyl; and

R₄ is substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and

R₅, R_5’, R_5” and R_5” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C₁-6 alkyl, preferably unsubstituted C_1-6 alkyl; alternatively, R₅ and R₅· and/or R_{5 "} and Rs- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; and

Re· and Re· are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; q is 1 , 2 or 3;

m is 1 or 2;

n is 1 or 2; and wherein when one of Ri or Rr is halogen and the other is hydrogen, m is 1 and n is 1 , then at least one of R_5, Rs·_, Rs- and Rs is a substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred further embodiment, the compound of formula (I) is selected from:

] 6-bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazole;

[2] 5-bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazole;

[3] 2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazole;

[4] 5-bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazole;

[5] 5-bromo-1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazole;

[6] 5-bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)propyl)-1 -methyl-1 H- benzo[d]imidazole;

[7] 5-bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-6-fluoro- 1 /-/-benzo[d]imidazole;

[8] 5-bromo-1 -ethyl-6-fluoro-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazole;

[9] 6-bromo-1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazole;

[10] 5-bromo-2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazole;

[11 ] 5-bromo-2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazole;

[12] 5-bromo-2-((R)-1-((3S,5R)-3,5-dimethylpiperazin-1-yl)butyl)-1 -methyl-1 H- benzo[d]imidazole;

[13] 5-bromo-2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazole; [14] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-6-yl)-N,N-dimethyl-4-phenylpiperidin-4-amine;

[15] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[16] 3-(4-(dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - ethyl-1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[17] 3-(4-(dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - ethyl-1 /-/-benzo[d]imidazol-6-yl)piperidin-4-yl)phenol;

[18] 1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-benzo[d]imidazol-5- yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[19] 3-(4-(dimethylamino)-1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[20] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-/V-methyl-4-phenylpiperidin-4-amine;

[21 ] 3-(1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-4-(methylamino)piperidin-4-yl)phenol;

[22] 3-(4-(dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - methyl-1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[23] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[24] 3-(4-(dimethylamino)-1 -(1 -methyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)- 1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[25] 3-(1 -(2-(1 -(1 ,4-diazepan-1 -yl)butyl)-1 -ethyl-1 /-/-benzo[d]imidazol-5-yl)-4- (dimethylamino)piperidin-4-yl)phenol;

[26] 3-(4-(dimethylamino)-1 -(1 -ethyl-2-(1 -(piperazin-1 -yl)butyl)-1 H- benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[27] 1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-benzo[d]imidazol-5- yl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin-4-amine;

[28] 1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-benzo[d]imidazol-5- yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4-amine;

[29] 3-(4-(dimethylamino)-1 -(1 -methyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)propyl)- 1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[30] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine;

[31 ] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine; [32] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine;

[33] L/1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-benzo[d]imidazol-5- yl)-/V1 ,/V2-dimethylethane-1 ,2-diamine;

[34] (R)-3-(4-(dimethylamino)-1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl)-1 H-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[35] (S)-3-(4-(dimethylamino)-1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)- 1 H-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[36] 1 -(2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-4-(4-methoxyphenyl)-N,N-dimethylpiperidin-4- amine;

[37] 1 -(2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-4-(4-methoxyphenyl)-N,N-dimethylpiperidin-4- amine;

[38] (1 S,4s)-N4-(2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-N1 ,N1 -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[39] (1 R,4s)-N4-(2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-N1 ,N1 -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[40] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-6-yl)methyl)-N,N-dimethyl-4-phenylpiperidin-4-amine;

[41 ] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[42] 1 -((1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-benzo[d]imidazol-5- yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[43] 1 -((2-(1 -(1 ,4-diazepan-1 -yl)butyl)-1 -ethyl-1 /-/-benzo[d]imidazol-5-yl)methyl)- /V,/V-dimethyl-4-phenylpiperidin-4-amine;

[44] 1 -((1 -ethyl-2-(1 -(piperazin-1 -yl)butyl)-1 /-/-benzo[d]imidazol-5-yl)methyl)- /V,/V-dimethyl-4-phenylpiperidin-4-amine;

[45] 3-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - ethyl-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[46] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[47] 3-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - methyl-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[48] 3-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)propyl)- 1 -ethyl-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[49] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine; [50] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[51 ] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[52] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[53] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[54] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[55] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[56] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[57] 4-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - ethyl-6-fluoro-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[58] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-N,N-dimethyl-4-phenylpiperidin-4-amine;

[59] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-N,N-dimethyl-4-phenylpiperidin-4-amine;

[60] 3-(4-(dimethylamino)-1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 /-/-benzo[c/]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[61 ] 3-(4-(dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 /-/-benzo[c/]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[62] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[63] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[64] 3-(4-(dimethylamino)-1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 H-benzo[c/]imidazol-5-yl)methyl)piperidin-4-yl);

[65] 3-(4-(dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 H-benzo[c/]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[66] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine; [67] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[68] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[69] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[70] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[71 ] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine;

[72] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[73] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[74] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[75] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[76] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[77] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

[78] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpipendin- 4-amine; and

[79] 1 -((2-((/?M -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin- 4-amine;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another aspect, the invention refers to a process for the preparation of a compound of formula (I) as defined above. The obtained reaction products may, if desired, be purified by conventional methods, such as crystallization and chromatography. Where the processes described below for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form of a compound of the invention is the crystalline form, including such form in pharmaceutical composition. In the case of salts and also solvates of the compounds of the invention the additional ionic and solvent moieties must also be non-toxic. The compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.

The compounds of formula (I) can be obtained by following the method described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. The compounds of formula (I) may be prepared by a one to three step process as described in Scheme 1. The reactions steps are shown in Scheme 1 below in more detail:

Scheme 1 wherein Ri, Rr, R₂, R₃, R₄, R_5-5”, X, W, m and n have the same meaning as indicated above for a compound of formula (I) and LG is a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate.

In this sense, in another aspect, the invention refers to a process for the preparation of a compound of formula (I):

wherein Ri, Rr, R₂, R₃, R₄, R_5-5”, X, m and n are as defined above for a compound of formula (I); said process comprising: treating a compound of formula (V):

with a compound of formula (VI):

wherein Ri, Rr, R₂, R₃, R₄, R_5-5”, X, m and n have the same meaning as indicated above for a compound of formula (I) and LG is a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate.

In a more particular embodiment, a compound of formula (I) is prepared by reacting a compound of formula (V) with a suitable nucleophilic reagent of formula (VI), in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K₂CO₃ or N,N-diisopropylethylamine; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating. Alternatively, the reactions can be carried out under microwave heating and optionally using an activating agent, such as sodium or potassium iodide.

In a particular embodiment, the invention refers to a process for the preparation of a compound of formula (V), comprising reacting a compound of formula (IV):

with a suitable halogenating agent, such as N-bromosuccinimide in the presence of a suitable solvent, such as carbon tetrachloride. In a more particular embodiment, the compound of formula (V) can be prepared by reacting a compound of formula (IV) with a suitable halogenating agent, such as N-bromosuccinimide in the presence of a suitable solvent, such as carbon tetrachloride, at a suitable temperature, between room temperature and 100 °C, preferably heating. The reaction may be carried out in the presence of a radical initiator, such as light or benzoyl peroxide.

Alternatively, a compound of formula (V) can be prepared by converting the hydroxyl group of a compound of formula (IX):

into a leaving group, wherein Ri, Rr, R₂, and R₄, have the same meaning as indicated above for a compound of formula (I). For instance, by using methanesulphonyl chloride in the presence of a suitable base such as pyridine, at a suitable temperature, between room temperature and 100 °C.

In another particular embodiment, the invention refers to a process for obtaining a compound of formula (IX) comprising condensing a compound of formula (II):

with compound of formula (VIII):

wherein Ri, Rr, R₂, R₄, and X have the same meaning as indicated above for a compound of formula (l)using the conditions described for Step 1. In a preferred embodiment, the process is carried out in the presence of a suitable condensing agent, such as polyphosphoric acid, at a suitable temperature, preferably heating.

In a particular embodiment, the invention also refers to a process for the preparation of a compound of formula (IV) comprising treating a compound of formula (II):

with a compound of formula (III):

wherein Ri, Rr, R₂, R₃, R₄, R_5-5”, X, m and n have the same meaning as indicated before. In a more particular embodiment, the compound of formula (IV) can be prepared by treating a compound of formula (II) with a suitable acid of formula (III) in the presence of a suitable condensing agent, such as polyphosphoric acid, at a suitable temperature, preferably heating.

In another aspect, the invention refers to a process for the preparation of a compound of formula (I):

said process comprising treating a compound of formula (II):

with a compound of formula (VII):

wherein Ri, Rr, R₂, R3, R₄, R5-5”, X, m and n have the same meaning as indicated above. In a preferred embodiment, the process is carried out in the presence of a suitable condensing agent, such as polyphosphoric acid, at a suitable temperature, preferably heating. In addition, certain compounds of the present invention can also be obtained by functional group interconversion over compounds of formula (I) or any of the intermediates shown in Scheme 1. As a matter of example: -a compound in which Ri is halogen may be converted to a compound in which X is a bond and Ri is

by reaction with a compound of formula (X):

under Buchwald-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP, DavePhos or XPhos, using a suitable base such as sodium tert- butoxide or cesium carbonate, in a suitable solvent such as toluene or 1 ,4-dioxane, at a suitable temperature, preferably heating;

-a compound in which Ri is halogen may be converted to a compound in which X is NR₆ and Ri is

by reaction with a compound of formula (XI):

using the Buchwald-Hartwig conditions described above;

-a compound in which Ri is halogen may be converted to a compound in which X is Chh and Ri is

by reaction with a compound of formula (XII):

by coupling in the presence of a Pd catalyst such as palladium acetate and a phosphine ligand, such as XPhos, using a suitable base, such as cesium carbonate, in a suitable solvent, such as tertbutanol, at a suitable temperature, preferably heating and optionally under microwave irradiation.

A compound of formula (XII) may be obtained by reaction of a compound of formula (X) with potassium (bromomethyl)trifluoroborate using a suitable base such as triethylamine, in a suitable solvent such as mixture of tetrahydrofuran/terbutanol, at a suitable temperature, preferably heating.

The compounds of formula (II), (III), (VI), (VII), (VIII), (X) and (XI) used in the methods disclosed above are commercially available or can be synthesized following common procedures described in the literature and exemplified in the synthesis of some intermediates. In some of the processes described above it may be necessary to protect the reactive or labile groups present with suitable protecting groups, such as for example Boc (tert- butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups, and common silyl protecting groups for the protection of the hydroxyl group. The procedures for the introduction and removal of these protecting groups are well known in the art and can be found thoroughly described in the literature.

In addition, a compound of formula (I) can be obtained in enantiopure form by resolution of a racemic compound of formula I either by chiral preparative HPLC or by crystallization of a diastereomeric salt or co-crystal or by using a homochiral intermediate, such as a homochiral hydroxyacid of formula VIII. Alternatively, the resolution step can be carried out at a previous stage, using any suitable intermediate.^'

In another aspect, the invention refers to the use of a compound selected from

for the manufacture of a compound of formula (I), wherein Ri, Rr, R₂, R₃, R₄, R_5-5”, X, m and n have the same meaning as indicated before.

Turning to another aspect, the invention also relates to the therapeutic use of the compounds of general formula (I). As mentioned above, compounds of general formula (I) show a strong affinity to the subunit a2d and more preferably to the a2d-1 subunit of voltage-gated calcium channels. In a more preferred embodiment of the invention compounds of general formula (I) show a strong affinity both to the subunit a2d and more preferably to the a2d-1 subunit of voltage-gated calcium channels as well as to the m- receptor and can behave as agonists, antagonists, inverse agonists, partial antagonists or partial agonists thereof. Therefore, compounds of general formula (I) are useful as medicaments.

Another aspect of the invention refers to a pharmaceutical composition which comprises a compound according to the invention as described above according to formula (I) or a pharmaceutically acceptable salt thereof, prodrug, solvate or steroisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The present invention thus provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants. The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.

Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.

Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.

Another aspect of the invention refers to a compound of formula (I) as described above, or a pharmaceutical acceptable salt or isomer thereof for use as a medicament.

Another aspect of the invention refers to a compound of formula (I), or a pharmaceutically acceptable salt or isomer thereof, for use in the treatment or prophylaxis of pain. Preferably, the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, including central neuropathic pain and peripheral neuriopathic pain, allodynia or hyperalgesia. This may include mechanical allodynia or thermal hyperalgesia.

Another aspect of the invention refers to the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of pain. In a preferred embodiment the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, including central neuropathic pain and peripheral neuriopathic pain, allodynia or hyperalgesia, also preferably including mechanical allodynia or thermal hyperalgesia.

Another aspect of this invention relates to a method of treating or preventing pain which method comprises administering to a patient in need of such a treatment or prevention a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Among the pain syndromes that can be treated or prevented are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, including central neuropathic pain and peripheral neuriopathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia.

The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.

EXAMPLES

In the next preparation examples the preparation of both intermediates compounds as well as compounds according to the invention are disclosed.

The following abbreviations are used in the examples:

ACN: acetonitrile

Aq: aqueous

Anh: anhydrous

Chx: cyclohexane

DCM: dichloromethane

DMF dimethylformamide

DavePhos: 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

EtOAc: ethyl acetate

h: hours

HPLC: high performance liquid chromatography

MeOH: methanol

MS: mass spectrometry

Min: minutes

NBS: /V-bromosuccinimide

Quant: quantitative Rt: retention time

r.t: room temperature

Sat: saturated

Sol: solution

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Wt: weight

XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

The following methods were used to determine the HPLC-MS spectra:

METHOD A: Column Acquity UPLC BEH C18 2.1 x 50 mm, 1 .7 pm, flow rate 0.61 mL/min; temperature 35 °C; A: NH4HCO3 10 mM, B: ACN, C: MeOH + 0.1 % formic acid; gradient 0.3 min 9

8% A, 98%A to 0:95:5 A:B:C in 2.7 min; 0:95:5 A:B:C to 100% B in 0.1 min; isocratic 100% B 2 min.

METHOD B: Column Acquity UPLC BEH C18 2.1 X 50 mm, 1.7 pm, flow rate 0.60 mL /min; temperature 35 °C; A: NH4HCO3 I O mM, B: ACN; gradient 0.3 min 90% A, 90% A to 5% A in 2.7 min, isocratic 5% A 0.7 min.

METHOD C: Column Acquity UPLC BEH C18 2.1 X 50 mm, 1 .7 pm, flow rate 0.60 mL /min; temperature 35 °C; A: NH4HCO3 10 mM pH 10.6, B: ACN; gradient 0.3 min 90% A, 90% A to 5% A in 2.7 min, isocratic 5% A 0.7 min.

METHOD D: Column Bonus RP 2.1 x 50 mm, 1 .8 pm, flow rate 0.5 mL/min; temperature 35 °C; A: NH4HCO3 10mM; B: ACN; Gradient: 90% A to 5% A in 4 min, isocratic 5% A 1 min.

METHOD E: Column Acquity BEH C18 2.1 x 50 mm, 1 .7 pm; flow rate 0.6 mL min; temperature 40 °C; A: Water + 0.1 % TFA, B: ACN + 0.1 % TFA; gradient 95% A to 5% A in 4 min, 4% A to 0% A in 0.2 min, isocratic 0% A 0.48 min. METHOD F: Column Acquity BEH C18 2.1 x 100 mm, 1 .7 pm; flow rate 0.3 mL/min; temperature 30 °C; A: ACONH4 5 mM, B: ACN; gradient: 1 min 90% A, 90% A to 85% A in 1 min, 85% A to 45% A in 2.5 min, 45% A to 10% A in 1 .5 min, isocratic 10% A 2 min.

Synthesis of examples

Example 1. 6-Bromo-2-(1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazole.

Step a. 6-Bromo-2 -butyl-1 -ethyl-1 H-benzo[d]imidazole.

To a solution of 5-bromo-/V1 -ethylbenzene-1 ,2-diamine (1.5 g, 7.1 mmol) in polyphosphoric acid (15 g), pentanoic acid (0.9 g, 8.5 mmol) was added and the reaction mixture was heated at 100 °C for 5 h. The mixture was cooled at 0 °C, NHs aq sol was added and the product was extracted with AcOEt and washed with water. The combined organic layers were dried over anh Na2SC>4, filtered and concentrated to dryness to give the title compound (1 .8 g, Yield: 92%).

Step b. 6-Bromo-2-(1 -bromobutyl)-1 -ethyl-1 H-benzo[d]imidazole.

To a solution of the compound obtained in step a (0.5 g, 1.8 mmol) in CCU (20 ml_), NBS (0.4 g, 2.1 mmol) and benzoyl peroxide (52 mg, 0.2 mmol) were added and the mixture was heated at 70 °C overnight. The reaction mixture was filtered and the filtrate was evaporated under vacuum to give the title compound (0.7 g, Yield: quant).

Step c. Title compound.

To a solution of the compound obtained in step b (0.7 g, 1.9 mmol) in anh ACN (40 ml_), TEA (1 ml_, 7.5 mmol) and Kl (31 mg, 0.2 mmol) were added and the reaction mixture was stirred at r.t. for 20 min. (2R,6S)-2,6-Dimethylpiperazine (0.5 g, 4.7 mmol) was added portion wise and the mixture was heated at 90 °C overnight. The mixture was concentrated under vacuum and the crude product was dissolved in EtOAc and washed with aq NaHCC>3 sat sol. The organic layer was dried over anh Na2SC>4, filtered and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient Chx to EtOAc (100%) to give the title compound (0.5 g, Yield: 73%). HPLC-MS (A ) Rt, 1.93 min; ESI+-MS m/z: 393.1 (M+1 ).

This method was used for the preparation of examples 2-9 using suitable starting materials:

Examples 10 and 11. 5-bromo-2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - ethyl-1 H-benzo[d]imidazole and 5-bromo-2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin- 1 -yl)butyl)-1 -ethyl-1 H-benzo/tf]imidazole. Starting from the compound obtained in example 2, a chiral preparative SFC separation [column: Chiralpak 1C (4.6x250) mm, 5m, temperature: 35 °C; flow: 3 mL/min, isocratic conditions: CC>₂/0.2% TEA in I PA (70:30), ABPR pressure: 1500 psi] was carried out to give the title compounds.

Examples 12 and 13. 5-bromo-2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - methyl-1 H-benzo[cf]imidazole and 5-bromo-2-((S)-1 -((3S,5/?)-3,5- dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H-benzo[cf|imidazole.

Starting from the compound obtained in example 4, a chiral preparative SFC separation [column: Chiralpak IG (20x250) mm, 5um, temperature: 40 °C; flow: 50 mL/min, isocratic conditions: 20:80 MeOH:CC>2 (0.2% v/v NH₃)] was carried out to give the title compounds.

Example 14. 1 -(2-(1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-6-yl)-A/,A/-dimethyl-4-phenylpiperidin-4-amine.

A schlenk flask charged with the compound obtained in example 1 (80 mg, 0.2 mmol), 3-(4-(dimethylamino)piperidin-4-yl)phenol dihydrochloride. (68 mg, 0.24 mmol), DavePhos (16 mg, 0.04 mmol), Pd2dba3 (19 mg, 0.02 mmol) and NaOtBu (78 mg, 0.8 mmol) was evacuated and backfilled with argon. Dioxane (3 mL), degassed by means of bubbling argon to the solution for 5 min, was added and the reaction mixture was heated at 100 °C overnight. The suspension was filtered through celite, washed with EtOAc and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (1 :1 ) to give the title compound (47 mg, Yield: 44%).

HPLC-MS (Method A): Rt, 1.99 min; ESI+-MS m/z: 517.3 (M+1 )

This method was used for the preparation of examples 15-33 using suitable starting materials:

Examples 34 and 35. (/?)-3-(4-(dimethylamino)-1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4- diazepan-1 -yl)butyl)-1 H-benzo[cf]imidazol-5-yl)piperidin-4-yl)phenol and (S)-3-(4- (dimethylamino)-l -(1 -ethyl-2 -(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[cf]imidazol-5-yl)piperidin-4-yl)phenol.

Starting from the compound obtained in example 19, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 11 mL/min, eluent: n- Heptane/(IPA + 0.33% DEA) 70/30 v/v; tn: 10.1', . 18.1'] was carried out to give the title compounds.

Examples 36 and 37. 1 -(2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl- 1 H-benzo[cf]imidazol-5-yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4-amine and 1 -(2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[cf]imidazol-5-yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4-amine.

Starting from the compound obtained in example 31 , a chiral preparative HPLC separation [column: Chiralpak IC, temperature: ambient; flow: 13 mL/min, eluent: n- Heptane/(EtOH + 0.33% DEA) 80/20 v/v; tn: 26.6', . 27.2'] was carried out to give the title compounds.

Examples 38 and 39. (1 S,4s)-/V4-(2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 H-benzo[cf]imidazol-5-yl)-/V1 ,L/1 -dimethyl-1 -phenylcyclohexane- 1 ,4-diamine and (1 /?,4s)-/V4-(2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - ethyl-1 H-benzo[cf]imidazol-5-yl)-/V1 ,L/1 -dimethyl-1 -phenylcyclohexane-1 ,4- diamine.

Step a. (1 S,4s)-W4-(2-(1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[cf]imidazol-5-yl)-/V1 ,L/1 -dimethyl-1 -phenylcyclohexane-1 ,4-diamine.

Starting from the compound obtained in example 1 (163 mg, 0.4 mmol) and following the procedure described in example 10, the title compound was obtained (37 mg, Yield: 17%).

HPLC-MS (Method A): Rt, 1.93 min; ESI+-MS m/z: 517.4(M+1 ). Step b. Title compounds.

Starting from the compound obtained in step a, a chiral preparative HPLC separation [column: Chiralpak IC, temperature: ambient; flow: 12 mL/min, eluent n-Heptane/(EtOH + 0.33% DEA) 80/20 v/v; tn: 13.7', . 16.5'] was carried out to give the title compounds.

Example 40. 1 -((2-(1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-6-yl)methyl)-A/,A/-dimethyl-4-phenylpiperidin-4-amine.

Step a. ((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -ium-1 - yl)methyl)trifluoroborate.

A schlenk flask charged with /V,/V-dimethyl-4-phenylpiperidin-4-amine (1 .2 g, 5.8 mmol) and potassium (bromomethyl)trifluoroborate (1.4 g, 7 mmol), was evacuated and backfilled with argon. THF:tBuOH (2:1 , 54 ml_), degassed by means of bubbling argon to the solution for 5 min, was added and the reaction mixture was heated at 80 °C overnight. The mixture was dried under vacuum and the crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (9:1 ) to give the title compound (1 .3 g, Yield: 77%).

Step b. Title compound.

A sealed tube charged with the compound obtained in example 1 (80 mg, 0.2 mmol), the compound obtained in step a (105 mg, 0.4 mmol), Pd(OAc)₂ (8.2 mg, 0.04 mmol), XPhos (35 mg, 0.07 mmol) and CS2CO3 (200 mg, 0.6 mmol), was evacuated and backfilled with argon. Dioxane:H₂0 (9:1 , 4 ml_), degassed by means of bubbling argon to the solution for 5 min, was added and the reaction mixture was stirred at 1 10 °C overnight. The solvent was removed under vacuum and the residue was dissolved in EtOAc and washed with aq NaHCOs sat sol_. The combined organic layers were dried over Na2SC>4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (4:1 ) to give the title compound (7 mg, Yield: 6%).

HPLC-MS (Method A): Rt, 1.93 min; ESI+-MS m/z: 531.4(M+1 ). This method was used for the preparation of examples 41-57 using suitable starting materials:

Examples 58 and 59. 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl- 1 H-benzo[cf]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine and 1 - ((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H-benzo[cf]imidazol- 5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine.

Starting from the compound obtained in example 41 , a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 12 mL/min, eluent: n- Heptane/(IPA + 0.33% DEA) 90/10 v/v; tn: 9', . 15'] was carried out to give the title compounds. Examples 60 and 61. 3-(4-(dimethylamino)-1 -((2-((/?)-1 -((3S,5/?)-3,5- dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H-benzo[cf]imidazol-5-yl)methyl)piperidin- 4-yl)phenol and 3-(4-(dimethylamino)-1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 H-benzo[cf]imidazol-5-yl)methyl)piperidin-4-yl)phenol

Starting from the compound obtained in example 45, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent: n- Heptane/(IPA + 0.33% DEA) 80/20 v/v; tn: 6.5', t¾: 9.0'] was carried out to give the title compounds.

Examples 62 and 63. 1 -((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - methyl-1 H-benzo[cf]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine and 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[cf]imidazol-5-yl)methyl)-A/,A/-dimethyl-4-phenylpiperidin-4-amine.

Starting from the compound obtained in example 46, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 12 mL/min, eluent: n- Heptane/(IPA + 0.33% DEA) 85/15 v/v; tn: 6.9', t¾: 9.4'] was carried out to give the title compounds.

Examples 64 and 65. 3-(4-(dimethylamino)-1 -((2-((/?)-1 -((3S,5/?)-3,5- dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H-benzo[cf]imidazol-5- yl)methyl)piperidin-4-yl) and 3-(4-(dimethylamino)-1 -((2-((S)-1 -((3S,5/?)-3,5- dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H-benzo[cf]imidazol-5- yl)methyl)piperidin-4-yl)phenol.

Starting from the compound obtained in example 47, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent: n- Heptane/(IPA + 0.33% DEA) 85/15 v/v; tn: 12.5', . 19.9'] was carried out to give the title compounds.

Examples 66 and 67. 1 -((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl- 1 H-benzo[cf]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine and 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-A/,A/-dimethylpiperidin-4-amine.

Starting from the compound obtained in example 49, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent: n- Heptane/(IPA + 0.33% DEA) 80/20 v/v; tn: 5.4', t¾: 6.9'] was carried out to give the title compounds. Examples 68 and 69. 1 -((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - methyl-1 H-benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine and 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 H-benzo[cf]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine.

Starting from the compound obtained in example 50, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent: n- Heptane/(IPA + 0.33% DEA) 85/15 v/v; tn: 6.9', t¾: 9.0'] was carried out to give the title compounds.

Examples 70 and 71. 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl- 1 H-benzo[cf]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V-dimethylpiperidin-4- amine and 1 -((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-A/,A/-dimethylpiperidin-4-amine.

Starting from the compound obtained in example 51 , a chiral preparative HPLC separation [column: Chiralpak IG, (4.6x250) mm, 5 m, temperature: ambient; flow: 1 mL/min, eluent: n-Hexane /(EtOH + 0.1 % DEA) 85/15 v/v] was carried out to give the title compounds.

Examples 72 and 73. 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl- 1 H-benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine and 1 -((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[cf]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine.

Starting from the compound obtained in example 53, a chiral preparative SFC separation [column: Chiralpak IG (20x250) mm, 5um, temperature: 40 °C; flow: 50 mL/min, isocratic conditions: 40:60 EtOH:C0₂ (0.2% v/v NH₃)] was carried out to give the title compounds.

Examples 74 and 75. 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl- 1 H-benzo[cf]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine and 1 -((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[cf]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine.

Starting from the compound obtained in example 54, a chiral preparative HPLC separation [column: Chiralpak IG (4.6x250) mm, 5m, temperature: ambient; flow: 1 mL/min, isocratic conditions: eluent: n-Hexane/(EtOH + 0.1 % DEA) 85/15 v/v] was carried out to give the title compounds. Examples 76 and 77. 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - methyl-1H-benzo[cf]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine and 1 -((2-((/?)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 H-benzo[d]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine.

Starting from the compound obtained in example 55, a chiral preparative SFC separation [column: Chiralpak IG (20x250) mm, 5um, temperature: 40 °C; flow: 50 mL/min, isocratic conditions: 40:60 EtOH:C0₂ (0.2% v/v NH₃)] was carried out to give the title compounds.

Examples 78 and 79. 1 -((2-((S)-1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - methyl-1H-benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine and 1 -((2-((/? -1 -((3S,5/?)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 H-benzo[cf]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine.

Starting from the compound obtained in example 56, a chiral preparative SFC separation [column: Chiralpak IG (20x250) mm, 5um, temperature: 40 °C; flow: 50 mL/min, isocratic conditions: 40:60 EtOH:C0₂ (0.2% v/v NH₃)] was carried out to give the title compounds.

Examples of biological activity

This invention is aimed at providing a series of compounds which show pharmacological activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage-gated calcium channels or dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage gated calcium channels, and the m-opiod receptor (MOR or mu-opioid receptor) and especially compounds which have a binding expressed as K, responding to the following scales:

K_ί(a,₂d-1 ) is preferably < 10000 nM, more preferably < 5000 nM, or even more preferably < 500 nM.

Ki(p) is preferably < 1000 nM, more preferably < 500 nM, even more preferably < 100 nM.

Binding assay to human a2d-1 subunit of Cav2.2 calcium channel.

Human a2d-1 enriched membranes (2.5 pg) were incubated with 15 nM of radiolabeled [3H]-Gabapentin in assay buffer containing Hepes-KOH 10 mM, pH 7.4. NSB (non specific binding) was measured by adding 10 mM pregabalin. The binding of the test compound was measured at either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki). After 60 min incubation at 27 °C, binding reaction was terminated by filtering through Multiscreen GF/C (Millipore) presoaked in 0.5 % polyethyleneimine in Vacuum Manifold Station, followed by 3 washes with ice-cold filtration buffer containing 50 mM Tris-HCI, pH 7.4.

Filter plates were dried at 60 °C for 1 h and 30mI of scintillation cocktail were added to each well before radioactivity reading.

Readings were performed in a Trilux 1450 Microbeta radioactive counter (Perkin Elmer).

Binding assay to human m-opioid receptor

Transfected CHO-K1 cell membranes (20 pg) were incubated with [³H]-DAMGO (1 nM) in assay buffer containing Tris-HCI 50 mM, MgCh 5 mM at pH 7.4.

NBS (non-specific binding) was measured by adding 10 mM naloxone. The binding of the test compound was measured at either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki). Plates were incubated at 27 °C for 60 min. After the incubation period, the reaction mixture was then transferred to Multiscreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice- cold 10 mM Tris-HCI (pH 7.4).

Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail.

Results:

The following scale has been adopted for representing the binding to the a,₂d-1 subunit of voltage-gated calcium channels expressed as K,:

+ K_ί(a₂d-1) >= 5000 nM

++ 500nM <= K_ί(a₂d-1) <5000 nM

+++ K_ί(a₂d-1) <500 nM Preferably, when K,(a₂d-1 ) > 5000 nM, the following scale has been adopted for representing the binding to the a₂d-1 subunit of voltage-gated calcium channels:

+ K_ί(a₂d-1) > 5000 nM or inhibition ranges between 1 % and 50 %

The following scale has been adopted for representing the binding to m-opioid receptor expressed as K,:

+ K, (m) >= 500 nM

++ 100 nM <= K,(m) < 500 nM

+++ K_ΐ(m) < 100 nM

Preferably, when K, (m) > 500 nM, the following scale has been adopted for

representing the binding to the m -receptor:

+ K, (m) > 500 nM or inhibition ranges between 1 % and 50 %. a₂d-1 binding results of the compounds prepared in the present invention are shown in Table 1 :

Table 1

The results of the binding for the a2d-1 and the m-opioid receptor are shown in Table 2:

Table 2

Claims

1 . A compound of formula (I):

wherein

RI is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, and a group of the following formula (A):

wherein

Wi is carbon or nitrogen; R₇ and R_7' are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; and

R₃ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and substituted or unsubstituted heterocyclyl; wherein when the alkyl is substituted the substituents are selected from the group consisting of hydrogen, halogen, C_1-6 alkyl, and substituted or unsubstituted heterocyclyl;

R₅, R_5', R_5” and R_5” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C₂- 6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₅ and R₅· and/or R_{5 "} and Rs- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl;

R₆ is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, and [ChblqNR^Re”; wherein

R^ and R₆- are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; and

q is 1 , 2, or 3;

m is 1 or 2; n is 1 or 2; wherein when one of Ri or Rr is halogen and the other is hydrogen, m is 1 and n is 1 , then at least one of R_5, Rs·_, Rs- and R₅ is a substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2- 6 alkynyl; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

2. Compound according to claim 1 , wherein R2 is substituted or unsubstituted C1-6 alkyl.

3. Compound according to claim 1 or 2 wherein R4 is substituted or unsubstituted C1-6 alkyl.

4. Compound according to any one of claims 1 to 3 wherein R3 is selected from hydrogen and unsubstituted C1-6 alkyl.

5. Compound according to claim any one of claims 1 to 4 wherein Ri is a group of formula (A):

wherein

Wi is carbon or nitrogen; R₇ and R₇ are independently selected from the group consisting of hydrogen and substituted or unsubstituted Ci-₆ alkyl; and

Re is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl and ORs·, wherein

Re’ is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted Ci-₆ alkyl.

6. Compound according to claim 5 wherein Wi is nitrogen.

7. Compound according to claim 5 or 6, wherein R₇ and R₇· are unsubstituted Ci-₆ alkyl.

8. Compound according to any one of claims 1 to 7 wherein said compound is selected from the group consisting of: 6-Bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazole;

[4] 5-bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazole; [5] 5-bromo-1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazole;

[7] 5-bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-6- fluoro-1 /-/-benzo[d]imidazole;

[10] 5-Bromo-2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl- 1 H-benzo[d]imidazole;

[1 1 ] 5-bromo-2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-

1 H-benzo[d]imidazole;

[12] 5-BiOmo-2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl- 1 H-benzo[d]imidazole;

[13] 5-bromo-2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl- 1 H-benzo[d]imidazole;

[14] 1 -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-6-yl)-N,N-dimethyl-4-phenylpiperidin-4-amine;

[16] 3-(4-(dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[17] 3-(4-(dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 /-/-benzo[d]imidazol-6-yl)piperidin-4-yl)phenol;

[18] 1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazol-5-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[19] 3-(4-(dimethylamino)-1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl)-1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[22] 3-(4-(dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[24] 3-(4-(dimethylamino)-1 -(1 -methyl-2-(1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl)-1 H-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[25] 3-(1 -(2-(1 -(1 ,4-diazepan-1 -yl)butyl)-1 -ethyl-1 /-/-benzo[d]imidazol-5-yl)- 4-(dimethylamino)piperidin-4-yl)phenol;

[27] 1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazol-5-yl)-4-(3-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine;

[28] 1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazol-5-yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine;

[29] 3-(4-(dimethylamino)-1 -(1 -methyl-2-(1 -(4-methyl-1 ,4-diazepan-1 - yl)propyl)-1 /-/-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[31 ] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine;

[32] 1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)-4-(4-methoxyphenyl)-/V,/V-dimethylpiperidin-4- amine;

[33] L/1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazol-5-yl)-/V1 ,/V2-dimethylethane-1 ,2-diamine;

[35] (S)-3-(4-(dimethylamino)-1 -(1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl)-1 H-benzo[d]imidazol-5-yl)piperidin-4-yl)phenol;

[38] (1 S,4s)-N4-(2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 - ethyl-1 H-benzo[d]imidazol-5-yl)-N1 ,N1 -dimethyl-1 -phenylcyclohexane- 1 ,4-diamine;

[39] (1 R,4s)-N4-(2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 - ethyl-1 H-benzo[d]imidazol-5-yl)-N1 ,N1 -dimethyl-1 -phenylcyclohexane- 1 ,4-diamine;

[40] 1 -((2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-6-yl)methyl)-N,N-dimethyl-4-phenylpiperidin-4- amine;

[41 ] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4- amine;

[42] 1 -((1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H- benzo[d]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4- amine;

[43] 1 -((2-(1 -(1 ,4-diazepan-1 -yl)butyl)-1 -ethyl-1 /-/-benzo[d]imidazol-5- yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[44] 1 -((1 -ethyl-2-(1 -(piperazin-1 -yl)butyl)-1 /-/-benzo[d]imidazol-5- yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[45] 3-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[46] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4- amine;

[47] 3-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4- yl)phenol;

[48] 3-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)propyl)-1 -ethyl-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4- yl)phenol;

[49] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[50] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[51 ] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[52] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[53] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[54] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[55] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[56] 1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[57] 4-(4-(dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-6-fluoro-1 /-/-benzo[d]imidazol-5-yl)methyl)piperidin-4- yl)phenol;

[58] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-N,N-dimethyl-4-phenylpiperidin-4- amine;

[59] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-N,N-dimethyl-4-phenylpiperidin-4- amine;

[61 ] 3-(4-(dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -ethyl-1 H-benzo[c/]imidazol-5-yl)methyl)piperidin-4-yl)phenol;

[62] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4- amine;

[63] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4- amine;

[64] 3-(4-(Dimethylamino)-1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 /-/-benzo[c/]imidazol-5-yl)methyl)piperidin-4-yl);

[65] 3-(4-(dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-1 -methyl-1 H-benzo[c/]imidazol-5-yl)methyl)pipericlin-4- yl)phenol;

[66] 1 -((2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[67] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[68] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[69] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[70] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[71] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-fluorophenyl)-/V,/V- dimethylpiperidin-4-amine;

[72] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[73] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[74] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[75] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -ethyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[76] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[77] 1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(3-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine;

[78] 1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[d]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine; and

[79] 1 -((2-((/? -1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-1 -methyl-1 H- benzo[c/]imidazol-5-yl)methyl)-4-(4-methoxyphenyl)-/V,/V- dimethylpiperidin-4-amine.

9. Process for the preparation of a compound of formula (I) according to claim 1 :

said process comprising:

treating a compound of formula (V):

with a compound of formula (VI):

wherein

Ri , Rr, R2, R3, R4, R5-5 , X, W, m and n have the same meaning as indicated in any one of claims 1 to 7; and LG is a leaving group.

10. Process for the preparation of a compound of formula (I) according to claim 1 :

said process comprising: treating a compound of formula (II):

with a compound of formula (VII):

wherein

Ri, Rr, R2, R3, R4, R5-5 , X, W, m and n have the same meaning as indicated in any one of claims 1 to 7.

1 1. Use of a compound selected from

wherein

Ri, Rr, R2, R3, R4, R5-5”, X, m and n have the same meaning as indicated in any one of claims 1 to 7 and LG is a leaving group for the manufacture of a compound according to claim 1.

12. Compound according to any one of claims 1 to 8 for use as a medicament.

13. Compound according to any one of claims 1 to 8, for use in the treatment and/or prophylaxis of diseases and/or disorders mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and the m-opioid receptor.

14. Compound for use according to claim 13, where the disease or disorder is pain, especially neuropathic pain, inflammatory pain, and chronic pain or other pain conditions involving allodynia and/or hyperalgesia, depression, anxiety and attention-deficit-/hyperactivity disorder.

15. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.