RELATED CONDITIONS

FIELD OF THE INVENTION

The present invention relates to new compounds that show dual pharmacological 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). 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.

BACKGROUND OF THE INVENTION

The adequate management of pain represents 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.; 2011 ; 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 correlated to comorbidities, such as depression, anxiety and insomnia, which leads to important productivity losses and socio-economical burden (Goldberg, D.S., McGee, S.J.; 2011 ; 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 al.; Pharmacol. Rev.; 2015; 67; 821 -870). The VGCC are assembled through interactions of different subunits, namely a1 (Caval ), b (CavP) a2d (Cava26) and g (Ca _v y). The ot1 subunits are the key porous forming units of the channel complex, being responsible for Ca ²⁺ conduction and generation of Ca ²⁺ influx. The a2d, b, and g subunits are auxiliary, although they are very important for the regulation of the channel since they increase the expression of a1 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 _v 3.1 , Ca _v 3.2, and Ca _v 3.3), and high voltage-activated L- (Ca _v 1 .1 through Ca _v 1 .4), N- (Ca _v 2.2), P/Q-(Ca _v 2.1 ), and R-(Ca _v 2.3) 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; 679-692; Zamponi et al. , 2015; Neumaier et al.; 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 Cav1 .2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Cav3) channels are the target of ethosuximide, widely used in absence epilepsy. Ziconotide, a peptide blocker of N-type (Cav2.2) calcium channels, has been approved as a treatment of intractable pain.

The Ca _v 1 and Ca _v 2 subfamilies contain an auxiliary a2d subunit which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain (Perret and Luo, 2009; Vink and Alewood; British J. Pharmacol.; 2012; 167; 970- 989). 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 post-translationally cleaved and then linked by disulfide bonds. Four genes encoding a2d subunits have now been cloned. The 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 non-neuronal. 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; 220-228; Dolphin, A.C.; Nat. Rev. Neurosci.; 2012; 13; 542-555; Dolphin, A.C.; Biochim. Biophys. Acta; 2013; 1828; 1541 - 1549).

The Ca _v a26-l subunit may play an important role in neuropathic pain development (Perret and Luo, 2009; Vink and Alewood, 2012). Biochemical data have indicated a significant Ca _v a26-l , but not Ca _v a26-2, 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 _v ot ₂ 5-l subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Ca _v ot26-l subunit contributes to neuropathic allodynia.

The Ca _v a28-l subunit (and the Ca _v ot26-2, but not Ca _v a28-3 and Ca _v ot26-4, subunits) is the binding site for gabapentin which has anti-allodynic/hyperalgesic properties in patients and animal models. Because injury-induced Ca _v a28-l 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 _v ot26-l 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 _v ot26-l subunit can block nerve injury-induced Ca _v ot26-l upregulation and prevent the onset of allodynia and reserve established allodynia.

As above mentioned, the a2d 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 _v a28-1 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; Vink and Alewood, 2012, Zamponi et al., 2015).

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. Consequently, 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; 12(1 1 ); 1084-1095). In fact, positive synergistic interaction for several compounds, including analgesics, has been described (Schroder et al; J. Pharmacol. Exp. Ther.; 201 1 ; 337; 312-320; Zhang et al.; Cell Death Dis.; 2014; 5; e1 138; Gilron et al., 2013).

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, A.L.; Nat. Chem. Biol.; 2008; 4; 682-690).

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).

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.

In this way, the present invention relates to compounds having a complementary dual mechanism of action (m-receptor agonist and blocker of the a ₂ d subunit, in particular the a ₂ d-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).

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 have also affinity towards the m-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):

wherein:

Wi, W ₂ , W ₃ and W ₄ is N, CH or C with the proviso that one or two of W ₁ , W ₂ , W ₃ and W ₄ are N while the others are CH or C; n is 0 or 1 ;

R ₁ is a hydrogen atom; a branched or unbranched C1-6 alkyl radical; a halogen atom; a branched or unbranched C1-6 alcoxy radical; -CN; a substituted or unsubstituted aryl radical, a substituted or unsubstituted 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O and S; or a moiety selected from:

Ri _a is a hydrogen atom; a branched or unbranched C _1-6 alkyl radical; a halogen atom; a branched or unbranched Ci- ₆ alcoxy radical; -CN; a substituted or unsubstituted aryl radical or a substituted or unsubstituted 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O and S;

W ₅ is -NR ₅ and A is CH or

Ws is -(CH ₂ ) _p - and A is N;

R ₅ is a hydrogen atom or a branched or unbranched C _1-6 alkyl radical; p is 0 or 1 ;

Ri _b and Ri _c are independently from one another a hydrogen atom; a branched or unbranched C _1-6 alkyl radical; or

Ri _b and Ri _c together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched C _1-6 alkyl radical or a branched or unbranched C _1-6 alcoxy radical;

Ri _d is a hydrogen atom; -OH; a branched or unbranched C _1-6 alkyl radical; a branched or unbranched C _1-6 alcoxy radical; -CN; a C _1-6 haloalkyl radical; or a halogen atom;

Ri _e and Ri _f are independently from one another a hydrogen atom; a branched or unbranched C _1-6 alkyl radical; or

Ri _e and Ri _f together with the bridging nitrogen form a 4, 5 or 6 membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched Ci- ₆ alkyl radical or a branched or unbranched Ci- ₆ alcoxy radical;

Ri _g is a substituted or unsubstituted aryl radical or a substituted or unsubstituted 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O and S;

R ₂ is a hydrogen atom; a branched or unbranched Ci- ₆ alkyl radical; or a substituted or unsubstituted -(CH ₂ ) _q -0-Ci- ₆ alkyl radical; q is 1 , 2, 3 or 4;

R ₃ is a 6 to 10 membered heterocycloalkyl radical containing at least an heteroatom selected from N, O and S and which can be optionally substituted by one or more branched or unbranched C _1-6 alkyl radical, a substituted or unsubstituted aryl radical or a branched or unbranched C _1-6 alcoxy radical;

R ₄ is a branched or unbranched C _1-6 alkyl radical;

or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

It is also an aspect of the invention different processes for the preparation of compounds of formula (I).

Another aspect of the invention refers to the use of such compounds of general formula (I) for the treatment and/or prophylaxis of a2d-1 mediated disorders and more preferably for the treatment and/or prophylaxis of disorders mediated by the a2d-1 subunit of voltage-gated calcium channels and/or the m-receptor. The compounds of the present invention are particularly suited for the treatment of pain, specially neuropathic pain, and pain related or pain derived conditions.

A further aspect of the invention refers to pharmaceutical compositions comprising one or more compounds of general formula (I) with at least one pharmaceutically acceptable excipient. The pharmaceutical compositions in accordance with the invention can be adapted in order to be administered by any route of administration, be it orally or parenterally, such as pulmonarily, nasally, rectally and/or intravenously. Therefore, the formulation in accordance with the invention may be adapted for topical or systemic application, particularly for dermal, subcutaneous, intramuscular, intra-articular, intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous, vaginal, oral or parenteral application.

DETAILED DESCRIPTION OF THE INVENTION

The invention first relates to compounds of general formula (I)

wherein:

Wi, W ₂ , W ₃ and W ₄ is N, CH or C with the proviso that one or two of W ₁ , W ₂ , W ₃ and W ₄ are N while the others are CH or C; n is 0 or 1 ;

R ₁ is a hydrogen atom; a branched or unbranched C1-6 alkyl radical; a halogen atom; a branched or unbranched C1-6 alcoxy radical; -CN; a substituted or unsubstituted aryl radical, a substituted or unsubstituted 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O and S; or a moiety selected from:

Ri _a is a hydrogen atom; a branched or unbranched C _1-6 alkyl radical; a halogen atom; a branched or unbranched Ci- ₆ alcoxy radical; -CN; a substituted or unsubstituted aryl radical or a substituted or unsubstituted 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O and S;

W ₅ is -NR ₅ and A is CH or

Ws is -(CH ₂ ) _p - and A is N;

R ₅ is a hydrogen atom or a branched or unbranched C _1-6 alkyl radical; p is 0 or 1 ;

Ri _b and Ri _c are independently from one another a hydrogen atom; a branched or unbranched C _1-6 alkyl radical; or

Ri _b and Ri _c together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched C _1-6 alkyl radical or a branched or unbranched C _1-6 alcoxy radical;

Ri _d is a hydrogen atom; -OH; a branched or unbranched C _1-6 alkyl radical; a branched or unbranched C _1-6 alcoxy radical; -CN; a C _1-6 haloalkyl radical; or a halogen atom;

Ri _e and Ri _f are independently from one another a hydrogen atom; a branched or unbranched C _1-6 alkyl radical; or

Ri _e and Ri _f together with the bridging nitrogen form a 4, 5 or 6 membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched C _1-6 alkyl radical or a branched or unbranched C _1-6 alcoxy radical;

Ri _g is a substituted or unsubstituted aryl radical or a substituted or unsubstituted 5 or 6-membered heteroaryl radical having at least one heteroatom selected from N, O and S; R ₂ is a hydrogen atom; a branched or unbranched Ci- ₆ alkyl radical; or a substituted or unsubstituted -(CH ₂ ) _q -0-Ci- ₆ alkyl radical; q is 1 , 2, 3 or 4;

R ₃ is a 6 to 10 membered heterocycloalkyl radical containing at least an heteroatom selected from N, O and S and which can be optionally substituted by one or more branched or unbranched C _1-6 alkyl radical, a substituted or unsubstituted aryl radical or a branched or unbranched C _1-6 alcoxy radical;

R ₄ is a branched or unbranched C _1-6 alkyl radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

Unless otherwise stated, the compounds of the invention are also meant to include isotopically-labelled forms i.e. 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 at least one hydrogen atom by a deuterium or tritium, or the replacement of at least one carbon by ¹³ C- or ¹⁴ C-enriched carbon, or the replacement of at least one nitrogen by ¹⁵ N-enriched nitrogen are within the scope of this invention.

The compounds of general formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable 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, solvates or prodrugs.

“Halogen” or“halo” as referred in the present invention represents fluorine, chlorine, bromine or iodine. When the term“halo” is combined with other substituents, such as for instance“Ci- ₆ haloalkyl” or“C _1-6 haloalkoxy” it means that the alkyl or alkoxy radical can respectively contain at least one halogen atom. A leaving group is a group that in a heterolytic bond cleavage keeps the electron pair of the bond. Suitable leaving groups are well known in the art and include Cl, Br, I and -O- SO2R’, wherein R’ is F, Ci-4-alkyl, Ci-4-haloalkyl, or optionally substituted phenyl. The preferred leaving groups are Cl, Br, I, tosylate, mesylate, nosylate, triflate, nonaflate and fluorosulphonate.

“C1-6 alkyl”, as referred to in the present invention, are saturated aliphatic radicals. They may be linear (unbranched) or branched and are optionally substituted. Ci- ₆ -alkyl as expressed in the present invention means an alkyl radical of 1 , 2, 3, 4, 5 or 6 carbon atoms. Preferred alkyl radicals according to the present invention include but are not restricted to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, pentyl, n-pentyl, 1 ,1 - dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl or 1 -methylpentyl. The most preferred alkyl radical are C1-4 alkyl, such as methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1 -methylpropyl, 2-methylpropyl or 1 ,1 -dimethylethyl. Alkyl radicals, as defined in the present invention, are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a C1-6- alkoxy radical, a Ci- ₆ -alkyl radical, a Ci- ₆ -haloalcoxy radical, a Ci- ₆ -haloalkyl radical, CN, a trihaloalkyl radical and a hydroxyl group.

“C1-6 alkylamino” as referred to in the present invention, is understood as meaning a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 carbon atoms which is bonded to an amino group. The alkylamino radical is bonded to the molecule through the alkyl chain.

“Ci- ₆ alkoxy” as referered to in the present invention, is understood as meaning an alkyl radical/group as defined above attached via oxygen linkage to the rest of the molecule. Examples of alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy or tert-butoxy.

An alkoxyalkyl C1-6 group/radical as referered to in the present invention, is understood as meaning a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 atoms which is bonded to an alkoxy group, as defined above. The alkoxyalkyl is bonded to the molecule through the alkyl chain. A preferred alkoxyalkyl group/radical is a methoxymethyl or methoxyethyl group. “C3-6 Cycloalkyl” as referred to in the present invention, is understood as meaning saturated and unsaturated (but not aromatic), cyclic hydrocarbons having from 3 to 6 carbon atoms which can optionally be unsubstituted, mono- or polysubstituted. Examples for cycloalkyl radical preferably include but are not restricted to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl radicals, as defined in the present invention, are optionally mono-or polysubstituted by substitutents independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a Ci- ₆ -alkoxy radical, a Ci- ₆ -haloalcoxy radical, a Ci- ₆ -haloalkyl radical, an aryl radical, an amino radical, a Ci- ₆ alkylamino radical, a di(Ci- ₆ )alkylamino radical, a trihaloalkyl radical and a hydroxyl group.

A cycloalkylalkyl group/radical C1-6, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 atoms which is bonded to a cycloalklyl group, as defined above. The cycloalkylalkyl radical is bonded to the molecule through the alkyl chain. A preferred cycloalkylalkyl group/radical is a cyclopropylmethyl group or a cyclopentylpropyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for cycloalkylalkyl group/radical, according to the present invention, are independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a Ci- ₆ -alkoxy radical, a Ci- ₆ -haloalcoxy radical, a C1-6- haloalkyl radical, a trihaloalkyl radical and a hydroxyl group.

“Heterocycloalkyl” as referred to in the present invention, are understood as meaning saturated and unsaturated (but not aromatic), generally 5, 6 or 7 membered cyclic hydrocarbons which can optionally be unsubstituted, mono- or polysubstituted and which have at least one heteroatom in their structure selected from N, O and S. Examples for heterocycloalkyl radical preferably include but are not restricted to pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyrane, tetrahydrofurane, dioxane, dioxolane, oxazolidine, piperidine, piperazine, homopiperazine, morpholine, azepane or diazepane. Heterocycloalkyl radicals, as defined in the present invention, are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a C1-6- alkoxy radical, a Ci- ₆ -haloalkoxy radical, a Ci- ₆ -haloalkyl radical, a trihaloalkyl radical and a hydroxyl group. More preferably heterocycloalkyl in the context of the present invention are 6 or 7-membered ring systems optionally at least monosubstituted.

A heterocycloalkylalkyl group/radical C1-6, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 atoms which is bonded to a heterocycloalklyl group, as defined above. The heterocycloalkylalkyl radical is bonded to the molecule through the alkyl chain. A preferred heterocycloalkylalkyl group/radical is a piperidinemethyl group wherein the alkyl chain is optionally branched or substituted. Preferred substituents for heterocycloalkylalkyl group/radical, according to the present invention, are independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a Ci- ₆ -alkoxy radical, a Ci- ₆ -haloalcoxy radical, a Ci- ₆ - haloalkyl radical, an aryl radical, an amino radical, a Ci- ₆ alkylamino radical, a di(Ci- ₆ )alkylamino radical, a trihaloalkyl radical and a hydroxyl group.

“Aryl” as referred to in the present invention, is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. These aryl radicals may optionally be mono-or polysubstituted by substitutents independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a Ci- ₆ -alkoxy radical, a Ci- ₆ -haloalcoxy radical, a Ci- ₆ -haloalkyl radical and a hydroxyl group. Preferred examples of aryl radicals include but are not restricted to phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl, indanyl or anthracenyl radicals, which may optionally be mono- or polysubstituted, if not defined otherwise. More preferably aryl in the context of the present invention are 6- membered ring systems optionally at least monosubstituted.

An arylalkyl radical C1-6, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 carbon atoms which is bonded to an aryl group, as defined above. The arylalkyl radical is bonded to the molecule through the alkyl chain. A preferred arylalkyl radical is a benzyl group or a phenethyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for arylalkyl radicals, according to the present invention, are independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a Ci- ₆ -alkoxy radical, a Ci- ₆ -haloalcoxy radical, a Ci- ₆ -haloalkyl radical, a trihaloalkyl radical and a hydroxyl group.

“Heteroaryl” as referred to in the present invention, is understood as meaning heterocyclic ring systems which have at least one aromatic ring and may optionally contain one or more heteroatoms from the group consisting of N, O and S and may optionally be mono- or polysubstituted by substituents independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a Ci- ₆ -alkoxy radical, a Ci- ₆ -haloalkoxy radical, a Ci- ₆ - haloalkyl radical, a trihaloalkyl radical and a hydroxyl group. Preferred examples of heteroaryls include but are not restricted to furan, benzofuran, thiophene, thiazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, imidazole, imidazo[4,5-b]pyridine, isoxazole, oxadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole or quinazoline. More preferably heteroaryl in the context of the present invention are 5 or 6-membered ring systems optionally at least monosubstituted.

Heteroarylalkyl group/radical C1-6 as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 carbon atoms which is bonded to an heteroaryl group, as defined above. The heteroarylalkyl radical is bonded to the molecule through the alkyl chain. A preferred heteroarylalkyl radical is a piridinylmethyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for heteroarylalkyl radicals, according to the present invention, are independently selected from a halogen atom, a Ci- ₆ -alkyl radical, a Ci- ₆ -alkoxy radical, a Ci- ₆ -haloalcoxy radical, a Ci- ₆ -haloalkyl radical, a trihaloalkyl radical and a hydroxyl group.

“Heterocyclic ring” or“heterocyclic system”, as defined in the present invention, comprise any saturated, unsaturated or aromatic carbocyclic ring systems which are optionally at least mono-substituted and which contain at least one heteroatom as ring member. Preferred heteroatoms for these heterocyclyl groups are N, S or O. Preferred substituents for heterocyclyl radicals, according to the present invention, are F, Cl, Br, I, NH2, SH, OH, SO2, CF ₃ , carboxy, amido, cyano, carbamyl, nitro, phenyl, benzyl, - SO2NH2, C1-6 alkyl and/or Ci- ₆ -alkoxy.

The term "C1- ₃ alkylene" is understood as meaning a divalent alkyl group like -CH2- or - CH2-CH2- or -CH2-CH2-CH2-.

The term“ring system” according to the present invention refers to 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“ring system” thus defined comprises saturated, unsaturated or aromatic carbocyclic rings which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted and may be joined to other carbocyclic ring systems such as aryl radicals, heteroaryl radicals, cycloalkyl radicals etc.

The terms“condensed”,“annulated” or“annelated” are also used by those skilled in the art to designate this kind of join. The term “salt” is to be understood as meaning any form of the active compound 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 this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions. The definition particularly includes physiologically acceptable salts, this term must be understood as equivalent to “pharmacologically acceptable salts”.

The term“pharmaceutically acceptable salts” in the context of this invention means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly as a result of the counter-ion) when used in an appropriate manner for a treatment, particularly applied or used in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the invention - normally an acid (deprotonated) - such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used on humans and/or mammals. Salts with alkali and alkali earth metals are particularly preferred, as well as those formed with ammonium cations (NH ₄ ⁺ ). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the invention - normally protonated, for example in nitrogen - such as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e. salts of a specific active compound with physiologically tolerated organic or inorganic acids - particularly when used on humans and/or mammals. Examples of this type of salts are those formed with: hydrochloric acid, hydrobromic acid, sulphuric 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 term“solvate” 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 including hydrates and alcoholates, e.g. methanolate. 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 compounds of the invention: 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 prodrug of a compound of formula (I) is within the scope of the invention. Particularly favored prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

In a particular and preferred embodiment, Wi is N and W ₂ , W ₃ , and W ₄ are C or CH.

In another particular and preferred embodiment, W ₂ is N and W ₁ , W ₃ , and W ₄ are C or CH.

In yet another particular and preferred embodiment, W ₄ is N and W ₁ , W ₂ , and W ₃ are C or CH.

In another particular and preferred embodiment of the invention, Ri is selected from

wherein W ₅ , A, Rib, Ri _c , Rid, Rie, Rif and Ri _g are as defined before.

In a still more particular and prefered embodiment Ri represents: wherein W ₅ , A, Ri _b , Ri _c and Ri _d have the meaning as defined above.

In another particular and preferred embodiment of the invention, Ri _a represents a hydrogen atom or a methyl radical.

In another particular and preferred embodiment of the invention, W ₅ represents a -NR ₅ radical and A represents a CH.

In another particular and preferred embodiment of the invention, R ₅ represents a hydrogen atom.

In another particular and preferred embodiment of the invention, W ₅ represents a - (CH ₂ ) _p - radical, p being as defined above and A represents a N.

In another particular and preferred embodiment of the invention, Ri _b and Ri _c independently represent a methyl or ethyl radical and still more preferably, both represents a methyl radical.

In another particular and preferred embodiment of the invention, Ri _e represents a methyl radical and Ri _f represents a hydrogen atom.

In another particular and preferred embodiment of the invention, Ri _g represents a phenyl radical.

In a still more particular and preferred embodiment of the invention, Ri _e represents a methyl radical, Ri _f represents a hydrogen atom and Ri _g represents a phenyl radical.

In another particular and preferred embodiment of the invention, R ₂ is a radical selected from: methyl, ethyl, n-propyl and -(CH ₂ ) ₂ -OCH ₃ . In another particular and preferred embodiment of the invention, R ₃ is a radical selected from:

wherein R _a , R _t> , R _c and R _d are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical, preferably methyl or ethyl.

In another particular and preferred embodiment of the invention, R ₄ represents a branched or unbranched C1-6 alkyl radical, more preferable ethyl or n-propyl.

In an even more particular and preferred embodiment R ₄ represents n-propyl.

A preferred embodiment of the invention is represented by a compound of general formula (I):

wherein Ri _a represents a hydrogen atom or a methyl radical;

W1 is N;

W ₂ , W ₃ , and W ₄ are C or CH;

R1 is selected from

W ₅ is -NR ₅ ;

R ₅ is a hydrogen atom or a branched or unbranched C _1-6 alkyl radical;

A is CH;

Ri _b and Ri _c both represents a methyl radical;

Ri _d is a hydrogen atom, -OH, a branched or unbranched C _1-6 alkyl radical, a branched or unbranched C _1-6 alcoxy radical, -CN, a C _1-6 haloalkyl radical or halogen atom;

Ri _e represents a methyl radical;

Ri _f represents a hydrogen atom;

Ri _g represents a phenyl group;

R ₂ is a group selected from: methyl, ethyl, n-propyl and -(CH2)2-OCH3;

R ₃ is a group selected from:

R _a is a radical selected from hydrogen atom, methyl and ethyl;

R _b is a radical selected from hydrogen atom, methyl and ethyl;

R _c is a radical selected from hydrogen atom, methyl and ethyl;

R _d is a radical selected from hydrogen atom, methyl and ethyl;

R ₄ represents a branched or unbranched C _1-6 alkyl radical, more preferable ethyl or n- propyl; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

Another preferred embodiment of the invention is represented by a compound of general formula (I):

wherein Ri _a represents a hydrogen atom or a methyl radical;

W ₁ is N;

W ₂ , W ₃ , and W ₄ are C or CH

R ₁ is selected from

W ₅ is -(CH ₂ )p-;

p is 0, 1 ;

A is N;

Ri _b and Ri _c both represents a methyl radical;

Ri _d is a hydrogen atom, -OH, a branched or unbranched C _1-6 alkyl radical, a branched or unbranched C _1-6 alcoxy radical, -CN, a C _1-6 haloalkyl radical or halogen atom;

Ri _e represents a methyl radical;

Ri _f represents a hydrogen atom;

Ri _g represents a phenyl radical;

R ₂ is a radical selected from: methyl, ethyl, n-propyl and -(CH ₂ ) ₂ -OCH ₃ ;

R _{3 IS} a radical selected from:

R _a is a radical selected from hydrogen atom, methyl and ethyl;

R _b is a radicalselected from hydrogen atom, methyl and ethyl;

R _c is a radical selected from hydrogen atom, methyl and ethyl;

R _d is a radical selected from hydrogen atom, methyl and ethyl;

R ₄ represents a branched or unbranched C _1-6 alkyl radical, more preferable ethyl or n- propyl; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

A preferred embodiment of the invention is represented by a compound of general formula (I):

wherein Ri _a represents a hydrogen atom or a methyl radical;

W ₂ is N;

Wi, W ₃ , and W ₄ are C or CH;

Ri is selected from

W ₅ is NR ₅ ;

R ₅ is a hydrogen atom or a branched or unbranched C _1-6 alkyl radical;

A is CH;

Ri _b and Ri _c both represents a methyl radical;

Ri _d is a hydrogen atom, -OH, a branched or unbranched C _1-6 alkyl radical, a branched or unbranched C _1-6 alcoxy radical, -CN, a C _1-6 haloalkyl radical or halogen atom;

Ri _e represents a methyl radical;

Ri _f represents a hydrogen atom;

Ri _g represents a phenyl radical;

R ₂ is a radical selected from: methyl, ethyl, n-propyl and -(CH2)2-OCH3;

R _{3 IS} a radical selected from:

R _a is a radical selected from hydrogen atom, methyl and ethyl;

R _b is a radical selected from hydrogen atom, methyl and ethyl;

R _c is a radical selected from hydrogen atom, methyl and ethyl;

R _d is a radical selected from hydrogen atom, methyl and ethyl;

R ₄ represents a branched or unbranched C _1-6 alkyl radical, more preferable ethyl or n- propyl; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

Another preferred embodiment of the invention is represented by a compound of general formula (I):

wherein Ri _a represents a hydrogen atom or a methyl radical;

W ₂ is N;

Wi, W ₃ , and W ₄ are C or CH;

Ri is selected from

W ₅ is -(CH ₂ )p-; p is 0, 1 ;

A is N;

Ri _b and Ri _c both represents a methyl radical;

Ri _d is a hydrogen atom, -OH, a branched or unbranched C _1-6 alkyl radical, a branched or unbranched C _1-6 alcoxy radical, -CN, a C _1-6 haloalkyl radical or halogen atom;

Ri _e represents a methyl radical;

Ri _f represents a hydrogen atom;

Ri _g represents a phenyl radical;

R ₂ is a group selected from: methyl, ethyl, n-propyl and -(CH ₂ ) ₂ -OCH ₃ ;

R ₃ is a group selected from:

R _a is a radical selected from hydrogen atom, methyl and ethyl;

R _b is a radical selected from hydrogen atom, methyl and ethyl;

R _c is a radical selected from hydrogen atom, methyl and ethyl;

R _d is a radical selected from hydrogen atom, methyl and ethyl;

R ₄ represents a branched or unbranched C _1-6 alkyl radical, more preferable ethyl or n- propyl; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

A preferred embodiment of the invention is represented by a compound of general formula (I):

wherein Ri _a represents a hydrogen atom or a methyl radical; W ₄ is N;

W ₁ , W ₂ , and W ₃ are C or CH;

R ₁ is selected from

Ws is -NR ₅ ;

R ₅ is a hydrogen atom or a branched or unbranched C _1-6 alkyl radical;

A is CH;

Ri _b and Ri _c both represents a methyl radical;

Ri _d is a hydrogen atom, -OH, a branched or unbranched C _1-6 alkyl radical, a branched or unbranched C _1-6 alcoxy radical, -CN, a C _1-6 haloalkyl radical or halogen atom;

Ri _e represents a methyl radical;

Ri _f represents a hydrogen atom;

Ri _g represents a phenyl radical;

R ₂ is a radical selected from: methyl, ethyl, n-propyl and -(CH2)2-OCH3;

R _{3 IS} a radicalselected from:

R _a is a radical selected from hydrogen atom, methyl and ethyl;

R _b is a radical selected from hydrogen atom, methyl and ethyl;

R _c is a radical selected from hydrogen atom, methyl and ethyl;

R _d is a radical selected from hydrogen atom, methyl and ethyl;

R ₄ represents a branched or unbranched C _1-6 alkyl radical, more preferable ethyl or n- propyl; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. Another preferred embodiment of the invention is represented by a compound of general formula (I):

wherein Ri _a represents a hydrogen atom or a methyl radical;

W ₄ is N;

W1, W ₂ , and W ₃ are C or CH;

R1 is selected from

W ₅ is -(CH ₂ ) _p -;

p is 0, 1 ;

A is N;

Ri _b and Ri _c both represents a methyl radical;

Ri _d is a hydrogen atom, -OH, a branched or unbranched C1-6 alkyl radical, a branched or unbranched C1-6 alcoxy radical, -CN, a C1-6 haloalkyl radical or halogen atom;

Ri _e represents a methyl radical;

Ri _f represents a hydrogen atom;

Ri _g represents a phenyl radical;

R ₂ is a radical selected from: methyl, ethyl, n-propyl and -(CH ₂ ) ₂ -OCH ₃ ;

R3 IS a radical selected from:

R _a is a radical selected from hydrogen atom, methyl and ethyl;

R _b is a radical selected from hydrogen atom, methyl and ethyl;

R _c is a radical selected from hydrogen atom, methyl and ethyl;

R _d is a radical selected from hydrogen atom, methyl and ethyl;

R ₄ represents a branched or unbranched C alkyl radical, more preferable ethyl or n- propyl; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

The compounds of the present invention represented by the above described general formula (I) may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of double bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

The preferred compounds of the invention showing affinity towards the subunit a2d-1 of voltage-gated calcium channels (VGCC) and the m-opiod receptor are selected from the following group:

[1 ] 2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5-b]pyridine;

[2] 6-Bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl-7-methyl-3/-/- imidazo[4,5-b]pyridine;

[3] 2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-7-methyl-3/-/-imidazo[4,5- fc*] pyridine;

[4] 6-Bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- fc*] pyridine;

[5] 6-Bromo-3-ethyl-2-(1-(4-methyl-1 ,4-diazepan-1-yl)butyl)-3/-/-imidazo[4,5-t)]pyridine;

[6] 6-Bromo-3-ethyl-2-(1 -(4-ethyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridine;

[7] 3-Ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridine; [8] (S)-6-Bromo-3-ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- pyridine;

[9] (R)-6-Bromo-3-ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- pyridine;

[10] 6-Bromo-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3-propyl-3/-/-imidazo[4,5- pyridine;

[1 1 ] 6-Bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- pyridine;

[12] 6-Bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- c]pyridine;

[13] 6-Bromo-3-methyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- c]pyridine;

[14] 6-Bromo-2-(1 -(4-ethyl-1 ,4-diazepan-1 -yl)butyl)-3-propyl-3/-/-imidazo[4,5-b]pyridine;

[15] 6-Bromo-2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3,7-dimethyl-3/-/- imidazo[4,5-b]pyridine;

[16] 3-Ethyl-6-fluoro-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridine;

[17] 3-Ethyl-2-(1 -(4-ethyl-1 ,4-diazepan-1 -yl)butyl)-6-fluoro-3/-/-imidazo[4,5-b]pyridine;

[18] 1 -Ethyl-6-fluoro-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-imidazo[4,5-b]pyridine;

[19] 6-Bromo-3-ethyl-2-((R)-1 -((R)-3-methylpiperazin-1 -yl)butyl)-3/-/-imidazo[4,5- pyridine;

[20] 6-Bromo-3-ethyl-2-((S)-1 -((R)-3-methylpiperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[21 ] 3-Ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5-c]pyridine;

[22] 6-Bromo-3-ethyl-2-((S)-1 -((R)-6-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[23] 6-Bromo-3-ethyl-2-((S)-1 -((S)-6-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[24] 6-Bromo-3-ethyl-2-((R)-1 -((S)-6-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[25] 6-Bromo-3-ethyl-2-((R)-1 -((R)-6-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[26] 6-Bromo-1 -ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-imidazo[4,5-b]pyridine;

[27] 6-Bromo-3-ethyl-2-((R)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[28] 6-Bromo-3-ethyl-2-((S)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine; [29] 6-Bromo-3-ethyl-7-methyl-2-((/?)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-3/-/- imidazo[4,5-5]pyridine;

[30] 6-Bromo-3-ethyl-7-methyl-2-((S)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-3/-/- imidazo[4,5-b]pyridine;

[31 ] 1 -Ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 /-/-imidazo[4,5-c]pyridine;

[32] 1 -Ethyl-2-((R)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-1 /-/-imidazo[4,5-c]pyridine;

[33] 1 -Ethyl-2-((S)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-1 /-/-imidazo[4,5-c]pyridine;

[34] 3-Ethyl-2-((S)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-3/-/-imidazo[4,5-c]pyridine;

[35] 3-Ethyl-2-((R)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-3/-/-imidazo[4,5-c]pyridine;

[36] 6-Bromo-1 -ethyl-2-((R)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-1 /-/-imidazo[4,5- b]pyridine;

[37] 6-Bromo-1 -ethyl-2-((S)-1 -((S)-3-methylpiperazin-1 -yl)butyl)-1 /-/-imidazo[4,5- b]pyridine;

[38] 2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-6-(pyridin-4-yl)-3/-/- imidazo[4,5-b]pyridine;

[39] 1 -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H-imidazo[4,5-b]pyridin- 6-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[40] 3-(4-(Dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/- imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)phenol;

[41 ] 3-(4-(Dimethylamino)-1 -(2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl- 3/-/-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)phenol;

[42] 3-(4-(Dimethylamino)-1 -(2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3- ethyl-3/-/-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)phenol;

[43] 1 -(3-Ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)-/V,/V-dimethyl-4 - phenylpiperidin-4-amine;

[44] 3-(4-(Dimethylamino)-1 -(3-ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridin-6-yl)piperidin-4-yl)phenol;

[45] 1 -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- b]pyridin-6-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[46] 3-(4-(Dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methyl- 3/-/-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)phenol;

[47] 1 -(3-Ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)- /V,/V-dimethyl-4-phenylpiperidin-4-amine;

[48] 3-(4-(Dimethylamino)-1 -(3-ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/- imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)phenol;

[49] 3-(4-(Dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-propyl- 3/-/-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)phenol; [50] (1 S,4s)-/V ⁴ -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-propyl-3/-/- imidazo[4, 5-6]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[51 ] 1 -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-(2-methoxyethyl)-3/-/- imidazo[4,5-b]pyridin-6-yl)-/V,/V-dimethyl-4-phenylpiperidin -4-amine;

[52] 3-(4-(Dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-(2- methoxyethyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl )phenol;

[53]; 1 -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-5-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[54] 3-(4-(Dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/- imidazo[4,5-b]pyridin-5-yl)piperidin-4-yl)phenol;

[55] (1 S,4s)-/V ⁴ -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-(2-methoxyethyl)-3/-/- imidazo[4, 5-b]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[56] (1 S,4s)-/V ⁴ -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-5-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenyl cyclohexane-1 ,4-diamine;

[57] 1 -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)propyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-6-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[58] 3-(4-(Dimethylamino)-1 -(2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)propyl)-3-ethyl- 3/-/-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)phenol;

[59] (1 S,4s)-/V4-(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)propyl)-3-ethyl-3/-/- imidazo[4,5-b]pyridin-6-yl)-/V1 ,/V1 -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[60] (1 S,4s)-/V ⁴ -(2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3H- imidazo[4,5-b]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[61 ] (1 R,4s)-N ⁴ -(2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3H- imidazo[4,5-b]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[62] (1 S,4s)-/V ⁴ -(2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3H- imidazo[4,5-b]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[63] 1 -(2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-5-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[64] 1 -(2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-5-yl)-/V,/V-dimethyl-4-phenylpiperidin-4-amine;

[65] (1 R,4r)-/V ⁴ -(2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3H- imidazo[4,5-b]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[66] (1 S,4r)-/V ⁴ -(2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3H- imidazo[4,5-b]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[67] 3-((1 R,4s)-1 -(Dimethylamino)-4-((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-3-methyl-3/-/-imidazo[4,5-b]pyridin-6-yl)amino)cyc lohexyl)phenol; [68] 3-((1 S,4s)-1 -(Dimethylamino)-4-((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-3-methyl-3/-/-imidazo[4,5-ib]pyridin-6-yl)amino)cy clohexyl)phenol;

[69] 3-((1 S,4r)-1 -(Dimethylamino)-4-((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-3-methyl-3/-/-imidazo[4,5-t)]pyridin-6-yl)amino)cy clohexyl)phenol;

[70] 3-((1 R, 4r)-1 -(Dimethylamino)-4-((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 - yl)butyl)-3-methyl-3/-/-imidazo[4,5-b]pyridin-6-yl)amino)cyc lohexyl)phenol;

[71 ] (1 S,4s)-/V ⁴ -(3-Ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)-/V ¹ ,/V ¹ - dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[72] (1 S,4s)-/V*-(3-Ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3H-imidazo[4,5- b]pyridin-6-yl)-/V ¹ ,/V ¹ -dimethyl-1 -phenylcyclohexane-1 ,4-diamine;

[73] 1 -((2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-am ine;

[74] 3-(4-(Dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3- ethyl-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl) phenol;

[75] 3-(4-(Dimethylamino)-1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3- ethyl-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl) phenol;

[76] 3-(4-(Dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methyl- 3/-/-imidazo[4,5-c]pyridin-6-yl)methyl)piperidin-4-yl)phenol ;

[77] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-am ine;

[78] 1 -((2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-/V,/V-dimethyl-4-phenylpiperidin-4-am ine;

[79] 3-(4-(Dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-(2- methoxyethyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperid in-4-yl)phenol;

[80] 3-(4-(Dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)propyl)-3-ethyl- 3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl)phenol ;

[81] 3-(4-(Dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl- 3/-/-imidazo[4,5-b]pyridin-5-yl)methyl)piperidin-4-yl)phenol ;

[82] 1 -((3-Ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)-/V,/V- dimethyl-4-phenylpiperidin-4-amine;

[83] (S)-1 -((3-Ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)- /V,/V-dimethyl-4-phenylpiperidin-4-amine;

[84] (R)- 1 -((3-Ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)- /V,/V-dimethyl-4-phenylpiperidin-4-amine;

[85] 3-(4-(Dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methyl- 3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl)phenol ; [86] 3-(4-(Dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3- methyl-3/-/-imidazo[4,5-t)]pyridin-6-yl)methyl)piperidin-4-y l)phenol;

[87] 3-(4-(Dimethylamino)-1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3- methyl-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl )phenol;

[88] 3-(4-(Dimethylamino)-1 -((2-(1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-propyl- 3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl)phenol ;

[89] 3-(4-(Dimethylamino)-1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3- propyl-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl )phenol;

[90] 3-(4-(Dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3- propyl-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl )phenol;

[91] 3-(4-(Dimethylamino)-1 -((3-ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/- imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[92] (S)-3-(4-(Dimethylamino)-1 -((3-ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/- imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[93] (R)-3-(4-(Dimethylamino)-1 -((3-ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/- imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[94] (S)-/V,/V-Dimethyl-1 -((3-methyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin- 6-yl)methyl)-4-phenylpiperidin-4-amine;

[95] (R)-/V,/V-Dimethyl-1 -((3-methyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5-b]pyridin- 6-yl)methyl)-4-phenylpiperidin-4-amine;

[96] (R)-3-(4-(Dimethylamino)-1 -((3-ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[97] (S)-3-(4-(Dimethylamino)-1 -((3-ethyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[98] (R)-3-(4-(Dimethylamino)-1 -((3-methyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[99] (S)-3-(4-(Dimethylamino)-1 -((3-methyl-2-(1 -(piperazin-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[100] 1 -((2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-/V,/V-diethyl-4-phenylpiperidin-4-ami ne;

[101 ] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-/V,/V-diethyl-4-phenylpiperidin-4-ami ne;

[102] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpip eridin-4-amine;

[103] 1 -((2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-4-(4-methoxyphenyl)-/V,/V-dimethylpip eridin-4-amine; [104] 1 -((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpip eridin-4-amine;

[105] 1 -((2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-methyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)-4-(3-methoxyphenyl)-/V,/V-dimethylpip eridin-4-amine;

[106] (S)-/V,/V-Dimethyl-4-phenyl-1 -((2-(1 -(piperazin-1 -yl)butyl)-3-propyl-3/-/- imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-amine;

[107] (R)-/V,/V-Dimethyl-4-phenyl-1 -((2-(1 -(piperazin-1 -yl)butyl)-3-propyl-3/-/- imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4-amine;

[108] (S)-3-(4-(Dimethylamino)-1 -((2-(1 -(piperazin-1 -yl)butyl)-3-propyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[109] (R)-3-(4-(Dimethylamino)-1 -((2-(1 -(piperazin-1 -yl)butyl)-3-propyl-3/-/-imidazo[4,5- b]pyridin-6-yl)methyl)piperidin-4-yl)phenol;

[1 10] 3-(4-(Dimethylamino)-1 -((2-((S)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3,7- dimethyl-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4- yl)phenol;

[1 1 1 ] 3-(4-(Dimethylamino)-1 -((2-((R)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3,7- dimethyl-3/-/-imidazo[4,5-b]pyridin-6-yl)methyl)piperidin-4- yl)phenol;

[1 12] (S)-3-((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridin-6-yl)oxy)-/V-methyl-3-phenylpropan-1 -amine;

[1 13] (S)-3-((2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridin-6-yl)oxy)-/V-methyl-3-phenylpropan-1 -amine;

[1 14] (R)-3-((2-((R)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridin-6-yl)oxy)-/V-methyl-3-phenylpropan-1 -amine;

[1 15] (R)-3-((2-((S)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridin-6-yl)oxy)-/V-methyl-3-phenylpropan-1 -amine;

[1 16] 3-ethyl-6-fluoro-2-((R)-1 -((R)-5-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[1 17] 3-ethyl-6-fluoro-2-((R)-1 -((S)-5-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine;

[1 18] 3-ethyl-6-fluoro-2-((S)-1 -((R)-5-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine; and

[1 19] 3-ethyl-6-fluoro-2-((S)-1 -((S)-5-methyl-1 ,4-diazepan-1 -yl)butyl)-3/-/-imidazo[4,5- b]pyridine. or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof. Among all the compounds described in the general formula (I), the following compounds of general formula (la), showing dual affinity towards the subunit a2d-1 of voltage-gated calcium channels (VGCC) and the m-receptor, are preferred:

wherein n, W ₅ , A, Ri _a , Rib, Ric, Rid, R2 and R3 have the meaning as defined above or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

In another aspect, the invention refers to the processes for the preparation of the compounds of general formula (I):

The different reactions of the synthetic process of the invention as well as reactions for preparing the intermediate compounds for such reactions are depicted in Scheme 1 :

Scheme 1 wherein Ri, Ri _a , R2, R3, R ₄ , Wi, W ₂ , W3, W ₄ and n have the meanings as defined above and LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate).

A compound of general formula (I) can be obtained directly, in one-step reaction, by treating a compound of general formula (II):

wherein R ₁ , Ri _a , R ₂ , W ₁ , W ₂ , W ₃ , W ₄ and n have the meanings as defined above, with an acid of general formula (VII):

wherein Rs and R ₄ meanings as defined above, in the presence of a suitable condensing agent, such as polyphosphoric acid, at a suitable temperature, preferably between 50 and 150 °C. Alternativelly, a compound of general formula (I) can be obtained through a three step process, as follows:

• Step 1 : A compound of general formula (IV):

can be prepared by treating a compound of general formula (II)

wherein Ri, Ri _a , R ₂ , W ₁ , W ₂ , W ₃ , W ₄ and n have the meanings as defined above, with an acid of general formula (III): wherein R ₄ has the meaning as defined above, in the presence of a suitable condensing agent, such as polyphosphoric acid, at a suitable temperature, preferably between 50 and 150 °C.

Step 2 : A compound of general formula (V):

wherein LG represents a leaving group, can be prepared by reacting a compound of formula (IV):

wherein Ri, Ri _a , R ₂ , W ₁ , W ₂ , W ₃ , W ₄ and n have the meanings as defined above, with a suitable halogenating agent, such as bromine in the presence of a suitable solvent, such as acetic acid, at a suitable temperature, preferably between room temperature and 100 °C.

• Step 3: A compound of general formula (I):

can be prepared comprising the reaction of a compound of general formula (V):

wherein R ₁ , Ri _a , R ₂ , W ₁ , W ₂ , W ₃ , W ₄ , R ₄ and n have the meanings as defined above and LG represents a leaving group, with a suitable nucleophilic reagent of general formula (VI): R ₃ H

(VI) wherein R3 has the meaning as defined above, in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K ₂ CO ₃ or /V,/V-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 activating agent such as sodium iodide or potassium iodide can be used.

Alternatively, a compound of general formula (V):

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

wherein Ri, Ri _a , R ₂ , W ₁ , W ₂ , W ₃ , W ₄ , R ₄ and n have the meanings as defined above, into a leaving group. 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.

A compound of general formula (IX): may be obtained by condensing a compound of general formula (II)

with compound of general formula (VIII): wherein R ₄ has de meaning as defined above, using the conditions for the above described step 1.

In addition, certain compounds of the present invention can also be obtained by functional group interconversion over compounds of general formula (I) or any of the intermediates shown in Scheme 1. As a matter of example:

· a compound in which R ₂ is hydrogen can be converted to a compound in which

R ₂ is C alkyl by reaction with a suitable halo-Ci- ₆ alkyl derivative in the presence of a base, such as sodium hydride, in a suitable solvent, such as dimethylformamide, at a suitable temperature, such as room temperature.

• a compound in which Ri is halogen may be converted to a compound in which Ri is aryl or heteroaryl by coupling using a Pd catalyst such as tetrakis triphenylphosphine palladium(O) or palladium acetate, using a suitable base such as potassium carbonate, in a suitable solvent such as dimethoxyethane or mixtures dimethoxyethane/water, at a suitable temperature, preferably heating and optionally under microwave irradiation.

• a compound in which Ri is halogen may be converted to a compound in which Ri is:

wherein W ₅ , A, Ri _b , Ri _c and Ri _d have the meaning as defined above, by reaction with a compound of general formula (X) or (XI):

under standard Buchwald-Hartwig arylation conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipailadium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP 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.

Or, alternatively, by reaction with a compound of general formula (XII):

by coupling using a Pd catalyst such as palladium acetate, using a suitable base such as potassium carbonate, in a suitable solvent such as tert- butanol, at a suitable temperature, preferably heating and optionally under microwave irradiation.

A compound of general formula (XII) may be obtained by reaction of a compound of general 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.

• a compound in which Ri is halogen may be converted to a compound in which Ri is OH by reaction with a boronic ester, such as 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) in the presence of a Pd catalyst such as (1 ,1 - bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, in a suitable solvent, such as 1 ,4-dioxane at a suitable temperature, such as heating, followed by treatment with H2O2 in a suitable solvent such as acetic acid, at a suitable temperature such as room temperature.

• a compound in which Ri is OH may be converted to a compound in which Ri is

by alkylation with a compound of general formula (XIII):

wherein R^, Ri _g , Ri _h and LG have the meanings as defined above, in the presence of a base such as sodium hydride, in a suitable solvent, such as dimethylformamide, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out under microwave heating. Additionally, an activating agent such as sodium iodide or potassium iodide can be used.

The compounds of general formula (II), (III), (VI), (VII), (VIII), (X), (XI) and (XIII) used in the methods and schemes 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 general formula (I) can be obtained in enantiopure form by resolution of a racemic compound of general formula (I) either by chiral preparative HPLC or by crystallization of a diastereomeric salt or co-crystal. Alternatively, the resolution step can be carried out at a previous stage, using any suitable intermediate.

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. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

Another particular aspect is represented by the intermediate compounds used for preparation of compounds of general formula (I).

In a particular embodiment, these intermediate compounds for the preparation of the compounds of general formula (I) are selected from:

• Potassium ((4-(dimethylamino)-4-phenylpiperidin-1 -yl)methyl)trifluoroborate and

• tert- Butyl (3-chloro-3-phenylpropyl)(methyl)carbamate.

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.

They are suitable for 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/or the m-receptor. In this sense, compounds of general formula (I) are suitable for the treatment and/or prophylaxis of 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 (ADHD).

The compounds of general formula (I) are especially suited for the treatment of pain, especially neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia. PAIN is defined by the International Association for the Study of Pain (IASP) as“an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified.

In a preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of allodynia and more specifically mechanical or thermal allodynia.

In another preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of hyperalgesia.

In yet another preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of neuropathic pain and more specifically for the treatment and/or prophylaxis of hyperpathia.

A related aspect of the invention refers to the use of compounds of general formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and/or the m-receptor, as explained before.

Another related aspect of the invention refers to a method for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d- 1 subunit of voltage-gated calcium channels and/or the m-receptor, as explained before comprising the administration of a therapeutically effective amount of a compound of general formula (I) to a subject in need thereof.

Another aspect of the invention is a pharmaceutical composition, which comprises at least a compound of general formula (I) or a pharmaceutically acceptable salt, prodrug, isomer or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

The pharmaceutical composition of the invention can be formulated as a medicament in different pharmaceutical forms comprising at least a compound binding to the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and/or the m- receptor and optionally at least one further active substance and/or optionally at least one auxiliary substance.

The auxiliary substances or additives can be selected among carriers, excipients, support materials, lubricants, fillers, solvents, diluents, colorants, flavour conditioners such as sugars, antioxidants and/or agglutinants. In the case of suppositories, this may imply waxes or fatty acid esters or preservatives, emulsifiers and/or carriers for parenteral application. The selection of these auxiliary materials and/or additives and the amounts to be used will depend on the form of application of the pharmaceutical composition.

The pharmaceutical composition in accordance with the invention can be adapted to any form of administration, be it orally or parenterally, for example pulmonarily, nasally, rectally and/or intravenously

Preferably, the composition is suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal administration.

The composition of the invention can be formulated for oral administration in any form preferably selected from the group consisting of tablets, dragees, capsules, pills, chewing gums, powders, drops, gels, juices, syrups, solutions and suspensions. The composition of the present invention for oral administration may also be in the form of multiparticulates, preferably microparticles, microtablets, pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.

Suitable preparations for parenteral applications are solutions, suspensions, reconstitutable dry preparations or sprays. The compounds of the invention can be formulated as deposits in dissolved form or in patches, for percutaneous application.

Skin applications include ointments, gels, creams, lotions, suspensions or emulsions. The preferred form of rectal application is by means of suppositories.

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 the 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.

The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans may preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day. The following examples are merely illustrative of certain embodiments of the invention and cannot be considered as restricting it in any way.

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 intermediates and examples:

ACN: Acetonitrile

Ar: Argon

tBuOH: tert- Butanol

CH: Cyclohexane

DCM: Dichloromethane

DMF: Dimethylformamide

EtOAc: Ethyl acetate

Et ₂ 0: Diethyl ether

EtOH: Ethanol

h: Hour/s

HPLC: High-performance liquid chromatography

MeOH: Methanol

MS: Mass spectrometry

Min: Minutes

Quant: Quantitative

Rt: Retention time

rt: Room temperature

sat: Saturated

sol: Solution

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

TEA: EtsN, Triethylamine

Wt: Weight

Analytical Methods

METHOD A Column Aquity UPLC BEH C18 2.1 x 50 mm, 1 .7 qm, flow rate 0.61 mL/min; A: NH4HCO3 10 mM, B: ACN, C: MeOH + 0.1 % formic acid; gradient 0.3 min 98% 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 2 min 100% B.

METHOD B

Column Acquity UPLC BEH C18 2.1 x50 mm, 1 .7 qm; flow rate 0.61 mL/min; A: NH4HCO3 10mM; B: ACN; Gradient: 0.3 min in 98% A, 98% A to 5% A in 2.52 min, isocratic 1 .02 min 5% A.

METHOD C

Column Acquity UPLC BEH C18 2.1 x50 mm, 1 .7 qm; flow rate 0.60 mL/min; A: NH4HCO3 10mM; B: ACN; Gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 0.7 min 5% A.

METHOD D

Column Aquity UPLC BEH C18 2.1 x 50 mm, 1.7 qm, flow rate 0.61 mL/min; A:

NH4HCO3 10 mM, B: ACN; gradient 0.3 min 98% A, 98% to 0% A in 2.7 min; isocratic 2 min 0% A.

METHOD E

Column Acquity UPLC BEH C18 2.1 x50 mm, 1 .7 qm; flow rate 0.60 mL/min; A: HCO2NH4 10mM; B: ACN; Gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 0.7 min 5% A.

METHOD F

Column Acquity UPLC BEH C18 2.1 x50 mm, 1 .7 qm; flow rate 0.60 mL/min; A: NH4HCO3 10mM pH 10.6; B: ACN; Gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 0.7 min 5% A.

METHOD G

Column Aquity UPLC BEH C18 2.1 x 50 mm, 1.7 qm, flow rate 0.61 mL/min; A:

NH4HCO3 I O mM, B: ACN,; gradient 0.3 min 98% A, 98%A to 100% B in 2.65 min; isocratic 2.05 min 100% B.

METHOD H

Column Acquity UPLC BEH C18 2.1x50 mm, 1 .7 qm; flow rate 0.60 mL/min; A: ACONH4 10mM; B: ACN; Gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 0.7 min 5% A.

Column Aquity UPLC BEH C18 2.1 x 50 mm, 1 .7 qm, flow rate 0.61 mL/min; A: NH4HCO3 10 mM pH 10.6, B: ACN, C: MeOH + 0.1 % formic acid; gradient 0.3 min 98% 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 2 min 100% B.

METHOD J Column Aquity UPLC BEH C18 2.1 x 50 mm, 1 .7 pm, flow rate 0.6 mL/min; A: Water +0.1 % TFA; B: ACN + 0.1 % TFA; gradiente 95% A to 5% A in 4 min, 5% A to100% B in 0.02 min, isocratic 0.48 min 100 % B.

Synthesis of Intermediates

Intermediate 1. Potassium ((4-(dimethylamino)-4-phenylpiperidin-1 - yl)methyl)trifluoroborate.

To a suspension of /V,/V-dimethyl-4-phenylpiperidin-4-amine dihydrochloride (50 mg, 0.18 mmol) in THF/tBuOH (2:1 ) under argon atmosphere, TEA (55.3 mI_, 0.397 mmol) was added and the mixture was stirred at rt for 10 min. Then, potassium (bromomethyl)trifluoroborate (39.8 mg, 0.198 mmol) was added portion wise and the reaction was heated at reflux for 48 h. The solvent was removed under vacuum and the crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (90:10) to give the title compound (125 mg, Yield: 58%).

Boc

Intermediate 2. ferf-Butyl (3-chloro-3-phenylpropyl)(methyl)carbamate

To a solution of 3-chloro-N-methyl-3-phenylpropan-1 -amine hydrochloride (7.0 gr, 31 .8 mmol) in tBuOH (27 ml_), 2N NaOH solution (31 ml_, 63.6 mmol), and B0C2O (7.6 g, 33.5 mmol, 1 .02 eq) were added and the reaction mixture was stirred at r.t 10 min. NaCI sat sol was added and the product was extracted with DCM. The combined organic layers were dried over Mg ₂ S0 ₄ and concentrated filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, CH:CH/EtOAc (1 :1 ) to give the title compound (6.92 g, Yield: 77%).

Synthesis of Examples Example 1. 2-(1 -((3S,5/?)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H-imidazo[4,5- b]pyridine.

Step a. 2-Butyl-3H-imidazo[4,5-b]pyridine.

To a solution of pyridine-2, 3-diamine (2.0 g, 18.33 mmol) in polyphosphoric acid (30 g), pentanoic acid (2.4 ml_, 22 mmol) was added and the reaction mixture was stirred at 100 °C for 5 h. The reaction crude was cooled at 0 °C and aqueous ammonia was added. The product was extracted with EtOAc and washed with water. The combined organic layers were dried over Na2S0 ₄ , filtered and concentrated to dryness to give the title compound as a brown solid (2.55 g, Yield: 80%).

Step b. 2-Butyl-3-ethyl-3H-imidazo[4,5-b]pyridine.

To a suspension of sodium hydride (26.2 mg, 0.6 mmol, 60% wt dispersion in mineral oil) in DMF (2 ml_), the compound obtained in step a was added (100 mg, 0.571 mmol) and the reaction mixture was stirred at rt for 2 h. Then, the mixture was cooled to 0 °C and iodoethane (93.5 mg, 0.599 mmol) dissolved in DMF (2 ml.) was added. The mixture was stirred at rt overnight. The DMF was removed under vacuum and the crude was diluted in EtOAc and aqueous NaHCOs sat sol. The product was extracted with EtOAc and the combined organic layers were dried over Na2S0 ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient CH to EtOAc to give the title compound (58.0 mg, Yield: 50%).

Step c. 2-(1 -Bromobutyl)-3-ethyl-3H-imidazo[4,5-b]pyridine.

A solution of the compound obtained in step b (98 mg, 0.482 mmol) and sodium acetate (39.5 mg, 0.482 mmol) in glacial acetic acid (5 ml.) was heated at 50 °C. Then a solution of bromine in acetic acid (38 mI_, 0.725 mmol) was added drop wise. The reaction mixture was stirred at 50 °C for 5 h and at room temperature overnight. The crude was concentrated under vacuum; the residue was dissolved in EtOAc and washed with an aqueous NaHSOs sat sol and water. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient CH to EtOAc to give the title compound (50 mg, Yield: 37%). Step d. Title compound.

To a solution of the compound obtained in step c (48 mg, 0.170 mmol), TEA (95 mI_, 0.68 mmol), Kl (2.8 mg, 0.017 mmol) in anhydrous ACN (3 ml_), (2R,6S)-2,6- dimethylpiperazine (38.8 mg, 0.340 mmol) was added and the reaction mixture was heated to 90 °C and stirred for 8 h at this temperature. ACN was removed under vacuum and the residue was diluted with EtOAc and washed with aqueous NaHCCh sat sol. The combined organic layers were dried over Na2S0 ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (98:2) to give the title compound (30 mg, Yield: 56%).

HPLC-MS (B): Rt, 1.3 min; ESI+-MS m/z: 316.3.

This method was used for the preparation of Examples 2-3 using suitable starting materials:

Example 4. 6-Bromo-2-(1 -((3S,5/?)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridine.

Step a. 6-Bromo-2-butyl-3-ethyl-3H-imidazo[4,5-b]pyridine. Starting from 5-bromo-N ² -ethylpyridine-2, 3-diamine (520 mg, 2.40 mmol) and following the experimental procedure described in step a of Example 1 , the title compound was obtained (320 mg, Yield: 47%). Step b. 6-Bromo-2-(1 -bromobutyl)-3-ethyl-3H-imidazo[4,5-b]pyridine.

Starting from the compound obtained in step a (2.3 g, 8.15 mmol) and following the experimental procedure described in step c of Example 1 , the title compound was obtained (1.5 g, Yield: 51%). Step c. Title compound.

Starting from the compound obtained in step b (190 mg, 0.526 mmol) and following the experimental procedure described in step d of Example 1 , the title compound was obtained (185 mg, Yield: 89%).

HPLC-MS (A): Rt, 1.88 min; ESI+-MS m/z: (394.0).

This method was used for the preparation of Examples 5-37 using suitable starting materials:

^* The individual enantiomers were obtained using an additional chiral HPLC separation.

Example 38. 2-(1 -((3S,5/?)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-6-(pyridin-4- yl)-3H-imidazo[4,5-b]pyridine.

Step a. (2/?,6S)-ferf-Butyl 4-(1 -(6-bromo-3-ethyl-3H-imidazo[4,5-b]pyridin-2- yl)butyl)-2,6-dimethylpiperazine-1 -carboxylate.

To a solution of the compound obtained in Example 4 (1.8 g, 4.56 mmol), TEA (1.3 ml_, 9.13 mmol) in anhydrous DCM, di-fe/f-butyl dicarbonate (1.25 g, 5.71 mmol) was added under Ar atmosphere and the reaction mixture was stirred at rt overnight. The reaction crude was washed with aqueous NaHCC>3 sat sol, brine and water. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (8:2) to give the title compound (1.45 g, Yield: 64%).

Step b. (2S,6/?)-ferf-Butyl 4-(1 -(3-ethyl-6-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2- yl)butyl)-2,6-dimethylpiperazine-1 -carboxylate.

To a solution of the compound obtained in step a (110 mg, 0.22 mmol), K2CO3 (61.5 mg, 0.45 mmol), Pd(PPh3)4 (10 mg, 0.009 mmol) in a mixture DME/H2O (1 :1 ) under Ar atmosphere, pyridin-4-ylboronic acid (41 mg, 0.33 mmol) was added and the reaction mixture was heated under MW irradiation (130 °C, 150 W) for 30 min. The solvent was removed under vacuum and the crude was diluted in EtOAc and washed with aqueous NaHCC>3 sat sol. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (95:5) to give the title compound (70 mg, Yield: 64%).

Step c. Title compound.

To a solution of the compound obtained in step b (70 mg, 0.142 mmol) in anhydrous DCM (5 ml_), TFA (10 mg, 0.088 mmol) was added and the reaction mixture was stirred at rt overnight. Aqueous NaHCOs sat sol was added and the mixture was extracted with DCM. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (95:5) to give the title compound (50 mg, Yield: 90%). HPLC-MS (D): Rt,1.44 min; ESI+-MS m/z: (497.3). Example 39. rac-1 -(2-(1 -((3/?,5S)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridin-6-yl)-/V,/V-dimethyl-4-phenylpiperidin -4-amine.

Step a. (2/?,6S)-ferf-Butyl 4-(1 -(6-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)-3- ethyl-3H-imidazo[4,5-b]pyridin-2-yl)butyl)-2,6-dimethylpiper azine-1 -carboxylate.

To a solution of the compound obtained in step a of the Example 38 (150 mg, 0.3 mmol), Pd ₂ (dba) ₃ (14 mg, 0.015 mmol), XPhos (29.0 mg, 0.06 mmol), NaO‘Bu (99.1 mg, 1.03 mmol) in anhydrous dioxane (3 ml.) under argon atmosphere, N,N-dimethyl-4- phenylpiperidin-4-amine dihydrochloride was added. The reaction mixture was stirred at 1 10 °C for 4 h. Then, the reaction mixture was filtered through celite and solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (95:5) to give the title compound (130 mg, Yield: 70%). Step b. Title compound.

Starting from the compound obtained in step a (130 mg, 0.2 mmol) and following the experimental procedure described in step c of Example 38, the title compound was obtained (100 mg, Yield: 92%).

HPLC-MS (D): Rt,1.8 min; ESI+-MS m/z: (518.4).

This method was used for the preparation of Examples 40-72 using suitable starting materials

The individual enantiomers were obtained using an additional chiral HP C separation.

Example 73. 1 -((2-(1 -((3S,5/?)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridin-6-yl)methyl)-/V,/V-dimethyl-4-phenylpi peridin-4-amine.

Step a. (2S,6/?)-ferf-Butyl 4-(1 -(6-((4-(dimethylamino)-4-phenylpiperidin-1 - yl)methyl)-3 -ethyl -3H-imidazo[4,5-b]pyridin-2-yl)butyl)-2,6-dimethylpiperazine -1 - carboxylate

To a solution of the compound obtained in step a of the Example 38 (210 mg, 0.425 mmol), Pd(OAc)2 (1 1.5 mg, 0.051 mmol), XPhos (48.6 mg, 0.101 mmol) and CsCCh (415.2 mg, 1.27 mmol) in‘BuOH under argon atmosphere, Intermediate 1 (231 mg, 0.764 mmol) was added and the reaction mixture was stirred at 100 °C overnight. The solvent was removed under vacuum and the residue was diluted in EtOAc and washed with aqueous NaHCCh sat sol. The combined organic layers were washed with NaCI, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography silica gel, to give the title compound (136.0 mg, Yield: 49%).

Step b. Title compound.

Starting from the compound obtained in step a (133.0 mg, 0.210 mmol) and following the experimental procedure described in step c of Example 38, the title compound was obtained (75.0 mg, Yield: 68%).

HPLC-MS (E): Rt,1.57 min; ESI+-MS m/z: (532.2). This method was used for the preparation of Examples 74 to 1 11 using suitable starting materials.

^* The individual enantiomers were obtained using an additional chiral H 'LC separation.

Examples 112, 113, 114 and 115. (S)-3-((2-((S)-1 -((3S,5/?)-3,5-Dimethylpiperazin-1 - yl)butyl)-3-ethyl-3H-imidazo[4,5-fe]pyridin-6-yl)oxy)-/V-met hyl-3-phenylpropan-1 - amine, (S)-3 -((2 -((/?) -1 -((3S,5/?)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H- imidazo[4,5-b]pyridin-6-yl)oxy)-/V-methyl-3-phenylpropan-1 -amine, (/?)- 3-((2-((/?)-1 - ((3S,5/?)-3,5-Dimethylpiperazin-1 -yl)butyl)-3 -ethyl -3H-imidazo[4,5-b]pyridin-6- yl)oxy)-/V-methyl-3-phenylpropan-1 -amine and (/?)-3-((2-((S)-1 -((3S,5/?)-3,5- Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H-imidazo[4,5-b]pyridin-6-yl)oxy)-yV- methyl-3-phenylpropan-1 -amine.

Step a. (2-(1 -((3S,5/?)-4-(ferf-Butoxycarbonyl)-3,5-dimethylpiperazin-1 -yl)butyl)-3- ethyl-3H-imidazo[4,5-b]pyridin-6-yl)boronic acid.

To a solution of the compound obtained in step a of Example 38 (180 mg, 0.364 mmol), in dioxane (9 ml.) under Ar atmosphere, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (138.7 mg, 0.546 mmol), potassium acetate (71.45 mg, 0.73 mmol), 1 ,T- [bis(diphenylphosphino)ferrocene] palladium dichloride (13.3 mg, 0.018 mmol) were added and the reaction mixture was refluxed overnight. Then, the mixture was filtered through decalite, washed with EtOAc and the solvent was removed under vacuum to give the title compound (100 mg, Yield: 64%).

Step b. (2S,6/?)-ferf-Butyl 4-(1 -(3-ethyl-6-hydroxy-3H-imidazo[4,5-b]pyridin-2- yl)butyl)-2,6-dimethylpiperazine-1 -carboxylate.

To the compound obtained in step a (100 mg, 0.218 mmol), CH3COOH (62 mI_, 1 .088 mmol) and H2O2 (13 mI_, 0.43 mmol) were added at 0 °C. The mixture was allowed to reach rt and stirred for 45 min. Then, the mixture was filtered through decalite, the solvent was removed under vacuum and the crude product was purified by flash chromatography, silica gel, EtOAc/MeOH (97:3) to give the title compound (35 mg, Yield: 37 %).

Step c. (2S,6/?)-ferf-Butyl 4-(1 -(6-(3-((ferf-butoxycarbonyl)(methyl)amino)-1 - phenylpropoxy)-3-ethyl-3H-imidazo[4,5-b]pyridin-2-yl)butyl)- 2,6- dimethylpiperazine-1 -carboxylate.

To a solution of the compound obtained in step b (326 mg, 0.755 mmol) in anhydrous DMF (2 ml.) at 0 °C, sodium hydride (75.5 mg, 1.88 mmol, 60% wt dispersion in mineral oil) was added in portions and the mixture was stirred for 30 min at rt. Intermediate 2 (429 mg, 1.51 mmol) was added and the reaction mixture was stirred at 65 °C overnight. Then, NaHCC>3 aqueous sat sol was added and the product was extracted with EtOAc/Et20 (1 :1 ), washed with NaCI sat sol and water. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, DCM/MeOH (95:) to give the title compound (197 mg, Yield: 38%). Step d. 3-((2-(1 -((3S,5/?)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-3H-imidazo[4,5- b]pyridin-6-yl)oxy)-/V-methyl-3-phenylpropan-1 -amine.

Starting from the compound obtained in step c (259 mg, 0.381 mmol) and following the experimental procedure described in step c of Example 38, the title compound was obtained (175 mg, Yield: 96%).

Step e. Title compounds.

Starting from the product obtained in step d, a chiral preparative HPLC separation (column: Chiralcel ADH; temperature: ambient; flow: 12 mL/min; eluent: n- Heptane/(EtOH + 0,33% DEA) 93:7 v/v) was carried out to give the title compounds.

Following the experimental procedure described in Example 1 the following compounds were prepared.

Examples 116, 117, 118 and 119. 3-Ethyl-6-fluoro-2-((/?)-1 -((/?)-5-methyl-1 ,4- diazepan-1 -yl)butyl)-3H-imidazo[4,5-b]pyridine, 3-ethyl-6-fluoro-2-((/?)-1 -((S)-5- methyl-1 ,4-diazepan-1 -yl)butyl)-3H-imidazo[4,5-b]pyridine, 3-ethyl-6-fluoro-2-((S)- 1 -((/?)-5-methyl-1 ,4-diazepan-1 -yl)butyl)-3H-imidazo[4,5-b]pyridine and 3-ethyl-6- fluoro-2-((S)-1 -((S)-5-methyl-1 ,4-diazepan-1 -yl)butyl)-3H-imidazo[4,5-b]pyridine.

Examples 116, 117, 118 and 1 19 were directly separated using preparative HPLC: column Chiralpak IC 20x250 mm, 5 pm; temperature: r.t; eluent: n-Heptane/IPA/Et2NH 98/2/0.1 v/v/v; flow rate 15 mL/min; Rt1 : 24.9 min; Rt2: 27.9 min; Rt: 3: 35.0 min; Rt4:

48.9 min.

Examples of biological activity 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 pM pregabalin. The binding of the test compound was measured at either one concentration (% inhibition at 1 mM or 10 pM) or five different concentrations to determine affinity values (K,). 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 [ ³ H]-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 mM or 10 mM) or five different concentrations to determine affinity values (K,). 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.

The following scale has been adopted for representing the binding to the a2d-1 receptor, expressed as Ki:

+ Kί-a2d-1 >= 3000 nM

++ 500nM < Kί-a2d-1 <3000 nM

+++ 100nM < Kί-a2d-1 <500 nM

++++ Kί-a2d-1 <100 nM

Preferably, when K,(a ₂ d-1 ) > 3000 nM, the following scale has been adopted for representing the binding to the a, ₂ d-1 subunit of voltage-gated calcium channels:

+ K _ί (a ₂ d-1) > 3000 nM or inhibition ranges between 1 % and 50 %

For the m-opioid receptor, the following scale has been adopted for representing the binding, expressed as Ki:

+ Ki (m) >= 500 nM

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

+++ K _ί (m) < 100 nM Preferably, when K,(m) > 500 nM, the following scale has been adopted for representing the binding to the m-opioid receptor:

+ K,(m) > 500 nM or % inhibition ranges between 1 % and 50 %

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

Table 1