WO2020120606A1

WO2020120606A1 - New pyrrolidine-2-carboxylic acid derivatives for treating pain and pain related conditions

Info

Publication number: WO2020120606A1
Application number: PCT/EP2019/084717
Authority: WO
Inventors: Anita Wegert; Menno-Cornelis-Franciscus MONNEE; Wouter DE GRAAF
Original assignee: Esteve Pharmaceuticals, S.A.
Priority date: 2018-12-12
Filing date: 2019-12-11
Publication date: 2020-06-18

Abstract

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

Description

NEW PYRROLIDINE-2-CARBOXYLIC ACID DERIVATIVES FOR TREATING PAIN

AND PAIN RELATED CONDITIONS

FIELD OF THE INVENTION

The present invention relates to new compounds that show pharmacological activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d- 1 subunit of voltage-gated calcium channels or dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage-gated calcium channels, and the m-opiod receptor (MOR or mu-opioid). 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 (Cava25) and g (Ca_vy). The a1 subunits are the key porous forming units of the channel complex, being responsible for Ca²⁺ conduction and generation of Ca²⁺ 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_v3.1 , Ca_v3.2, and Ca_v3.3), and high voltage-activated L- (Ca_v1.1 through Ca_v1.4), N- (Ca_v2.2), P/Q-(Ca_v2.1), and R-(Ca_v2.3) types, depending on the channel forming Cava subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo; Neurotherapeutics; 2009; 6; 679-692; 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_v1 and Ca_v2 subfamilies contain an auxiliary a2d subunit which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain (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_va23-1 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<x25-1, but not Ca_v<x25-2, 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<x₂5-1 subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Ca_v<x25-1 subunit contributes to neuropathic allodynia.

The Ca_v<x25-1 subunit (and the Ca_v<x25-2, but not Ca_v<x25-3 and Ca_v<x25-4, subunits) is the binding site for gabapentin which has anti-allodynic/hyperalgesic properties in patients and animal models. Because injury-induced Ca_v<x25-1 expression correlates with neuropathic pain, development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability, injury-induced Ca_v<x25-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn. Intrathecal antisense oligonucleotides against the Ca_v<x25-1 subunit can block nerve injury-induced Ca_v<x25-1 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<x25-1 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, 113-6 (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 a2d subunit, in particular the a2d-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 in preferred embodiments 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 is -O- or -NR_a;

R_a is a hydrogen atom or a branched or unbranched Ci-e alkyl radical; n and m are independently from one another 0 or 1 ;

Ri and R_å are independently from one another a hydrogen atom; a branched or unbranched Ci-e alkyl radical; a halogen atom; a branched or unbranched Ci-e alkoxy radical; a -CN radical; a hydroxyl radical; or a Ci-₆ haloalkyl radical;

Rs is W₂ is -O- or -NR_3CI; p and q are independently from one another 0 or 1 ; v’ and v” are independently 1 or 2;

R3_a and R_3b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or

R3_a and R3_b 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-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;

R3_C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a - CN radical; a Ci-e haloalkyl radical; or a -NR_bR_c radical;

R_b and R_c are a hydrogen atom or a branched or unbranched Ci-e alkyl radical;

R_3d is a hydrogen atom or a branched or unbranched Ci-e alkyl radical;

R₄ is a hydrogen atom or a -C(0)R_4a radical;

R_4a is a hydrogen atom; a branched or unbranched C_1-6 alkyl radical; a branched or unbranched C_1-6 alkoxy radical; a -(CH₂)_r-NR_4bR_4c radical; a - 0CH(CH₃)0C(0)CH(CH₃)2 radical; or a -NR_4g-(CH₂)s-CH(R_4f)-NR_4eR4d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;

R₄ , R_4C, R_4d, R_4e, R_4g are independently from one another a hydrogen atom; or a branched or unbranched Ci-₆ alkyl radical;

R_4f is a hydrogen atom or a -COR_4h radical;

R_4h is a hydroxyl radical or a branched or unbranched Ci-₆ alkyl radical;

Re is a -C(0)R_5a radical or an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;

Re_a is a hydroxyl radical, a branched or unbranched Ci-₆ alkoxy radical; a -(ChhX- NRsbRsc radical; a -0CH(CH₃)0C(0)CH(CH₃)2 radical; or a -NR_5g-(CH2)v-CH(R_5f)- NR5eR5d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;

Re_b, Re_c, Re_d, Re_e, Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci-₆ alkyl radical;

Re_f is a hydrogen atom or a -CORs_h radical;

Re_h is a hydroxyl radical or a branched or unbranched Ci-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, especially neuropathic pain, central neuropathic pain and/or peripheral 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 is -O- or -NR_a;

R_a is a hydrogen atom or a branched or unbranched Ci-e alkyl radical; n and m are independently from one another 0 or 1 ; Ri and R_å are independently from one another a hydrogen atom; a branched or unbranched Ci-e alkyl radical; a halogen atom; a branched or unbranched Ci-e alkoxy radical; a -CN radical; a hydroxyl radical; or a Ci-₆ haloalkyl radical;

Rs is

W_å is -O- or -NR_3d; p and q are independently from one another 0 or 1 ; v’ and v” are independently 1 or 2;

R_3a and R_3b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or

R_3a and R_3b 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-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;

R_3C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a - -CN radical; a Ci-e haloalkyl radical; or a -NR_bR_c radical;

R_b and R_c are a hydrogen atom or a branched or unbranched Ci-e alkyl radical;

R_3d is a hydrogen atom or a branched or unbranched Ci-e alkyl radical; R₄ is a hydrogen atom or a -C(0)R_4a radical;

R_4a is a hydrogen atom; a branched or unbranched Ci-₆ alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(CH2)_r-NR4_bR4_c radical; a - 0CH(CH₃)0C(0)CH(CH₃)2 radical; or a -NR_4g-(CH₂)s-CH(R_4f)-NR_4eR4d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;

R_4b, R_4c,R_4d, R_4e, R_4g are independently from one another a hydrogen atom; or a branched or unbranched Ci-₆ alkyl radical;

R_4f is a hydrogen atom or a -COR_4h radical;

R_4h is a hydroxyl radical or a branched or unbranched Ci-₆ alkyl radical;

Re_a is a hydroxyl radical, a branched or unbranched Ci-e alkoxy radical; a -(CH₂)_t- NRsbRsc radical; a -0CH(CH₃)0C(0)CH(CH₃)₂ radical; or a -NR_5g-(CH₂)_v.CH(R_5f)- NR5eR5d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;

Re_f is a hydrogen atom or a -CORs_h radical;

Re_h is a hydroxyl radical or a branched or unbranched Ci-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 ¹³C- or ¹⁴C-enriched carbon, or the replacement of at least one nitrogen by ¹⁵N-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-e haloalkyl” or“Ci-e 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.

“Protecting group” is a group that is chemically introduced into a molecule to avoid that a certain functional group from that molecule undesirably reacts in a subsequent reaction. Protecting groups are used, among others, to obtain chemoselectivity in chemical reactions. The preferred protecting group in the context of the invention are Boc (te/f-butoxycarbonyl) or Teoc (2-(trimethylsilyl)ethoxycarbonyl).

“C1 -6 alkyl”, as referred to in the present invention, are saturated aliphatic radicals. They may be 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 -di ethyl propyl, 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 branched or unbranched Ci-₆-alkoxy radical, a branched or unbranched Ci-₆-alkyl radical, a Ci-₆-haloalkoxy radical, a Ci-₆-haloalkyl radical, CN, a trihaloalkyl radical, hydroxyl group and an amino radical such as -NR’R” wherein R’ and R” are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical .

“Ci-₆ alkoxy” as referered to in the present invention, is understood as meaning an alkyl 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.

“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 or 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 branched or unbranched Ci-₆-alkyl radical, a branched or unbranched Ci-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.

“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 branched or unbranched Ci-₆-alkyl radical; a branched or unbranched Ci-₆-alkoxy radical, a Ci-₆-haloalcoxy radical, a Ci-₆-haloalkyl radical; a trihaloalkyl radical or 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.

“Heteroaryl” as referred to in the present invention, is understood as meaning heterocyclic ring systems which have at least one aromatic ring and contain one or more heteroatoms from the group consisting of N, O or S and may optionally be mono- or polysubstituted by substituents independently selected from a halogen atom, a branched or unbranched Ci-₆-alkyl radical, a branched or unbranched Ci-₆-alkoxy radical, a Ci-e- 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.

“Heterocyclic system”, as defined in the present invention, comprises 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, CF₃, carboxy, amido, cyano, carbamyl, nitro, phenyl, benzyl, -SO2NH2, C_1-6 alkyl and/or Ci-₆-alkoxy.

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 “room temperature” in the context of this invention as the meaning of temperature between 20 and 25°C.

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 (NhV). 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 -0-.

In another particular and preferred embodiment, m is 0 and n is 0.

In another particular and preferred embodiment of the invention, Ri and R_å are independently from one another a hydrogen atom or a halogen atom, more preferable fluorine or chlorine.

In another particular and preferred embodiment of the invention R3 is in meta position.

In another particular and preferred embodiment of the invention R3 is selected from: wherein W_å, p, q, R_3a, R_3b and R_3C are as defined above.

In another particular and preferred embodiment of the invention R_3a and R_3b are independently from one another a branched or unbranched Ci-e alkyl radical, more preferable methyl.

In another particular and preferred embodiment of the invention, R_3C is a hydrogen atom or a halogen atom, more preferable fluorine.

In another particular and preferred embodiment of the invention R₄ is a hydrogen atom.

In another particular and preferred embodiment of the invention Rs_a is a hydroxyl radical or a branched or unbranched Ci-₆ alkoxy radical, preferably a methoxy radical.

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

wherein Ri, R_å, R₃, R₄ and R₅ are as defined above; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

A still more particularly preferred embodiment of the invention is represented by compounds of general formula (I’a): wherein Ri and R_å are independently from one another a hydrogen atom or a halogen atom, more preferable fluorine or chlorine;

R₃ is selected from:

W_å is -O- or -NR3d; p and q are independently from one another 0 or 1 ;

R_3a and R_3b are independently from one another a C_1-6 alkyl radical, more preferable methyl;

R_3C is a hydrogen atom or a halogen atom, more preferable fluorine;

R_3d is a hydrogen atom or a branched or unbranched C_1-6 alkyl radical;

R₄ is a hydrogen atom; R_4a is a hydrogen atom; a branched or unbranched Ci-₆ alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(CH2)_r-NR4_bR4c radical; a - 0CH(CH₃)0C(0)CH(CH₃)2 radical; or a -NR_4g-(CH₂)s-CH(R_4f)-NR_4eR4d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;

R_4b, R_4C, R_4d, R_4e, R_4g are independently from one another a hydrogen atom; or a branched or unbranched Ci-₆ alkyl radical;

R_4f is a hydrogen atom or a -COR_4h radical;

R_4h is a hydroxyl radical or a branched or unbranched Ci-₆ alkyl radical;

Re_a is a hydroxyl radical or a branched or unbranched Ci-e alkoxy radical, preferably a methoxy radical; 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.

In a particular and preferred embodiment of the invention, the compounds of general formula (I) are represented by the S,S-isomers according to the following general formula (la): wherein Wi, Ri, R₂, R₃, R₄ and R₅ are as defined before.

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

[1] (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy)

pyrrolidine-2-carboxylic acid;

[2] (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy)

pyrrolidine-2-carboxylic acid;

[3] (2S,4S)-4-(4-((((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl)

phenoxy)pyrrolidine-2-carboxylic acid;

[4] (2S,4S)-4-(4-((((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl)

phenoxy)pyrrolidine-2-carboxylic acid;

[5] (2S,4S)-4-(3-((((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl)

phenoxy)pyrrolidine-2-carboxylic acid;

[6] (2S,4S)-4-(3-((((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl)

phenoxy)pyrrolidine-2-carboxylic acid;

[7] (2S,4S)-4-(3-chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)

phenoxy)pyrrolidine-2-carboxylic acid;

[8] (2S,4S)-4-(3-chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)

phenoxy)pyrrolidine-2-carboxylic acid;

[9] (2S,4S)-4-(2-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy)

pyrrolidine-2-carboxylic acid;

[10] (2S,4S)-4-(3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[11] (2S,4S)-4-(3-chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)phenoxy)pyrrolidine-2-carboxylic acid;

[12] (2S,4S)-4-(3-chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)phenoxy)pyrrolidine-2-carboxylic acid; [13] (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[14] (2S,4S)-4-(3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[15] (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)oxy)phenoxy)

pyrrolidine-2-carboxylic acid;

[16] (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[17] (2S,4S)-4-(3-(((1 s,4R)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[18] (2S,4S)-4-(3-(((1 s,3R)-3-(dimethylamino)-3-phenylcyclobutyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[19] (2S,4S)-4-(3-(((1 r,3S)-3-(dimethylamino)-3-phenylcyclobutyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[20] (2S,4S)-4-(4-chloro-3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[21] (2S,4S)-4-(2-chloro-3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[22] (2S,4S)-4-(2-chloro-5-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-3-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[23] (2S,4S)-4-(4-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[24] (2S,4S)-4-(2-chloro-3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[25] (2S,4S)-4-(2-chloro-5-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-3-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[26] (2S,4S)-4-(5-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-2,3- difluorophenoxy)pyrrolidine-2-carboxylic acid and

[27] (2S,4S)-4-(5-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-2,3- difluorophenoxy)pyrrolidine-2-carboxylic acid; 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 (lb) or (lc) are preferred for showing dual affinity towards the subunit a2d-1 of voltage-gated calcium channels (VGCC) and the m-opioid receptor (MOR): wherein W_å, Ri, R_å, R3_a, R3_band R3_C are as defined before; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

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

[8] (2S,4S)-4-(3-chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)

phenoxy)pyrrolidine-2-carboxylic acid;

[12] (2S,4S)-4-(3-chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)phenoxy)pyrrolidine-2-carboxylic acid; [13] (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[14] (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[15] (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)oxy)phenoxy)

pyrrolidine-2-carboxylic acid;

[16] (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[18] (2S,4S)-4-(3-(((1s,3R)-3-(dimethylamino)-3-phenylcyclobutyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[19] (2S,4S)-4-(3-(((1r,3S)-3-(dimethylamino)-3-phenylcyclobutyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid;

[22] (2S,4S)-4-(2-chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-3-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[23] (2S,4S)-4-(4-chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[24] (2S,4S)-4-(2-chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[25] (2S,4S)-4-(2-chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-3-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[26] (2S,4S)-4-(5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-2,3- difluorophenoxy)pyrrolidine-2-carboxylic acid and

[27] (2S,4S)-4-(5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-2,3- difluorophenoxy)pyrrolidine-2-carboxylic acid; 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).

Several procedures have been developed for obtaining all the compounds of the invention. These procedures will be explained below in methods A and B.

METHOD A Method A represents a first process for synthesizing compounds according to general formula (I). Method A allows the preparation of compounds of general formula (A1 ) that is compounds of general formula (I) where Wi is -0-, namely Method A1 , and compounds of general formula (A2) that is compounds of general formula (I) where Wi is -N-, namely Method A2.

Method A1

A compound of general formula (A1):

wherein Ri , R₂, R₃, R₄, Rs, m and n have the meanings as defined above, can be prepared by treating a pyrrolidine derivative of general formula (lla):

wherein R₄, Rs and m have the meanings as defined above with a suitable derivative of general formula (Ilia):

wherein Ri , R2, R3 and n have the meanings as defined above, under Mitsunobu conditions using a suitable coupling agent, such as cyanomethylenetributylphosphorane (CM BP) or diisopropyl azodicarboxylate in the presence of a phosphine, such as triphenylphosphine, in the presence of a suitable solvent, such as toluene or tetrahydrofuran, at a suitable temperature, between room temperature and 100 °C, preferably room temperature. Method A2

A compound of general formula (A2):

wherein Ri , R2, R3, R4, Rs, Ra, m and n have the meanings as defined above, can be prepared by treating a pyrrolidine derivative of general formula (Mb):

lib wherein R4, Rs, Ra and m have the meanings as defined above, with a suitable derivative of general formula (lllb):

wherein Ri , R2, R3 and n have the meanings as defined above and Z is a halogen atom under the following reaction conditions:

a) For n = 0, the reaction may be carried out under Buchwad-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP 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 110 °C;

b) For n = 1 the reaction may be carried out under alkylation conditions, in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K₂CO₃ or A/./V-diisopropylethylamine, at a suitable temperature comprised between room temperature and the reflux temperature.

METHOD B

Method B represents an alternative process for synthesizing compounds according to general formula (I). Method B allows the preparation of compounds of general formula (I) from a compound of general formula (V):

wherein Ri, R₂, R₄, Rs, Wi, m and n have the meanings as defined above and Y represents a group that can be converted into R3 under the following conditions:

When Y is a halogen atom: a compound in which R3 is linked to the aryl group via a nitrogen atom (W2 = -NR3_d, q = 0) may be prepared by reaction of a compound of general formula (V) with a compound of general formula (VI) or (VII):

under Buchwald-Hartwig conditions, using suitable reagents, such as tris(dibenzylideneacetone)-dipalladium (0) (Pd2(dba)3), 4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (Xantphos) or 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (Ru-Phos) in the presence of a base, such as cesium carbonate, in suitable solvents, such as 1 ,4-dioxane, and with conventional heating at a suitable temperature, between 80 °C and 110 °C; When Y is an -NHR_3d (amino) group: a compound in which R₃ is linked to the aryl group via a nitrogen atom (W₂ = -NR_3d, p = 0 or 1) may be prepared by reaction of a compound of general formula (V) with a compound of general formula (VIII) or (IX) when p= 0 or a compound of general formula (X) or (XI) when p=1 :

by means of a reductive amination reaction, using suitable reagents, such as sodium triacetoxyborohydride or sodium borohydride, using suitable solvents mixtures such as methanol and acetonitrile, and at a suitable temperature, such as room temperature;

When Y is an -CH₂NHR_{3 1} (aminomethyl) group: a compound in which R₃ is linked to the aryl group via a -CH₂NR_{3 1} moiety (W₂ = -NR_3d, q = 1) may be prepared by reaction of a compound of general formula (V) with a compound of general formula (VIII) or (IX) when p= 0 or a compound of general formula (X) or (XI) when p=1 using the reductive amination conditions previously described;

When Y is a -OH group: a compound in which R₃ is linked to the aryl group via an oxygen atom (W₂ = O, q = 0) may be prepared by reaction of a compound of general formula (V) with a compound of general formula (XII) or (XIII): by means of a Mitsunobu reaction under the conditions described in the Method A1.

Alternatively, the above-described transformations for introducing the group R3 over a compound of general formula (V) can also be applied for introducing the group R3 over a compound of general formula (IV) to give a compound of general formula (III) as shown by the dotted arrow in the Scheme 1.

The intermediate of general formula (V) can be prepared by reaction of a compound of general formula (lla) or (Mb):

with a compound of general formula (IV):

wherein Ri , R2 and n have the meanings as defined above, Z represents a hydroxyl or an halogen group and Y represents a group that can be converted into R3; under the conditions described in Method A (including Method A1 and Method A2).

The different reactions of methods A (including method A1 and A2) and B as well as the reactions for preparing the intermediate compounds for such reactions are depicted in Scheme 1 :

(lla) W1 =OH

(Mb) W1=NR_a

Scheme 1

wherein Ri, R₂, R₃, R₄, Rs, Wi, m and n have the meanings as defined above, Z represents a hydroxyl or an halogen group and Y represents a group that can be converted into R₃.

In addition, the functional groups present in the compounds of general formula (I) or any intermediate described in Scheme 1 may be transformed at any stage of the synthesis. For example, an aromatic ring may be halogenated in the presence of N- chlorosuccinimide, using a suitable solvent such as acetonitrile with stirring at a convenient temperature such as room temperature.

The compounds of general formula (lla), (Mb), (Ilia), (lllb), (IV), (VI), (VII), (VIII), (IX), (X), (XI), (XII) 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, ethyl or tert- buty ester for the carboxylic acid group 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 particular, the simultaneous removal of the ethyl ester and Boc groups may be carried out in aqueous HCI, optionally in the presence of a suitable co-solvent like acetonitrile, and at a suitable reaction temperature, e.g. heating at 60 °C.

In addition, a compound of 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.

Compounds of general formula (I) for wich R₄ contains a Protecting Group (PG), such as Boc or 2-(trimethylsilyl)ethylcarbamate, can be used as intermediates useful for the preparation of other compounds of general formula (I) as defined above.

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

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-((( 1s, 4R)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-((((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-((((7s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-((((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-((((7s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-chloro-5-((( 1s, 4R)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(2-((( 1s, 4R)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate; • 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-bro o-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate ;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-bromo-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((7s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(3-((( 1s, 4R)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-hydroxyphenoxy)pyrrolidine-1 ,2- dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)oxy)phenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,4S)-4-(dimethylamino)-4-(3- fluorophenyl)cyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,4R)-4-(dimethylamino)-4-(3- fluorophenyl)cyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate;

• l-(ferf-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,3R)-3-(dimethylamino)-3- phenylcyclobutyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,3S)-3-(dimethylamino)-3- phenylcyclobutyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-3-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(2-chloro-5-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-3-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(4-chloro-3-((( 1s, 4R)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate; • 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(2-chloro-3-((( 1s, 4R)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S, 4S)-4-(2-chloro-5-((( 1s, 4R)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-3-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate;

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-2,3-difluorophenoxy)pyrrolidine-1 ,2- dicarboxylate and

• 1-(te/f-Butyl) 2-methyl (2S,4S)-4-(5-(((7s,4R)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-2,3-difluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.

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, central neuropathic pain and/or peripheral 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, central neuropathic pain and/or peripheral 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, central neuropathic pain and/or peripheral 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 above.

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 above 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 or comprising at least a compound binding to the subunit a2d, especially the a2d-1 subunit of voltage gated calcium channels and 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.

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

The following abbreviations are used in the intermediates and examples:

ACN: Acetonitrile

AcOH: Acetic acid

Anh: Anhydrous

Aq: Aqueous

BOC2O: Di-te/f-butyl dicarbonate

Cone: Concentrated CMBP: Cyanomethylenetributylphosphorane

DIAD: Diisopropyl azodicarboxylate

DCM: Dichloromethane

ESI: Electrospray ionization

EtOAc: Ethyl acetate

Et2<D: Diethyl ether

EtOH: Ethanol

Eq. Equivalents

h: Hour/s

HPLC: High-performance liquid chromatography

LCMS: Liquid chromatography mass spectrometry

M: Molar

MeOH: Methanol

MS: Mass spectrometry

Min: Minutes

Quant: Quantitative

Rt: Retention time

Ru-Phos : 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

rt: Room temperature

Sat: Saturated

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

TEA: EΐbN, Triethylamine

Wt: Weight

XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

The following methods were used to generate the HPLC or LCMS data:

Method A: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 30 x 2.1 mm, 3.5m, Temp: 25 °C, Flow: 1 mUmin, Gradient: to = 5% A, ti_.e_mm = 98% A, t3_min = 98% A, Post time: 1.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.

Method B: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 30 x 2.1 mm, 3.5m, Temp: 25 °C, Flow: 1 mUmin, Gradient: to = 5% A, ti_.6min = 98% A, t3_min = 98% A, Post time: 1.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.

Method C: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Phenomenex GeminiNX C18, 50 x 2.0 mm, 3m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3_.5_min = 98% A, te_min = 98% A, Post time: 2 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.

Method D: Apparatus: Agilent 1100 Bin. Pump: G1312A, degasser; autosampler, ColCom, DAD: Agilent G1315B, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 50 x 2.1 mm, 3.5m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3_.5_min = 98% A, te_min = 98% A, Post time: 2 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.

Method E: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315C, 210 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000; column: Waters XSelect™ CSH C18, 50 x 2. 1 mm, 3.5m, Temp: 25 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t3_.5_min = 98% A, te_min = 98% A, Post time: 2 min, Eluent A: acetonitrile, Eluent B: 10 mM ammoniumbicarbonate in water (pH = 9.5); Rt = x.yy min, M+H = xxx.x, xx.x% product.

Method F: Apparatus: Agilent 1260 Bin. Pump: G1312B, degasser; autosampler, ColCom, DAD: Agilent G1315D, 220-320 nm, MSD: Agilent LC/MSD G6130B ESI, pos/neg 100-1000, ELSD Alltech 3300 gas flow 1.5 ml/mi n, gas temp: 40° C; column: Waters XSelect™ C18, 50 x 2. 1 mm, 3.5m, Temp: 35 °C, Flow: 0.8 mUmin, Gradient: to = 5% A, t 3_.5_{m in} = 98% A, te_min = 98% A, Post time: 2 min; Eluent A: 0.1% formic acid in acetonitrile, Eluent B: 0.1% formic acid in water): Rt = x.yy min, M+H = xxx.x, xx.x% product.

Method G: Apparatus: Waters /Class; Bin. Pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210-320 nm, SQD: SQD2 ESI, pos/neg 100-800; ELSD: gas pressure 40 psi, drift tube temp: 50°C ; column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5m, Temp: 25 °C, Flow: 0.6 mUmin, Gradient: to = 5% A, t2_.o_min = 98% A, t2 _{m n} - 98%

A, Post time: 0.3 min, Eluent A: acetonitrile, Eluent B: 10 mM ammonium bicarbonate in water (pH = 9.5): Rt = x.yy min, M+H = xxx.x, xx.x% product.

MS parameters: Source: ESI, Capillary voltage: 3000 V, Drying gas flow: 12 L/min, Nebulizer Pressure 60 psig, Drying Gas Temp: 350 °C, Fragmentor 70, MS scan: MS range 100-1000 (positive and negative mode), scan speed: 0.84 sec/cycle; Flow into MS 0.8 mL/min.

The following methods were used to purify compounds by reverse phase (MPLC) column chromatography:

[XSelect] Instrument type: Reveleris™ prep MPLC; column: Waters XSelect CSH C18 (145 x 25 mm, 10p); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 10 mM ammoniumbicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammoniumbicarbonate in water; Gradient: t = 0 min 50% B, t = 4 min 50% B, t = 16 min 100% B, t = 21 min 100% B, or Gradient: t = 0 min 5% B, t = 1 min 5% B, t = 2 min 20%

B, t = 20 min 60% B, t = 21 min 100% B, t = 26 min 100% B; Detection UV: 220, 254, 340 nm.

[Gemini] Instrument type: Reveleris™ prep MPLC; Column: Phenomenex Gemini C18 (185 x 25 mm, 10p); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 10 mM ammoniumbicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammoniumbicarbonate in water; Gradient: t = 0 min 50% B, t = 4 min 50% B, t = 16 min 100% B, t = 21 min 100% B, or Gradient: t = 0 min 5% B, t = 1 min 5% B, t = 2 min 20% B, t = 17 min 60% B, t = 18 min 100% B, t = 23 min 100% B; Detection UV: 220, 254, 340 nm.

Synthesis of Intermediates

Intermediate 1. 3-(((7r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)amino)phenol.

To a solution of 4-(dimethylamino)-4-phenylcyclohexan-1-one (1.5 g, 6.90 mmol) in MeOH (20 ml_) / ACN (20 ml_) were added 3-aminophenol (0.753 g, 6.90 mmol) and AcOH (0.996 ml_, 17.26 mmol). The resulting solution was stirred at rt overnight. Sodium triacetoxyborohydride (3.66 g, 17.26 mmol) was added and the mixture was stirred at rt for 2 h. Sodium borohydride (0.783 g, 20.71 mmol) was added and the mixture was stirred for another hour. The mixture was concentrated. DCM (75 ml_) was added and the suspension was filtered off. The filtrate was concentrated, which afforded 2.28 g of crude material. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 350 mg (16%) of the title compound (first eluting isomer on LCMS, stereoconfiguration: trans-isomer). LCMS (method B): Rt, 2.01 Min; ESI m/z\ 311.2 [M+H]⁺.

Intermediate 2. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate.

A reaction vial was charged with 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (156 mg, 0.635 mmol) and intermediate 1 (197 mg, 0.635 mmol) in dry toluene (10 mL) and the dark suspension was flushed with nitrogen. CMBP (0.333 mL, 1.269 mmol) was added; the vial was sealed, and the dark suspension was stirred at 100 °C overnight. The mixture was concentrated in vacuo, followed by purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 24 g, gradient DCM / (5-100% DCM/MeOH (9:1)) in 25 Min, 100% DCM/MeOH (9:1) for 15 Min). Pure fractions were pooled together and concentrated in vacuo to afford 128 mg (31 %) of the title compound as a glass-like solid. LCMS (method B): Rt, 2.38 Min; ESI m/z. 538.4 [M+H]⁺. Purity according to LCMS: 83.7%.

Intermediate 3. 3-(((7s,4s)-4-(Dimethylamino)-4-phenylcyclohexyl)amino)phenol.

Intermediate 3 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one and 3- aminophenol according to the method described for intermediate 1. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 287 mg (16%) of the title compound (second eluting isomer on LCMS, stereoconfiguration tentatively: cis- isomer). LCMS (method B): Rt, 2.15 Min; ESI m/z\ 31 1.2 [M+H]⁺.

Intermediate 4. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 4 was obtained from 1-(te/f-butyl) 2-methyl (2S, 4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (119 mg, 0.483 mmol) and intermediate 3 (150 mg, 0.483 mmol) following the synthesis and purification method as described for intermediate 2. Yield 181 mg (41 %) as a foam. LCMS (method B): Rt, 2.50 Min; ESI m/z\ 538.4 [M+H]⁺. Purity according to LCMS: 60%

Intermediate 5. 4-((((7r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)amino)methyl) phenol.

Intermediate 5 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (1.5 g, 6.90 mmol) and 4-hydroxybenzylamine (0.850 g, 6.90 mmol) following the same method as described for intermediate 1. Purification by preparative LCMS (twice) afforded 362 mg (16%) of the title compound (first eluting isomer on LCMS, stereoconfiguration: trans isomer). LCMS (method B): Rt, 1.90 Min; ESI m/z\ 325.2 [M+H]⁺.

Intermediate 6. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-((((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 6 was obtained from 1-(te/f-butyl) 2-methyl (2S, 4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (1 13 mg, 0.462 mmol), intermediate 5 (150 mg, 0.462 mmol) and 2 Eq. of CMBP (0.243 mL, 0.925 mmol) following the synthesis method as described for intermediate 2. Purification by preparative LCMS (XSelect CSH C18, basic eluent gradient) yielded 81 mg (31 %) of the title compound as an oil. LCMS (method B): Rt, 2.32 Min; ESI m/z\ 552.4 [M+H]⁺.

Intermediate 7. 4-((((7s,4s)-4-(Dimethylamino)-4-phenylcyclohexyl)amino)methyl) phenol.

Intermediate 7 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (1.5 g, 6.90 mmol) and 4-hydroxybenzylamine (0.850 g, 6.90 mmol) following the same synthesis method as described for intermediate 1. Purification by preparative LCMS (XSelect CSH C18, basic eluent gradient) afforded 517 mg (23%) of the title compound (second eluting isomer on LCMS, stereoconfiguration: cis-isomer). LCMS (method B): Rt, 2.09 Min; ESI m/z\ 325.3 [M+H]⁺.

Intermediate 8. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(4-((((7s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 8 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (1 13 mg, 0.462 mmol), intermediate 7 (150 mg, 0.462 mmol) and 2 Eq. of CMBP (0.243 mL, 0.925 mmol) following the synthesis method as described for intermediate 2. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 67 mg (26%) of the title compound as an oil. LCMS (method B): Rt, 2.50 Min; ESI m/z\ 552.4 [M+H]⁺.

Intermediate 9. 3-((((7r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)amino) methyl)phenol.

Intermediate 9 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (1.765 g, 8.12 mmol) and 3-(aminomethyl)phenol (1.0 g, 8.12 mmol) following the same method as described for intermediate 1 , using 2.5 eq of sodium triacetoxyborohydride (4.30 g, 20.30 mmol). Purification by flash column chromatography (pre-packed silica cartridge Grace Resol v™ 40 g, gradient DCM / (5-100% DCM/(7 M NH₃ in MeOH) (9:1) in 55 Min) afforded 498 mg (18%) of the title compound (first eluting isomer on LCMS, stereoconfiguration: trans-isomer). LCMS (method B): Rt, 1.97 Min; ESI m/z\ 325.2 [M+H]⁺.

Intermediate 10. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-((((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 10 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (144 mg, 0.586 mmol), intermediate 9 (200 mg, 0.586 mmol) and 2 Eq. of CMBP (0.307 mL, 1.171 mmol) following the synthesis method as described for intermediate 2. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 145 mg (44%) of the title compound as an oil. LCMS (method B): Rt, 2.40 Min; ESI m/z\ 552.4 [M+H]⁺.

Intermediate 11. 3-((((7s,4s)-4-(Dimethylamino)-4-phenylcyclohexyl)amino) methyl)phenol.

Intermediate 11 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (1.765 g, 8.12 mmol) and 3-(aminomethyl)phenol (1.0 g, 8.12 mmol) following the same synthesis and purification method as described for intermediate 9. Yield: 653 mg (20%) (second eluting isomer on LCMS, stereoconfiguration: cis-isomer). LCMS (method B): Rt, 2.18 Min; ESI m/z\ 325.2 [M+H]⁺. Purity according to LCMS: 81.6%. Intermediate 12. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-((((7s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)amino)methyl)phenoxy)pyrrolidine-1,2-dicarboxylate.

Intermediate 12 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (155 mg, 0.632 mmol), intermediate 11 (250 mg, 0.632 mmol) and 2 Eq. of CMBP (0.332 ml_, 1.264 mmol) following the synthesis method as described for intermediate 2. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 138 mg (39%) of the title compound as an oil. LCMS (method B): Rt, 2.55 Min; ESI m/z. 552.4 [M+H]⁺.

Intermediate 13. 3-Chloro-5-(((7r,4r)-4-(dimethylamino)-4-phenylcyclohexyl) amino)phenol.

Intermediate 13 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (757 mg, 3.48 mmol) and 3-amino-5-chlorophenol (500 mg, 3.48 mmol) following the same method as described for intermediate 1. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 124 mg (10%) of the title compound (first eluting isomer on LCMS, stereoconfiguration: trans-isomer). LCMS (method B): Rt, 2.10 Min; ESI m/z. 345.2 [M+H]⁺, Cl-isotope pattern. Purity according to LCMS: 70.1%.

Intermediate 14. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((7 ,4S)-4-

(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy)pyrrolidine-1,2- dicarboxylate.

Intermediate 14 was obtained from 1-(te/f-butyl) 2-methyl (2S, 4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (88 mg, 0.36 mmol), intermediate 13 (124 mg, 0.36 mmol) and 2 Eq. of CMBP (0.189 ml_, 0.719 mmol) following the synthesis method and purification method as described for intermediate 2. Yield: 85 mg (34%) as a glass-like solid. LCMS (method B): Rt, 2.55 Min; ESI m/z\ 572.3 [M+H]⁺, Cl-isotope pattern. Purity according to LCMS: 84.2%.

Intermediate 15. 3-Chloro-5-(((7s,4s)-4-(dimethylamino)-4-phenylcyclohexyl) amino)phenol.

Intermediate 15 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (757 mg, 3.48 mmol) and 3-amino-5-chlorophenol (500 mg, 3.48 mmol) following the same synthesis and purification method as described for intermediate 13. Yield: 70 mg (5.8%) (second eluting isomer on LCMS, stereoconfiguration: cis-isomer). LCMS (method B): Rt, 2.31 Min; ESI m/z\ 345.2 [M+H]⁺, Cl-isotope pattern.

Intermediate 16. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((7s,4f?)-4-

(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2- dicarboxylate.

Intermediate 16 was obtained from 1-(te/f-butyl) 2-methyl (2S, 4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (49.8 mg, 0.203 mmol), intermediate 15 (70 mg, 0.203 mmol) and 2 Eq. of CMBP (0.106 mL, 0.406 mmol) similar to 14. Yield: 52 mg (33%) as a foam. LCMS (method B): Rt, 2.65 Min; ESI m/z. 572.4 [M+H]⁺, Cl-isotope pattern. Purity according to LCMS: 75.1%.

Intermediate 17. 2-(((7s,4s)-4-(Dimethylamino)-4-phenylcyclohexyl)amino)phenol.

Intermediate 17 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one ( 1.5 g, 6.9 mmol) and 2-aminophenol (753 mg, 6.9 mmol) following the same method as described for intermediate 1 , using 2.5 Eq. of sodium triacetoxyborohydride (3.66 g, 17.26 mmol|). Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 438 mg (17%) of the title compound (second eluting isomer on LCMS, stereoconfiguration: cis-isomer). LCMS (method B): Rt, 2.24 Min; ESI m/ . 311.2 [M+H]⁺. Purity according to LCMS: 84.8%.

Intermediate 18. l-(fert-Butyl) 2-methyl (2S,4S)-4-(2-(((7s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)amino)phenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 18 was prepared in 2 batches from 1-(te/f-butyl) 2-methyl (2S,4R)-4- hydroxypyrrolidine-1 ,2-dicarboxylate (batch 1 : 79 mg, 0.322 mmol & batch 2: 243 mg, 0.992 mmol), intermediate 17 (batch 1 : 100 mg, 0.322 mmol & batch 2: 308 mg, 0.992 mmol) and 2 Eq. of CMBP (batch 1 : 0.169 mL, 0.644 mmol & batch 2: 0.521 mL, 1.984 mmol) as described for intermediate 2. Yield: batch 1 : 39 mg (22%) & batch 2: 144 mg (27%). LCMS (method B): Rt, 2.69 Min; ESI m/z 538.4 [M+H]⁺. Intermediate 19. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.

Intermediate 19 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (200 mg, 0.815 mmol), 3-bromo-5-fluorophenol (156 mg, 0.815 mmol) and 2 Eq. of CMBP (0.428 ml_, 1.631 mmol) in dry toluene (5 mL) following the synthesis method as described for intermediate 2. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, DCM isocratic for 20 Min), gave 279 mg (76%) of the title compound as an oil. LCMS (method B): Rt, 2.31 Min; ESI m/z. 362.1 & 364.1 [M-(q4H_d)+H]⁺, Br-isotope pattern. Purity according to LCMS: 92.5%.

Intermediate 20. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.

To a nitrogen flushed mixture of intermediate 19 (334 mg, 0.799 mmol), CS2CO3 (710 mg, 2.178 mmol), (7s, 4s)-/\/¹ ,/\/¹-dimethyl-1-phenylcyclohexane-1 , 4-diamine (159 mg, 0.726 mmol) and XantPhos (21.00 mg, 0.036 mmol) in 1 ,4-dioxane (extra dry) (10 mL) was added Pd2(dba)3 (66.5 mg, 0.073 mmol) under a nitrogen atmosphere and the mixture was stirred at 110 °C overnight. After cooling down to room temperature the mixture was filtered over a small pad of kieselguhr and concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM to 100% DCM/MeOH (9: 1)) in 55 Min afforded 102 mg (25%) of the title compound as an oil. LCMS (method B): Rt, 2.59 Min; ESI m/z. 556.4 [M+H]⁺.

Intermediate 21. 1 -(fert-Butyl) 2-methyl (2S, 4S)-4-(3-bromo-5-fluorophenoxy) pyrrolidine-1 ,2-dicarboxylate. A solution of 1-(te/f-butyl) 2-methyl (2S, 4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (400 g, 1.631 mmol), 3-bromo-5-chlorophenol (338 mg, 1.631 mmol) and triphenylphosphine (513 mg, 1.957 mmol) in dry THF (12 ml_) was cooled to 0 °C. A solution of DIAD (0.317 ml_, 1.631 mmol) in dry THF (4 ml_) was added dropwise. The dark solution was stirred at room temperature for 1 hour. More DIAD (0.063 ml_, 0.326 mmol) in dry THF (2 ml_) was added and the mixture was stirred at room temperature. After stirring overnight the mixture was concentrated in vacuo. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, DCM isocratic for 30 Min), followed by further purification (pre-packed silica cartridge GraceResolv™ 40 g, gradient 5% EtOAc/heptane to 75% EtOAc/heptane in 55 Min) afforded 618 mg (87%) of the title compound as an oil. LCMS (method B): Rt, 2.40 Min; ESI m/z\ 378.0 & 380.0 [M-(C4HS)+H]⁺, Br-CI-isotope pattern.

Intermediate 22. (1r, ή-N¹, A/^Af-TrimethyM -phenylcyclohexane-l, 4-diamine.

Intermediate 22 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (400 mg, 1.841 mmol) and methylamine (2 M solution in MeOH) (2.30 ml_, 4.6 mmol) following the method as described for intermediate 1 , using 2.5 Eq. of sodium triacetoxyborohydride (975 mg, 4.6 mmol) as reducing agent. Purification by purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (10-100% DCM/(7 M NH₃ in MeOH) (9:1) in 45 Min, 100% DCM/(7 M NH3 in MeOH) (9: 1) for 30 min) afforded 116 mg (27%) of the title compound (first eluting isomer on LCMS, stereoconfiguration: trans-isomer). LCMS (method B): Rt, 1.74 Min; ESI m/z\ 233.2 [M+H]⁺.

Intermediate 23. (7s, AsyN', A/^Af-TrimethyM -phenylcyclohexane-l, 4-diamine.

Intermediate 23 was obtained from 4-(dimethylamino)-4-phenylcyclohexan-1-one (400 mg, 1.841 mmol) and methylamine (2 M solution in MeOH) (2.30 ml_, 4.6 mmol) following the same synthesis and purification method as described for intermediate 22. Yield: 162 mg (37%) (second eluting isomer on LCMS, stereoconfiguration: cis-isomer). LCMS (method B): Rt, 2.03 Min; ESI m/z 233.2 [M+H]⁺.

Intermediate 24. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((7s,4f?)-4-

(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)phenoxy)pyrrolidine-1 ,2- dicarboxylate.

To a nitrogen flushed mixture of intermediate 21 (303 mg, 0.697 mmol), intermediate 23 ( 7s, 4s)-/\/¹ ,/\/¹ ,/\/⁴-trimethyl-1-phenylcyclohexane-1 , 4-diamine (162 mg, 0.697 mmol), CS2CO3 (681 mg, 2.091 mmol) and Ru-Phos (16.27 mg, 0.035 mmol) in dry 1 ,4-dioxane (10 ml_), Pd2(dba)3 (63.8 mg, 0.070 mmol) was added and the resulting mixture was stirred at 1 10 °C for 48 h. The mixture was filtered over a small pad of kieselguhr and concentrated to dryness. Purification (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (5-100% DCM/MeOH (9: 1)) in 55 Min afforded 240 mg of 24. Additional purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 129 mg (29%) of the title compound as a glass-like solid. LCMS (method B): Rt, 2.87 Min; ESI m/z. 586.4 [M+H]⁺, Cl-isotope pattern. Purity according to LCMS: 93.4%.

Intermediate 25. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-chloro-5-(((7 ,4S)-4-

Intermediate 25 was obtained from intermediate 21 (189 mg, 0.435 mmol) and intermediate 22 (101 mg, 0.435 mmol), following the same synthesis and purification method as described for intermediate 24. Yield: 73 mg (28%) as a glass-like solid. LCMS (method B): Rt, 2.60 Min; ESI m/z\ 586.4 [M+H]⁺, Cl-isotope pattern.

Intermediate 26. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 26 was obtained from intermediate 19 (232 mg, 0.555 mmol) and intermediate 22 (129 mg, 0.555 mmol), following the same synthesis method (heating overnight) as described for intermediate 24. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) afforded 138 mg (43%) of the title compound as a glass-like solid. LCMS (method B): Rt, 2.54 Min; ESI m/z\ 570.3 [M+H]⁺.

Intermediate 27. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 27 was obtained from intermediate 19 (540 mg, 1.291 mmol) and intermediate 23 (300 mg, 1.291 mmol), using 0.1 Eq of Ru-Phos (60.2 mg, 0.129 mmol), 0.05 Eq. of Pd2(dba)3 (59.1 mg, 0.065 mmol) and 1.5 Eq. of CS2CO3 (631 mg, 1.937 mmol) as described for intermediate 24 with heating at 80 °C for ~ 40 h. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (5-80% DCM/MeOH (9:1)) in 54 Min) afforded 252 mg (34%) of the title compound as a foam. LCMS (method B): Rt, 2.69 Min; ESI m/z\ 570.4 [M+H]⁺. Intermediate 28. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-hydroxyphenoxy)pyrrolidine- 1 ,2-dicarboxylate.

o Boc

Intermediate 28 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (1 g, 4.08 mmol), 5 Eq. of resorcinol (2.245 g, 20.39 mmol) and 1.3 Eq. of CMBP (0.428 ml_, 1.631 mmol) following the synthesis method as described for intermediate 2. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, 3% EtOAc/heptane to 60% EtOAc/heptane in 40 Min, flowrate 40 mL/min) afforded 623 mg (45%) of the title compound as a solid. LCMS (method B): Rt, 2.04 Min; ESI m/z\ 282.0 [M-(C₄H₈)+H]⁺.

Intermediate 29. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-((('/r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)oxy)phenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 29 was obtained from intermediate 28 (268 mg, 0.716 mmol), and (is, 4s)- 4-(dimethylamino)-4-phenylcyclohexan-1-ol (157 mg, 0.716 mmol) according to the synthesis method as described for intermediate 2. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM to 100% DCM/MeOH (9: 1)) in 40 Min, 100% DCM/MeOH (9:1) for 15 Min) afforded 326 mg (85%) of compound 29 (stereoconfiguration: trans-isomer). LCMS (method B): Rt, 2.50 Min; ESI m/z\ 539.2 [M+H]⁺.

Intermediate 30. ( /r,4r)-1 -(3-Fluorophenyl)-A/¹,A/¹,Af⁴-trimethylcyclohexane-1,4- diamine.

Intermediate 30 was obtained from 4-(dimethylamino)-4-(3-fluorophenyl)cyclohexan-1- one (350 mg, 1.487 mmol) and 2.5 Eq. of methylamine (33% in EtOH) (0.436 ml_, 3.72 mmol) following the method as described for intermediate 22, using 2.5 Eq. of sodium triacetoxyborohydride (788 mg, 3.72 mmol) as reducing agent. Purification by purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (5-100% DCM/(7 M NH₃ in MeOH) (9: 1) in 40 Min, 100% DCM/(7 M NH₃ in MeOH) (9: 1) for 15 min) afforded 99 mg (26%) of the title compound as a solid (first eluting isomer on LCMS, stereoconfiguration: trans-isomer). LCMS (method C): Rt, 2.68 Min; ESI m/z 251.2 [M+H]⁺.

Intermediate 31. (7s,4s)-1 -(3-Fluorophenyl)-A/¹,A/¹,Af⁴-trimethylcyclohexane-1,4- diamine.

Intermediate 31 was obtained according to the synthesis and purification method described for compound 30. Yield: 178 mg (44%) as an oil (second eluting isomer on LCMS, stereoconfiguration: cis-isomer). LCMS (method C): Rt, 3.21 Min; ESI m/z. 251.2 [M+H]⁺. Purity according to LCMS: 92.5%.

Intermediate 32. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,4S)-4-(dimethylamino)-4-

(3-fluorophenyl)cyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.

Intermediate 32 was obtained from intermediate 19 (165 mg, 0.395 mmol) and intermediate 30 (99 mg, 0.395 mmol), according to the method described for intermediate 27 using 1.2 Eq. of Cs₂C0₃ (155 mg, 0.475 mmol) with heating at 1 10 °C overnight. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (1-30% DCM/MeOH (9: 1) in 50 Min, followed by a gradient of 30-50% DCM/MeOH (9:1) in 20 Min) gave 135 mg (58%) of the title compound as a foam. LCMS (method C): Rt, 4.33 Min; ESI m/ . 588.2 [M+H]⁺.

Intermediate 33. 1 -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,4/?)-4-(dimethylamino)-4-

Intermediate 33 was obtained from intermediate 19 (297 mg, 0.711 mmol) and intermediate 31 ( (178 mg, 0.711 mmol) according to the method described for 32. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / (3-55% DCM/MeOH (9: 1) in 54 Min) afforded 244 mg (58%) of compound 33 as a foam. LCMS (method C): Rt, 4.68 Min; ESI m/z. 588.4 [M+H]⁺. Purity according to LCMS: 90.4%.

Intermediate 34. fert-Butyl (3-oxo-1 -phenylcyclobutyl)carbamate.

tert- Butyl (1-(4-bromophenyl)-3-oxocyclobutyl)carbamate (500 mg, 1.470 mmol) was dissolved in 1 ,4-dioxane (extra dry) (10 mL) under an atmosphere of argon. Triethylamine (369 pL, 2.65 mmol) was added and the solution was degassed using argon in an ultrasonic bath (5 min). Next, tris(dibenzylideneacetone)dipalladium (0) (67.3 mg, 0.073 mmol) and S-Phos (60.3 mg, 0.147 mmol) were added, followed by the addition of triethylsilane (1 187 pL, 7.35 mmol). The reaction mixture was capped, and the reaction mixture was heated to 100 °C (pre-heated oil bath) for 1 h. After cooling down to room temperature the reaction mixture was diluted with DCM (75 mL) and successively washed with 1 M aqueous KHSCL solution (75 mL) and saturated aqueous NaHCCh solution (75 mL). Each time the aqueous layer was extracted with additional DCM (20 mL). The combined organic layers were washed with brine (75 mL), dried over anhydrous Na2sC>4. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was dissolved in DCM and filtered over a nylon microfilter and the filtrate was concentrated to dryness. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient heptane to 50% EtOAc/heptane in 35 Min) afforded 361 mg (93%) of the title compound as an oil, which crystallised upon standing. LCMS (method B): Rt, 2.09 Min; ESI m/z. 206.0 [M-(C₄H₈)+H]⁺.

Intermediate 35. fert-Butyl (3-(methylamino)-1 -phenylcyclobutyl)carbamate, mixture of diastereoisomers.

Intermediate 35 was obtained from intermediate 34 (370 mg, 1.416 mmol) and 2.5 Eq. of methylamine (33% in EtOH) (0.441 mL, 3.54 mmol) following the method as described for the preparation of intermediate 30, using 1.4 Eq. of sodium triacetoxyborohydride (420 mg, 1.98 mmol) as reducing agent. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient DCM / MeOH (9: 1) to 100% DCM/(7 M NHs in MeOH) (9: 1) in 60 Min) afforded 206 mg (52%) of the title compound as mixture of diastereoisomers. LCMS (method B): Rt, 1.96 Min; ESI m/ . 277.2 [M+H]⁺.

Intermediate 36. Benzyl (3-((fert-butoxycarbonyl)amino)-3-phenylcyclobutyl) (methyl)carbamate, mixture of diastereoisomers.

Intermediate 35 (200 mg, 0.724 mmol) was dissolved in dry THF (4 ml_) under an atmosphere of argon. Solid Na2CC>3 (153 mg, 1.447 mmol) was added, followed by the addition of benzyl chloroformate (0.114 ml_, 0.796 mmol) and the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and water was added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na₂S0₄. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 12 g, gradient heptane to 60% EtOAc/heptane in 40 Min) afforded 268.9 mg (91 %) of the title compound (mixture of diastereoisomers). LCMS (method B): Rt, 2.36 Min; ESI m/z. 41 1.2 [M+H]⁺. Intermediate 37. Benzyl (3-(dimethylamino)-3-phenylcyclobutyl)(methyl) carbamate, mixture of diastereoisomers.

Intermediate 37 was prepared in 2 steps from compound 36. Step 1 : Intermediate 36 (268 mg, 0.653 mmol) was dissolved in dry DCM (6.5 ml_) (dried over activated MS 4A) under an atmosphere of nitrogen. TFA (1.0 ml_, 13.06 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and co-evaporated twice with DCM to give 369 mg of the crude TFA-salt. The crude material was dissolved in DCM, water was added and aqueous layer was basified to ~ pH 10 using solid Na2CC>3. Subsequently, the layers were separated and the aqueous layer was extracted with DCM (3 x). The organic layers combined, dried over anhydrous Na2SC>4. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The free amine (217.2 mg) was used immediately for the next reaction. Step 2: Methanol (9 ml_) was added, followed by 10 Eq. of formaldehyde (37 wt% solution in water) (0.491 ml_, 6.53 mmol) and AcOH (0.1 13 ml_, 1.959 mmol). The reaction mixture was stirred at room temperature for a couple of Min, after which sodium triacetoxyborohydride (554 mg, 2.61 mmol) was added slowly in one portion. After stirring overnight at rt the reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM (50 ml_) and saturated aqueous NaHCCh solution (50 ml_). The layers were separated and an aqueous layer was extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to give 214.8 mg (97% over 2 steps) of 37 as mixture of diastereoisomers. LCMS (method B): Rt, 2.25 & 2.32 Min; ESI m/z\ 339.2 [M+H]⁺.

Intermediate 38. A/^A/^A^-TrimethyM-phenylcyclobutane-l, 3-diamine, mixture of diastereoisomers.

Intermediate 37 (214 g, 0.632 mmol) was dissolved in MeOH (6 ml_). The solution was flushed with nitrogen gas for 3 min. Palladium (10% on activated carbon) (67.3 mg, 0.063 mmol) was added and H2 (g) was bubbled through the solution for 3 min. Next, the reaction stirred was stirred under an atmosphere of hydrogen (balloon) at room temperature for 1 h. The reaction mixture was filtered over kieselguhr and the residue was rinsed with EtOAc and MeOH. The filtrate was concentrated under reduced pressure to obtain the compound 38 (mixture of diastereoisomers) (129 mg, quantitative yield) as a thin film, which solidified upon standing. LCMS (method A): Rt, 1.68 & 1.74 Min; ESI m/z\ 205.1 [M+H]⁺.

Intermediate 39. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7s,3/?)-3-(dimethylamino)-3- phenylcyclobutyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 39 was obtained from intermediate 19 (264 mg, 0.631 mmol) and intermediate 38 (mixture of diastereoisomers) (129 mg, 0.631 mmol) according to the method described for intermediate 32. Purification by flash column chromatography (pre packed silica cartridge GraceResolv™ 24 g, gradient DCM / 5% DCM/MeOH (9:1) in 38 Min) afforded 81 mg (23.7%) of the target compound (stereoconfiguration: cis-isomer), which slowly solidified upon standing. LCMS (method B): Rt, 2.39 Min; ESI m/z. 542.2 [M+H]⁺.

Intermediate 40. l -(fert-Butyl) 2-methyl (2S,4S)-4-(3-(((7r,3S)-3-(dimethylamino)-3- phenylcyclobutyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine-1 ,2-dicarboxylate.

Intermediate 40 was obtained together with diastereoisomer 39. Yield: 79 mg (23%) (stereoconfiguration: trans-isomer). LCMS (method A): Rt, 2.34 Min; ESI m/z\ 542.2 [M+H]⁺. Purity according to LCMS: 77.9%. Intermediate 41. l -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((7 ,4S)-4- (dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine -1 ,2-dicarboxylate.

To solution of intermediate 26 (797 g, 1.399 mmol) in anhydrous ACN (10 ml_) N- chlorosuccinimide (187 mg, 1.399 mmol) was added. The solution was stirred at rt overnight and concentrated to afford crude 992 mg of a mixture of Cl-regioisomers. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, gradient DCM / (5-40% DCM/MeOH (9: 1)) in 75 Min, (40-100% DCM/MeOH (9: 1)) in 37.5 Min, 100% DCM/MeOH (9: 1) for 25 Min), followed by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, isocratic 50% (EtOAc/heptane (+ 2% TEA), 50 mL/min for 3 h) and flash column chromatography (pre packed silica cartridge GraceResolv™ 120 g, isocratic 40% (EtOAc/heptane (+ 2% TEA), 50 mL/min for 30 min) gave 148 mg (17%) of the title compound (stereoconfiguration: trans-isomer). LCMS (method A): Rt, 2.46 Min; ESI m/z\ 604.3 [M+H]⁺, Cl-isotope pattern.

Intermediate 42. l -(fert-Butyl) 2-methyl (2S,4S)-4-(2-chloro-3-(((7 ,4S)-4- (dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine -1 ,2-dicarboxylate.

Intermediate 42 was obtained together with its regioisomer 41. Yield: 1 13 mg (13%) (stereoconfiguration: trans-isomer). LCMS (method A): Rt, 2.43 Min; ESI m/z\ 604.3 [M+H]⁺, Cl-isotope pattern.

Intermediate 43. l -(fert-Butyl) 2-methyl (2S,4S)-4-(2-chloro-5-(((7 ,4S)-4- (dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-3-fluorophenoxy)pyrrolidine -1 ,2-dicarboxylate. Intermediate 43 was obtained together with its regioisomer 41. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, gradient DCM / (5-40% DCM/MeOH (9: 1)) in 75 Min, (40-100% DCM/MeOH (9: 1)) in 37.5 Min, 100% DCM/MeOH (9: 1) for 25 Min), followed by flash column chromatography (pre packed silica cartridge GraceResolv™ 120 g, isocratic 50% (EtOAc/heptane (+ 2% TEA), 50 mL/min for 3 h) afforded 129 mg (15%) of the title compound (stereoconfiguration: trans-isomer). LCMS (method A): Rt, 2.46 Min; ESI m/z\ 604.2 [M+H]⁺, Cl-isotope pattern.

Intermediate 44. l -(fert-Butyl) 2-methyl (2S,4S)-4-(4-chloro-3-(((7s,4/?)-4- (dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine -1 ,2-dicarboxylate.

Intermediate 44 was prepared from intermediate 27 (690 mg, 1.211 mmol) and N- chlorosuccinimide (162 mg, 1.211 mmol) according to the method described for intermediate 41. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, gradient heptane to 50% EtOAc/heptane (+ 2% EΐbN) in 3 h), followed by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, DCM / (30-65% DCM/MeOH (9:1) in 75 Min) and flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, isocratic 25% (EtOAc/heptane (+ 2% TEA), 50 mL/min for 60 min) gave 203 mg (27%) of the title compound as a solid (stereoconfiguration: cis-isomer). LCMS (method A): Rt, 2.67 Min; ESI m/z\ 604.2 [M+H]⁺, Cl-isotope pattern. Intermediate 45. l-(fert-Butyl) 2-methyl (2S,4S)-4-(2-chloro-3-(((7s,4F?)-4- (dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-5-fluorophenoxy)pyrrolidine -1,2-dicarboxylate.

Intermediate 45 was obtained together with its regioisomer 44. Yield: 134 g (18%) (stereoconfiguration: cis-isomer). LCMS (method A): Rt, 2.63 Min; ESI m/z\ 604.3 [M+H]⁺, Cl-isotope pattern.

Intermediate 46. l-(fert-Butyl) 2-methyl (2S,4S)-4-(2-chloro-5-(((7s,4f?)-4- (dimethylamino)-4-phenylcyclohexyl)(methyl)amino)-3-fluorophenoxy)pyrrolidine -1,2-dicarboxylate.

Intermediate 46 was obtained together with its regioisomer 44. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, gradient heptane to 50% EtOAc/heptane (+ 2% EΐbN) in 3 h), followed by flash column chromatography (pre-packed silica cartridge GraceResolv™ 120 g, DCM / (30-65% DCM/MeOH (9:1) in 75 Min) and flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, isocratic 30% (EtOAc/heptane (+ 2% TEA), 50 mL/min for 60 min) gave 134 mg (18%) of the title compound as a solid (stereoconfiguration: cis- isomer). LCMS (method A): Rt, 2.66 Min; ESI m/z\ 604.3 [M+H]⁺, Cl-isotope pattern.

Intermediate 47. l-(fert-Butyl) 2-methyl (2S, 4S)-4-(5-bromo-2,3-difluorophenoxy) pyrrolidine-1 ,2-dicarboxylate.

Intermediate 47 was obtained from 1-(te/f-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (469 mg, 1.914 mmol), 5-bromo-2,3-difluorophenol (400 mg, 1.914 mmol) and 1.6 Eq. of CMBP (0.803 ml_, 3.06 mmol) following the synthesis method as described for intermediate 2. Purification by flash column chromatography (pre-packed silica cartridge GraceResolv™ 40 g, gradient 3% EtOAc/heptane to 50% EtOAc/heptane in 25 Min) gave 672.6 mg (81 %) of the title compound as a crystalline solid. LCMS (method B): Rt, 2.25 Min; ESI m/z\ 380.0 & 382.0 [M-(q4H_d)+H]⁺, Br-isotope pattern.

Intermediate 48. l -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((7r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-2,3-difluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.

Intermediate 48 was obtained from intermediate 47 1 and intermediate 22 (80 mg, 0.44 mmol), according to the method described for intermediate 32. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 87 mg (43%) of the title compound (stereoconfiguration: trans-isomer). LCMS (method A): Rt, 2.43 Min; ESI m/z\ 588.3 [M+H]⁺.

Intermediate 49. l -(fert-Butyl) 2-methyl (2S,4S)-4-(5-(((7s,4/?)-4-(dimethylamino)-4- phenylcyclohexyl)(methyl)amino)-2,3-difluorophenoxy)pyrrolidine-1 ,2- dicarboxylate.

Intermediate 49 was obtained from intermediate 47 (150 mg, 0.344 mmol) and intermediate 23 (80 mg, 0.44 mmol), according to the method described for intermediate 32. Purification by preparative LC (XSelect CSH C18, basic eluent gradient) yielded 70 mg (34%) of the title compound (stereoconfiguration: cis-isomer). LCMS (method A): Rt, 2.62 Min; ESI m/z\ 588.3 [M+H]⁺.

Synthesis of Examples

Example 1. (2S,4S)-4-(3-(((7r,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)amino) phenoxy)pyrrolidine-2-carboxylic acid.

Aqueous 1 M HCI solution (5 ml_, 5 mmol) was added to intermediate 2 (128 mg, 0.238 mmol) and the resulting solution was stirred at 60 °C overnight. The mixture was concentrated in vacuo (60 °C) and the residue was purified by preparative LC (XSelect CSH C18, basic eluent gradient). Pure fractions were pooled together and concentrated in vacuo (60 °C), followed by co-evaporation with ACN to afford 46 mg (45%) of the title compound as a solid.

This procedure was used for the preparation of examples 2 to 27 from the corresponding intermediates.

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 mM pregabalin. The binding of the test compound was measured at either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki).. After 60 min incubation at 27 °C, binding reaction was terminated by filtering through Multiscreen GF/C (Millipore) presoaked in 0.5 % polyethyleneimine in Vacuum Manifold Station, followed by 3 washes with ice-cold filtration buffer containing 50 mM Tris-HCI, pH 7.4.

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

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

Binding assay to human m-opioid receptor

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

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

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

The following scale has been adopted for representing the binding to the a2d-1 subunit of the voltage-gated calcium channel, expressed as Ki:

+ (<c2d-1) >= 3000 nM

++ 500nM < (<c2d-1) <3000 nM

+++ 100nM < (<c2d-1) <500 nM

++++ K, (a2d-1) <100 nM

Preferably, when K,(a₂d-1) > 3000 nM, the following scale has been adopted for representing the binding to the a₂d-1 subunit of voltage-gated calcium channels: + K(a₂d-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:

+ (m) >= 500 nM

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

+++ K(m) < 100 nM

Preferably, when K (m) > 500 nM, the following scale has been adopted for representing the binding to the m -receptor: + K (m) > 500 nM or inhibition ranges between 1 % and 50 %.

The K results for the a2d-1 subunit of the voltage-gated calcium channel are shown in Table 1 : Table 1

The Ki results for the a2d-1 subunit of the voltage-gated calcium channel and the m- opioid receptor for the dual compounds are shown in Table 2:

Table 2

Claims

1. A compound of general formula (I):

wherein:

Wi is -O- or -NR_a;

Rs is

W_å is -O- or -NR3d; p and q are independently from one another 0 or 1 ; v’ and v” are independently 1 or 2;

R _a and R _b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or

R _a and R _b 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-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;

R _C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a— CN radical; a Ci-e haloalkyl radical; or a -NR_bR_c radical;

R_b and R_c are a hydrogen atom or a branched or unbranched Ci-e alkyl radical;

R_3d is a hydrogen atom or a branched or unbranched Ci-e alkyl radical;

R₄ is a hydrogen atom or a -C(0)R_4a radical;

R_4a is a hydrogen atom; a branched or unbranched C_1-6 alkyl radical; a branched or unbranched C_1-6 alkoxy radical; a -(CH₂)_r-NR_4bR_4c radical; a 0CH(CH₃)0C(0)CH(CH₃)2 radical; or a -NR_4g-(CH₂)s-CH(R_4f)-NR_4eR4d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;

R_4b, R_4c,R_4d, R_4e, R_4g are independently from one another a hydrogen atom; or a branched or unbranched C alkyl radical;

R_4f is a hydrogen atom or a -COR_4h radical;

R_4h is a hydroxyl radical or a branched or unbranched C alkyl radical; R₅ is a -C(0)R_5a radical or an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;

Re_b, Re_c, Re_d, Re_e, Reg are independently from one another a hydrogen atom; or a branched or unbranched C1 -6 alkyl radical;

Re_f is a hydrogen atom or a -CORs_h radical;

Re_h is a hydroxyl radical or a branched or unbranched C1 -6 alkyl radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

2. A compound according to claim 1 wherein Wi is O.

3. A compound according to claim 1 wherein m is 0 and n is 0.

4. A compound according to claim 1 wherein Ri and R_å are independently from one another a hydrogen atom or a halogen atom, more preferable fluorine or chlorine.

5. A compound according to claim 1 wherein R₃ is in meta position.

6. A compound according to clam 1 wherein R₃ is selected from:

wherein W_å, p, q, R_3a, R3_b and R_3c are as defined in claim 1.

7. A compound according to claim 1 wherein R_3a and are independently from one another a Ci-e alkyl radical, more preferable methyl.

8. A compound according to claim 1 wherein R_3C is a hydrogen atom or a halogen atom, more preferable fluorine. 9. A compound according to claim 1 wherein R_{4 IS} a hydrogen atom.

10. A compound according to claim 1 wherein Rs_a is a hydroxyl radical or a branched or unbranched Ci-₆ alkoxy radical, preferably a methoxy radical.

11. A compound according to claim 1 with the general formula (I’a):

wherein Ri, R_å, R₃, R₄ and R₅ are as defined in claim 1 ; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

12. A compound according to claim 1 having the general formula (la):

wherein Wi, Ri, R_å, R₃, R₄ and R₅ are as defined in claim 1 ; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

13. A compound according to claim 1 selected from the following list:

[1] (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy) pyrrolidine-2-carboxylic acid;

[2] (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy) pyrrolidine-2-carboxylic acid;

[3] (2S,4S)-4-(4-((((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl) phenoxy)pyrrolidine-2-carboxylic acid;

[4] (2S,4S)-4-(4-((((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl) phenoxy)pyrrolidine-2-carboxylic acid;

[5] (2S,4S)-4-(3-((((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl) phenoxy)pyrrolidine-2-carboxylic acid;

[6] (2S,4S)-4-(3-((((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)methyl) phenoxy)pyrrolidine-2-carboxylic acid;

[7] (2S,4S)-4-(3-chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino) phenoxy)pyrrolidine-2-carboxylic acid;

[8] (2S,4S)-4-(3-chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino) phenoxy)pyrrolidine-2-carboxylic acid;

[9] (2S,4S)-4-(2-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)phenoxy) pyrrolidine-2-carboxylic acid;

[10] (2S,4S)-4-(3-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)amino)-5-fluoro phenoxy)pyrrolidine-2-carboxylic acid;

[11] (2S,4S)-4-(3-chloro-5-(((1 s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)

(methyl)amino)phenoxy)pyrrolidine-2-carboxylic acid;

[12] (2S,4S)-4-(3-chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)phenoxy)pyrrolidine-2-carboxylic acid;

[13] (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)- 5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[14] (2S,4S)-4-(3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)- 5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[15] (2S,4S)-4-(3-(((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)oxy)phenoxy) pyrrolidine-2-carboxylic acid;

[16] (2S,4S)-4-(3-(((1r,4S)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)

(methyl)amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[17] (2S,4S)-4-(3-(((1 s,4R)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)

(methyl)amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[18] (2S,4S)-4-(3-(((1s,3R)-3-(dimethylamino)-3-phenylcyclobutyl)(methyl)amino)- 5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[20] (2S,4S)-4-(4-chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[21] (2S,4S)-4-(2-chloro-3-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[23] (2S,4S)-4-(4-chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)

(methyl)amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[24] (2S,4S)-4-(2-chloro-3-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)

(methyl)amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[25] (2S,4S)-4-(2-chloro-5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)

(methyl)amino)-3-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[26] (2S,4S)-4-(5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)- 2,3-difluorophenoxy)pyrrolidine-2-carboxylic acid and

[27] (2S,4S)-4-(5-(((1s,4R)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl)amino)- 2,3-difluorophenoxy)pyrrolidine-2-carboxylic acid; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

14. A compound according to claim 1 having the general formula (lb) or (lc):

wherein W_å, Ri, R_å, R3_a, R3_b and R3_C are as defined in claim 1 ; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

15. A compound according to claim 13 selected from the following list:

[17] (2S,4S)-4-(3-(((1 s,4R)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)

(methyl)amino)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid;

[19] (2S,4S)-4-(3-(((1r,3S)-3-(dimethylamino)-3-phenylcyclobutyl)(methyl)amino)-5- fluorophenoxy)pyrrolidine-2-carboxylic acid; [22] (2S,4S)-4-(2-chloro-5-(((1r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)(methyl) amino)-3-fluorophenoxy)pyrrolidine-2-carboxylic acid;

16. Process for the preparation of a compound of general formula (A1) particular case of compounds of formula (I) according to claim 1 for which Wi is -0-, or (A2), particular case of compounds of formula (I) according to claim 1 for which Wi is -

NRa-:

wherein Ri , R₂, R₃, R₄, Rs, R_a, m and n are as defined in claim 1 comprising: a) The treatment of a pyrrolidine derivative of general formula (lla)

wherein R₄, R₅ and m are as defined in claim 1 with a derivative of general formula (Ilia):

wherein Ri , R₂, R₃ and n are as defined in claim 1 , under Mitsunobu conditions a coupling agent, such as cyanomethylenetributylphosphorane (CM BP) or diisopropyl azodicarboxylate in the presence of a phosphine, such as triphenylphosphine, in the presence of a solvent, such as toluene or tetrahydrofuran, at a temperature, between room temperature and 100 °C, preferably room temperature; or

b) The treatment of a pyrrolidine derivative of general formula (lib):

wherein R4, R₅, R_a and m are as defined in cairn 1 , with a derivative of general formula (lllb):

wherein Ri , R₂, R₃ and n are as defined in claim 1 and Z is a halogen atom under the following reaction conditions:

a) For n = 0, the reaction may be carried out under Buchwad-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone) dipalladium(O) or palladium acetate, and a ligand, preferably a phosphine ligand such as BINAP or XPhos, using a base such as sodium tert- butoxide or cesium carbonate, in a solvent such as toluene or 1 ,4-dioxane, at a suitable temperature, preferably 110 °C.

b) For n = 1 the reaction may be carried out under alkylation conditions, in a solvent such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K₂CO₃ or A/./V-diisopropylethylamine, at a temperature comprised between room temperature and the reflux temperature.

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

wherein Ri, R₂, R₃, R₄, Rs, Wi, m and n are as defined in claim 1 , from a compound of general formula (V):

wherein Ri, R₂, R₃, R₄, Rs, Wi, m and n are as defined in claim 1 and Y represents a group that can be converted into R₃ under the following conditions: o When Y is a halogen atom: a compound in which R₃ is linked to the aryl group via a nitrogen atom, W₂ = -NR_3d and q = 0, by reaction of a compound of general formula (V) with a compound of general formula (VI) or (VII):

under Buchwald-Hartwig conditions, using reagents, such as tris(dibenzylideneacetone)-dipalladium (0) (Pd₂(dba)₃), 4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (Xantphos) or 2-dicyclohexyl phosphine-2', 6'-diisopropoxybiphenyl (Ru-Phos) in the presence of a base, such as cesium carbonate, in solvents, such as 1 ,4-dioxane, and with conventional heating at a temperature between 80 °C and 110 °C; or

o When Y is an -NHR_3d (amino) group: a compound in which R₃ is linked to the aryl group via a nitrogen atom, W₂ = -NR_3d and p = 0 or 1 , by reaction of a compound of general formula (V) with a compound of general formula (VIII) or (IX) when p= 0 or a compound of general formula (X) or (XI) when P=1 :

by means of a reductive amination reaction, using reagents, such as sodium triacetoxyborohydride or sodium borohydride, using solvents mixtures such as methanol and acetonitrile, and at a temperature, such as room temperature;

or o When Y is an -CH₂NHR₃₁ (aminomethyl) group: a compound in which R₃ is linked to the aryl group via a -CH₂NR₃₁ moiety, W₂ = -NR_3d and q = 1 , by reaction of a compound of general formula (V) with a compound of general formula (VIII) or (IX) when p= 0 or a compound of general formula (X) or (XI) when p=1 using the same reductive amination conditions described; or o When Y is a -OH group: a compound in which R₃ is linked to the aryl group via an oxygen atom, W₂ = O and q = 0, by reaction of a compound of general formula (V) with a compound of general formula (XII) or (XIII):

by means of a Mitsunobu reaction under the conditions described in claim 15.

18. A compound according to any of claims 1 to 15 for use as a medicament.

19. A compound according to any of claims 1 to 15, for use in the treatment and/or prophylaxis of diseases and/or disorders mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and/or the m-opioid receptor.

20. A compound for use according to claim 19 , where the disease or disorder is pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain, inflammatory pain, and chronic pain or other pain conditions involving allodynia and/or hyperalgesia, depression, anxiety and attention-deficit-/hyperactivity disorder.

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