WO2020021021A1

WO2020021021A1 - Ortho substituted phenoxypropylamino and benzyloxypropylamino derivatives having multimodal activity against pain

Info

Publication number: WO2020021021A1
Application number: PCT/EP2019/070062
Authority: WO
Inventors: Carmen Almansa Rosales; Marina VIRGILI-BERNADO; Monica Alonso-Xalma
Original assignee: Esteve Pharmaceuticals, S.A.
Priority date: 2018-07-27
Filing date: 2019-07-25
Publication date: 2020-01-30

Abstract

The present invention relates to ortho substituted phenoxypropylamino and benzyloxypropylamino derivatives having pharmacological activity towards the α2δ subunit of the voltage-gated calcium channel, in particular to ortho substituted phenoxypropylamino and benzyloxypropylamino derivatives having dual pharmacological activity towards both the α2δ subunit of the voltage-gated calcium channel and the sigma-1 (σ1 ) receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

Description

ESTEVE PHARMACEUTICALS, S.A.

ORTHO SUBSTITUTED PHENOXYPROPYLAMINO AND BENZYLOXYPROPYLAMINO DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN FIELD OF THE INVENTION The present invention relates to compounds having pharmacological activity towards the a₂dsubunit of the voltage-gated calcium channel. In particular, the present invention relates to compounds having dual pharmacological activity towards both the a₂dsubunit of the voltage-gated calcium channel, and the sigma-1 ( s1) receptor. More particularly, the present invention relates to ortho substituted phenoxypropylamino and benzyloxypropylamino derivatives having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

BACKGROUND OF THE INVENTION The adequate management of pain constitutes an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved (Turk DC, Wilson HD, Cahana A. Lancet; 2011, 377, 2226-2235). Pain affects a big portion of the population with an estimated prevalence of 20 % and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which leads to important productivity losses and socio- economical burden (Goldberg DS, McGee SJ, BMC Public Health, 2011, 11, 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, 821-70). The VGCC are assembled through interactions of different subunits, namelya1 (Ca_va1), ^ (Ca_v b)a₂d (Ca_va₂d) and g (Ca_v g). ESTEVE PHARMACEUTICALS, S.A.

The a₁ subunits are the key porous forming units of the channel complex, being responsible for the Ca²⁺ conduction and generation of Ca²⁺ influx. The a₂d, b, and g subunits are auxiliary, although very important for the regulation of the channel, since they increase the expression of the 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 (Cav3.1, Cav3.2, and Cav3.3), and high voltage-activated L- (Cav1.1 through Cav1.4), N-(Cav2.2), P/Q-(Cav2.1), and R-(Cav2.3) types, depending on the channel forming CaV ^ subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo, Neurotherapeutics.2009, 6, 679-92; Zamponi et al., 2015 supra; Neumaier 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 (Perret and Luo, 2009, supra; Vink and Alewood, Br J Pharmacol.2012, 167, 970-89). The Cav1 and Cav2 subfamilies contain an auxiliary a₂dsubunit, which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain. To date, there are four known a₂dsubunits, each encoded by a unique gene and all possessing splice variants. Eacha₂d protein is encoded by a single messenger RNA and is posttranslationally cleaved and then linked by disulfide bonds. Four genes encoding a₂d subunits have now been cloned. a₂d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution. The a₂d-2 and a₂d-3 subunits were subsequently cloned from brain. The most recently identified subunit, a₂d-4, is largely nonneuronal. The human a₂d-4 protein sequence shares 30, 32 and 61% identity with the human a₂d-1, a₂d-2 and a₂d-3 subunits, respectively. The gene structure of all a₂d subunits is similar. All a₂d subunits show several splice variants ESTEVE PHARMACEUTICALS, S.A.

(Davies et al., Trends Pharmacol Sci.2007, 28, 220-8.; Dolphin AC, Nat Rev Neurosci. 2012, 13, 542-55, Biochim Biophys Acta.2013, 1828, 1541-9). The Ca_va₂d-1 subunit may play an important role in neuropathic pain development (Perret and Luo, 2009, supra; Vink and Alewood, 2012, supra). Biochemical data have indicated a significant Ca_va₂d-1, but not Ca_va₂d-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 Cava₂d-1 subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Cava₂d-1 subunit contributes to neuropathic allodynia. The Cava₂d-1 subunit (and the Cava₂d-2, but not Cava₂d-3 and Cava₂d-4, subunits) is the binding site for gabapentin which has anti-allodynic/ hyperalgesic properties in patients and animal models. Because injury-induced Ca_va₂d-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_va₂d-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 Cava₂d-1 subunit can block nerve injury-induced Cava₂d-1 upregulation and prevent the onset of allodynia and reserve established allodynia. As mentioned above, 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_va₂d subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management. Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009, supra; Vink and Alewood, 2012, supra, Zamponi et al., 2015, supra). ESTEVE PHARMACEUTICALS, S.A.

The sigma-1 ( s1) receptor was discovered 40 years ago and initially assigned to a new subtype of the opioid family. This receptor is expressed both in the endoplasmic reticulum and in the plasma membrane and plays an important role in the regulation of intracellular calcium concentration. A signaling pathway associated with the activation of the s1 receptor has not been described, although it is believed that it has an amplification function of activation of intracellular cascades. In this sense, the s1 receptor regulates and modulates the activity of numerous voltage-dependent ion channels, including Ca2+-, K+-, Na+, Cl-, SK, and NMDA channels and the IP3 receptor. It is also known that the s1 receptor is linked to analgesia, since s1 receptor agonists counteract opioid receptor mediated analgesia, while s1 receptor antagonists, such as haloperidol, potentiated it (Chien CC, Pasternak GW. Neurosci. Lett.1995, 190, 137- 9). Many additional preclinical evidences have indicated a clear role of the s1 receptor in the treatment of pain (Zamanillo D, Romero L, Merlos M, Vela JM. Eur. J. Pharmacol, 2013, 716, 78-93). The development of the s1 receptor knockout mice, which show no obvious phenotype and perceive normally sensory stimuli, was a key milestone in this endeavour. In physiological conditions the responses of the s1 receptor knockout mice to mechanical and thermal stimuli were found to be undistinguishable from WT ones but they were shown to possess a much higher resistance to develop pain behaviours than WT mice when hypersensitivity entered into play. Hence, in the s1 receptor knockout mice, capsaicin did not induce mechanical hypersensitivity, both phases of formalin-induced pain were reduced, and cold and mechanical hypersensitivity were strongly attenuated after partial sciatic nerve ligation or after treatment with paclitaxel, which are models of neuropathic pain. Many of these actions were confirmed by the use of s1 receptor antagonists and led to the advancement of one compound, S1RA, into clinical trials for the treatment of different pain states. Compound S1RA exerted a substantial reduction of neuropathic pain and anhedonic state following nerve injury (i.e., neuropathic pain conditions) and, as demonstrated in an operant self- administration model, the nerve-injured mice, but not sham-operated mice, acquired the operant responding to obtain it (presumably to get pain relief), indicating that s1 receptor antagonism relieves neuropathic pain and also address some of the ESTEVE PHARMACEUTICALS, S.A.

comorbidities (i.e., anhedonia, a core symptom in depression) related to pain states (Romero et al. Br J Pharmacol.2012, 166, 2289-306). 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, 1084-95). In fact, positive synergistic interaction for several compounds, including analgesics, has been described (Schröder et al., J Pharmacol Exp Ther.2011, 337, 312-20. Erratum in: J Pharmacol Exp Ther.2012, 342, 232; Zhang et al., Cell Death Dis.2014, 5:e1138; Gilron et al., 2013, supra). Given the significant differences in pharmacokinetics, metabolisms and bioavailability, reformulation of drug combinations (multi-component drugs) is challenging. Further, two drugs that are generally safe when dosed individually cannot be assumed to be safe in combination. In addition to the possibility of adverse drug-drug interactions, if the theory of network pharmacology indicates that an effect on phenotype may derive from hitting multiple targets, then that combined phenotypic perturbation may be efficacious or deleterious. The major challenge to both drug combination strategies is ESTEVE PHARMACEUTICALS, S.A.

the regulatory requirement for each individual drug to be shown to be safe as an individual agent and in combination (Hopkins et al, Nat Chem Biol.2008, 4, 682-90). An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008, supra). As described above, the s1 receptor, as well as thea₂d1 subunit, modulate intracellular calcium concentration and the activity of voltage-dependent calcium channels. There is also robust clinical and pre-clinical evidence linking both targets with the treatment of chronic neuropathic pain. Thus, the present application, also relates to the advantages of having dual activity, for the a₂d-1 subunit of voltage-gated calcium channels and the s1 receptor, in the same molecule to treat chronic pain. Accordingly, there is still a need to find compounds that have an alternative or improved pharmacological activity in the treatment of pain, being both effective and showing the desired selectivity, and having good“drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion. The authors of the present invention, have found a serie of compounds that show a primary pharmacological activity towards the a₂dsubunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel, or compounds that show dual pharmacological activity towards both the a₂dsubunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel and the s1 receptor resulting in an innovative, effective, complementary and alternative solution for the treatment of pain. In view of the existing results of the currently available therapies and clinical practices, the present invention offers a solution by developing compounds binding to a single target or by combining in a single compound binding to two different targets relevant ESTEVE PHARMACEUTICALS, S.A.

for the treatment of pain. This was mainly achieved by providing the compounds according to the invention that bind to the a₂dsubunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel, or both to the s1 receptor and to the a₂dsubunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel.

SUMMARY OF THE INVENTION In this invention a family of structurally distinct ortho substituted phenoxypropylamino and benzyloxypropylamino derivatives, encompassed by formula (I), which have a pharmacological activity towards the a₂d ^subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel, or which have a dual pharmacological activity towards both the a₂dsubunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel and the s1 receptor, were identified thus solving the above problem of identifying alternative or improved pain treatments by offering such compounds. The main object of the invention is directed to a compound having binding to the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel for use in the treatment of pain.

Another object of the invention is directed to a compound having a dual activity binding to the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel and the ^ ^ receptor for use in the treatment of pain.

As this invention is aimed at providing a compound or a chemically related series of compounds which act as ligands of the a₂dsubunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel and the s1 receptor it is a very preferred embodiment if the compound has a binding expressed as Ki responding to the following scales:

K_i ( s1) is preferably < 1000 nM, more preferably < 500 nM, even more preferably < 100 nM.

Ki(a₂d-1) is preferably < 10000 nM, more preferably < 5000 nM, even more preferably < 500 nM or even more preferably < 100 nM. ESTEVE PHARMACEUTICALS, S.A.

The invention is directed in a main aspect to a compound of general Formula (I),

wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁, Y₂ and n are as defined below in the detailed description. A further object of the invention refers to the processes for preparation of compounds of general formula (I). A still further object of the invention refers to the use of intermediate compounds for the preparation of a compound of general formula (I). It is also an object of the invention a pharmaceutical composition comprising a compound of formula (I). Finally, it is an object of the invention the use of compound as a medicament and more particularly for the treatment of pain and pain related conditions.

DETAILED DESCRIPTION OF THE INVENTION As this invention is aimed at providing a compound or a chemically related series of compounds which act as ligands of the a₂dsubunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel or as ligands of thea₂dsubunit, in particular thea₂d- 1 subunit, of the voltage-gated calcium channel and the s1 receptor it is a very preferred embodiment if the compound has a binding expressed as Ki responding to the following scales: ESTEVE PHARMACEUTICALS, S.A.

Ki(a₂d-1) is preferably < 10000 nM, more preferably < 5000 nM, even more preferably < 500 nM or even more preferably < 100 nM.

Advantageously, the compounds according to the present invention would in addition show one or more the following functionalities: blockade of thea₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel and s1 receptor antagonism. It has to be noted, though, that functionalities“antagonism” and“agonism” are also sub- divided in their effect into subfunctionalities like partial agonism or inverse agonism. Accordingly, the functionalities of the compound should be considered within a relatively broad bandwidth. A further advantage of using designed multiple ligands is a lower risk of drug-drug interactions compared to cocktails or multi-component drugs, thus involving simpler pharmacokinetics and less variability among patients. Additionally, this approach may improve patient compliance and broaden the therapeutic application in relation to monomechanistic drugs, by addressing more complex aetiologies. It is also seen as a way of improving the R&D output obtained using the“one drug-one target” approach, which has been questioned over the last years [Bornot A, Bauer U, Brown A, Firth M, Hellawell C, Engkvist O. Systematic Exploration of Dual-Acting Modulators from a Combined Medicinal Chemistry and Biology Perspective. J. Med. Chem, 56, 1197-1210 (2013)].

In its broader aspect, the present invention is directed to compounds of general Formula (I): ESTEVE PHARMACEUTICALS, S.A.

wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁, Y₂, and n are as defined in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I)

wherein ESTEVE PHARMACEUTICALS, S.A. X is selected from a bond, -[C(RaRb)]p-, -[CH2]pC(O)[CH2]q-, -[CH2]pC(O)N(Rz)[CH2]q-, - [CH2]pN(Rz)C(O)[CH2]q- and -[CH2]pN(Rz)[CH2]q-; Ra is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; R_b is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R_a and R_b, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl; R_z is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)- p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4 or 5;

n is 0 or 1; Y₁ is–C(R₁₀R_10’)-; wherein R₁₀ and R_10’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R10 and R10’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl; ESTEVE PHARMACEUTICALS, S.A.

Y₂ is–C(R_10’’R_10’’’)-; wherein R10’’ and R10’’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R10’’ and R10’’’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl;

wherein W1 is–N- or–CH-;

oxygen;

with the proviso that ESTEVE PHARMACEUTICALS, S.A.

when W₁ is–CH-,then W₂ is

m is 0, 1 or 2; m’ is 0, 1 or 2; wherein m+m’ is 1, 2, 3 or 4; r is 0, 1 or 2; r’ is 0, 1 or 2; wherein r +r’ is 1, 2, 3 or 4;

t is 0, 1, 2, 3, 4 or 5;

R5, R5’, R5’’ and R5’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R5 and R5’ and/or R5’’ and R5’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; alternatively, R5 and R5’ and/or R5’’ and R5’’’ taken together with the carbon atom to which they are attached form a carbonyl group; ESTEVE PHARMACEUTICALS, S.A.

R₆, R_6’, R_6’’ and R_6’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R6, R6’ and/or R6’’, R6’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; alternatively, R₆ and R_6’ and/or R_6’’ and R_6’’’ taken together with the carbon atom to which they are attached form a carbonyl group; R₇ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, -OR₇₁ and -CN; wherein R₇₁ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; R₈ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl,substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR81,– NR81R81’ and–C(O)R81; wherein R81 and R81’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl,substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylheterocyclyl; ESTEVE PHARMACEUTICALS, S.A.

R₂ is selected from substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; R3 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; R_3’ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; R₄ and R_4’ are independently selected from halogen, -R₄₁, -OR₄₁, -NO₂, -NR₄₁R_41’, - NR₄₁C(O)R_41’, -NR₄₁S(O)₂R_41’, -S(O)₂NR₄₁R_41’, -NR₄₁C(O)NR_41’R_41’’, -SR₄₁ , -S(O)R₄₁, - S(O)₂R₄₁,–CN, haloalkyl, haloalkoxy, -C(O)OR₄₁, -C(O)NR₄₁R_41’, -OCH₂CH₂OR₄₁, - NR₄₁S(O)₂NR_41’R_41’’ and -C(CH₃)₂OR₄₁; wherein R₄₁, R_41’ and R_41’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; These compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another embodiment, these compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof. In a particular embodiment the following proviso applies: when X is -[CH2]pC(O)N(Rz)[CH2]q- or -[CH2]pN(Rz)[CH2]q- and q is 0, then W1 is–CH- ; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention is a compound of general Formula (I)

wherein X is selected from a bond, -[C(R_aR_b)]_p-, -[CH₂]_pC(O)[CH₂]_q-, -[CH₂]_pC(O)N(R_z)[CH₂]_q-, - [CH₂]_pN(R_z)C(O)[CH₂]_q- and -[CH₂]_pN(R_z)[CH₂]_q-; R_a is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; R_b is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, Ra and Rb, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;

Rz is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)-C1-6 alkyl; p is 0, 1, 2, 3, 4 or 5; ESTEVE PHARMACEUTICALS, S.A.

q is 0, 1, 2, 3, 4 or 5;

n is 0 or 1; Y1 is–C(R10R10’)-; wherein R10 and R10’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₁₀ and R_10’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl;

Y₂ is–C(R_10’’R_10’’’)-; wherein R_10’’ and R_10’’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R_10’’ and R_10’’’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl;

ESTEVE PHARMACEUTICALS, S.A. wherein

W1 is–N- or–CH-;

oxygen; with the proviso that

when W1 is–CH-,then

m is 0, 1 or 2;

m’ is 0, 1 or 2;

wherein m+m’ is 1, 2, 3 or 4;

r is 0, 1 or 2;

r’ is 0, 1 or 2;

wherein r +r’ is 1, 2, 3 or 4; t is 0, 1, 2, 3, 4 or 5; ESTEVE PHARMACEUTICALS, S.A.

R₅, R_5’, R_5’’ and R_5’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R5 and R5’ and/or R5’’ and R5’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; alternatively, R₅ and R_5’ and/or R_5’’ and R_5’’’ taken together with the carbon atom to which they are attached form a carbonyl group;

wherein the alkyl, alkenyl or alkynyl defined in R₅, R_5’ R_5’’ and R_5’’’, if substituted, is substituted with one or more substituent/s selected from–OR₅₁, halogen, - CN, haloalkyl, haloalkoxy and–NR₅₁R_51’;

wherein the cycloalkyl, as defined in R₅-R_5’ and/or R_5’’-R_5’’’, if substituted, is substituted with one or more substituent/s selected from halogen, -R₅₁, - OR₅₁, -NO₂, -NR₅₁R_51’, -NR₅₁C(O)R_51’, -NR₅₁S(O)₂R_51’, -S(O)₂NR₅₁R_51’, - NR₅₁C(O)NR_51’R_51’’, -SR₅₁ , -S(O)R₅₁, -S(O)₂R₅₁, –CN, haloalkyl, haloalkoxy, -C(O)OR₅₁, -C(O)NR₅₁R_51’, -OCH₂CH₂OR₅₁, - NR₅₁S(O)₂NR_51’R_51’’ and -C(CH₃)₂OR₅₁; preferably selected from halogen, - R51, -OR51, -NR51R51’, -CN, haloalkyl and haloalkoxy;

wherein R51, R51’ and R51’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; ESTEVE PHARMACEUTICALS, S.A.

R₆, R_6’, R_6’’ and R_6’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R6, R6’ and/or R6’’, R6’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; alternatively, R₆ and R_6’ and/or R_6’’ and R_6’’’ taken together with the carbon atom to which they are attached form a carbonyl group;

wherein the alkyl, alkenyl or alkynyl defined in R₆,

R_6’’ and R_6’’’, if substituted, is substituted with one or more substituent/s selected from–OR₆₁, halogen, - CN, haloalkyl, haloalkoxy and–NR₆₁R_61’;

wherein the cycloalkyl, as defined in R₆-R_6’ and/or R_6’’-R_6’’’, if substituted, is substituted with one or more substituent/s selected from halogen, -R₆₁, - OR₆₁, -NO₂, -NR₆₁R_61’, -NR₆₁C(O)R_61’, -NR₆₁S(O)₂R_61’, -S(O)₂NR₆₁R_61’, - NR₆₁C(O)NR_61’R_61’’, -SR₆₁ , -S(O)R₆₁, -S(O)₂R₆₁, –CN, haloalkyl, haloalkoxy, -C(O)OR₆₁, -C(O)NR₆₁R_61’, -OCH₂CH₂OR₆₁, - NR₆₁S(O)₂NR_61’R_61’’ and -C(CH₃)₂OR₆₁; preferably selected from halogen, - R₆₁, -OR₆₁, -NR₆₁R_61’, -CN, haloalkyl and haloalkoxy; wherein R61, R61’ and R61’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;

R7 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, -OR71 and -CN; wherein ESTEVE PHARMACEUTICALS, S.A.

the alkyl, alkenyl or alkynyl defined in R₇, if substituted, is substituted with one or more substituent/s selected from–OR71, halogen, -CN, haloalkyl and haloalkoxy; wherein R₇₁ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R₈ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl,substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR₈₁,– NR₈₁R₈₁’ and–C(O)R₈₁; wherein R₈₁ and R₈₁’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl,substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylheterocyclyl;

wherein the alkyl, alkenyl or alkynyl defined in R8, if substituted, is substituted with one or more substituent/s selected from–OR82, halogen, -CN, haloalkyl and haloalkoxy; and wherein the aryl, heterocyclyl or cycloalkyl, also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl, defined in R8, if substituted, it is substituted with one or more ESTEVE PHARMACEUTICALS, S.A.

substituent/s selected from halogen, -R₈₂, -OR₈₂, -NO₂, -NR₈₂R_82’, - NR82C(O)R82’, -NR82S(O)2R82’, -S(O)2NR82R82’, - NR82C(O)NR82’R82’’, -SR82 , -S(O)R82, -S(O)2R82, –CN, haloalkyl, haloalkoxy, -C(O)OR82, - C(O)NR82R82’, -OCH2CH2OR82, -NR82S(O)2NR82’R82’’ and -C(CH3)2OR82; wherein R₈₂, R_82’ and R_82’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R₂ is selected from substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; wherein the aryl or heterocyclyl in R₂, if substituted, is substituted with one or more substituent/s selected from halogen, -R₂₁, -OR₂₁, -NO₂, -NR₂₁R_21’, -NR₂₁C(O)R_21’, -NR₂₁S(O)₂R_21’, -S(O)₂NR₂₁R_21’, - NR₂₁C(O)NR_21’R_21’’, -SR₂₁ , -S(O)R₂₁, -S(O)₂R₂₁, –CN, haloalkyl, haloalkoxy, -C(O)OR₂₁, - C(O)NR₂₁R_21’, -OCH₂CH₂OR₂₁, -NR₂₁S(O)₂NR_21’R_21’’ and -C(CH₃)₂OR₂₁; wherein R₂₁, R_21’ and R_21’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R3 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; wherein, the alkyl, alkenyl or alkynyl defined in R3, if substituted, is substituted with one or more substituent/s selected from–OR31, halogen, -CN, haloalkyl, haloalkoxy and -NR31R31’; wherein the cycloalkyl in R3, also in alkylcycloalkyl, if substituted, is substituted with one or more substituent/s selected from halogen, -R31, - ESTEVE PHARMACEUTICALS, S.A.

OR₃₁, -NO₂, -NR₃₁R_31’, -NR₃₁C(O)R_31’, -NR₃₁S(O)₂R_31’, -S(O)₂NR₃₁R_31’, - NR31C(O)NR31’R31’’, -SR31 , -S(O)R31, -S(O)2R31, –CN, haloalkyl, haloalkoxy, -C(O)OR31, -C(O)NR31R31’, -OCH2CH2OR31, - NR31S(O)2NR31’R31’’ and -C(CH3)2OR31; preferably selected from halogen, - R31, -OR31, -NR31R31’, -CN, haloalkyl and haloalkoxy;

wherein R₃₁, R_31’ and R_31’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R_3’ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; wherein, the alkyl, alkenyl or alkynyl defined in R_3’, if substituted, is substituted with one or more substituent/s selected from–OR₃₂, halogen, -CN, haloalkyl, haloalkoxy and -NR₃₂R_32’; wherein R₃₂ and R_32’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R4 and R4’ are independently selected from halogen, -R41, -OR41, -NO2, -NR41R41’, - NR41C(O)R41’, -NR41S(O)2R41’, -S(O)2NR41R41’, -NR41C(O)NR41’R41’’, -SR41 , -S(O)R41, - S(O)2R41,–CN, haloalkyl, haloalkoxy, -C(O)OR41, -C(O)NR41R41’, -OCH2CH2OR41, - NR41S(O)2NR41’R41’’ and -C(CH3)2OR41; whereinR41, R41’ and R41’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; ESTEVE PHARMACEUTICALS, S.A.

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from–OR13, halogen, -CN, haloalkyl, haloalkoxy and -NR13R13’; wherein R₁₃ and R_13’ are independently selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C_2-6 alkynyl;

the aryl, heterocyclyl or cycloalkyl, also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from halogen, -R₁₄, -OR₁₄, -NO₂, -NR₁₄R_14’, - NR₁₄C(O)R_14’, -NR₁₄S(O)₂R_14’, -S(O)₂NR₁₄R_14’, - NR₁₄C(O)NR_14’R_14’’, -SR₁₄ , -S(O)R₁₄, - S(O)₂R₁₄,–CN, haloalkyl, haloalkoxy, -C(O)OR₁₄, -C(O)NR₁₄R_14’, -OCH₂CH₂OR₁₄, - NR₁₄S(O)₂NR_14’R_14’’ and -C(CH₃)₂OR₁₄;

wherein R₁₄, R_14’ and R_14’’ are independently selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I^’) ESTEVE PHARMACEUTICALS, S.A.

(I’) wherein R1, R2, R3, R3’, R4, R4’, X and n are as defined in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I^a)

wherein R₁, R₃, R_3’, R₄, R_4’, R₉, R_9’, X, Y₁, Y₂ and n are as defined in the detailed description, ESTEVE PHARMACEUTICALS, S.A.

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

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I^a’)

(I^a’) wherein R₁, R₃, R_3’, R₄, R_4’, R₉, R_9’, X and n are as defined in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I^b) ESTEVE PHARMACEUTICALS, S.A.

wherein R₁, R₃, R_3’, R₄, R_4’, R₉, R_9’, X, Y₁, Y₂ and n are as defined below in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I^b’)

ESTEVE PHARMACEUTICALS, S.A.

(I^b’), wherein R₁, R₃, R_3’, R₄, R_4’, R₉, R_9’, X and n are as defined below in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I^c)

ESTEVE PHARMACEUTICALS, S.A.

(I^c), wherein R1, R3, R3’, R4, R4’, R9, R9’, X, Y1, Y2 and n are as defined below in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I^c’)

(I^c’), wherein R1, R3, R3’, R4, R4’, R9, R9’, X and n are as defined below in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound of general Formula (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c) or (I^c’),

(I^a),

ESTEVE PHARMACEUTICALS, S.A.

ESTEVE PHARMACEUTICALS, S.A.

(I^b’),

(I^c’),

wherein R9 and R9’ are independently selected from hydrogen, halogen, -R21, -OR21, -NO2, -NR21R21’, -NR21C(O)R21’, -NR21S(O)2R21’, -S(O)2NR21R21’, - NR21C(O)NR21’R21’’, -SR21 , -S(O)R21, -S(O)2R21,–CN, haloalkyl, haloalkoxy, - C(O)OR21, -C(O)NR21R21’, -OCH2CH2OR21, -NR21S(O)2NR21’R21’’ and - C(CH3)2OR21; ESTEVE PHARMACEUTICALS, S.A.

wherein R₂₁, R₂₁’ and R₂₁’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl. optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment, the following compound is excluded:

.

For clarity purposes, all groups and definitions described in the present description and referring to compounds of general Formula (I), also apply to compounds of general Markush Formulae (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c) and (I^c’), (where applicable), and to all intermediate of synthesis, when those groups are present in the mentioned general Markush formulae, since compounds of general Markush Formulae (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c) and (I^c’), are included within the scope of the larger definition of general Markush Formula (I).

For clarity purposes, the general Markush Formula (I) ESTEVE PHARMACEUTICALS, S.A.

is equivalent to

wherein only– CH2- is included into the brackets, and n means the number of times that–CH2- is repeated. The same would apply, when applicable, to general Markush Formulae (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c) and (I^c’), and to all intermediates of synthesis. In addition, and for clarity purposes, it should further be understood that naturally if n is 0, the oxygen atom and/or the phenyl group are still present, when applicable, in general Markush Formulae (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c) and (I^c’), and to all intermediates of synthesis.

For clarity purposes, the expression e.g.“the cycle in Ra-Rb“, means the cycle resulting when Ra and Rb form, together with the atom(s) to which they are attached. This cycle can then be substituted or not. This definition is also generally applicable and can be also applied as a definition of any other cycle (preferably cycloalkyls, heterocycls or aryls) formed from two different functional groups like e.g.“the cycle in R_i-R_i’“ means ESTEVE PHARMACEUTICALS, S.A.

the cycle resulting when R_i and R_i’ form a cycle together with the atom(s) to which they are attached. This cycle can then be substituted or not. For clarity purposes, reference is also made to the following statements below in the definitions of substitutions on alkyl etc. or aryl etc. that“wherein when different radicals R1 to R81’ are present simultaneously in Formula (I) they may be identical or different”. This statement is reflected in the below general Formula (I^3’) being derived from and falling into the definition of R₁ within Formula (I),

wherein R5, R5’, R5’’, R5’’’, R6, R6’, R6’’, R6’’’, W1, W2, m’, r and r’ are as defined in the description. In addition, R5a, R5a’ and ma are added. As said above, this statement is thus reflected in that R_5a, R_5a are or could be different from R₅ and R₅’ or not. m_a being 0 or 1 naturally resulting from m being 0, 1 or 2. The same would be applicable mutatis mutandis for general Formulas like general Formula (I) as well as the other general Formulas above and to all intermediates of synthesis.

The above formula I³’ can be illustrated by the following two compounds listed as examples 125 and 126 in the present patent application: ESTEVE PHARMACEUTICALS, S.A.

Example 125

Example 126

,

wherein R1 in the above examples i

, respectively. In the above examples, R5 can be hydrogen on one carbon and methyl on the adjacent carbon. Hence when different radicals R5, R5’, R5’’, R5’’’, R6, R6’, R6’’ and R6’’’ are present simultaneously in Formula (I) they may each have different meanings.

In a further embodiment the following proviso applies: If any of m, m’, r or r’ is 2, any of R5, R5’, R5’’ and R5’’’ as well as R6, R6’, R6’’ and R6’’’, that thus occurs twice attached to neighbouring carbon atoms, can be different. ESTEVE PHARMACEUTICALS, S.A.

The same would be applicable mutatis mutandis for general Formulas like general Formula (I) as well as the other general Formulas (I), (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c) and (I^c’), above and to all intermediates of synthesis.

In the context of this invention, alkyl is understood as meaning saturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses e.g. -CH₃ and -CH₂-CH₃. In these radicals, C_1-2-alkyl represents C1- or C2-alkyl, C_1-3-alkyl represents C1-, C2- or C3-alkyl, C_1-4-alkyl represents C1-, C2-, C3- or C4-alkyl, C_1-5-alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl, C_1-6-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl, C_1-7-alkyl represents C1-, C2-, C3-, C4- , C5-, C6- or C7-alkyl, C_1-8-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8- alkyl, C_1-10-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C_1-18-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. The alkyl radicals are preferably methyl, ethyl, propyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1- methylpentyl, if substituted also CHF2, CF3 or CH2OH etc. Preferably alkyl is understood in the context of this invention as C1-8alkyl like methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; preferably is C1-6alkyl like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more preferably is C_1-4alkyl like methyl, ethyl, propyl or butyl. Alkenyl is understood as meaning unsaturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -CH=CH-CH3. The alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in the context of this invention alkenyl is C2-10-alkenyl or C2-8-alkenyl like ethylene, propylene, butylene, pentylene, hexylene, heptylene or octylene; or is C2-6- alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C2-4-alkenyl, like ethylene, propylene, or butylenes. Alkynyl is understood as meaning unsaturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -C=C-CH3 (1-propinyl). Preferably alkynyl in the context of this invention is C2-10- alkynyl or C2-8-alkynyl like ethyne, propyne, butyene, pentyne, hexyne, heptyne, or ESTEVE PHARMACEUTICALS, S.A.

octyne; or is C_2-6-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C_2-4- alkynyl like ethyne, propyne, butyene, pentyne, or hexyne. In connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl and O-alkyl - unless defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen (F, Cl, Br, I), -NR_kR_k’, -SR_k, -S(O)R_k, -S(O)₂R_k, -OR_k, - C(O)R_k, -C(O)OR_k, -CN, -C(O)NR_kR_k’, haloalkyl, haloalkoxy, being R_k represented by R_13, R_31, R_32, R_51, R_61, R₇₁ or R₈₂ (being R_k’ represented by R₁₃’_, R₃₁’_, R₃₂’_, R₅₁’_, R₆₁’_, R₇₁’ or R₈₂’_; being R_k’’ represented by R₁₃’’_, R₃₁’’_, R₃₂’’_, R₅₁’’_, R₆₁’’_, R₇₁’’ or R₈₂’’)_; wherein R₁ to R₈₂’’ andR_z and R_a and R_b are as defined in the description, and wherein when different radicals R₁ to R₈₂’’ andR_z are present simultaneously in Formula I they may be identical or different. Most preferably in connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl, substituted is understood in the context of this invention that any alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl which is substituted with one or more of halogen (F, Cl, Br, I), -NRkRk’, -ORk, -CN,–SRk, haloalkyl, haloalkoxy, being Rk represented by R13, R31, R32, R51, R61, R71 or R82, (being Rk’ represented by R13’, R31’, R32’, R51’, R61’, R71’ or R82’; being Rk’’ represented by R13’’, R31’’, R32’’, R51’’, R61’’, R71’’ or R82’’); wherein R1 to R82’’ and R_z are as defined in the description, and wherein when different radicals R₁ to R₈₂’’_’ and R_z and R_a and R_b are present simultaneously in Formula I they may be identical or different. More than one replacement on the same molecule and also on the same carbon atom is possible with the same or different substituents. This includes for example 3 hydrogens being replaced on the same C atom, as in the case of CF3, or at different places of the same molecule, as in the case of e.g. -CH(OH)-CH=CH-CHCl2. In the context of this invention haloalkyl is understood as meaning an alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g.–CH2Cl,–CH2F,–CHCl2,–CHF2,–CCl3,–CF3 and -CH2-CHCI2. Preferably haloalkyl is understood in the context of this invention as halogen- substituted C1-4-alkyl representing halogen substituted C1-, C2-, C3- or C4-alkyl. The ESTEVE PHARMACEUTICALS, S.A.

halogen-substituted alkyl radicals are thus preferably methyl, ethyl, propyl, and butyl. Preferred examples include–CH2Cl,–CH2F,–CHCl2,–CHF2, and–CF3. In the context of this invention haloalkoxy is understood as meaning an–O-alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g.–OCH₂Cl,–OCH₂F,–OCHCl₂,–OCHF₂,–OCCl₃,–OCF₃ and - OCH₂-CHCI₂. Preferably haloalkoxy is understood in the context of this invention as halogen-substituted -OC_1-4-alkyl representing halogen substituted C1-, C2-, C3- or C4- alkoxy. The halogen-substituted alkyl radicals are thus preferably O-methyl, O-ethyl, O-propyl, and O-butyl. Preferred examples include–OCH₂Cl,–OCH₂F,–OCHCl₂,– OCHF₂, and–OCF₃. In the context of this invention cycloalkyl is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted. Furthermore, C_3-4- cycloalkyl represents C3- or C4-cycloalkyl, C_3-5-cycloalkyl represents C3-, C4- or C5- cycloalkyl, C3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl, C3-7-cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl represents C3-, C4-, C5- , C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl represents C4- or C5-cycloalkyl, C4-6- cycloalkyl represents C4-, C5- or C6-cycloalkyl, C_4-7-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C_5-6-cycloalkyl represents C5- or C6-cycloalkyl and C_5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl. Preferably in the context of this invention cycloalkyl is C3-8cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C3-7cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C3-6cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl. Aryl is understood as meaning 5 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, 9H- fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times ESTEVE PHARMACEUTICALS, S.A.

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

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

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

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

Preferably in the context of this invention heterocyclyl is defined as a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. Preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. Preferred examples of heterocyclyls include oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, , benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, tetrahydroisoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, especially is pyridine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyrane, pyrazole, imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane and pyrrolidine. In the context of this invention oxopyrrolidine is understood as meaning pyrrolidin-2- one. An N-containing heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains a nitrogen and optionally one or more further heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains a nitrogen and optionally one or more further heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepam, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzimidazole, indazole, benzothiazole, benzodiazole, morpholine, indoline, triazole, isoxazole, pyrazole, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, quinolone, ESTEVE PHARMACEUTICALS, S.A.

isoquinoline, tetrahydrothienopyridine, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, carbazole or thiazole. In the context of this invention, a cyclic amide is defined as a subgroup of a heterocyclyl (as defined above) formed through the cyclization of a carbon sequence, containing at least the sequence

forming part of the cycle. Said cyclic amide may optionally be fused to a ring system. Preferably the cyclic amide is an“indoline-2-one”. A cyclic amide may be substituted or unsubstituted as defined for heterocyclyl above.In the context of this invention, a cyclic urea is defined as a subgroup of a heterocyclyl (as defined above) formed through the cyclization of a carbon sequence containing at least the sequence

forming part of the cycle. Said cyclic urea may optionally be fused to a ring system. Preferably the cyclic urea is“1H-benzo[d]imidazol-2(3H)-one”. A cyclic urea may be substituted or unsubstituted as defined for heterocyclyl above.

In connection with aromatic heterocyclyls (heteroaryls), non-aromatic heterocyclyls, aryls and cycloalkyls, when a ring system falls within two or more of the above cycle definitions simultaneously, then the ring system is defined first as an aromatic heterocyclyl (heteroaryl) if at least one aromatic ring contains a heteroatom. If no aromatic ring contains a heteroatom, then the ring system is defined as a non-aromatic heterocyclyl if at least one non-aromatic ring contains a heteroatom. If no non-aromatic ring contains a heteroatom, then the ring system is defined as an aryl if it contains at least one aryl cycle. If no aryl is present, then the ring system is defined as a cycloalkyl if at least one non-aromatic cyclic hydrocarbon is present. An heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of ESTEVE PHARMACEUTICALS, S.A.

nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, quinolone, isoquinoline, tetrahydrothienopyridine, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, benzodioxolane, benzodioxane, carbazole, oxaspirodecan or thiazole; In general, such a heterocyclyl may contain between 3 and 32 atoms in the rings (preferably 4 to 20 atoms in the rings, or most preferably 5 to 18 atoms in the rings). Thus, a heterocyclyl may contain between 3 and 12 atoms in the ring (preferably 4 to 10 atoms in the ring, or 5 to 8 atoms in the ring, or 5 to 6 atoms in the ring) in case of a heterocyclyl of one saturated or unsaturated ring. Such a heterocyclyl may also contain between 5 and 22 atoms in both rings together (preferably 6 to 16 atoms in both rings together, or 7 to 12 atoms in both rings together or 8 to 10 atoms in both rings together) in case of a heterocyclyl of two saturated or unsaturated rings. Such a heterocyclyl may also contain between 7 and 32 atoms in the 3 rings together (preferably 10 to 22 atoms in the three rings together, or 12 to 20 atoms in the three rings together or 10 to 18 atoms in the three rings together) in case of a heterocyclyl of three saturated or unsaturated rings.

In the context of this invention alkylaryl is understood as meaning an aryl group (see above) being connected to another atom through a C1-6-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylaryl is understood as meaning an aryl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups. Most preferably alkylaryl is benzyl (i.e.–CH2-phenyl). In the context of this invention alkylheterocyclyl is understood as meaning an heterocyclyl group being connected to another atom through a C1-6-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylheterocyclyl is understood as meaning an heterocyclyl group ESTEVE PHARMACEUTICALS, S.A.

(see above) being connected to another atom through 1 to 4 (-CH₂-) groups. Most preferably alkylheterocyclyl is–CH2-pyridine. In the context of this invention alkylcycloalkyl is understood as meaning an cycloalkyl group being connected to another atom through a C1-6-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylcycloalkyl is understood as meaning a cycloalkyl group (see above) being connected to another atom through 1 to 4 (-CH₂-) groups. Most preferably alkylcycloalkyl is–CH₂-cyclopropyl. Preferably, the aryl is a monocyclic aryl. More preferably the aryl is a 5, 6 or 7 membered monocyclic aryl. Even more preferably the aryl is a 5 or 6 membered monocyclic aryl. Preferably, the heteroaryl is a monocyclic heteroaryl. More preferably the heteroaryl is a 5, 6 or 7 membered monocyclic heteroaryl. Even more preferably the heteroaryl is a 5 or 6 membered monocyclic heteroaryl. Preferably, the non-aromatic heterocyclyl is a monocyclic non-aromatic heterocyclyl. More preferably the non-aromatic heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic heterocyclyl. Even more preferably the non-aromatic heterocyclyl is a 5 or 6 membered monocyclic non-aromatic heterocyclyl. Preferably, the cycloalkyl is a monocyclic cycloalkyl. More preferably the cycloalkyl is a 3, 4, 5, 6, 7 or 8 membered monocyclic cycloalkyl. Even more preferably the cycloalkyl is a 3, 4, 5 or 6 membered monocyclic cycloalkyl. In connection with aryl (including alkyl-aryl), cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkyl-heterocyclyl), substituted is understood - unless defined otherwise - as meaning substitution of the ring-system of the aryl or alkyl-aryl, cycloalkyl or alkyl-cycloalkyl; heterocyclyl or alkyl-heterocyclyl with one or more of halogen (F, Cl, Br, I), -Rk ,-ORk, -CN, -NO2 , -NRkRk’, -C(O)ORk, NRkC(O)Rk’ , -C(O)NRkRk’ , - NRkS(O)2Rk’ , =O, -OCH2CH2OH, -NRkC(O)NRk’Rk’’, -S(O)2NRkRk’, -NRkS(O)2NRk’Rk’’, haloalkyl, haloalkoxy, -SRk, -S(O)Rk, -S(O)2Rk or C(CH3)ORk, or substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl, substituted or ESTEVE PHARMACEUTICALS, S.A.

unsubstituted alkylheterocyclyl, with R_k, R_k’ and R_k’’ independently being either H or a saturated or unsaturated, linear or branched, substituted or unsubstituted C1-6-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted C1-6-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted–O-C1-6-alkyl (alkoxy); a saturated or unsaturated, linear or branched, substituted or unsubstituted– S-C_1-6-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted -C(O)-C_1-6-alkyl-group; a saturated or unsaturated, linear or branched, substituted or unsubstituted -C(O)-O-C_1-6-alkyl-group; a substituted or unsubstituted aryl or alkyl-aryl; a substituted or unsubstituted cycloalkyl or alkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl or alkyl-heterocyclyl, being R_k one of R_14, R_21, R_31, R_51, R₆₁ or R_82, (being R_k’ one of R₁₄’_, R₂₁’_, R₃₁’_, R₅₁’_, R₆₁’ or R₈₂’_, being R_k’’ one of R₁₄’’_, R₂₁’’_, R₃₁’’_, R₅₁’’_, R₆₁’’ or R₈₂’’_; wherein R₁ to R₈₂’’ and R_z and R_a and R_b are as defined in the description, and wherein when different radicals R₁ to R₈₂’’ and R_z and R_a and R_b are present simultaneously in Formula I they may be identical or different. Most preferably in connection with aryl (including alkyl-aryl), cycloalkyl (including alkyl- cycloalkyl), or heterocyclyl (including alkyl-heterocyclyl), substituted is understood in the context of this invention that any aryl, cycloalkyl and heterocyclyl which is substituted is substituted (also in an alyklaryl, alkylcycloalkyl or alkylheterocyclyl) with one or more of halogen (F, Cl, Br, I), -Rk ,-ORk, -CN , -NO2 , -NRkRk’’’ , NRkC(O)Rk’, - NR_kS(O)₂R_k’ , -S(O)₂NR_kR_k’, -NR_kC(O)NR_k’R_k’’, haloalkyl, haloalkoxy,–SR_k , -S(O)R_k or S(O)₂R_k, or substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, being R_k one of R_14, R_21, R_31, R_51, R61 or R82, (being Rk’ one of R14’, R21’, R31’, R51’, R61’ or R82’; being Rk’’ one of R14’’, R21’’, R31’’, R51’’, R61’’ or R82’’; wherein R1 to R82’’ and Rz and Ra and Rb are as defined in the description, and wherein when different radicals R1 to R82’’ and Rz and Ra and Rb are present simultaneously in Formula I they may be identical or different. In connection with cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl- heterocyclyl), substituted is also understood - unless defined otherwise - as meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl; non-aromatic heterocyclyl or non aromatic alkyl-heterocyclyl with

(leading to a spiro structure) and/or with =O. ESTEVE PHARMACEUTICALS, S.A.

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

Moreover, in connection with cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl-heterocyclyl), substituted is also understood - unless defined otherwise - as meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl; non- aromatic heterocyclyl or non aromatic alkyl-heterocyclyl with =O. A ring system is a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with “joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings. The term“polycyclic ring system” means that the ring system is made of two or more rings joined by sharing at least one atom. The term“leaving group” means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-) or mesylate. The term“salt” is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes via ionic interactions. Please note that“or a corresponding salt thereof” does also mean“or a corresponding pharmaceutically acceptable salt thereof”. This does apply to all below described ESTEVE PHARMACEUTICALS, S.A.

embodiments and uses of“salt” being thus equivalent to“pharmaceutically acceptable salt”. The term“physiologically acceptable salt” means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals. These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH₄, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts. Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals. By this is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid. The compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid. Any compound that is a solvate of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. The term“solvate” according to this invention is to be understood as meaning any form of the active ESTEVE PHARMACEUTICALS, S.A.

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

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

Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon or of a nitrogen by ¹⁵N-enriched nitrogen are within the scope of this invention. This would especially also apply to the provisos described above so that any mentioning of hydrogen or any“H” in a formula would also cover deuterium or tritium. The compounds of formula (I) as well as their salts or solvates of the compounds 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 ESTEVE PHARMACEUTICALS, S.A.

levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts. This applies also to its solvates or prodrugs.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein X is selected from a bond, -[C(R_aR_b)]_p-, -[CH₂]_pC(O)[CH₂]_q-, -[CH₂]_pC(O)N(R_z)[CH₂]_q-, - [CH₂]_pN(R_z)C(O)[CH₂]_q- and -[CH₂]_pN(R_z)[CH₂]_q-; R_a is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; R_b is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R_a and R_b, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;

Rz is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)-C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein X is selected from a bond, -[C(RaRb)]p-, -[CH2]pC(O)[CH2]q-, -[CH2]pC(O)N(Rz)[CH2]q-, - [CH2]pN(Rz)C(O)[CH2]q- and -[CH2]pN(Rz)[CH2]q-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein ESTEVE PHARMACEUTICALS, S.A.

R_z is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)-C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein Y₁ is–C(R₁₀R₁₀’)-; wherein R₁₀ and R₁₀’ are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; alternatively, R10 and R10’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, ESTEVE PHARMACEUTICALS, S.A.

preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein Y₁ is–C(R₁₀R₁₀’)-; wherein R₁₀ and R₁₀’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein Y₂ is–C(R₁₀’’R₁₀’’’)-; wherein R₁₀’’ and R₁₀’’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein Y2 is–C(R10’’R10’’’)-; wherein R10’’ and R10’’’ are both hydrogen; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein

wherein R5, R5’, R5’’, R5’’’, R6, R6’, R6’’, R6’’’, W1, W2, m’, r and r’ are as defined in the description, R5a and R5a’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R5a and R5a’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; alternatively, R5a and R5a’ taken together with the carbon atom to which they are attached form a carbonyl group; and ma is 0 or 1; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the following proviso applies:

when W₁ is–CH-,then

In a further embodiment the following proviso applies: m+m’ is 1, 2, 3 or 4.

In a further embodiment the following proviso applies: r +r’ is 1, 2, 3 or 4.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted aromatic heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroayl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₃ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R3 is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₃ is substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R3’ is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₄ and R₄’ are both -R₄₁; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₄ and R_4’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R5, R5’, R5’’ and R5’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R5, R5’, R5’’ and R5’’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₆, R₆’, R_6’’ and R₆’’’ are independently selected from hydrogen, halogen and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₆, R₆’, R_6’’ and R₆’’’ are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R7 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -OR71 and -CN; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₈ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR₈₁,–NR₈₁R₈₁’ and–C(O)R₈₁; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R8 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR81,– NR81R81’ and–C(O)R81; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₉ and R_9’ are both -R₂₁; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R9 and R9’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₁₀ and R₁₀’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₁₀ and R₁₀’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R10’’ and R10’’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R10’’ and R10’’’ are both hydrogen ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₁₃ and R₁₃’ are independently selected from hydrogen and unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₁₄, R₁₄’ and R₁₄’’ are independently selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R21, R21’ and R21’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₃₁, R₃₁’ and R₃₁’’ are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R32 and R32’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R41, R41’ and R41’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₅₁, R₅₁’ and R₅₁’’ are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R61, R61’ and R61’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R71 is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₈₁ and R₈₁’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylheterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₈₁ and R₈₁’ are independently selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R82, R82’ and R82’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₃ is substituted or unsubstituted C_1-6 alkyl; wherein, the alkyl defined in R₃, if substituted, is substituted with one or more substituent/s selected from–OR₃₁, halogen, -CN, haloalkyl, haloalkoxy and -NR31R31’; wherein R₃₁ and R₃₁’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₆, R₆’, R_6’’ and R₆’’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; alternatively, R6 and R6’ and/or R6’’ and R6’’’ taken together with the carbon atom to which they are attached form a carbonyl group; wherein the alkyl defined in R₆, R₆’ R₆’’ and R₆’’’, if substituted, is substituted with one or more substituent/s selected from–OR₆₁, halogen, -CN, haloalkyl, haloalkoxy and–NR₆₁R₆₁’; wherein R₆₁ and R₆₁’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R7 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -OR71 and -CN; wherein the alkyl defined in R7, if substituted, is substituted with one or more substituent/s selected from–OR71, halogen, -CN, haloalkyl and haloalkoxy; wherein R71 is selected from hydrogen and substituted or unsubstituted C1- 6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R₈ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR₈₁,–NR₈₁R₈₁’ and–C(O)R₈₁; wherein R₈₁ and R₈₁’ are independently selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted heterocyclyl; wherein the alkyl in R₈, if substituted, is substituted with one or more substituent/s selected from–OR₈₂, halogen, -CN, haloalkyl and haloalkoxy; and wherein the aryl or heterocyclyl, defined in R₈, if substituted, it is substituted with one or more substituent/s selected from halogen, -R₈₂, -OR₈₂, -NO₂, - NR₈₂R₈₂’, -NR₈₂C(O)R₈₂’, -NR₈₂S(O)₂R₈₂’, -S(O)₂NR₈₂R₈₂’, - NR82C(O)NR82’R82’’, -SR82 , -S(O)R82, -S(O)2R82, –CN, haloalkyl, haloalkoxy, -C(O)OR82, -C(O)NR82R82’, -OCH2CH2OR82, - NR82S(O)2NR82’R82’’ and -C(CH3)2OR82; wherein R82, R82’ and R82’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from–OR13, halogen, -CN, haloalkyl, haloalkoxy and -NR13R13’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein the aryl, heterocyclyl or cycloalkyl, also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from halogen, -R₁₄, -OR₁₄, -NO₂, -NR₁₄R₁₄’, - NR₁₄C(O)R₁₄’, -NR₁₄S(O)₂R₁₄’, -S(O)₂NR₁₄R₁₄’, - NR₁₄C(O)NR₁₄’R₁₄’’, -SR₁₄ , -S(O)R₁₄, -S(O)₂R₁₄,–CN, haloalkyl, haloalkoxy, -C(O)OR₁₄, -C(O)NR₁₄R₁₄’, -OCH₂CH₂OR₁₄, - NR₁₄S(O)₂NR₁₄’R₁₄’’ and -C(CH₃)₂OR₁₄; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the aryl or heterocyclyl in R2, if substituted, is substituted with one or more substituent/s selected from halogen, -R21, -OR21, -NO2, -NR21R21’, -NR21C(O)R21’, -NR21S(O)2R21’, - S(O)2NR21R21’, - NR21C(O)NR21’R21’’, -SR21 , -S(O)R21, -S(O)2R21,–CN, haloalkyl, ESTEVE PHARMACEUTICALS, S.A.

haloalkoxy, -C(O)OR₂₁, -C(O)NR₂₁R₂₁’, -OCH₂CH₂OR₂₁, -NR₂₁S(O)₂NR₂₁’R₂₁’’ and - C(CH3)2OR21; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R₃, if substituted, is substituted with one or more substituent/s selected from–OR₃₁, halogen, -CN, haloalkyl, haloalkoxy and -NR₃₁R₃₁’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the cycloalkyl in R3, also in alkylcycloalkyl, if substituted, is substituted with one or more substituent/s selected from halogen, -R31, -OR31, -NO2, -NR31R31’, -NR31C(O)R31’, - NR31S(O)2R31’, -S(O)2NR31R31’, - NR31C(O)NR31’R31’’, -SR31 , -S(O)R31, -S(O)2R31,–CN, haloalkyl, haloalkoxy, -C(O)OR31, -C(O)NR31R31’, -OCH2CH2OR31, - NR31S(O)2NR31’R31’’ and -C(CH3)2OR31; preferably selected from halogen, -R31, -OR31, -NR31R31’, -CN, haloalkyl and haloalkoxy; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R3’, if substituted, is substituted with one or more substituent/s selected from–OR32, halogen, -CN, haloalkyl, haloalkoxy and -NR₃₂R₃₂’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R₅, R₅’ R₅’’ and R₅’’’, if substituted, is substituted with one or more substituent/s selected from–OR₅₁, halogen, - CN, haloalkyl, haloalkoxy and–NR₅₁R₅₁’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the cycloalkyl, as defined in R5-R5’ and/or R5’’-R5’’’, if substituted, is substituted with one or more substituent/s selected from halogen, -R51, - OR51, -NO2, -NR51R51’, -NR51C(O)R51’, -NR51S(O)2R51’, -S(O)2NR51R51’, - NR51C(O)NR51’R51’’, -SR51 , -S(O)R51, -S(O)2R51, –CN, haloalkyl, haloalkoxy, -C(O)OR51, -C(O)NR51R51’, -OCH2CH2OR51, - NR51S(O)2NR51’R51’’ and -C(CH3)2OR51; preferably selected from halogen, -R51, -OR51, -NR51R51’, -CN, haloalkyl and haloalkoxy; ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R₆,

R_6’’ and R_6’’’, if substituted, is substituted with one or more substituent/s selected from–OR₆₁, halogen, -CN, haloalkyl, haloalkoxy and–NR₆₁R₆₁’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the cycloalkyl, as defined in R6-R6’ and/or R6’’-R6’’’, if substituted, is substituted with one or more substituent/s selected from halogen, -R61, -OR61, -NO2, -NR61R61’, - NR₆₁C(O)R₆₁’, -NR₆₁S(O)₂R₆₁’, -S(O)₂NR₆₁R₆₁’, - NR₆₁C(O)NR₆₁’R₆₁’’, -SR₆₁ , -S(O)R₆₁, -S(O)₂R₆₁,–CN, haloalkyl, haloalkoxy, -C(O)OR₆₁, -C(O)NR₆₁R₆₁’, -OCH₂CH₂OR₆₁, - NR₆₁S(O)₂NR₆₁’R₆₁’’ and -C(CH₃)₂OR₆₁; preferably selected from halogen, -R₆₁, -OR₆₁, -NR61R61’, -CN, haloalkyl and haloalkoxy; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R7, if substituted, is substituted with one or more substituent/s selected from–OR71, halogen, -CN, haloalkyl and haloalkoxy; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein X is a bond, -[C(R_aR_b)]_p-, -[C(R_aR_b)]_pC(O)[C(R_cR_d)]_q-, -[C(R_aR_b)]_pC(O)N(R_z)[C(R_cR_d)]_q- or -[C(R_aR_b)]_pN(R_z)C(O)[C(R_cR_d)]_q-, -[C(R_aR_b)]_pN(R_z)[C(R_cR_d)]_q-; R_z is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)-C1-6 alkyl; Ra is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; Rb is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, Ra and Rb, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl; ESTEVE PHARMACEUTICALS, S.A.

R_c is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; Rd is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein X is a bond, -[C(R_aR_b)]_p-, -[C(R_aR_b)]_pC(O)[C(R_cR_d)]_q-, -[C(R_aR_b)]_pC(O)N(R_z)[C(R_cR_d)]_q- or -[C(R_aR_b)]_pN(R_z)C(O)[C(R_cR_d)]_q-, -[C(R_aR_b)]_pN(R_z)[C(R_cR_d)]_q-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein R_z is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and - C(O)-C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein Ra is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein R_c is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein Rd is selected from hydrogen, substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein X is selected from a bond, -[C(R_aR_b)]_p-, -[CH₂]_pC(O)[CH₂]_q-, -[CH₂]_pC(O)N(R_z)[CH₂]_q-, - [CH₂]_pN(R_z)C(O)[CH₂]_q- and -[CH₂]_pN(R_z)[CH₂]_q-; preferably X is selected from a bond, -CH₂-, -CH₂CH₂-, -C(O)-, -CH₂C(O)-, -CH₂CH₂C(O)-, -C(O)N(CH₂CH₃)-, -NHC(O)-, - NHC(O)CH₂-, -NHC(O)CH₂CH₂-, -N(CH₃)C(O)-, -CH₂NH-, -CH₂N(C(O)(CH₂CH₃))-, - N(C(O)(CH₂CH₃))-, -N(CH₃)-, -NH-, -NHCH₂- and -NHCH₂CH₂- and/or Ra is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably Ra is hydrogen; and/or R_b is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably Rb is hydrogen; and/or Ra and Rb, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl; and/or ESTEVE PHARMACEUTICALS, S.A.

R_z is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)-C1-6 alkyl; preferably Rz is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, and -C(O)-C1-6 alkyl; more preferably Rz is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl and substituted or unsubstituted–C(O)OCH₂CH₃; and/or p is 0, 1, 2, 3, 4 or 5; preferably p is 0, 1 or 2; and/or q is 0, 1, 2, 3, 4 or 5; preferably q is 0, 1 or 2; and/or n is 0 or 1; and/or Y₁ is–C(R₁₀R₁₀’)-; preferably Y₁ is–CH₂-; and/or Y2 is–C(R10’’R10’’’)-;preferably Y2 is–CH2-;

ESTEVE PHARMACEUTICALS, S.A.

xygen; and/or

m is 0, 1 or 2;

and/or

m’ is 0, 1 or 2;

and/or

r is 0, 1 or 2;

and/or

r’ is 0, 1 or 2;

and/or ESTEVE PHARMACEUTICALS, S.A.

t is 0, 1, 2, 3, 4 or 5; preferably t is 0, 1 or 2; and/or R2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; preferably R2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted aromatic heterocyclyl, more preferably R2 is a substituted or unsubstituted group selected from phenyl and thiophen; and/or R₃ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; preferably R₃ is hydrogen or substituted or unsubstituted C_1-6 alkyl; more preferably R₃ is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted ethyl; and/or R₃’ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably R_3’ is hydrogen; and/or R4 and R4’ are independently selected from halogen, -R41, -OR41, -NO2, -NR41R41’, - NR41C(O)R41’, -NR41S(O)2R41’, -S(O)2NR41R41’, -NR41C(O)NR41’R41’’, -SR41 , -S(O)R41, -S(O)₂R₄₁,–CN, haloalkyl, haloalkoxy, -C(O)OR₄₁, -C(O)NR₄₁R₄₁’, -OCH₂CH₂OR₄₁, - NR₄₁S(O)₂NR₄₁’R₄₁’’ and -C(CH₃)₂OR₄₁; preferably R₄ and R_4’ are both -R₄₁, more preferably R₄ and R_4’ are both hydrogen; and/or R5, R5’, R5’’ and R5’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R5, R5’, R5’’ and R5’’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; more preferably R5, R5’, R5’’ ESTEVE PHARMACEUTICALS, S.A.

and R₅’’’ are independently selected from hydrogen and substituted or unsubstituted methyl; and/or R5 and R5’ and/or R5’’ and R5’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; and/or

R₅ and R₅’ and/or R₅’’ and R₅’’’ taken together with the carbon atom to which they are attached form a carbonyl group; and/or R₆, R₆’, R₆’’ and R₆’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₆, R₆’, R₆’’ and R₆’’’ are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; preferably R₆, R₆’, R₆’’ and R₆’’’ are independently selected from hydrogen and substituted or unsubstituted methyl; preferably R₆’ is hydrogen; preferably R₆, R₆’, R₆’’ and R₆’’’ are all hydrogen; and/or R6, R6’ and/or R6’’, R6’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; and/or R₆ and R₆’ and/or R₆’’ and R₆’’’ taken together with the carbon atom to which they are attached form a carbonyl group; and/or

R7 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, - ESTEVE PHARMACEUTICALS, S.A.

OR₇₁ and -CN; preferably R₇ is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -OR71 and -CN; more preferably R7 is selected from hydrogen, fluorine, substituted or unsubstituted methyl, -OH, -OCH3 and -CN; and/or R8 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR₈₁,–NR₈₁R₈₁’ and–C(O)R₈₁; preferably R₈ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR₈₁,–NR₈₁R₈₁’ and– C(O)R₈₁; more preferably R₈ is selected from hydrogen, fluorine, substituted or unsubstituted methyl, substituted or unsubstituted isobutyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted oxadiazolyl , -O-isopropyl, -N(CH₃)₂, -N(CH₃)(benzyl), - N(CH₃)(isopropyl) and–C(O)-piperidine; and/or R9 and R9’ are independently selected from hydrogen, halogen, -R21, -OR21, -NO2, - NR21R21’, -NR21C(O)R21’, -NR21S(O)2R21’, -S(O)2NR21R21’, - NR21C(O)NR21’R21’’, -SR21 , -S(O)R21, -S(O)2R21, –CN, haloalkyl, haloalkoxy, -C(O)OR21, -C(O)NR21R21’, - OCH₂CH₂OR₂₁, -NR₂₁S(O)₂NR₂₁’R₂₁’’ and -C(CH₃)₂OR₂₁;preferably R₉ and R₉’ are both -R₂₁; more preferably R₉ and R₉’ are both hydrogen; and/or R10 and R10’ are independently selected from hydrogen, substituted or unsubstituted C1- 6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R10 and R10’ are both hydrogen and/or R10 and R10’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl; and/or ESTEVE PHARMACEUTICALS, S.A.

R₁₀’’ and R₁₀’’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2- 6 alkynyl; preferably R10’’ and R10’’’ are both hydrogen; and/or R10’’ and R10’’’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl; and/or R₁₃ and R₁₃’ are independently selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C_2-6 alkynyl; and/or R₁₄, R₁₄’ and R₁₄’’ are independently selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; and/or R₂₁, R₂₁’ and R₂₁’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; and/or R31, R31’ and R31’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; and/or R32 and R32’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2- 6 alkynyl; and/or ESTEVE PHARMACEUTICALS, S.A.

R₄₁, R₄₁’ and R₄₁’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R41 is hydrogen; and/or R51, R51’ and R51’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; and/or R₆₁, R₆₁’ and R₆₁’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; and/or R₇₁ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₇₁ is selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably R₇₁ is selected from hydrogen and substituted or unsubstituted methyl; and/or R81 and R81’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl,substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylheterocyclyl; preferably R81 and R81’ are independently selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted heterocyclyl; more preferably R81 and R81’ are independently selected from substituted or unsubstituted methyl, substituted or unsubstituted isopropyl, substituted or unsubstituted benzyl and substituted or unsubstituted piperidinyl; and/or ESTEVE PHARMACEUTICALS, S.A.

R₈₂, R₈₂’ and R₈₂’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R82, R82’ andR82’’ are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl; more preferably R82, R82’ andR82’’ are independently selected from hydrogen and substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R_a as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Rb as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Ra-Rb as defined in any of the embodiments of the present invention, the cycloalkyl is C3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Rz as defined in any of the embodiments of the present invention, the alkyl is C1-6 alkyl like methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2- methylpropyl; and/or the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; more preferably the C_1-6 alkyl is methyl or ethyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or the cycloalkyl is C3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R2 as defined in any of the embodiments of the present invention, the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; preferably the aryl is phenyl; and/or the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, indoline-2-one and quinazoline; preferably the heterocyclyl is thiophen;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R3 as defined in any of the embodiments of the present invention, the alkyl is C1-6 alkyl like methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2- methylpropyl; ESTEVE PHARMACEUTICALS, S.A. and/or the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; preferably the C1-6 alkyl is methyl or ethyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or the cycloalkyl is C_3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R3’ as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; ESTEVE PHARMACEUTICALS, S.A.

and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R4 and R4’ as defined in any of the embodiments of the present invention, the alkyl is C1-6 alkyl like methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2- methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R5, R5’, R5’’ and R5’’’ as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; preferably the C1-6 alkyl is methyl; ESTEVE PHARMACEUTICALS, S.A.

and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R5 and R5’ and/or R5’’ and R5’’’ as defined in any of the embodiments of the present invention, the cycloalkyl is C3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C_3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C_3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R6, R6’, R6’’ and R6’’’ as defined in any of the embodiments of the present invention, ESTEVE PHARMACEUTICALS, S.A.

the alkyl is C_1-6 alkyl like methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2- methylpropyl; and/or the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; preferably the C_1-6 alkyl is methyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R6, R6’ and/or R6’’, R6’’’ as defined in any of the embodiments of the present invention, the cycloalkyl is C3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₇ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; preferably the C_1-6 alkyl is methyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R8 as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C1-6 alkyl is methyl or isobutyl; ESTEVE PHARMACEUTICALS, S.A.

and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or the cycloalkyl is C_3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C_3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C_3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R9 and R9’ as defined in any of the embodiments of the present invention, the alkyl is C1-6 alkyl like methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2- methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R10 and R10’ as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R10 and R10’ as defined in any of the embodiments of the present invention, the cycloalkyl is C3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R10’’ and R10’’’ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R10’’ and R10’’’ as defined in any of the embodiments of the present invention, the cycloalkyl is C3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₁₃ and R₁₃’ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R14, R14’ and R14’’ as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; ESTEVE PHARMACEUTICALS, S.A.

and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or the cycloalkyl is C_3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C_3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C_3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and/or the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; and/or the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, ESTEVE PHARMACEUTICALS, S.A.

pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, indoline-2-one and quinazoline;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₂₁, R₂₁’ and R₂₁’’ as defined in any of the embodiments of the present invention,

the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C_1-6 alkyl is methyl, ethyl or propyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R31, R31’ and R31’’ as defined in any of the embodiments of the present invention,

the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R32 and R32’ as defined in any of the embodiments of the present invention,

the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; ESTEVE PHARMACEUTICALS, S.A. and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₄₁, R₄₁’ and R₄₁’’ as defined in any of the embodiments of the present invention,

the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C1-6 alkyl is methyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R51, R51’ and R51’’ as defined in any of the embodiments of the present invention,

the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R61, R61’ and R61’’ as defined in any of the embodiments of the present invention,

the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C1-6 alkyl is methyl; ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R71 as defined in any of the embodiments of the present invention,

the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2-methylpropyl; preferably the C_1-6 alkyl is methyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₈₁ and R₈₁’ as defined in any of the embodiments of the present invention,

the alkyl is C_1-6 alkyl like methyl, ethyl, propyl, butyl,pentyl, hexyl, isopropyl, or 2- methylpropyl; more preferably the alkyl is methyl; and/or the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C_1-6 alkyl is methyl or isopropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or the cycloalkyl is C3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; ESTEVE PHARMACEUTICALS, S.A. and/or the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; more preferably the aryl is phenyl; and/or the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyrane, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, indoline-2-one and quinazoline; preferably the heterocyclyl is piperidinyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R82, R82’ and R82’’ as defined in any of the embodiments of the present invention, ESTEVE PHARMACEUTICALS, S.A.

the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C1-6 alkyl is methyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein X is selected from a bond, -[C(RaRb)]p-, -[CH2]pC(O)[CH2]q-, -[CH2]pC(O)N(Rz)[CH2]q-, - [CH2]pN(Rz)C(O)[CH2]q- and -[CH2]pN(Rz)[CH2]q-; preferably X is a bond, -CH2-, - CH2CH2-, -C(O)-, -CH2C(O)-, -CH2CH2C(O)-, -C(O)N(CH2CH3)-, -NHC(O)-, - NHC(O)CH2-, -NHC(O)CH2CH2-, -N(CH3)C(O)-, -CH2NH-, -CH2N(C(O)(CH2CH3))-, - N(C(O)(CH2CH3))-, -N(CH3)-, -NH-, -NHCH2- or -NHCH2CH2-;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein ESTEVE PHARMACEUTICALS, S.A.

R_a is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably Ra is hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R_b is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R_b is hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R_a and R_b, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein Rz is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)-C1-6 alkyl; preferably R_z is selected from hydrogen and -C(O)-C_1-6 alkyl; more preferably R_z is selected from hydrogen, substituted or unsubstituted–C(O)-ethyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein p is 0, 1, 2, 3, 4 or 5; preferably p is 0, 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein q is 0, 1, 2, 3, 4 or 5; preferably q is 0, 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein n is 0 or 1; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein Y₁ is–C(R₁₀R₁₀’)-; preferably Y₁ is–CH₂-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein Y₂ is–C(R₁₀’’R₁₀’’’)-; preferably Y₂ is–CH₂-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein W1 is–N- or–CH-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein t is 0, 1, 2, 3, 4 or 5; preferably t is 0, 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; preferably R2 is selected from substituted or unsubstituted aryl and substituted or unsubstituted aromatic heterocyclyl, more preferably R2 is a substituted or unsubstituted group selected from phenyl and thiophen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₃ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; preferably R₃ is hydrogen or substituted or unsubstituted C1-6 alkyl; more preferably R3 is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted ethyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; preferably R3 is substituted ESTEVE PHARMACEUTICALS, S.A.

or unsubstituted C_1-6 alkyl; more preferably R₃ is substituted or unsubstituted methyl or substituted or unsubstituted ethyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₃’ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably R_3’ is hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₄ and R₄’ are independently selected from halogen, -R₄₁, -OR₄₁, -NO₂, -NR₄₁R₄₁’, - NR₄₁C(O)R₄₁’, -NR₄₁S(O)₂R₄₁’, -S(O)₂NR₄₁R₄₁’, -NR₄₁C(O)NR₄₁’R₄₁’’, -SR₄₁ , -S(O)R₄₁, -S(O)₂R₄₁,–CN, haloalkyl, haloalkoxy, -C(O)OR₄₁, -C(O)NR₄₁R₄₁’, -OCH₂CH₂OR₄₁, - NR41S(O)2NR41’R41’’ and -C(CH3)2OR41; preferably R4 and R4’ are both -R41, more preferably R4 and R4’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R5, R5’, R5’’ and R5’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₅, R₅’, R₅’’ and R₅’’’ are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably R₅, R₅’, R₅’’ and R₅’’’ are independently selected from hydrogen and substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R6, R6’, R6’’ and R6’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R6, R6’, R6’’ and R6’’’ are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably R₆, R₆’, R₆’’ and R₆’’’ are independently selected from hydrogen and substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₇ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, - OR71 and -CN; preferably R7 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, -OR71 and -CN; more preferably R7 is selected from hydrogen, fluorine, substituted or unsubstituted methyl, -OH, -OCH3 and -CN; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₇ is hydrogen, halogen, a substituted or unsubstituted methyl, -OH, -O-methyl or–CN; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₈ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR81,–NR81R81’ and–C(O)R81; preferably R8 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR81,–NR81R81’ and– C(O)R81; more preferably R8 is selected from hydrogen, fluorine, substituted or unsubstituted methyl, substituted or unsubstituted isobutyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophenyl, substituted or ESTEVE PHARMACEUTICALS, S.A.

unsubstituted pyridinyl, substituted or unsubstituted oxadiazolyl, -O-isopropyl,– N(CH3)2,–N(CH3)(benzyl),–N(CH3)(isopropyl), and–C(O)-piperidinyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₉ and R₉’ are independently selected from hydrogen, halogen, -R₂₁, -OR₂₁, -NO₂, - NR₂₁R₂₁’, -NR₂₁C(O)R₂₁’, -NR₂₁S(O)₂R₂₁’, -S(O)₂NR₂₁R₂₁’, - NR₂₁C(O)NR₂₁’R₂₁’’, -SR₂₁ , -S(O)R₂₁, -S(O)₂R₂₁, –CN, haloalkyl, haloalkoxy, -C(O)OR₂₁, -C(O)NR₂₁R₂₁’, - OCH₂CH₂OR₂₁, -NR₂₁S(O)₂NR₂₁’R₂₁’’ and -C(CH₃)₂OR₂₁; preferably R₉ and R_9’ are both -R₂₁; more preferably R₉ and R_9’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₁₀ and R₁₀’ are independently selected from hydrogen, substituted or unsubstituted C_1- 6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;preferably R10 and R10’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ESTEVE PHARMACEUTICALS, S.A. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R10’’ and R10’’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2- ₆ alkynyl; preferably R₁₀’’ and R₁₀’’’ are both hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₄₁, R₄₁’ and R₄₁’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₄₁ is hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R71 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R71 is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; more preferably R71 is selected from hydrogen and substituted or unsubstituted methyl; ESTEVE PHARMACEUTICALS, S.A.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₈₁ and R₈₁’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl,substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylheterocyclyl; preferably R₈₁ and R₈₁’ are independently selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted heterocyclyl; preferably R₈₁ and R₈₁’ are independently selected from substituted or unsubstituted methyl, substituted or unsubstituted isopropyl, substituted or unsubstituted benzyl and substituted or unsubstituted piperidinyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R82, R82’ and R82’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R82 and R82’ are independently selected from hydrogen and substituted or unsubstituted methyl; ESTEVE PHARMACEUTICALS, S.A.

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a preferred embodiment p is 0, 1 or 2. In a preferred embodiment q is 0, 1 or 2. In a preferred embodiment n is 0 or 1. In a preferred embodiment m is 0, 1 or 2. In a preferred embodiment m’ is 0, 1 or 2. In a preferred embodiment r is 0, 1 or 2. In a preferred embodiment r’ is 0, 1 or 2. In a preferred embodiment t is 0, 1 or 2. In a preferred embodiment X is selected from a bond, -CH2-, -CH2CH2-, -C(O)-, -CH2C(O)-, -CH2CH2C(O)-, - C(O)N(CH2CH3)-, -NHC(O)-, -NHC(O)CH2-, -NHC(O)CH2CH2-, -N(CH3)C(O)-, - ESTEVE PHARMACEUTICALS, S.A.

CH₂NH-, -CH₂N(C(O)(CH₂CH₃))-, -N(C(O)(CH₂CH₃))-, -N(CH₃)-, -NH-, -NHCH₂- and - NHCH2CH2-. In a preferred embodiment Ra is hydrogen. In a preferred embodiment R_b is hydrogen. In a preferred embodiment R_a and R_b are both hydrogen. In a preferred embodiment

,

In a preferred embodiment

selected from

-R1, -CH2R1, -CH2CH2R1, -C(O)R1, -CH2C(O)R1, -CH2CH2C(O)R1, - C(O)N(CH2CH3)R1, -NHC(O)R1, -NHC(O)CH2R1, -NHC(O)CH2CH2R1, - N(CH3)C(O)R1, -CH2NHR1, -CH2N(C(O)(CH2CH3))R1, -N(C(O)(CH2CH3))R1, - N(CH3)R1, -NHR1, -NHCH2R1 and -NHCH2CH2R1. ESTEVE PHARMACEUTICALS, S.A.

In a preferred embodiment Rz is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl and substituted or unsubstituted–C(O)OCH2CH3. In a preferred embodiment Y1 is–CH2-. In a preferred embodiment Y₂ is–CH₂-. In a preferred embodiment Y₁ and Y₂ are both–CH₂-. In a preferred embodiment R₂ is a substituted or unsubstituted group selected from phenyl and thiophen. In a preferred embodiment R₃ is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted ethyl. In a preferred embodiment R₃’ is hydrogen. In a preferred embodiment R₃ is hydrogen, substituted or unsubstituted methyl or substituted or unsubstituted ethyl, while R₃’ is hydrogen. In a preferred embodiment R3 and R3’ are both hydrogen. In a preferred embodiment R4 is hydrogen. ESTEVE PHARMACEUTICALS, S.A.

In a preferred embodiment R4’ is hydrogen. In a preferred embodiment R4 and R4’ are both hydrogen. In a preferred embodiment R₅ is hydrogen or substituted or unsubstituted methyl. In a preferred embodiment R₅’ is hydrogen. In a preferred embodiment R₅ is hydrogen or substituted or unsubstituted methyl, while R₅’ is hydrogen. In a preferred embodiment R₅ is substituted or unsubstituted methyl, while R₅’ is hydrogen. In a preferred embodiment R₅ and R₅’ are both hydrogen. In a preferred embodiment R₅ and R₅’ taken together with the carbon atom to which they are attached form a carbonyl group. In a preferred embodiment R5’’ is hydrogen. In a preferred embodiment R₅’’’ is hydrogen. In a preferred embodiment ESTEVE PHARMACEUTICALS, S.A.

R₅’’ and R₅’’’ are both hydrogen. In a preferred embodiment R5’’ and R5’’’ taken together with the carbon atom to which they are attached form a carbonyl group. In a preferred embodiment R₆ is selected from hydrogen and substituted or unsubstituted methyl. In a preferred embodiment R₆’ is hydrogen. In a preferred embodiment R₆ is selected from hydrogen and substituted or unsubstituted methyl, while R₆’ is hydrogen. In a preferred embodiment R₆ is substituted or unsubstituted methyl, while R₆’ is hydrogen. In a preferred embodiment R₆ and R₆’ are both hydrogen. In a preferred embodiment R₆ and R₆’ taken together with the carbon atom to which they are attached form a carbonyl group. In a preferred embodiment R₆’’ is selected from hydrogen and substituted or unsubstituted methyl. In a preferred embodiment R₆’’’ is hydrogen. In a preferred embodiment ESTEVE PHARMACEUTICALS, S.A.

R₆’’ is selected from hydrogen and substituted or unsubstituted methyl, while R₆’’’ is hydrogen. In a preferred embodiment R₆’’ is substituted or unsubstituted methyl, while R₆’’’ is hydrogen. In a preferred embodiment R₆’’ and R₆’’’ are both hydrogen. In a preferred embodiment R₆’’ and R₆’’’ taken together with the carbon atom to which they are attached form a carbonyl group. In a preferred embodiment R₇ is selected from hydrogen, fluorine, substituted or unsubstituted methyl, -OH, - OCH_3, -CH₂OH, -CH₂OCH_3, and–CN. In a preferred embodiment R₈ is selected from hydrogen, fluorine, substituted or unsubstituted methyl, substituted or unsubstituted isobutyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted oxadiazolyl, -O-isopropyl, –N(CH3)2, –N(CH3)(benzyl), – N(CH3)(isopropyl) and–C(O)-piperidinyl. In a preferred embodiment R₉ and R₉’ are both hydrogen. In a preferred embodiment R10 and R10’ are both hydrogen. In a preferred embodiment R10’’ and R10’’’ are both hydrogen. ESTEVE PHARMACEUTICALS, S.A.

In a preferred embodiment R10, R10’, R10’’ and R10’’’ are all hydrogen. In a preferred embodiment R41 is hydrogen. In a preferred embodiment R₇₁ is selected from hydrogen and substituted or unsubstituted methyl. In a preferred embodiment R₈₁ and R₈₁’ are independently selected from substituted or unsubstituted methyl, substituted or unsubstituted isopropyl, substituted or unsubstituted benzyl and substituted or unsubstituted piperidinyl. In a preferred embodiment R₈₁ is selected from substituted or unsubstituted methyl, substituted or unsubstituted isopropyl, substituted or unsubstituted benzyl and substituted or unsubstituted piperidinyl. In a preferred embodiment R₈₁’ is selected from substituted or unsubstituted methyl and substituted or unsubstituted isopropyl. In a preferred embodiment R81 is selected from substituted or unsubstituted methyl, substituted or unsubstituted isopropyl, substituted or unsubstituted benzyl and substituted or unsubstituted piperidinyl, while R₈₁’ is selected from substituted or unsubstituted methyl and substituted or unsubstituted isopropyl. In a preferred embodiment R81 is substituted or unsubstituted methyl, while R81’ is selected from substituted or unsubstituted methyl and substituted or unsubstituted isopropyl. ESTEVE PHARMACEUTICALS, S.A.

In a preferred embodiment R81 is selected from substituted or unsubstituted methyl, while R81’ is substituted or unsubstituted isopropyl. In a preferred embodiment R81 is substituted or unsubstituted benzyl, while R81’ is substituted or unsubstituted methyl. In a preferred embodiment R₈₁ and R₈₁’ are both substituted or unsubstituted methyl. In a preferred embodiment R₈₁ is substituted or unsubstituted isopropyl. In a preferred embodiment R₈₁ is substituted or unsubstituted piperidinyl. In a preferred embodiment R₈₂ and R₈₂’ are independently selected from hydrogen and substituted or unsubstituted methyl. In a preferred embodiment R82 is selected from hydrogen and substituted or unsubstituted methyl. In a preferred embodiment R82 is selected from hydrogen and substituted or unsubstituted methyl, while R82’ is substituted or unsubstituted methyl. In a preferred embodiment R₈₂ is hydrogen, while R₈₂’ is substituted or unsubstituted methyl. In a preferred embodiment ESTEVE PHARMACEUTICALS, S.A.

the halogen is fluorine, chlorine, iodine or bromine. In a preferred embodiment the halogen is fluorine. In a preferred embodiment the haloalkyl is–CF₃. In a preferred embodiment the haloalkoxy is–OCF₃.

In a preferred further embodiment, the compounds of the general Formula (I) are selected from

EX Chemical name 1 N-Methyl-3-(2-(4-methylpiperazin-1-yl)phenoxy)-3-phenylpropan-1-amine 2 N-methyl-3-phenyl-3-(2-(piperazin-1-yl)phenoxy)propan-1-amine (1) 3 3-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenoxy)-N-methyl-3-phenylpropan- 1-amine 4 N,N-dimethyl-1-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidin-4- amine 5 3-(2-(1,4-diazepan-1-yl)phenoxy)-N-methyl-3-phenylpropan-1-amine 6 N-methyl-3-(2-(4-methyl-1,4-diazepan-1-yl)phenoxy)-3-phenylpropan-1-amine ESTEVE PHARMACEUTICALS, S.A.

7 4-methyl-1-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1,4-diazepan-5-one 8 4-((dimethylamino)methyl)-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-ol 9 4-((benzyl(methyl)amino)methyl)-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-ol 10 4-((isopropyl(methyl)amino)methyl)-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-ol 11 N-benzyl-N-methyl-1-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidin-4- amine 12 N-methyl-3-(2-(4-phenethylpiperazin-1-yl)phenoxy)-3-phenylpropan-1-amine 13 3-(2-(4-benzylpiperazin-1-yl)phenoxy)-N-methyl-3-phenylpropan-1-amine 14 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1-phenethylpiperidin-4-amine 15 3-(1-(2-((2-(3-(methylamino)-1-phenylpropoxy)phenyl)amino)ethyl)piperidin-4- yl)phenol 16 N-methyl-3-((2-(4-phenethylpiperazin-1-yl)benzyl)oxy)-3-phenylpropan-1- amine 17 N-methyl-3-((2-(4-methyl-1,4-diazepan-1-yl)benzyl)oxy)-3-phenylpropan-1- amine 18 N-methyl-3-phenyl-3-(2-(4-phenylpiperazin-1-yl)phenoxy)propan-1-amine 19 N-methyl-3-(2-(4-(pyridin-2-yl)piperazin-1-yl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 20 N-methyl-3-((2-(4-phenethylpiperazin-1-yl)benzyl)oxy)-3-(thiophen-2- yl)propan-1-amine 21 (S)-N-methyl-3-(2-(4-methyl-1,4-diazepan-1-yl)phenoxy)-3-(thiophen-2- yl)propan-1-amine ESTEVE PHARMACEUTICALS, S.A.

22 (R)-N-methyl-3-(2-(4-methyl-1,4-diazepan-1-yl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 23 (R)-2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)-N-(2-(4-phenylpiperidin-1- yl)ethyl)aniline 24 (R)-3-(1-(2-((2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)phenyl)amino)ethyl)piperidin-4-yl)phenol 25 1-Methyl-4-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1,4-diazepan-5-one 26 4-methyl-1-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperazin-2-one 27 N-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(thiophen-2- ylmethyl)piperidine-4-carboxamide 28 N-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-2-(4-phenylpiperidin- 1-yl)acetamide 29 (S)-4-((4-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 30 (S)-3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenol 31 (R)-3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenol 32 (R)-3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3-(thiophen-2- yl)propan-1-amine 33 (S)-3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3-(thiophen-2- yl)propan-1-amine 34 4-((4-(2-(1-(3-fluorophenyl)-3-(methylamino)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 35 3-((1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)methyl)benzonitrile ESTEVE PHARMACEUTICALS, S.A.

36 (R)-N-methyl-3-(2-((4-(pyridin-3-yl)piperidin-1-yl)methyl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 37 (R)-N-methyl-3-(2-((4-(pyridin-2-yl)piperidin-1-yl)methyl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 38 (R)-4-((4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 39 1-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)-4-phenylpiperidine-4- carbonitrile 40 3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4-yl)phenol 41 3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenethyl)piperidin-4- yl)phenol 42 N-methyl-3-(2-((4-phenylpiperidin-1-yl)methyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 43 1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)-4-phenylpiperidin-4-ol 44 3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3-(thiophen-2- yl)propan-1-amine 45 3-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenethyl)piperazin-1- yl)phenol 46 N-methyl-3-(2-(2-(4-phenylpiperidin-1-yl)ethyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 47 3-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)phenol 48 N-methyl-3-(2-((4-phenylpiperazin-1-yl)methyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 49 3-(2-((4-(3-methoxyphenyl)piperidin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine ESTEVE PHARMACEUTICALS, S.A.

50 N-methyl-3-(2-((4-phenethylpiperazin-1-yl)methyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 51 3-(2-((4-(4-methoxybenzyl)piperazin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 52 3-(1-(2-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4-yl)phenol 53 4-((4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 54 3-(2-((4-(4-fluorobenzyl)piperazin-1-yl)methyl)phenoxy)-N-methyl-3-(thiophen- 2-yl)propan-1-amine 55 N-methyl-3-(2-((4-(pyridin-4-yl)piperidin-1-yl)methyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 56 N-methyl-3-(2-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 57 3-(2-((4-(2-isopropoxyethyl)piperazin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 58 2-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1-yl)-1- (piperidin-1-yl)ethanone 59 N-methyl-3-(2-((4-(pyridin-2-yl)piperidin-1-yl)methyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 60 3-(2-((4-isobutylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3-(thiophen-2- yl)propan-1-amine 61 3-(2-((4-methoxy-4-phenylpiperidin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 62 (1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)-4-phenylpiperidin-4- yl)methanol ESTEVE PHARMACEUTICALS, S.A.

63 3-(2-((4-(methoxymethyl)-4-phenylpiperidin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 64 N-methyl-3-(2-((4-(pyridin-4-ylmethyl)piperidin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 65 3-((4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 66 4-((1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)methyl)benzonitrile 67 4-(2-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)ethyl)benzonitrile 68 3-(2-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)ethyl)benzonitrile 69 N-methyl-3-(2-((4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidin-1- yl)methyl)phenoxy)-3-(thiophen-2-yl)propan-1-amine 70 N-(3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenyl)methanesulfonamide 71 N-methyl-3-(2-((4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1- yl)methyl)phenoxy)-3-(thiophen-2-yl)propan-1-amine 72 N-(3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenyl)acetamide 73 4-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4-yl)phenol 74 N-methyl-3-(2-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 75 N-methyl-3-(2-((4-(pyridin-2-ylmethyl)piperazin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine ESTEVE PHARMACEUTICALS, S.A.

76 3-fluoro-4-((4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin- 1-yl)methyl)benzonitrile 77 3-(2-((4-(3,5-dichloropyridin-4-yl)piperazin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 78 4-((4-(2-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 79 4-((4-(2-(3-amino-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 80 (R)-N-Methyl-3-(2-(2-morpholinoethyl)phenoxy)-3-(thiophen-2-yl)propan-1- amine 81 N-methyl-3-(2-((4-methyl-1,4-diazepan-1-yl)methyl)phenoxy)-3-phenylpropan- 1-amine 82 N-(2-(3-(methylamino)-1-phenylpropoxy)benzyl)-1-phenethylpiperidin-4-amine 83 3-(1-(2-(3-(methylamino)-1-phenylpropoxy)benzyl)piperidin-4-yl)phenol 84 3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3-phenylpropan-1- amine 85 N-methyl-3-phenyl-3-(2-((4-phenylpiperazin-1-yl)methyl)phenoxy)propan-1- amine 86 N-methyl-3-phenyl-3-(2-((4-(pyridin-2-yl)piperazin-1- yl)methyl)phenoxy)propan-1-amine 87 4-((4-(2-(3-(methylamino)-1-phenylpropoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 88 1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenethyl)-4-phenylpiperidin- 4-ol 89 (S)-N-methyl-3-(2-((4-(pyridin-2-yl)piperidin-1-yl)methyl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine ESTEVE PHARMACEUTICALS, S.A.

90 (R)-N-methyl-3-(2-(2-(4-(pyridin-2-yl)piperidin-1-yl)ethyl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 91 (R)-N-methyl-3-(2-(2-(pyrrolidin-1-yl)ethyl)phenoxy)-3-(thiophen-2-yl)propan-1- amine 92 (R)-N-methyl-3-(2-(2-(4-methylpiperazin-1-yl)ethyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 93 (R)-3-(2-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)ethyl)benzonitrile 94 (R)-N-(3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenyl)methanesulfonamide 95 (R)-3-(2-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)phenoxy)-N-methyl-3-(thiophen-2- yl)propan-1-amine 96 (R)-N-ethyl-3-(2-(2-(pyrrolidin-1-yl)ethyl)phenoxy)-3-(thiophen-2-yl)propan-1- amine 97 3-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(4- phenethylpiperazin-1-yl)propan-1-one 98 2-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(4- phenethylpiperazin-1-yl)ethanone 99 1-(4-benzylpiperazin-1-yl)-2-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)phenyl)ethanone 100 1-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)phenyl)ethanone 101 2-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(4-methylpiperazin- 1-yl)ethanone 102 (4-Methyl-1,4-diazepan-1-yl)(2-(3-(methylamino)-1- phenylpropoxy)phenyl)methanone ESTEVE PHARMACEUTICALS, S.A.

103 (2-(3-(methylamino)-1-phenylpropoxy)phenyl)(4-phenethylpiperazin-1- yl)methanone 104 1-Methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidine-4- carboxamide 105 1-benzyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidine-4- carboxamide 106 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1-phenethylpiperidine-4- carboxamide 107 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1-(thiophen-2- ylmethyl)piperidine-4-carboxamide 108 2-(4-(3-Hydroxyphenyl)piperidin-1-yl)-N-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)acetamide 109 3-(4-(3-hydroxyphenyl)piperidin-1-yl)-N-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)propanamide 110 N-((1-Benzylpiperidin-4-yl)methyl)-2-(3-(methylamino)-1-phenylpropoxy)aniline 111 1-benzyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidin-4-amine 112 4-((4-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-1- yl)methyl)benzonitrile 113 N-Methyl-3-(2-(1-methylpiperidin-4-yl)phenoxy)-3-phenylpropan-1-amine 114 N-methyl-3-phenyl-3-(2-(piperidin-4-yl)phenoxy)propan-1-amine 115 3-(2-(1-Benzylpiperidin-4-yl)phenoxy)-N-methyl-3-phenylpropan-1-amine 116 N-methyl-3-(2-(1-phenethylpiperidin-4-yl)phenoxy)-3-phenylpropan-1-amine 117 N-Ethyl-2-(3-(methylamino)-1-phenylpropoxy)-N-(1-phenethylpiperidin-4- yl)benzamide ESTEVE PHARMACEUTICALS, S.A.

118 N-Methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1- phenethylpiperidin-4-amine 119 1-benzyl-N-methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidin-4- amine 120 N-Methyl-3-phenyl-3-(2-((3S,5R)-3,4,5-trimethylpiperazin-1- yl)phenoxy)propan-1-amine 121 1-benzyl-N-methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidine- 4-carboxamide 122 N-methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1- phenethylpiperidine-4-carboxamide 123 N-(2-(3-(Methylamino)-1-phenylpropoxy)benzyl)-N-(1-phenethylpiperidin-4- yl)propionamide 124 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-N-(1-phenethylpiperidin-4- yl)propionamide 125 (R)-3-(2-(2-((S)-4,6-dimethyl-1,4-diazepan-1-yl)ethyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 126 (R)-3-(2-(2-((R)-4,6-dimethyl-1,4-diazepan-1-yl)ethyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine

In a very preferred embodiment, the compounds are selected which act as dual ligands of the ^ ^ ^ ^subunit, particularly the ^ ^ ^ ^ ^ ^subunit, of the voltage-gated calcium channel and the s1 receptor, and especially compounds which have a binding expressed as Ki responding to the following scales:

Ki ( s1) is preferably < 1000 nM, more preferably < 500 nM, even more preferably < 100 nM.

Ki( ^2 ^-1) is preferably < 10000 nM, more preferably < 5000 nM, even more preferably < 500 nM or even more preferably < 100 nM.

In the following the phrase“compound of the invention” is used. This is to be understood as any compound according to the invention as described above according to general Formula (I), (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c), (I^c’), (I^3’) and (IZ).

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

For the sake of clarity the expression“a compound according to Formula (I), wherein e.g. R1, R2, R3, R3’, R4, R4’, X, Y1, Y2 and n are as defined below in the detailed description” would (just like the expression“a compound of Formula (I) as defined in any one of claims e.g.1 to 8” found in the claims) refer to“a compound according to Formula (I)”, wherein the definitions of the respective substituents R1 etc. (also from the cited claims) are applied. In addition, this would also mean, though (especially in regards to the claims) that also one or more disclaimers defined in the description (or used in any of the cited claims like e.g. claim 1) would be applicable to define the respective compound. Thus, a disclaimer found in e.g. claim 1 would be also used to define the compound“of Formula (I) as defined in any one of the corresponding related claims e.g.1 to 8”. ESTEVE PHARMACEUTICALS, S.A.

In general the processes are described below in the experimental part. The starting materials are commercially available or can be prepared by conventional methods. In the following description, ther terms“process for the preparation” and“process for the production” are used in parallel and are interchangeable.

A preferred embodiment of the invention is a process for the production of a compound according to Formula (I), wherein, if not defined otherwise, R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁, Y₂ and n have the meanings defined in the description. LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate).

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein X represents a bond, and wherein R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ and n have the meanings as defined in the description, said process comprises treating a compound of formula (IIa),

wherein Q represents chloro, bromo, iodo or triflate, with a suitable N-containing cyclic reagent of formula (III-1)

under Buchwald-Hartwig conditions.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[C(RaRb)]p-, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2 and n and p have the meanings as defined in the description, said process comprises treating a compound of formula (IIb) ESTEVE PHARMACEUTICALS, S.A.

wherein r represents 0 to 4, with a N-containing cyclic reagent of formula (III-1)

under standard reductive amination conditions.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[C(RaRb)]p-, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2 and n and p have the meanings as defined in the description, said process comprises treating a compound of formula (IIa),

wherein Q represents chloro, bromo, iodo or triflate, with an organometallic reagent of formula (III-2)

wherein M represents a suitable organometallic group, preferably a boron or zinc reagent, and p has the meaning as defined in the description. ESTEVE PHARMACEUTICALS, S.A.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[CRaRb]pC(O)[CH2]q- and q is 0, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and q have the meanings as defined in the description, said process comprises treating a compound of formula (IIc’)

with a N-containing cyclic reagent of formula (III-1)

under conventional amidation conditions.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[CR_aR_b]_pN(R_z)C(O)[CH₂]_q-, and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ , n, p and q have the meanings as defined in the description, said process comprises treating a compound of formula (VI’)

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, p, q and Rz have the meanings as defined in the description, with a N-containing cyclic reagent of formula (III-1) ESTEVE PHARMACEUTICALS, S.A.

under conventional alkylation conditions.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[CRaRb]pN(Rz)C(O)[CH2]q-, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and q have the meanings as defined in the description, said process comprises treating an amino compound of formula (IId’)

wherein p and Rz have the meanings as defined in the description, with an acyl reagent of formula (III-3),

under amidation conditions, wherein Z represents OH or halogen and q has the meaning as defined in the description.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[CRaRb]pN(Rz)C(O)[CH2]q-, p is 0, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2 , n, p and q have the meanings as defined in the description, said process comprises reacting a compound of formula (IIa) ESTEVE PHARMACEUTICALS, S.A.

wherein Q represents chloro, bromo, iodo or triflate, with a carboxamido compound of formula (III-5)

under Ullmann arylation conditions, wherein q and Rz have the meanings as defined in the description.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[CR_aR_b]_pN(R_z)[CH₂]_q- and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂, n, p and q have the meanings as defined in the description, said process comprises treating an amino compound of formula (IId’)

wherein p and Rz have the meanings as defined in the description, with an aldehyde of formula (III-6),

ESTEVE PHARMACEUTICALS, S.A.

wherein q’ represents 0, 1, 2, 3 or 4.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein -X- represents -[CRaRb]pN(Rz)[CH2]q- and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and q have the meanings as defined in the description, said process comprises treating an amino compound of formula (IId’)

wherein p and Rz have the meanings as defined in the description, with an alkylating agent of formula (III-7),

. In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein n is 0, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIa) wherein G is OH,

with an alkylating agent of formula (VIII) ESTEVE PHARMACEUTICALS, S.A.

wherein Z represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein n is 0, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIa) wherein G is OH,

with an agent of formula (VIII) in the presence of an azo compound,

wherein Z represents OH.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein n is 0, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIa) wherein G is halogen, ESTEVE PHARMACEUTICALS, S.A.

with an agent of formula (VIII) in the presence of a strong base,

wherein Z represents OH.

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein n is 1, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIb)

with an agent of formula (VIII),

wherein either Z represents OH and G represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, or alternatively Z represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate and G represents OH. ESTEVE PHARMACEUTICALS, S.A.

In a particular embodiment there is a process for the production of a compound according to Formula (I),

a) wherein X represents a bond, and wherein R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ and n have the meanings as defined in the description, said process comprises treating a compound of formula (IIa),

under Buchwald-Hartwig conditions;

or ESTEVE PHARMACEUTICALS, S.A.

b) wherein -X- represents -[C(R_aR_b)]_p-, and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y2 and n and p have the meanings as defined in the description, said process comprises treating a compound of formula (IIb)

under standard reductive amination conditions;

or

c) wherein -X- represents -[C(RaRb)]p-, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2 and n and p have the meanings as defined in the description, said process comprises treating a compound of formula (IIa),

wherein Q represents chloro, bromo, iodo or triflate, with an organometallic reagent of formula (III-2) ESTEVE PHARMACEUTICALS, S.A.

wherein M represents a suitable organometallic group, preferably a boron or zinc reagent, and p has the meaning as defined in the description;

or d) wherein -X- represents -[CRaRb]pC(O)[CH2]q- and q is 0, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and q have the meanings as defined in the description, said process comprises treating a compound of formula (IIc’)

wherein with a N-containing cyclic reagent of formula (III-1)

under conventional amidation conditions;

or ESTEVE PHARMACEUTICALS, S.A.

e) wherein -X- represents -[CR_aR_b]_pN(R_z)C(O)[CH₂]_q-, and wherein R_a, R_b, R₁, R₂, R₃, R3’, R4, R4’, Y1, Y2 , n, p and q have the meanings as defined in the description, said process comprises treating a compound of formula (VI’)

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, p, q and Rz have the meanings as defined in the description, with a N-containing cyclic reagent of formula (III-1)

under conventional alkylation conditions;

or

f) wherein -X- represents -[CR_aR_b]_pN(R_z)C(O)[CH₂]_q-, and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂, n, p and q have the meanings as defined in the description, said process comprises treating an amino compound of formula (IId’)

ESTEVE PHARMACEUTICALS, S.A.

under amidation conditions, wherein Z represents OH or halogen and q has the meaning as defined in the description;

or g) wherein -X- represents -[CR_aR_b]_pN(R_z)C(O)[CH₂]_q-, p is 0, and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ , n, p and q have the meanings as defined in the description, said process comprises reacting a compound of formula (IIa)

under Ullmann arylation conditions, wherein q and Rz have the meanings as defined in the description; ESTEVE PHARMACEUTICALS, S.A.

or

h) wherein n is 0, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIa) wherein G is OH,

with an alkylating agent of formula (VIII)

wherein Z represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate;

or

i) wherein n is 0, and wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁ and Y₂ have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIa) wherein G is OH,

with an agent of formula (VIII) in the presence of an azo compound, ESTEVE PHARMACEUTICALS, S.A.

wherein Z represents OH;

or

j) wherein n is 0, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIa) wherein G is halogen,

with an agent of formula (VIII) in the presence of a strong base,

wherein Z represents OH;

or

k) wherein n is 1, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the description, said process comprises reacting a compound of formula (VIIb) ESTEVE PHARMACEUTICALS, S.A.

with an agent of formula (VIII),

wherein either Z represents OH and G represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, or alternatively Z represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate and G represents OH; or l) wherein -X- represents -[CR_aR_b]_pN(R_z)[CH₂]_q- and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂, n, p and q have the meanings as defined in the description, said process comprises treating an amino compound of formula (IId’)

wherein q’ represents 0, 1, 2, 3 or 4; ESTEVE PHARMACEUTICALS, S.A.

or m) wherein -X- represents -[CRaRb]pN(Rz)[CH2]q- and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and q have the meanings as defined in the description, said process comprises treating an amino compound of formula (IId’)

wherein R1 and q have the meanings as defined in the preceding claims and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate.

In a particular embodiment there is a process for the production of a compound according to Formula (I), by the reduction reaction of a carbonyl derivative with a suitable reductive reagent, preferably sodium borohydride, in an organic solvent, preferably MeOH, to afford a hydroxyl compound. ESTEVE PHARMACEUTICALS, S.A.

In a particular embodiment there is a process for the production of a compound according to Formula (I), by deprotection reaction of a compound of formula I that contains an amine protecting group such as a carbamate, preferably tert-butoxy carbonyl, by any suitable method, such as treatment with an acid, preferably HCl or trifluoroacetic acid in an appropriate solvent such as 1,4-dioxane, DCM, ethyl acetate or a mixture of an organic solvent and water. In a particular embodiment there is a process for the production of a compound according to Formula (I), by reductive amination reaction of a compound of formula I that contains an amino group with an aldehyde, preferably carried out with a reductive reagent, preferably sodium triacetoxyborohydride, in an organic solvent, preferably DCE, in the presence of an organic base, preferably DIPEA or TEA. Alternatively, the reaction can be carried out in the presence of an acid, preferably acetic acid. In a particular embodiment there is a process for the production of a compound according to Formula (I), by reaction of a compound of formula I that contains an amino group with an alkylating reagent, in the presence of a base, preferably DIPEA or K₂CO₃, in an organic solvent, preferably acetonitrile, at suitable temperature, such as in the range of 0-120 ºC. In a particular embodiment there is a process for the production of a compound according to Formula (I), by reaction of a compound of formula I that contains an amino group with a vinyl derivative, in an organic solvent, preferably 2-methoxyethanol, at suitable temperature, such as in the range of 20-140 ºC.

A particular embodiment of the invention refers to the use of a compound of Formula (II), ESTEVE PHARMACEUTICALS, S.A.

wherein Z represents OH or halogen, R2, R3, R3’, R4, R4’, Y1, Y2 and n have the meanings as defined in the description, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula (IIa),

wherein Q represents chloro, bromo, iodo or triflate, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IIa-LG),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Q represents chloro, bromo, iodo or triflate, R₂, R₄, R_4’, Y₁, Y₂ and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). ESTEVE PHARMACEUTICALS, S.A.

A particular embodiment of the invention refers to the use of a compound of Formula (IIb),

wherein R2, R3, R3’, R4, R4’, Y1, Y2, n and r have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IIb’),

wherein R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂, n and r have the meanings as defined in the description, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula (IIb-LG),

ESTEVE PHARMACEUTICALS, S.A.

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R2, R4, R4’, Y1, Y2, n and r have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IIb’-LG),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R_a, R_b, R₂, R₄, R_4’, Y₁, Y₂, n and r have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IIc),

wherein R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂, n and p have the meanings as defined in the description, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula (IIc’), ESTEVE PHARMACEUTICALS, S.A.

wherein Ra, Rb, R2, R3, R3’, R4, R4’, Y1, Y2, n and p have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IIc-LG),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R2, R4, R4’, Y1, Y2, n and p have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IIc’-LG),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R_a, R_b, R2, R₄, R_4’, Y₁, Y₂, n and p have the meanings as defined in the description, for the preparation of compounds of Formula (I). ESTEVE PHARMACEUTICALS, S.A.

A particular embodiment of the invention refers to the use of a compound of Formula (IId),

wherein R2, R3, R3’, R4, R4’, Y1, Y2, n, p and Rz have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IId’),

wherein Ra, Rb, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and Rz have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IId-LG),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Ra, Rb, R2, R4, R4’, Y1, Y2, n, p and Rz have the meanings as defined in the description, for the preparation of compounds of Formula (I). ESTEVE PHARMACEUTICALS, S.A.

A particular embodiment of the invention refers to the use of a compound of Formula (IId’-LG),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Ra, Rb, R2, R4, R4’, Y1, Y2, n, p and Rz have the meanings as defined in the description, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula (III-1),

wherein R1 has the meaning as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (III-2’),

wherein p and R₁ have the meaning as defined in the description, and M represents a suitable organometallic group, preferably a boron or zinc reagent, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (III-2), ESTEVE PHARMACEUTICALS, S.A.

wherein p and Ra, Rb, R1 have the meaning as defined in the description, and M represents a suitable organometallic group, preferably a boron or zinc reagent, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (III-3),

wherein q and R1 have the meaning as defined in the description, and Z represents OH or halogen, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (III-4),

wherein q has the meaning as defined in the description, Z represents OH or halogen, and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (III-5),

ESTEVE PHARMACEUTICALS, S.A.

wherein q, R_z and R₁ have the meaning as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (III-6),

wherein q’ represents 0, 1, 2, 3 or 4 and R₁ has the meaning as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (III-7),

wherein q and R1 have the meaning as defined in the description, and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IV),

IV

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R₁, R₂, R₄, R_4’, Y₁, Y₂ and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). ESTEVE PHARMACEUTICALS, S.A.

A particular embodiment of the invention refers to the use of a compound of Formula (IVa),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R₁, R₂, R₄, R_4’, Y₁, Y₂ and n have the meanings as defined in the description, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula (IVb),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R1, R2, R4, R4’, Y1, Y2, p and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IVb’),

ESTEVE PHARMACEUTICALS, S.A.

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Ra, Rb, R1, R2, R4, R4’, Y1, Y2, p and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IVc),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R1, R2, R4, R4’, Y1, Y2, p and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IVc’),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Ra, Rb, R1, R2, R4, R4’, Y1, Y2, p and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IVd), ESTEVE PHARMACEUTICALS, S.A.

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Rz, R1, R2, R4, R4’, Y1, Y2, p and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IVd’),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R_a, R_b, R_z, R₁, R₂, R₄, R_4’, Y₁, Y_2, p and n have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IVf),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R1, R2, R4, R4’, Y1 and Y2 have the meanings as defined in the description, for the preparation of compounds of Formula (I). ESTEVE PHARMACEUTICALS, S.A. A particular embodiment of the invention refers to the use of a compound of Formula (IVg),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R₁, R₂, R₄, R_4’, Y₁ and Y₂ have the meanings as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (V),

wherein R3 and R3’ have the meaning as defined in the description, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula (VI),

wherein R2, R3, R3’, R4, R4’, Y1, Y2, n, p, q and Rz have the meanings as defined in the description, and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I). ESTEVE PHARMACEUTICALS, S.A.

A particular embodiment of the invention refers to the use of a compound of Formula (VI’),

wherein Ra, Rb, R2, R3, R3’, R4, R4’, Y1, Y2, n, p, q and Rz have the meanings as defined in the description, and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (VII),

wherein n, R1, R4, R4’ and X have the meanings as defined in the description, and G is OH or halogen, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (VIIa),

wherein R1, R4, R4’ and X have the meanings as defined in the description, and G is OH or halogen, for the preparation of compounds of Formula (I). ESTEVE PHARMACEUTICALS, S.A. A particular embodiment of the invention refers to the use of a compound of Formula (VIIb),

wherein R₁, R₄, R_4’ and X have the meanings as defined in the description, and G is OH or a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (VIII-A),

wherein R2, R3, R3’, Y1 and Y2 have the meaning as defined in the description, and Z represents OH or halogen, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (VIII-LG),

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, R₂, Y₁, and Y₂ have the meaning as defined in the description, and Z represents OH or halogen, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (IX), ESTEVE PHARMACEUTICALS, S.A.

wherein n, R₄, R_4’ have the meanings as defined in the description, and Z represents OH or halogen and G is OH or halogen, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula II, IIa, IIa-LG, IIb, IIb’, IIb-LG, IIb’-LG, IIc, IIc’, IIc-LG, IIc’-LG, IId, IId’, IId-LG, IId’-LG, III-1, III-2, III-2’, III-3, III-4, III-5, III-6, III-7, IV, IVa, IVb, IVb’, IVc, IVc’, IVd, IVd’, IVf, Vfg V, VI, VI’, VII, VIIa, VIIb, VIII-A, VIII-LG or IX

,

, , ESTEVE PHARMACEUTICALS, S.A.

ESTEVE PHARMACEUTICALS, S.A.

ESTEVE PHARMACEUTICALS, S.A.

, wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ , n, p, q, q’, r and R_z have the meanings as defined in the description, Q represents chloro, bromo, iodo or triflate, LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, have the meanings as defined in the description, M represents a suitable organometallic group, Z represents OH or halogen, and G is OH, halogen or a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I).

The obtained reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography. Where the above described processes for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

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

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

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration. In a preferred embodiment the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants. The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts. Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated. ESTEVE PHARMACEUTICALS, S.A.

Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day. The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs form part of the same composition, or be provided as a separate composition for administration at the same time or at different time. Another aspect of the invention refers to the use of a compound of the invention or a pharmaceutically acceptable salt or isomer thereof in the manufacture of a medicament. Another aspect of the invention refers to the compound of the invention or a pharmaceutically acceptable salt or isomer thereof for use as a medicament.

Another aspect of the invention refers to a compound of the invention according as described above according to general formula I, or a pharmaceutically acceptable salt or isomer thereof, for use as a medicament for the treatment of pain. Preferably the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia. This may include mechanical allodynia or thermal hyperalgesia. Another aspect of the invention refers to the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of pain. In a preferred embodiment the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, also preferably including mechanical allodynia or thermal hyperalgesia. Another aspect of this invention relates to a method of treating or preventing pain which method comprises administering to a patient in need of such a treatment a ESTEVE PHARMACEUTICALS, S.A.

therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Among the pain syndromes that can be treated are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia.

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

ESTEVE PHARMACEUTICALS, S.A. General Experimental Part

SYNTHESIS DESCRIPTION Two different general methods have been developed for obtaining the compounds of the invention, as described below in methods A and B, and further detailed in Schemes 1 to 8.

METHOD A A one-step process is described for the preparation of compounds of general formula (I) starting from a compound of formula (II), as shown in the following scheme:

Method A

wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁, Y₂ and n have the meanings as defined in claim 1, LG represents a leaving group, and Z represents a suitable functional group to perform such transformation, and R1-W represents a compound of formula III-1, III-2, III-3 or III-5, as it is detailed below in Schemes 1 to 5. In addition, the amino group NR₃R_3’ present in a compound of formula (I) can be incorporated later in the synthesis by reaction of a compound of formula (IV) wherein LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate) with an amine of formula (V) to render a compound of formula (I) as shown in the scheme above. The alkylation reaction is carried out in a suitable solvent, such as ethanol, dimethylformamide, dimethylsulfoxide or acetonitrile, preferably ethanol; using an excess of amine (V) or optionally in the presence of a base such as ESTEVE PHARMACEUTICALS, S.A.

K₂CO₃, N,N-diisopropylethylamine or triethylamine; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out under microwave heating. Additionally, an activating agent such as sodium iodide or potassium iodide can be used. Such transformation can also be performed starting from a compound of formula (II-LG) to prepare a compound of formula (II).

Scheme 1 The general synthetic route according to method A for preparing compounds of formula (I) wherein X represents a bond, resulting in compounds of formula (Ia) starting from a compound of formula (IIa) is represented in Scheme 1:

wherein R1, R2, R3, R3’, R4, R4’, Y1, Y2 and n have the meanings as defined in claim 1, Q represents chloro, bromo, iodo or triflate and LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate). The preparation of a compound of formula (Ia) from a compound of formula (IIa) is carried out by treating a compound of formula (IIa) with a suitable N-containing cyclic reagent of formula (III-1) under Buchwald-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP or XPhos, using a suitable base such as sodium tert-butoxide or cesium carbonate, in a suitable solvent such as toluene or 1,4-dioxane, at a suitable temperature, preferably heating. Alternatively, the reaction can be carried out under Ullmann arylation conditions, using a Cu catalyst such as copper iodide and a suitable ligand, preferably an amino ligand such as N¹,N²- ESTEVE PHARMACEUTICALS, S.A.

dimethylethane-1,2-diamine, in the presence of a suitable base such as potassium phosphate or potassium carbonate, in a suitable solvent such as 1,4-dioxane or dimethylformamide, at a suitable temperature, preferably heating.

Alternatively, the amino group NR3R3’ present in a compound of formula (Ia) or (IIa) can be incorporated later in the synthesis by reaction of a precursor compound of formula (IVa) or (IIa-LG), respectively, with an amine of formula (V) following the conditions described above in Method A.

Scheme 2 The general synthetic route according to method A for preparing compounds of formula (I) wherein -X- represents -[C(R_aR_b)]_p-, resulting in compounds of formula (Ib), starting from a compound of formula (IIa) or (IIb), is represented in Scheme 2:

wherein R₁, R₂, R₃, R_3’, R₄, R_4’, R_a, R_b, Y₁, Y₂, n and p have the meanings as defined in claim 1, LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate), Q represents chloro, bromo, iodo or triflate, M represents a suitable organometallic group (preferably a boron or zinc reagent) and r represents 0 to 4. ESTEVE PHARMACEUTICALS, S.A.

The preparation of a compound of formula (Ib) from an aldehyde compound of formula (IIb) can be carried out by treating a compound of formula (IIb) with a N-containing cyclic reagent of formula (III-1) under standard reductive amination conditions. The reaction is carried out in the presence of a reductive reagent, such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, in a suitable solvent, preferably tetrahydrofuran, dichloroethane or methanol, optionally in the presence of an acid (preferably acetic acid) or a base (preferably N,N- diisopropylethylamine). Alternatively, a compound of formula (Ib) can be prepared by reacting a compound of formula (IIa) with an organometallic reagent of formula (III-2), preferably a boron or zinc reagent. The coupling reaction is carried out under conventional coupling procedures described in the literature, using a suitable catalyst (preferably a Pd catalyst) and a suitable ligand (preferably a phosphine ligand), such as for example tetrakis(triphenylphosphine)palladium(0), or palladium acetate and XPhos, in the presence of a suitable base such as potassium carbonate or cesium carbonate, in a suitable solvent such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, or mixtures thereof with water. In addition, the amino group NR3R3’ present in a compound of formula (Ib), (IIa) or (IIb) can be incorporated later in the synthesis by reaction of a precursor compound of formula (IVb), (IIa-LG) or (IIb-LG), respectively, with an amine of formula (V), following the conditions described above in Method A.

Scheme 3 The general synthetic route according to method A for preparing compounds of formula (I) wherein -X- represents -[CH2]pC(O)[CH2]q- and q is 0, resulting in compounds of formula (Ic), starting from a compound of formula (IIc) is represented in Scheme 3: ESTEVE PHARMACEUTICALS, S.A.

wherein R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂, n and p have the meanings as defined in claim 1 and LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate). The preparation of a compound of formula (Ic) from an acid compound of formula (IIc) and a N-containing cyclic reagent of formula (III-1) can be carried out under conventional amidation conditions. As a way of example, the reaction is carried out using a suitable coupling reagent such as N-(3-dimethylaminopropyl)-N¢- ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), N-[(dimethylamino)-1H- 1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium

hexafluorophosphate N-oxide (HATU) or N,N,N¢,N¢-tetramethyl-O-(1H-benzotriazol-1- yl)uronium hexafluorophosphate (HBTU), optionally in the presence of 1- hydroxybenzotriazole, optionally in the presence of an organic base such as N- methylmorpholine or N,N-diisopropylethylamine, in a suitable solvent such as dichloromethane or dimethylformamide, and at a suitable temperature, preferably at room temperature. Alternatively, the amidation can be performed in two steps by first converting an acid of formula (IIc) into its corresponding acyl halide following standard conditions described in the literature, and then reacting it with a compound of formula (III-1) in a suitable solvent, such as dichloromethane, tetrahydrofuran, ethyl acetate or ethyl acetate-water mixtures; in the presence of an organic base such as triethylamine or N,N-diisopropylethylamine or an inorganic base such as K₂CO₃; and at a suitable temperature, preferably comprised between 0 ºC and room temperature. Additionally, an activating agent such as 4-dimethylaminopyridine can be used. In addition, the amino group NR3R3’ present in a compound of formula (Ic) or (IIc) can be incorporated later in the synthesis by reaction of a precursor compound of formula ESTEVE PHARMACEUTICALS, S.A.

(IVc) or (IIc-LG), respectively, with an amine of formula (V) following the conditions described above in Method A. This process can easily be adapted wherein -X- represents -[CRaRb]pC(O)[CH2]q- or - [CRaRb]pC(O)[CRcRd]q-, by choosing the corresponding reagents.

Scheme 4 The general synthetic route according to method A for preparing compounds of formula (I) wherein -X- represents -[CH₂]_pN(R_z)C(O)[CH₂]_q-, resulting in compounds of formula (Id), starting from a compound of formula (IId) or (IIa), is represented in Scheme 4:

wherein R1, R2, R3, R3’, R4, R4’, Rz, Y1, Y2, n, p and q have the meanings as defined in claim 1, LG represents a leaving group (such as chloro, bromo, iodo, mesylate, ESTEVE PHARMACEUTICALS, S.A.

tosylate, nosylate or triflate), Q represents chloro, bromo, iodo or triflate and Z represents OH or halogen (preferably bromo or chloro). The reaction between an amino compound of formula (IId) with an acyl reagent of formula (III-3) to render a compound of formula (Id) can be carried out under the amidation conditions described above in Scheme 3 for the preparation of compounds of formula (Ic). Alternatively, the compounds of formula (Id) can be prepared in 2 steps by treating a compound of formula (IId) with an acylating agent of formula (III-4) under the same amidation conditions to obtain a compound of formula (VI), followed by reaction with a N-containing cyclic reagent of formula (III-1), under conventional alkylation conditions such as those described in Method A for the reaction of a compound of formula (IV) with an amine of formula (V). Finally, a compound of formula (Id) wherein p is 0 can be alternatively prepared by reacting a compound of formula (IIa) with a carboxamido compound of formula (III-5). The reaction can be carried out under Ullmann arylation conditions, using a Cu catalyst such as copper iodide and a suitable ligand, preferably an amino ligand such as N¹,N²- dimethylethane-1,2-diamine, in the presence of a suitable base such as potassium phosphate, in a suitable solvent such as 1,4-dioxane or dimethylformamide, at a suitable temperature, preferably heating. Alternatively, the coupling reaction can be performed under standard Buchwald-Hartwig arylation conditions, using a suitable Pd catalyst and a suitable ligand (preferably a phosphine ligand). In addition, the amino group NR₃R_3’ present in a compound of formula (Id), (IIa) or (IId) can be incorporated later in the synthesis by reaction of a precursor compound of formula (IVd), (IIa-LG) or (IId-LG), respectively, with an amine of formula (V) following the conditions described above in Method A.. This process can easily be adapted wherein -X- represents -[CRaRb]pN(Rz)C(O)[CH2]q- , by choosing the corresponding reagents. Scheme 5 The general synthetic route according to method A for preparing compounds of formula (I) wherein -X- represents -[CH2]pN(Rz)[CH2]q- resulting in compounds of formula (Ie), starting from a compound of formula (IId) is represented in Scheme 5: ESTEVE PHARMACEUTICALS, S.A.

wherein R1, R2, R3, R3’, R4, R4’, Rz, Y1, Y2, n, p and q have the meanings as defined in claim 1, LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate) and q’ represents 0, 1, 2, 3 or 4. The preparation of a compound of formula (Ie) from an amino compound of formula (IId) can be carried out either under conventional reductive amination or alkylation conditions. When using reductive amination conditions, a compound of formula (IId) is reacted with an aldehyde of formula (III-6) under the conditions described above in Scheme 2 for the preparation of compounds of formula (Ib) from compounds of formula (IIb). When using alkylation conditions, a compound of formula (IId) is reacted with an alkylating agent of formula (III-7) following similar conditions as those described in Method A for the reaction of a compound of formula (IV) with an amine of formula (V).

METHOD B An alternative one-step process is described for the preparation of compounds of general formula (I) starting from a compound of formula (VII), as shown in the following scheme:

Method B ESTEVE PHARMACEUTICALS, S.A.

wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁, Y₂ and n have the meanings as defined in claim 1, Z represents OH or a leaving group, and G represents OH, halogen or a leaving group depending on the meaning of n. Specific reaction conditions are detailed below in Schemes 6 and 7. As it has been mentioned before, alternatively the amino group NR3R3’ present in a compound of formula (I) can be incorporated later in the synthesis by reaction of a precursor compound of formula (IV) with an amine of formula (V) following the conditions described above in Method A.

Scheme 6 The general synthetic route according to method B for preparing compounds of formula (I) wherein n is 0, resulting in compounds of formula (If), is represented in Scheme 6:

wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁ and Y₂ have the meanings as defined in claim 1, n is 0, Z represents OH or a leaving group, and G represents OH or halogen. Depending on the meaning of G and Z different reaction conditions will apply: a) When G is OH and Z represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, the alkylation reaction between a phenol of formula (VIIa) and an alkylating agent of formula (VIII) is carried out in a suitable solvent, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, dichloromethane or 1,4-dioxane; in the presence of a base such as K2CO3, Cs2CO3, sodium hydride or potassium tert-butoxide; ESTEVE PHARMACEUTICALS, S.A.

at a suitable temperature comprised between room temperature and the reflux temperature, or alternatively, the reactions can be carried out in a microwave reactor. Additionally, an activating agent such as sodium iodide can be used. b) When G is OH and Z represents OH, the reaction is carried out under conventional Mitsunobu conditions by treating a phenol of formula (VIIa) with an alcohol of formula (VIII) in the presence of an azo compound such as 1,1'- (azodicarbonyl)dipiperidine (ADDP), diisopropylazodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) and a phosphine such as tributylphosphine or triphenylphoshine. The Mitsunobu reaction is carried out in a suitable solvent, such as toluene or tetrahydrofuran; at a suitable temperature comprised between room temperature and the reflux temperature. c) When G is halogen and Z represents OH, the reaction is carried out under conventional aromatic nucleophilic substitution conditions by treating an alcohol of formula (VIII) with a compound of formula (VIIa) wherein G represents halogen (preferably fluoro), in the presence of a strong base such as sodium hydride or potassium tert-butoxide. The reaction is carried out in a suitable solvent, such as a polar aprotic solvent, preferably dimethylformamide, dimethylacetamide or dimethylsulfoxide; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. Alternatively, when G is bromo or iodo, the compound of formula (VIII) can be introduced under cross-coupling conditions, using a Pd or Cu catalyst and a suitable ligand.

Scheme 7 The general synthetic route according to method B for preparing compounds of formula (I) wherein n is 1, resulting in compounds of formula (Ig), is represented in Scheme 7: ESTEVE PHARMACEUTICALS, S.A.

wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in claim 1, n is 1, and either Z represents OH and G represents a leaving group or alternatively Z represents a leaving group and G represents OH. The reaction is carried out under standard alkylation reaction conditions such as those described in Scheme 6 above.

Scheme 8 The preparation of key compounds of formula (II) and (VII) from a common precursor of formula (IX) is summarized in Scheme 8 below:

ESTEVE PHARMACEUTICALS, S.A. wherein R1, R2, R3, R3’, R4, R4’, X, Y1, Y2 and n have the meanings as defined in claim 1, and G and Z have the meanings as defined above in Schemes 1 to 7, and R1-W represents a compound of formula III-1, III-2, III-3 or III-5 as defined above in Schemes 1 to 7. The preparation of a compound of formula (VII) from a compound of formula (IX) and a compound of formula (III) can be carried out under the reaction conditions described above in general Method A and further detailed in Schemes 1 to 5. The preparation of a compound of formula (II) or (II-LG) from a compound of formula (IX) and a compound of formula (VIII) can be carried out under the reaction conditions described above in general Method B and further detailed in Schemes 6 and 7.

The compounds of formula (III), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (V), (VIII) and (IX) used in the methods and schemes disclosed above are commercially available or can be synthesized following common procedures described in the literature. Moreover, certain compounds of the present invention can also be obtained starting from other compounds of formula (I) by appropriate conversion reactions of functional groups, in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions. As a way of example, some of these conversions include the acylation of an amino group to yield an acylamino group, the N-alkylation of an amino or carboxamido group to yield a further substituted compound, or the reductive amination of an amino group with an aldehyde to render a substituted amino group.

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- ESTEVE PHARMACEUTICALS, S.A.

butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups, and common silyl protecting groups for the protection of the hydroxyl group. The procedures for the introduction and removal of these protecting groups are well known in the art and can be found thoroughly described in the literature. In addition, a compound of formula (I) can be obtained in enantiopure form by resolution of a racemic compound of formula (I) either by chiral preparative HPLC or by crystallization of a diastereomeric salt or co-crystal. Alternatively, the resolution step can be carried out at a previous stage, using any suitable intermediate.

Examples The following abbreviations are used in the examples:

ACN: acetonitrile

ADDP: 1,1¢-(azodicarbonyl)dipiperidine

aq.: aqueous

BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

Boc: tert-butoxycarbonyl

CH: cyclohexane

conc.: concentrated

DCE: dichloroethane

DCM: dichloromethane

Deprot.: deprotection

DIAD: diisopropyl azodicarboxylate

DIBAL-H: diisobutylaluminum hydride

DIPEA: N,N-diisopropylethylamine

DMF: N,N-dimethylformamide

DMSO: dimethylsulfoxide

EtOAc: ethyl acetate ESTEVE PHARMACEUTICALS, S.A.

EtOH: ethanol

EX: example

h: hour/s

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HPLC: high performance liquid chromatography

INT: intermediate

MeOH: methanol

MS: mass spectrometry

Min: minutes

Pd(OAc)₂: palladium(II) acetate

Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)

Quant: quantitative

Ret.: retention

r.t.: room temperature

Sat: saturated

Sol.: solution

SPhos: 2-dicyclohexylphosphino-2¢,6¢-dimethoxybiphenyl

Teoc: 2-(trimethylsilyl)ethoxycarbonyl

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TMSI: trimethylsilyl iodide (or also named iodotrimethylsilane)

wt: weight

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

The following methods were used to determine the HPLC-MS spectra: ESTEVE PHARMACEUTICALS, S.A.

Method A

Column: Kinetex EVO 50 x 4.6 mm, 2.6 um

Temperature: 40 ºC

Flow: 2.0 mL/min

Gradient: NH4HCO3 pH 8 : ACN (95:5)---0.5min---(95:5)---6.5min---(0:100)---1min--- (0:100)

Sample dissolved approx.1mg/mL in NH₄HCO₃ pH 8/ ACN Method B

Column: Kinetex EVO 50 x 4.6 mm, 2.6 um

Temperature: 40 ºC

Flow: 1.5 mL/min

Gradient: NH₄HCO₃ pH 8 : ACN (95:5)---0.5min---(95:5)---6.5min---(0:100)---2min--- (0:100)

Sample dissolved approx.1mg/mL in NH₄HCO₃ pH 8/ ACN Method C

Column: Gemini C1830 x 4,6 mm, 3um

Temperature: 40 ºC

Flow: 1.5 mL/min

Gradient H2O-0.1%HCOOH / ACN (95:5)---0.5min---(95:5) ---8.5min-----(0:100)--- 1min---(0:100)

Sample dissolved approx.1mg/mL in ACN Method D

Column: Gemini-NX 30 x 4.6 mm, 3 um

Temperature: 40 ºC

Flow: 2.0 mL/min

Sample dissolved approx.1mg/mL in NH4HCO3 pH 8/ ACN

Method E

Column: Kromasil C18250 x 4,6 mm 5um ESTEVE PHARMACEUTICALS, S.A.

Temperature: 40 ºC

Flow: 1 mL/min

Gradient: H2O-0.1%HCOOH / ACN (100:0)---30min---(0:100)

Sample dissolved approx.4mg/mL in ACN/H2O 1:1 Method F

Column: Luna C₁₈250 x 4,6 mm 5um

Temperature: 40 ºC

Flow: 1 mL/min

Gradient: H₂O-0.1%HCOOH /ACN (100:0)---30min---(0:100)---10min---(0:100) Sample dissolved approx.1mg/mL in ACN

Synthesis of Intermediates Intermediate 1: (R)-2-(Trimethylsilyl)ethyl (3-(2-bromophenoxy)-3-(thiophen-2- yl)propyl)(methyl)carbamate

Step 1. (R)-3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol: A solution of (R)-3-chloro-1- (thiophen-2-yl)propan-1-ol (2.89 g, 16.2 mmol) and methylamine (40 wt% in EtOH, 14 mL, 162 mmol) in EtOH (74 mL) was heated in a sealed flask at 90 ºC overnight. The solvent was evaporated, the residue was dissolved in DCM and it was washed with 1 N NaOH, dried over MgSO₄, filtered and concentrated to dryness. The crude product (1.7 g) was slurried in methylcyclohexane:toluene (3:1, 6 vol, 10.2 mL) and heated at 60 ºC for 1 h. Then, it was allowed to cool down and it was stirred at r.t. for 1 h. The solids were filtered, washed with methylcyclohexane and dried under vacuum to provide the title compound (1.13 g, 41% yield). Step 2. (R)-3-(2-Bromophenoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine: To a solution of the product obtained in Step 1 (1.13 g, 6.6 mmol) and 1-bromo-2- ESTEVE PHARMACEUTICALS, S.A.

fluorobenzene (2.87 mL, 26.4 mmol) in DMSO (2 mL), under a N₂ atmosphere, potassium tert-butoxide (0.74 g, 6.6 mmol) was added and the reaction mixture was heated at 60 ºC for 8 h. It was then cooled to r.t., water was added and the aq. phase was extracted twice with EtOAc. The combined organic phases were dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4), to give the title compound (1.67 g, 78% yield). Step 3. Title compound: To a solution of the product obtained in Step 2 (1.67 g, 5.1 mmol) in DCM (5 mL), under a N₂ atmosphere, DIPEA (0.89 mL, 5.1 mmol) and a solution of 4-nitrophenyl (2-(trimethylsilyl)ethyl) carbonate (1.45 g, 5.1 mmol) in DCM (7 mL) were added and the mixture was stirred at r.t. overnight. NaHCO₃ sat. sol. was added and it was extracted twice with DCM. The combined organic phases were washed with 2 N NaOH solution, dried over MgSO₄, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (2.17 g, 91% yield).

This method was used for the preparation of Intermediates 2-4 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A. Intermediate 5: 2-(3-Chloro-1-(thiophen-2-yl)propoxy)benzaldehyde

Step 1.2-(3-Chloro-1-(thiophen-2-yl)propoxy)benzonitrile: To a solution of 3-chloro-1- (thiophen-2-yl)propan-1-ol (10 g, 52 mmol), triphenylphosphine (15 g, 57.2 mmol) and 2-hydroxybenzonitrile (6.8 g, 57.2 mmol) in dry THF (252 mL), cooled at 0 ºC, DIAD (11.5 mL, 58.3 mmol) was added dropwise and the mixture was stirred at r.t. overnight. The solvent was concentrated under vacuum and the residue was purified by flash chromatography, silica gel, gradient CH to EtOAc to give the title compound (13.9 g, 96% yield). Step 2. Title compound: To a solution of the product obtained in Step 1 (4 g, 14.4 mmol) in toluene (40 mL), cooled at 0 ºC, DIBAL-H (25 wt% solution in toluene, 13.5 mL, 20.2 mmol) was added dropwise and the reaction mixture was stirred at 0-5 ºC for 4 h. Then, 10% HCl aq. solution was slowly added to quench the reaction and the mixture was stirred at r.t. for 10 min. It was extracted with EtOAc and the combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (4 g, 38% yield).

This method was used for the preparation of Intermediate 6 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A.

(1) 1 M DIBAL-H in DCM was used in Step 2 Intermediate 7: 2-(2-(3-Chloro-1-(thiophen-2-yl)propoxy)phenyl)acetic acid

Step 1. Methyl 2-(2-(3-chloro-1-(thiophen-2-yl)propoxy)phenyl)acetate: To a solution of 3-chloro-1-(thiophen-2-yl)propan-1-ol (0.513 g, 3.0 mmol), tributylphosphine (1.13 mL, 4.5 mmol) and methyl 2-(2-hydroxyphenyl)acetate (0.5 g, 3.0 mmol) in dry THF (20 mL), ADDP (1.14 g, 4.5 mmol) was added and the mixture was stirred at r.t. overnight. The reaction mixture was filtered through a pad of Celite that was washed with THF, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (0.4 g, 41% yield). Step 2. Title compound: A solution of the compound obtained in Step 1 (0.4 g, 1.24 mmol) in a mixture of THF (6.2 mL) and 2 N LiOH aq. sol. (6.2 mL, 12.3 mmol) was heated at 50 ºC overnight. The solvent was evaporated, pH was adjusted to 4 with 6 N HCl and the aq. phase was extracted with DCM. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness to afford the title compound (0.36 g, 95% yield). This method was used for the preparation of Intermediate 8 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A.

Intermediate 9: tert-Butyl (3-(2-bromophenoxy)-3-phenylpropyl)(methyl)carbamate

In a sealed tube, a mixture of tert-butyl (3-chloro-3-phenylpropyl)(methyl)carbamate (4 g, 14.1 mmol), K2CO3 (5.84 g, 42.3 mmol), KI (234 mg, 1.41 mmol) and 2-bromophenol (2.4 g, 14.1 mmol) in ACN (92 mL) was heated at 60 ºC overnight. After cooling down to r.t., water was added and it was extracted with EtOAc. The combined organic phases were dried over MgSO₄, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (2.36 g, 40% yield).

This method was used for the preparation of Intermediate 10 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A.

Intermediate 11: tert-Butyl (3-(2-bromophenoxy)-3-(thiophen-2- yl)propyl)(methyl)carbamate

Step 1.2-(1-(2-Bromophenoxy)-3-chloropropyl)thiophene: To a solution of 3-chloro-1- (thiophen-2-yl)propan-1-ol (2 g, 11.3 mmol), triphenylphosphine (3.5 g, 13.6 mmol) and 2-bromophenol (1.96 g, 11.3 mmol) in dry THF (40 mL), cooled at 0 ºC under a N2 atmosphere, DIAD (2.64 mL, 13.6 mmol) was added dropwise and the mixture was stirred at r.t. overnight. The solvent was concentrated to dryness and the residue was slurried in hexane. The suspension was filtered, the collected solids were washed with hexane and discarded, and the filtrate was concentrated under vacuum to afford the title compound, that was used without further purification (3.85 g, quant. yield). Step 2. 3-(2-Bromophenoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine: In a sealed tube, a mixture of the product obtained in Step 1 (3.75 g, 11.3 mmol) and methylamine (33 wt% in EtOH, 30 mL, 226 mmol) was heated at 100 ºC overnight. Then, it was concentrated to dryness and the crude product was used in the next step without further purification (3.72 g, quant yield).

Step 3. Title compound: To a solution of the product obtained in Step 2 (3.7 g, 11.3 mmol) in tert-butanol (10 mL), 2 N NaOH solution (10 mL) and di-tert-butyl dicarbonate (2.5 g, 11.3 mmol) were added and the reaction mixture was stirred at r.t. overnight. Brine and DCM were added, the phases were separated and the aq. layer was ESTEVE PHARMACEUTICALS, S.A.

extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc to give the title compound (1.34 g, 28% combined yield for the 3 steps).

Intermediate 12: 2-(3-((tert-Butoxycarbonyl)(methyl)amino)-1-phenylpropoxy)benzoic acid

Step 1. Methyl 2-(3-((tert-butoxycarbonyl)(methyl)amino)-1-phenylpropoxy)benzoate: Following the experimental procedure described for the preparation of Intermediate 9, but using methyl 2-hydroxybenzoate instead of 2-bromophenol as starting material, the title compound was obtained (1.48 g, 63% yield).

Step 2. Title compound: To a solution of the compound obtained in Step 1 (1.48 g, 3.7 mmol) in a mixture of THF (7.5 mL) and water (7.5 mL), lithium hydroxide monohydrate (1.2 g, 30 mmol) was added and the reaction mixture was heated at 50 ºC overnight. The solvent was concentrated, pH was adjusted to 3 with 6 N HCl and it was extracted with EtOAc. The combined organic phases were dried over MgSO₄, filtered and concentrated to dryness to afford the title compound (1.1 g, 78% yield).

Intermediate 13. tert-Butyl (3-(2-aminophenoxy)-3-phenylpropyl)(methyl)carbamate

ESTEVE PHARMACEUTICALS, S.A.

Step 1. tert-Butyl methyl(3-(2-nitrophenoxy)-3-phenylpropyl)carbamate: Following the experimental procedure described in Step 1 of Intermediate 11, using tert-butyl (3- hydroxy-3-phenylpropyl)(methyl)carbamate and 2-nitrophenol as starting materials, the title compound was obtained (1.55 g, 63% yield). Step 2. Title compound: To a solution of the compound obtained in Step 1 (1.55 g, 4 mmol) in a mixture of EtOH-water 4:1 (33 mL), iron (2.2 g, 40 mmol) and ammonium chloride (107 mg, 2 mmol) were added and the mixture was heated to reflux for 4 h. It was allowed to cool down to r.t. and the suspension was filtered through a pad of Celite, that was washed with EtOH. The filtrate was concentrated to dryness to render the title compound that was used without further purification (1.24 g, 87% yield).

Intermediate 14: 2-(Trimethylsilyl)ethyl (3-(2-bromophenoxy)-3-(3- fluorophenyl)propyl)(methyl)carbamate

Step 1. 1-(3-Fluorophenyl)-3-(methylamino)propan-1-one hydrochloride: In a sealed tube, 1-(3-fluorophenyl)ethanone (7.5 g, 54.7 mmol), methylamine hydrochloride (4.43 g, 77 mmol) and paraformaldehyde (2.3 g, 65.6 mmol) were dissolved in EtOH (60 mL) and the mixture was heated at 100 ºC overnight. The solvent was partially evaporated, and the precipitated solids were filtered off. The filtrate was evaporated to dryness and the residue was slurried in EtOAc (150 mL). The solids were filtered, washed with EtOAc and dried under vacuum to afford the title compound (6.35 g, 40% yield).

Step 2. 1-(3-Fluorophenyl)-3-(methylamino)propan-1-ol: To a solution of the product obtained in Step 1 (6.35 g, 21.9 mmol) in MeOH (140 mL), cooled at 0-5 ºC, NaBH₄ (2.48 g, 65.6 mmol) was added portionwise and the mixture was stirred at 0-5 ºC for 1 h. NH₄Cl sat. sol. was then added and MeOH was distilled off. The aq. phase was extracted with CHCl₃ and finally with CHCl₃/MeOH (9:1). The combined organic extracts were dried over MgSO₄, filtered and concentrated to dryness to afford the title compound (2 g, 50% yield). ESTEVE PHARMACEUTICALS, S.A.

Step 3. 3-(2-Bromophenoxy)-3-(3-fluorophenyl)-N-methylpropan-1-amine: Following the experimental procedure described in Step 2 of Intermediate 1, using the compound obtained in Step 2, the title compound was obtained (2.96 g, 80% yield)

Step 4. Title compound: Following the experimental procedure described in Step 3 of Intermediate 1, starting from the product obtained in Step 3, the title compound was obtained (4 g, 96 % yield).

Intermediate 15: (R)-2-(Trimethylsilyl)ethyl methyl(3-(2-(2-oxoethyl)phenoxy)-3- (thiophen-2-yl)propyl)carbamate

Step 1. (R)-2-(Trimethylsilyl)ethyl (3-(2-(cyanomethyl)phenoxy)-3-(thiophen-2- yl)propyl)(methyl)carbamate: In a sealed tube, Pd2(dba)3 (91 mg, 0.1 mmol), SPhos (123 mg, 0.3 mmol) and potassium 2-cyanoacetate (0.79 g, 6.48 mmol) were charged and the tube was purged with argon. Then, a solution of Intermediate 1 (2.5 g, 4.98 mmol) in mesitylene (12.5 mL) was added and the reaction mixture was heated at 140 ºC overnight under an argon atmosphere. The solvent was then evaporated and the residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (1.8 g, 78% yield). Step 2. Title compound: To a solution of the product obtained in Step 1 (0.5 g, 1.08 mmol) in DCM (8 mL), cooled at -78 ºC, DIBAL-H (1 M solution in DCM, 3.25 mL, 3.25 mmol) was added dropwise and the reaction mixture was stirred at -78 ºC for 1.5 h. Then, potassium tartrate sat. sol. was added at -78 ºC, and the mixture was allowed to reach r.t.. The phases were separated and the aq. phase was extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄, filtered and concentrated to dryness to afford the title compound (406 mg, 81% yield). ESTEVE PHARMACEUTICALS, S.A.

Intermediate 16: (R)-2-(Trimethylsilyl)ethyl ethyl(3-(2-(2-oxoethyl)phenoxy)-3- (thiophen-2-yl)propyl)carbamate

Step 1. (R)-2-(Trimethylsilyl)ethyl (3-(2-allylphenoxy)-3-(thiophen-2- yl)propyl)(ethyl)carbamate: In a sealed tube, Pd(PPh3)4 (137 mg, 0.145 mmol), 2-allyl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.73 g, 4.3 mmol) and potassium carbonate (0.3 g, 2.17 mmol) were charged and the tube was purged with argon. Then, a solution of Intermediate 4 (0.7 g, 1.45 mmol) in 1,4-dioxane (18 mL) was added and the reaction was heated at 110 ºC for 4 h under an argon atmosphere. The reaction mixture was filtered through a pad of Celite, that was washed with EtOAc. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (478 mg, 74% yield). Step 2. Title compound: To a solution of the product obtained in Step 1 (478 mg, 1.07 mmol) in a mixture of THF-water (2:1, 22.5 mL), a solution of OsO4 (4 wt% aq. sol., 0.75 mL, 0.118 mmol) was added. It was stirred at r.t. for 10 min. and then NaIO4 (573 mg, 2.68 mmol) was added and the reaction mixture was stirred at r.t. for 15 min. The solvent was evaporated and the aq. phase was extracted with EtOAc. The combined organic extracts were dried over MgSO₄, filtered and concentrated to dryness to afford the title compound (448 mg, 93% yield). This method was used for the preparation of Intermediates 17-18 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A.

(

4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane was used in Step 1

Intermediate 20: 2-(Trimethylsilyl)ethyl (3-((2-bromobenzyl)oxy)-3-(thiophen-2- yl)propyl)(methyl)carbamate

Step 1. N-Benzyl-3-((2-bromobenzyl)oxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine: To a solution of 3-(benzyl(methyl)amino)-1-(thiophen-2-yl)propan-1-ol (0.45 g, 1.7 mmol) and tetrabutylammonium iodide (0.63 g, 1.7 mmol) in DMF (2.2 mL), cooled at 0 ºC, NaH (60 wt% dispersion in mineral oil, 0.14 g, 3.4 mmol) was added portionwise under a N2 atmosphere. The reaction was stirred at 0 ºC for 30 min and then a solution of 1-bromo-2-(bromomethyl)benzene (0.43 g, 1.7 mmol) in DMF (0.9 mL) was added. The reaction mixture was stirred at r.t. overnight. Water and EtOAc were added, the phases were separated and the aq. phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO₄, filtered and ESTEVE PHARMACEUTICALS, S.A.

concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient CH to EtOAc to give the title compound (0.335 g, 45% yield).

Step 2. Title compound: To a mixture of 2-(trimethylsilyl)ethanol (276 mg, 2.33 mmol) and K3PO4 (700 mg, 3 mmol) in toluene (2 mL), cooled at 0 ºC, a solution of triphosgene (231 mg, 0.78 mmol) in toluene (1 mL) was added dropwise and the mixture was stirred at r.t. for 1 h. Then, the reaction mixture was cooled at 0 ºC and a solution of the product obtained in Step 1 (335 mg, 0.78 mmol) in toluene (2 mL) was added and the mixture was stirred at r.t. overnight. NaHCO₃ sat. sol. was added and it was extracted with EtOAc. The combined organic phases were dried over MgSO₄, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc to give the title compound (201 mg, 60% yield).

Intermediate 21: tert-Butyl (3-((2-bromobenzyl)oxy)-3- phenylpropyl)(methyl)carbamate

Following the experimental procedure described in Step 1 of Intermediate 20, using tert-butyl (3-hydroxy-3-phenylpropyl)(methyl)carbamate (300 mg, 1.1 mmol) as starting material, the title compound was obtained (307 mg, 62% yield).

Synthesis of Examples General Deprotection Methods Method 1. Boc deprotection with TMSI. To a solution of the N-Boc protected compound (1 mmol) in dry ACN (45 mL), TMSI (2 mmol) was added dropwise. After stirring for 15 min at r.t., NaHCO₃ sat. solution and DCM were added and the mixture was stirred for additional 10 minutes. The phases were separated, the organic phase was dried over ESTEVE PHARMACEUTICALS, S.A.

MgSO₄ and concentrated to dryness, to afford the crude compound, which was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4). Method 2. Boc deprotection with TFA. A solution of the N-Boc protected compound (1 mmol) in a mixture of DCM (15 mL) and TFA (10 mmol) was stirred at r.t. until full conversion was achieved. The volatiles were evaporated and the residue was re- dissolved in DCM and washed with 1 M NaOH solution and brine, dried over MgSO₄ and concentrated. The crude compound was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4). Method 3. Boc deprotection with HCl. To a solution of the N-Boc protected compound (1 mmol) in dioxane (10 mL), HCl (4 N solution in dioxane, 10 mmol) was added under a N₂ atmosphere. The reaction was stirred at r.t. overnight. The solvent was evaporated and the residue was purified by eluting through an acidic ion exchange resin cartridge (SCX), to give the desired compound, which was further purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4). Method 4. Boc deprotection with ZnBr2. A solution of the N-Boc protected compound (1 mmol) in DCM (5 mL) was added to a stirred suspension of ZnBr₂ (5.7 mmol) in DCM (50 mL) under a N2 atmosphere. After stirring the mixture at r.t. overnight, water was added and it was stirred for 5 min. The layers were separated and the aq. phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated. The crude compound was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4). Method 5. Teoc deprotection with CsF. A solution of the N-Teoc protected compound (1 mmol) and cesium fluoride (5 mmol) in DMF (26 mL) was heated at 90 ºC for 1 h. The solvent was concentrated to dryness and the crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4).

Example 1: N-Methyl-3-(2-(4-methylpiperazin-1-yl)phenoxy)-3-phenylpropan-1-amine ESTEVE PHARMACEUTICALS, S.A.

Step 1. tert-Butyl methyl(3-(2-(4-methylpiperazin-1-yl)phenoxy)-3- phenylpropyl)carbamate: In a sealed tube, a mixture of Intermediate 9 (100 mg, 0.24 mmol), 1-methylpiperazine (36 mg, 0.36 mmol), Pd₂(dba)₃ (22 mg, 0.024 mmol), BINAP (30 mg, 0.048 mmol) and sodium tert-butoxide (46 mg, 0.48 mmol) in dry toluene (1.2 mL) was heated at 100 ºC overnight under an argon atmosphere. The reaction mixture was diluted with water and EtOAc, the phases were separated and the aq. phase was extracted with EtOAc. The combined organic fractions were dried over MgSO₄ and concentrated. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM to give the title compound (75 mg, 71% yield).

Step 2. Title compound: Starting from the compound obtained in Step 1 (75 mg, 0.17 mmol) and following General Deprotection Method 1, the title compound was obtained (25 mg, 43% yield).

HPLC retention time (method E): 10.37 min; MS: 340.3 (M+H).

This method was used for the preparation of Examples 2-24 using suitable starting materials:

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Example 25: 1-Methyl-4-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1,4-diazepan- 5-one ESTEVE PHARMACEUTICALS, S.A.

Step 1. tert-Butyl methyl(3-(2-(4-methyl-7-oxo-1,4-diazepan-1-yl)phenoxy)-3- phenylpropyl)carbamate: In a sealed tube, a mixture of Intermediate 9 (100 mg, 0.24 mmol), 1-methyl-1,4-diazepan-5-one (40 mg, 0.31 mmol), N¹,N²-dimethylethane-1,2- diamine (0.08 mL, 0.07 mmol), copper(I) iodide (14 mg, 0.07 mmol) and potassium phosphate (109 mg, 0.48 mmol) in 1,4-dioxane (2.3 mL) was heated at 100 ºC overnight under an argon atmosphere. Additional N¹,N²-dimethylethane-1,2-diamine (0.08 mL, 0.07 mmol) and copper(I) iodide (14 mg, 0.07 mmol) were added to the reaction mixture and it was heated at 120 ºC overnight under an argon atmosphere. The reaction mixture was filtered through a pad of Celite that was washed with DCM, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (39 mg, 35% yield). Step 3. Title compound: Starting from the compound obtained in Step 2 (39 mg, 0.08 mmol) and following General Deprotection Method 1, the title compound was obtained (13 mg, 42% yield).

HPLC retention time (method D): 3.26 min; MS: 368.2 (M+H). This method was used for the preparation of Examples 26-28 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A.

Example 29: (S)-4-((4-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin- 1-yl)methyl)benzonitrile

Step 1. Potassium ((4-(4-cyanobenzyl)piperazin-1-yl)methyl)trifluoroborate: In a sealed tube, 4-(piperazin-1-ylmethyl)benzonitrile (400 mg, 1.98 mmol) and potassium (bromomethyl)trifluoroborate (479 mg, 2.38 mmol) in a mixture of THF-tert-butanol (2:1, 1.6 mL) was heated at 80 ºC overnight. After cooling down to r.t., the precipitated solids were filtered, washed with THF and dried under vacuum to afford the title compound that was used in the next step without further purification (764 mg, overweight, quant. yield assumed). Step 2. (S)-2-(Trimethylsilyl)ethyl (3-(2-((4-(4-cyanobenzyl)piperazin-1- yl)methyl)phenoxy)-3-(thiophen-2-yl)propyl)(methyl)carbamate: In a sealed tube, a ESTEVE PHARMACEUTICALS, S.A.

mixture of Intermediate 2 (250 mg, 0.53 mmol), the product obtained in Step 1 (171 mg, 0.53 mmol), Pd(OAc)2 (21 mg, 0.096 mmol), XPhos (91 mg, 0.191 mmol) and Cs2CO3 (308 mg, 1.6 mmol) in a mixture of 1,4-dioxane-water (10:1, 3.8 mL) was heated at 110 ºC overnight under an argon atmosphere. The solvent was concentrated to dryness and the residue was diluted with EtOAc and NaHCO3 sat. sol. The phases were separated and the aq. phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄, filtered and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (192 mg, 58% yield).

Step 3. Title compound: Starting from the compound obtained in Step 2 (192 mg, 0.32 mmol) and following General Deprotection Method 5, the title compound was obtained (107 mg, 73% yield).

HPLC retention time (method B): 5.07 min; MS: 461.2 (M+H).

This method was used for the preparation of Examples 30-38 using suitable starting materials:

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Example 39: 1-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)-4- phenylpiperidine-4-carbonitrile ESTEVE PHARMACEUTICALS, S.A.

Step 1. 1-(2-(3-Chloro-1-(thiophen-2-yl)propoxy)benzyl)-4-phenylpiperidine-4- carbonitrile: A solution of Intermediate 5 (100 mg, 0.35 mmol), 4-phenylpiperidine-4- carbonitrile hydrochloride (79 mg, 0.35 mmol) and DIPEA (0.311 mL, 1.8 mmol) in DCE (1.5 mL) was stirred at r.t. for 30 min under a N₂ atmosphere. Then, sodium triacetoxyborohydride (151 mg, 0.71 mmol) was added and the reaction mixture was stirred at r.t. overnight. NaHCO₃ sat. sol. was added, the phases were separated and the aq. phase was extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (118 mg, 73% yield).

Step 2. Title compound: A solution of the compound obtained in Step 1 (118 mg, 0.26 mmol) and methylamine (33 wt% solution in EtOH, 1.6 mL, 13 mmol) was heated in a sealed tube at 100 ºC overnight. The solvent was evaporated to dryness, 1 N NaOH aq. sol. and DCM were added and the phases were separated. The aq. phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM:conc. NH3 (1:4:0.3) to give the title compound (73 mg, 63% yield).

HPLC retention time (method B): 5.28 min; MS: 446.2 (M+H). This method was used for the preparation of Examples 40-79 using suitable starting materials:

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Example 80: (R)-N-Methyl-3-(2-(2-morpholinoethyl)phenoxy)-3-(thiophen-2-yl)propan- 1-amine

ESTEVE PHARMACEUTICALS, S.A.

Step 1. (R)-2-(Trimethylsilyl)ethyl methyl(3-(2-(2-morpholinoethyl)phenoxy)-3- (thiophen-2-yl)propyl)carbamate: Following the experimental procedure described in Step 1 of Example 39, using Intermediate 15 (146 mg, 0.34 mmol) and morpholine (29 mg, 0.34 mmol) as starting materials, the title compound was obtained (78 mg, 46% yield).

Step 2. Title compound: Starting from the compound obtained in Step 1 (78 mg, 0.155 mmol) and following General Deprotection Method 5, the title compound was obtained (21 mg, 38% yield).

HPLC retention time (method B): 3.74 min; MS: 361.1 (M+H). This method was used for the preparation of Examples 81-96 using suitable starting materials:

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Example 97: 3-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(4- phenethylpiperazin-1-yl)propan-1-one ESTEVE PHARMACEUTICALS, S.A.

Step 1. 3-(2-(3-Chloro-1-(thiophen-2-yl)propoxy)phenyl)-1-(4-phenethylpiperazin-1- yl)propan-1-one: To a solution of Intermediate 8 (150 mg, 0.462 mmol) and 1- phenethylpiperazine (88 mg, 0.462 mmol) in dry DMF (4.5 mL), DIPEA (0.24 mL, 1.38 mmol) and HATU (175 mg, 0.462 mmol) were added and the reaction mixture was stirred at r.t. overnight. NaHCO3 sat. sol. was added and it was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over MgSO4 and concentrated to dryness to give the title compound (188 mg, 81% yield).

Step 2. Title compound: Following the experimental procedure described in Step 2 of Example 39, starting from the product obtained in Step 1 (188 mg, 0.378 mmol) and methylamine, the title compound was obtained (11 mg, 6% yield).

HPLC retention time (method B): 5.35 min; MS: 492.3 (M+H).

This method was used for the preparation of Examples 98-101 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A.

Example 102: (4-Methyl-1,4-diazepan-1-yl)(2-(3-(methylamino)-1- phenylpropoxy)phenyl)methanone

ESTEVE PHARMACEUTICALS, S.A.

Step 1. tert-Butyl methyl(3-(2-(4-methyl-1,4-diazepane-1-carbonyl)phenoxy)-3- phenylpropyl)carbamate: Following the experimental procedure described in Step 1 of Example 97, using Intermediate 12 (100 mg, 0.26 mmol) and 1-methyl-1,4-diazepane (29 mg, 0.26 mmol) as starting materials, the title compound was obtained (96 mg, 79% yield). Step 2. Title compound: Starting from the compound obtained in Step 1 (96 mg, 0.20 mmol) and following General Deprotection Method 3, the title compound was obtained (25 mg, 30% yield).

HPLC retention time (method D): 3.75 min; MS: 382.2 (M+H). This method was used for the preparation of Example 103 using suitable starting materials:

Example 104: 1-Methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidine-4- carboxamide

ESTEVE PHARMACEUTICALS, S.A.

Step 1. tert-Butyl methyl(3-(2-(1-methylpiperidine-4-carboxamido)phenoxy)-3- phenylpropyl)carbamate: Following the experimental procedure described in Step 1 of Example 97, using Intermediate 13 (118 mg, 0.33 mmol) and 1-methylpiperidine-4- carboxylic acid (47 mg, 0.33 mmol), the title compound was obtained (175 mg, overweight, quant. yield assumed).

Step 2. Title compound: Starting from the compound obtained in Step 1 and following General Deprotection Method 2, the title compound was obtained (43 mg, 34% combined yield for the 2 steps).

HPLC retention time (method F): 8.40 min; MS: 382.2 (M+H).

This method was used for the preparation of Examples 105-107 using suitable starting materials:

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Example 108: 2-(4-(3-Hydroxyphenyl)piperidin-1-yl)-N-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)acetamide

Step 1. tert-Butyl (3-(2-(2-chloroacetamido)phenoxy)-3- phenylpropyl)(methyl)carbamate: To a solution of Intermediate 13 (600 mg, 1.68 mmol) in ACN (8 mL), DIPEA (0.73 mL, 4.2 mmol) and 2-chloroacetyl chloride (0.16 mL, 2.02 mmol) were added dropwise under a N2 atmosphere. The mixture was stirred for 1 h at r.t. and then it was concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc to give the title compound (562 mg, 77% yield). Step 2. tert-Butyl (3-(2-(2-(4-(3-hydroxyphenyl)piperidin-1-yl)acetamido)phenoxy)-3- phenylpropyl)(methyl)carbamate: A solution of the product obtained in Step 1 (100 mg, 0.23 mmol) and 3-(piperidin-4-yl)phenol (49 mg, 0.27 mmol) in EtOH (10 mL) was heated in a sealed tube at 80 ºC for 3 days. The solvent was evaporated and the residue was dissolved in EtOAc. The organic phase was washed with 1 N NaOH aq. solution, dried over MgSO4 and concentrated to dryness to afford the title compound (128 mg, 96% yield). ESTEVE PHARMACEUTICALS, S.A.

Step 3. Title compound: Starting from the compound obtained in Step 2 (128 mg, 0.22 mmol) and following General Deprotection Method 2, the title compound was obtained (64 mg, 60% yield).

HPLC retention time (method A): 4.43 min; MS: 474.2 (M+H).

This method was used for the preparation of Example 109 using suitable starting materials:

Example 110: N-((1-Benzylpiperidin-4-yl)methyl)-2-(3-(methylamino)-1- phenylpropoxy)aniline

Step 1. tert-Butyl (3-(2-(((1-benzylpiperidin-4-yl)methyl)amino)phenoxy)-3- phenylpropyl)(methyl)carbamate: A solution of Intermediate 13 (150 mg, 0.42 mmol), 1-benzylpiperidine-4-carbaldehyde (102 mg, 0.50 mmol) and acetic acid (0.012 mL, 0.21 mmo) in DCM (5 mL), was stirred for 2 h at r.t. Then it was cooled to 0-5 ºC, sodium triacetoxyborohydride (178 mg, 0.84 mmol) was added and the reaction mixture was ESTEVE PHARMACEUTICALS, S.A.

stirred at r.t. overnight. In order to achieve full conversion, additional 1- benzylpiperidine-4-carbaldehyde (102 mg, 0.50 mmol) was added and the mixture was stirred at r.t. for 2 h. Again, it was cooled to 0-5 ºC, additional sodium triacetoxyborohydride (178 mg, 0.84 mmol) was added and the reaction mixture was stirred at r.t. overnight. DCM and NaHCO3 sat. sol. were added, the layers were separated and the aq. phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (143 mg, 62% yield).

Step 2. Title compound: Starting from the compound obtained in Step 1 (71 mg, 0.13 mmol), and following General Deprotection Method 2, the title compound was obtained (25 mg, 44% yield).

HPLC retention time (method A): 5.46 min; MS: 444.3 (M+H).

This method was used for the preparation of Example 111 using suitable starting materials:

Example 112: 4-((4-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-1- yl)methyl)benzonitrile ESTEVE PHARMACEUTICALS, S.A.

Step 1. 4-((4-(2-Methoxybenzyl)piperidin-1-yl)methyl)benzonitrile: A solution of 4-(2- methoxybenzyl)piperidine hydrochloride (0.5 g, 2.07 mmol), 4-formylbenzonitrile (0.271 g, 2.07 mmol) and DIPEA (1.44 mL, 8.27 mmol) in DCE (5 mL) was stirred at r.t. for 30 min. Then, sodium triacetoxyborohydride (0.877 g, 4.14 mmol) was added and the reaction mixture was stirred at r.t. overnight. It was then diluted with water and NaHCO₃ sat. sol. was added to adjust pH to >8. The aq. phase was extracted with DCM and the combined organic extracts were washed with brine, dried over MgSO₄ and concentrated to dryness to afford the title compound (0.663 g, quant. yield assumed). Step 2. 4-((4-(2-Hydroxybenzyl)piperidin-1-yl)methyl)benzonitrile: To a solution of the compound obtained in Step 1 (0.663 g, 2.07 mmol) in DCM (20 mL), cooled at -78 ºC, boron tribromide (1 M solution in DCM, 6.2 mL, 6.2 mmol) was added dropwise and the reaction mixture was stirred at r.t. overnight. Then it was cooled at 0-5 ºC and water was added. The resulting suspension was filtered and the collected solids were washed with water. The crude product thus obtained was purified by flash chromatography, C18, gradient NH4HCO3 pH 8 to ACN to give the title compound (250 mg, 40% yield).

Step 3. 4-((4-(2-(3-Chloro-1-(thiophen-2-yl)propoxy)benzyl)piperidin-1- yl)methyl)benzonitrile: Following the experimental procedure described in Step 1 of Intermediate 7, starting from the product obtained in Step 2 (250 mg, 0.82 mmol) and 3-chloro-1-(thiophen-2-yl)propan-1-ol (131 mg, 0.74 mmol), the title compound was obtained as a crude product that was used in the next step without purification (1.53 g, overweight, quant. yield assumed).

Step 4. Title compound: Following the experimental procedure described in Step 2 of Intermediate 11, starting from the product obtained in Step 3, the title compound was obtained after purification by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) and then additional purification by flash chromatography, C18, gradient NH4HCO3 pH 8 to ACN (5.3 mg, 2% combined yield for the 2 steps). ESTEVE PHARMACEUTICALS, S.A.

HPLC retention time (method B): 5.66 min; MS: 460.2 (M+H).

Example 113: N-Methyl-3-(2-(1-methylpiperidin-4-yl)phenoxy)-3-phenylpropan-1- amine

Step 1. tert-Butyl methyl(3-(2-(1-methylpiperidin-4-yl)phenoxy)-3- phenylpropyl)carbamate: Following the experimental procedure described in Step 1 of Intermediate 7, starting from tert-butyl (3-hydroxy-3-phenylpropyl)(methyl)carbamate (97 mg, 0.366 mmol) and 2-(1-methylpiperidin-4-yl)phenol (70 mg, 0.366 mmol), the title compound was obtained (74 mg, 46% yield).

Step 2. Title compound: Starting from the compound obtained in Step 1 (74 mg, 0.169 mmol), and following General Deprotection Method 2, the title compound was obtained (28 mg, 49% yield).

HPLC retention time (method D): 3.55 min; MS: 339.2 (M+H).

This method was used for the preparation of Example 114 using suitable starting materials:

ESTEVE PHARMACEUTICALS, S.A. Example 115: 3-(2-(1-Benzylpiperidin-4-yl)phenoxy)-N-methyl-3-phenylpropan-1- amine

Step 1.2-(1-Benzylpiperidin-4-yl)phenol: A solution of 2-(piperidin-4-yl)phenol (160 mg, 0.9 mmol), benzaldehyde (0.09 mL, 0.9 mmol) and acetic acid (0.057 mL, 0.99 mmol) in dry THF (5 mL) was stirred at r.t. for 30 min. Then, sodium triacetoxyborohydride (383 mg, 1.80 mmol) was added and the reaction mixture was stirred at r.t. overnight. It was then diluted with water and 1 N NaOH aq. sol. was added to adjust pH to >8. The aq. phase was extracted with DCM. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to afford the title compound (63 mg, 26% yield).

Step 2. tert-Butyl (3-(2-(1-benzylpiperidin-4-yl)phenoxy)-3- phenylpropyl)(methyl)carbamate: Following the experimental procedure described in Step 1 of Intermediate 7, starting from tert-butyl (3-hydroxy-3- phenylpropyl)(methyl)carbamate (62 mg, 0.23 mmol) and the product obtained in Step 1 (63 mg, 0.23 mmol), using toluene as solvent and heating the reaction mixture at 120 ºC overnight, the title compound was obtained (57 mg, 47% yield).

Step 3. Title compound: Starting from the compound obtained in Step 2 (57 mg, 0.11 mmol), and following General Deprotection Method 2, the title compound was obtained (15 mg, 33% yield).

HPLC retention time (method A): 4.99 min; MS: 415.3 (M+H).

This method was used for the preparation of Example 116 using suitable starting materials: ESTEVE PHARMACEUTICALS, S.A.

Example 117: N-Ethyl-2-(3-(methylamino)-1-phenylpropoxy)-N-(1-phenethylpiperidin- 4-yl)benzamide

Step 1. tert-Butyl methyl(3-(2-((1-phenethylpiperidin-4-yl)carbamoyl)phenoxy)-3- phenylpropyl)carbamate: Following the experimental procedure described in Step 1 of Example 97, starting from Intermediate 12 (108 mg, 0.28 mmol) and 1- phenethylpiperidin-4-amine hydrochloride (67 mg, 0.28 mmol), the title compound was obtained (158 mg, 98% yield).

Step 2. tert-Butyl (3-(2-(ethyl(1-phenethylpiperidin-4-yl)carbamoyl)phenoxy)-3- phenylpropyl)(methyl)carbamate: To a solution of the product obtained in Step 1 (158 mg, 0.276 mmol) in dry DMF (1.6 mL), NaH (60 wt% dispersion in mineral oil, 0.22 g, 0.55 mmol) was added portionwise under a N₂ atmosphere. After stirring for 30 min at r.t., ethyl iodide (0.022 mL, 0.276 mmol) was added and the reaction mixture was stirred ESTEVE PHARMACEUTICALS, S.A.

at r.t. overnight. Water and EtOAc were added, the phases were separated and the aq. phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give the title compound (118 mg, 71% yield).

Step 3. Title compound: Starting from the compound obtained in Step 2 (108 mg, 0.18 mmol), and following General Deprotection Method 3, the title compound was obtained (28 mg, 31% yield).

HPLC retention time (method A): 5.02 min; MS: 500.3 (M+H).

Example 118: N-Methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1- phenethylpiperidin-4-amine

Step 1. tert-Butyl methyl(3-(2-(methyl(1-phenethylpiperidin-4-yl)amino)phenoxy)-3- phenylpropyl)carbamate: To a solution of the product obtained in Step 1 of Example 14 (100 mg, 0.184 mmol) in MeOH (1 mL), formaldehyde (37 wt% aq. sol., 0.25 mL, 3.31 mmol) was added and the reaction mixture was stirred at r.t. for 30 min. Then, sodium triacetoxyborohydride (117 mg, 0.55 mmol) was added and the mixture was stirred at r.t. overnight. It was then diluted with DCM and NaHCO3 sat. sol., the layers were separated and the aq. phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (54 mg, 52% yield).

Step 2. Title compound: Following General Deprotection Method 2, starting from the compound obtained in Step 1 (54 mg, 0.097 mmol), the title compound was obtained (16 mg, 32% yield).

HPLC retention time (method A): 5.47 min; MS: 458.3 (M+H). ESTEVE PHARMACEUTICALS, S.A. This method was used for the preparation of Example 119 using suitable starting materials:

Example 120: N-Methyl-3-phenyl-3-(2-((3S,5R)-3,4,5-trimethylpiperazin-1- yl)phenoxy)propan-1-amine

Step 1. tert-Butyl methyl(3-phenyl-3-(2-((3S,5R)-3,4,5-trimethylpiperazin-1- yl)phenoxy)propyl)carbamate: Following the experimental procedure described in Step 2 of Example 117, using the product obtained in Step 1 of Example 3 (54 mg, 0.119 mmol) and methyl iodide as starting materials, the title compound was obtained (23 mg, 41% yield).

Step 2. Title compound: Following General Deprotection Method 2, starting from the compound obtained in Step 1 (23 mg, 0.049 mmol), the title compound was obtained (13 mg, 69% yield). ESTEVE PHARMACEUTICALS, S.A.

HPLC retention time (method E): 10.74 min; MS: 368.3 (M+H).

This method was used for the preparation of Examples 121-122 using suitable starting materials:

Example 123: N-(2-(3-(Methylamino)-1-phenylpropoxy)benzyl)-N-(1- phenethylpiperidin-4-yl)propionamide

ESTEVE PHARMACEUTICALS, S.A.

Step 1. tert-Butyl methyl(3-(2-((N-(1-phenethylpiperidin-4- yl)propionamido)methyl)phenoxy)-3-phenylpropyl)carbamate: To a solution of the product obtained in Step 1 of Example 82 (56 mg, 0.1 mmol) and TEA (0.042 mL, 0.30 mmol) in DCM (1 mL), cooled at 0 ºC, propionyl chloride (0.013 mL, 0.15 mmol) was added and the mixture was stirred at r.t. overnight. NaHCO3 sat. sol. was added and it was extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄, filtered and concentrated to dryness to give the title compound (75 mg, overweight, quant. yield assumed), that was used in next step without purification. Step 2. Title compound: Following General Deprotection Method 3, starting from the compound obtained in Step 1, the title compound was obtained (41 mg, 78% yield). HPLC retention time (method C): 2.63 min; MS: 514.3 (M+H).

This method was used for the preparation of Example 124 using suitable starting materials:

Examples 125 and 126: (R)-3-(2-(2-((S)-4,6-dimethyl-1,4-diazepan-1- yl)ethyl)phenoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine and (R)-3-(2-(2-((R)-4,6- dimethyl-1,4-diazepan-1-yl)ethyl)phenoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine ESTEVE PHARMACEUTICALS, S.A.

Step 1. 2-(Trimethylsilyl)ethyl ((3R)-3-(2-(2-(4,6-dimethyl-1,4-diazepan-1- yl)ethyl)phenoxy)-3-(thiophen-2-yl)propyl)(methyl)carbamate: Following the experimental procedure described in Step 1 of Example 39, starting from Intermediate 15 (116 mg, 0.268 mmol) and 1,6-dimethyl-1,4-diazepane (34 mg, 0.268 mmol), the title compound was obtained as a 1:1 mixture of diastereomers (80 mg, 55% yield). Step 2. Title compounds: Following General Deprotection Method 5, starting from the compound obtained in Step 1, the title compound was obtained as a 1:1 mixture of diastereomers. A chiral preparative HPLC separation (column: Chiralcel ODH; temperature: ambient; flow: 10 mL/min; eluent: n-Heptane/(EtOH + 0.2% DEA) 70/30 v/v) was carried out to give the title compounds. Example 125: HPLC retention time (method B): 3.82 min; MS: 402.2 (M+H).

Example 126: HPLC retention time (method B): 3.86 min; MS: 402.2 (M+H).

ESTEVE PHARMACEUTICALS, S.A. Table of Examples with binding to the s1 Receptor and the ^₂ ^-1 Subunit of the voltage-gated calcium channel: BIOLOGICAL ACTIVITY

Pharmacological study

Human ^₂ ^ ^ ^ subunit of Ca_v2.2 calcium channel ^assay

Human ^ ^ ^ ^ ^ enriched membranes (2.5 µg) were incubated with 15 nM of radiolabeled [3H]-Gabapentin in assay buffer containing Hepes-KOH 10mM, pH 7.4. NSB (non specific binding) was measured by adding 10 µM pregabalin. The binding of the test compound was measured at five different concentrations. After 60 min incubation at 27 ºC, 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-HCl, pH 7.4. Filter plates were dried at 60 ºC for 1 hour and 30 µl of scintillation cocktail were added to each well before radioactivity reading. Readings were performed in a Trilux 1450 Microbeta radioactive counter (Perkin Elmer).

Human ^₁ receptor radioligand assay

Transfected HEK-293 membranes (7 mg) were incubated with 5 nM of [³H](+)- pentazocine in assay buffer containing Tris-HCl 50 mM at pH 8. NBS (non-specific binding) was measured by adding 10 mM Haloperidol. The binding of the test compound was measured at five different concentrations. Plates were incubated at 37 °C for 120 minutes. After the incubation period, the reaction mix was then transferred to MultiScreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris–HCL (pH7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail. ESTEVE PHARMACEUTICALS, S.A. Results:

As this invention is aimed at providing a compound or a chemically related series of compounds which act as ligands of the ^₂ ^ ^ subunit of voltage-gated calcium channels or as dual ligands of the ^₂ ^ ^ subunit of voltage-gated calcium channels and the s1 receptor it is a very preferred embodiment in which the compounds are selected which act as single ligands of the ^ ^ ^ ^ subunit of voltage-gated calcium channels or as dual ligands of the ^ ^ ^ ^ subunit of voltage-gated calcium channels and the s1 receptor and especially compounds which have a binding expressed as K_i responding to the following scales:

K_i ( ^₂ ^-1) is preferably < 10000 nM, more preferably < 5000 nM, even more preferably < 500 nM or even more preferably < 100 nM.

The following scale has been adopted for representing the binding to s1 receptor expressed as Ki: + Ki ( s1) >= 1000 nM

++ 500 nM <= K_i ( s1) >= 1000 nM

+++ 100 nM <= K_i( s1) < 500 nM

The following scale has been adopted for representing the binding to the ^2 ^ ^ ^ subunit of voltage-gated calcium channels expressed as K_i: + Ki( ^2 ^-1) >= 5000 nM

++ 500nM <= Ki( ^2 ^-1) <5000 nM

+++ K_i( ^₂ ^-1) <500 nM ESTEVE PHARMACEUTICALS, S.A.

All compounds prepared in the present application exhibit binding to the ^₂ ^ subunit of voltage-gated calcium channels or binding both to the ^2 ^ subunit of voltage-gated calcium channels and the s1 receptor, in particular the following binding results are shown:

ESTEVE PHARMACEUTICALS, S.A.

ESTEVE PHARMACEUTICALS, S.A.

ESTEVE PHARMACEUTICALS, S.A.

ESTEVE PHARMACEUTICALS, S.A.

Claims

CLAIMS: 1. Compound of general formula (I),

wherein X is selected from a bond, -[C(R_aR_b)]_p-, -[CH₂]_pC(O)[CH₂]_q-, - [CH₂]_pC(O)N(R_z)[CH₂]_q-, -[CH₂]_pN(R_z)C(O)[CH₂]_q- and -[CH₂]_pN(R_z)[CH₂]_q-; R_a is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; Rb is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, Ra and Rb, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;

Rz is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(O)-C1-6 alkyl; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4 or 5;

n is 0 or 1; Y1 is–C(R10R10’)-; wherein R₁₀ and R₁₀’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₁₀ and R₁₀’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl;

Y₂ is–C(R₁₀’’R₁₀’’’)-; wherein R₁₀’’ and R₁₀’’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R_10’’ and R_10’’’ form, with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl;

wherein

W1 is–N- or–CH-;

W₂ is

, or oxygen; with the proviso that

when W₁ is–CH-,then W₂ is

m is 0, 1 or 2;

m’ is 0, 1 or 2;

wherein m+m’ is 1, 2, 3 or 4;

r is 0, 1 or 2;

r’ is 0, 1 or 2;

wherein r +r’ is 1, 2, 3 or 4;

t is 0, 1, 2, 3, 4 or 5; R₅, R₅’, R₅’’ and R₅’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R5 and R5’ and/or R5’’ and R5’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; alternatively, R₅ and R₅’ and/or R₅’’ and R₅’’’ taken together with the carbon atom to which they are attached form a carbonyl group;

R₆, R₆’, R₆’’ and R₆’’’ are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₆, R₆’ and/or R₆’’, R₆’’’ taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; alternatively, R₆ and R₆’ and/or R₆’’ and R₆’’’ taken together with the carbon atom to which they are attached form a carbonyl group;

R7 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, -OR71 and -CN; wherein R₇₁ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; R8 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl,substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -OR81,–NR81R81’ and–C(O)R81; wherein R₈₁ and R₈₁’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl,substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylheterocyclyl; R₂ is selected from substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; R₃ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; R₃’ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; R₄ and R₄’ are independently selected from halogen, -R₄₁, -OR₄₁, -NO₂, - NR₄₁R₄₁’, -NR₄₁C(O)R₄₁’, -NR₄₁S(O)₂R₄₁’, -S(O)₂NR₄₁R₄₁’, -NR₄₁C(O)NR₄₁’R₄₁’’, -SR41 , -S(O)R41, -S(O)2R41, –CN, haloalkyl, haloalkoxy, -C(O)OR41, - C(O)NR41R41’, -OCH2CH2OR41, -NR41S(O)2NR41’R41’’ and -C(CH3)2OR41; wherein R41, R41’ and R41’’ are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof; wherein the following compound is excluded:

2. Compound according to claim 1 wherein R₃ is selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl.

3. Compound according to claim 1 or 2 wherein R₂ is a substituted or unsubstituted group selected from phenyl and thiophen.

4. Compound according to any one of claims 1 to 3 wherein the compound of Formula (I) is a compound of Formula (I’), (I^a), (I^a’), (I^b), (I^b’), (I^c) or (I^c’),

wherein R9 and R9’ are independently selected from hydrogen, halogen, -R21, -OR21, -NO2, -NR21R21’, -NR21C(O)R21’, -NR21S(O)2R21’, -S(O)2NR21R21’, - NR21C(O)NR21’R21’’, -SR21 , -S(O)R21, -S(O)2R21,–CN, haloalkyl, haloalkoxy, - C(O)OR21, -C(O)NR21R21’, -OCH2CH2OR21, -NR21S(O)2NR21’R21’’ and - C(CH3)2OR21; wherein R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl.

5. Compound according to anyone of claims 1 to 4 wherein R₇ is hydrogen, halogen, a substituted or unsubstituted methyl, -OH, -O-methyl or -CN.

6. Compound according to anyone of claims 1 to 5 wherein R₈, is hydrogen, fluorine or a substituted or unsubstituted group selected from methyl, isobutyl, O-isopropyl, -N(CH₃)₂, -N(CH₃)(benzyl), -N(CH₃)(isopropyl), phenyl, , thiophenyl, pyridinyl, oxadiazolyl and -C(O)-piperidine.

7. Compound according to anyone of claims 1 to 6 wherein X is a bond, -CH₂-, - CH₂CH₂-, -C(O)-, -CH₂C(O)-, -CH₂CH₂C(O)-, -C(O)N(CH₂CH₃)-, -NHC(O)-, - NHC(O)CH₂-, -NHC(O)CH₂CH₂-, -N(CH₃)C(O)-, -CH₂NH-, - CH2N(C(O)(CH2CH3))-, -N(C(O)(CH2CH3))-, -N(CH3)-, -NH-, -NHCH2- or - NHCH2CH2-.

8. Compound according to anyone of claims 1 to 7 wherein

p is 0, 1, 2, 3, 4 or 5; preferably p is 0, 1 or 2.

9. Compound according to anyone of claims 1 to 8 wherein

q is 0, 1, 2, 3, 4 or 5; preferably q is 0, 1 or 2. 10. Compound according to any one of claims 1 to 9 wherein the compound is selected from 1 N-Methyl-3-(2-(4-methylpiperazin-1-yl)phenoxy)-3-phenylpropan-1- amine 2 N-methyl-3-phenyl-3-(2-(piperazin-1-yl)phenoxy)propan-1-amine (1) 3 3-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenoxy)-N-methyl-3- phenylpropan-1-amine 4 N,N-dimethyl-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-amine 5 3-(2-(1,4-diazepan-1-yl)phenoxy)-N-methyl-3-phenylpropan-1-amine 6 N-methyl-3-(2-(4-methyl-1,4-diazepan-1-yl)phenoxy)-3-phenylpropan- 1-amine 7 4-methyl-1-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1,4- diazepan-5-one 8 4-((dimethylamino)methyl)-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-ol 9 4-((benzyl(methyl)amino)methyl)-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-ol

10 4-((isopropyl(methyl)amino)methyl)-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-ol 11 N-benzyl-N-methyl-1-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-amine 12 N-methyl-3-(2-(4-phenethylpiperazin-1-yl)phenoxy)-3-phenylpropan- 1-amine 13 3-(2-(4-benzylpiperazin-1-yl)phenoxy)-N-methyl-3-phenylpropan-1- amine 14 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1-phenethylpiperidin- 4-amine 15 3-(1-(2-((2-(3-(methylamino)-1- phenylpropoxy)phenyl)amino)ethyl)piperidin-4-yl)phenol 16 N-methyl-3-((2-(4-phenethylpiperazin-1-yl)benzyl)oxy)-3- phenylpropan-1-amine 17 N-methyl-3-((2-(4-methyl-1,4-diazepan-1-yl)benzyl)oxy)-3- phenylpropan-1-amine 18 N-methyl-3-phenyl-3-(2-(4-phenylpiperazin-1-yl)phenoxy)propan-1- amine 19 N-methyl-3-(2-(4-(pyridin-2-yl)piperazin-1-yl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 20 N-methyl-3-((2-(4-phenethylpiperazin-1-yl)benzyl)oxy)-3-(thiophen-2- yl)propan-1-amine 21 (S)-N-methyl-3-(2-(4-methyl-1,4-diazepan-1-yl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 22 (R)-N-methyl-3-(2-(4-methyl-1,4-diazepan-1-yl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 23 (R)-2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)-N-(2-(4- phenylpiperidin-1-yl)ethyl)aniline 24 (R)-3-(1-(2-((2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)phenyl)amino)ethyl)piperidin-4-yl)phenol 25 1-Methyl-4-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1,4- diazepan-5-one 26 4-methyl-1-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperazin-2- one 27 N-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(thiophen- 2-ylmethyl)piperidine-4-carboxamide 28 N-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-2-(4- phenylpiperidin-1-yl)acetamide 29 (S)-4-((4-(2-(3-(Methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperazin-1-yl)methyl)benzonitrile 30 (S)-3-(1-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperidin-4-yl)phenol 31 (R)-3-(1-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperidin-4-yl)phenol 32 (R)-3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 33 (S)-3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 34 4-((4-(2-(1-(3-fluorophenyl)-3- (methylamino)propoxy)benzyl)piperazin-1-yl)methyl)benzonitrile 35 3-((1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin- 4-yl)methyl)benzonitrile 36 (R)-N-methyl-3-(2-((4-(pyridin-3-yl)piperidin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 37 (R)-N-methyl-3-(2-((4-(pyridin-2-yl)piperidin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 38 (R)-4-((4-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperazin-1-yl)methyl)benzonitrile 39 1-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)-4- phenylpiperidine-4-carbonitrile 40 3-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenol 41 3-(1-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)phenethyl)piperidin-4-yl)phenol 42 N-methyl-3-(2-((4-phenylpiperidin-1-yl)methyl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 43 1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)-4- phenylpiperidin-4-ol 44 3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3-(thiophen- 2-yl)propan-1-amine 45 3-(4-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)phenethyl)piperazin-1-yl)phenol 46 N-methyl-3-(2-(2-(4-phenylpiperidin-1-yl)ethyl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 47 3-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin- 1-yl)phenol 48 N-methyl-3-(2-((4-phenylpiperazin-1-yl)methyl)phenoxy)-3-(thiophen- 2-yl)propan-1-amine 49 3-(2-((4-(3-methoxyphenyl)piperidin-1-yl)methyl)phenoxy)-N-methyl- 3-(thiophen-2-yl)propan-1-amine 50 N-methyl-3-(2-((4-phenethylpiperazin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 51 3-(2-((4-(4-methoxybenzyl)piperazin-1-yl)methyl)phenoxy)-N-methyl- 3-(thiophen-2-yl)propan-1-amine 52 3-(1-(2-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenol 53 4-((4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin- 1-yl)methyl)benzonitrile 54 3-(2-((4-(4-fluorobenzyl)piperazin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 55 N-methyl-3-(2-((4-(pyridin-4-yl)piperidin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 56 N-methyl-3-(2-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)phenoxy)- 3-(thiophen-2-yl)propan-1-amine 57 3-(2-((4-(2-isopropoxyethyl)piperazin-1-yl)methyl)phenoxy)-N-methyl- 3-(thiophen-2-yl)propan-1-amine 58 2-(4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin- 1-yl)-1-(piperidin-1-yl)ethanone 59 N-methyl-3-(2-((4-(pyridin-2-yl)piperidin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 60 3-(2-((4-isobutylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3-(thiophen- 2-yl)propan-1-amine 61 3-(2-((4-methoxy-4-phenylpiperidin-1-yl)methyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 62 (1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)-4- phenylpiperidin-4-yl)methanol 63 3-(2-((4-(methoxymethyl)-4-phenylpiperidin-1-yl)methyl)phenoxy)-N- methyl-3-(thiophen-2-yl)propan-1-amine 64 N-methyl-3-(2-((4-(pyridin-4-ylmethyl)piperidin-1-yl)methyl)phenoxy)- 3-(thiophen-2-yl)propan-1-amine 65 3-((4-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin- 1-yl)methyl)benzonitrile 66 4-((1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin- 4-yl)methyl)benzonitrile 67 4-(2-(4-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperazin-1-yl)ethyl)benzonitrile 68 3-(2-(4-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperazin-1-yl)ethyl)benzonitrile 69 N-methyl-3-(2-((4-(5-methyl-1,2,4-oxadiazol-3-yl)piperidin-1- yl)methyl)phenoxy)-3-(thiophen-2-yl)propan-1-amine 70 N-(3-(1-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperidin-4-yl)phenyl)methanesulfonamide 71 N-methyl-3-(2-((4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1- yl)methyl)phenoxy)-3-(thiophen-2-yl)propan-1-amine 72 N-(3-(1-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperidin-4-yl)phenyl)acetamide 73 4-(1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin-4- yl)phenol 74 N-methyl-3-(2-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 75 N-methyl-3-(2-((4-(pyridin-2-ylmethyl)piperazin-1-yl)methyl)phenoxy)- 3-(thiophen-2-yl)propan-1-amine 76 3-fluoro-4-((4-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperazin-1-yl)methyl)benzonitrile 77 3-(2-((4-(3,5-dichloropyridin-4-yl)piperazin-1-yl)methyl)phenoxy)-N- methyl-3-(thiophen-2-yl)propan-1-amine 78 4-((4-(2-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 79 4-((4-(2-(3-amino-1-(thiophen-2-yl)propoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 80 (R)-N-Methyl-3-(2-(2-morpholinoethyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 81 N-methyl-3-(2-((4-methyl-1,4-diazepan-1-yl)methyl)phenoxy)-3- phenylpropan-1-amine 82 N-(2-(3-(methylamino)-1-phenylpropoxy)benzyl)-1-phenethylpiperidin- 4-amine 83 3-(1-(2-(3-(methylamino)-1-phenylpropoxy)benzyl)piperidin-4- yl)phenol 84 3-(2-((4-benzylpiperazin-1-yl)methyl)phenoxy)-N-methyl-3- phenylpropan-1-amine 85 N-methyl-3-phenyl-3-(2-((4-phenylpiperazin-1- yl)methyl)phenoxy)propan-1-amine 86 N-methyl-3-phenyl-3-(2-((4-(pyridin-2-yl)piperazin-1- yl)methyl)phenoxy)propan-1-amine 87 4-((4-(2-(3-(methylamino)-1-phenylpropoxy)benzyl)piperazin-1- yl)methyl)benzonitrile 88 1-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenethyl)-4- phenylpiperidin-4-ol 89 (S)-N-methyl-3-(2-((4-(pyridin-2-yl)piperidin-1-yl)methyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 90 (R)-N-methyl-3-(2-(2-(4-(pyridin-2-yl)piperidin-1-yl)ethyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 91 (R)-N-methyl-3-(2-(2-(pyrrolidin-1-yl)ethyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 92 (R)-N-methyl-3-(2-(2-(4-methylpiperazin-1-yl)ethyl)phenoxy)-3- (thiophen-2-yl)propan-1-amine 93 (R)-3-(2-(4-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperazin-1-yl)ethyl)benzonitrile 94 (R)-N-(3-(1-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)benzyl)piperidin-4-yl)phenyl)methanesulfonamide 95 (R)-3-(2-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)phenoxy)-N-methyl-3- (thiophen-2-yl)propan-1-amine 96 (R)-N-ethyl-3-(2-(2-(pyrrolidin-1-yl)ethyl)phenoxy)-3-(thiophen-2- yl)propan-1-amine 97 3-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(4- phenethylpiperazin-1-yl)propan-1-one 98 2-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(4- phenethylpiperazin-1-yl)ethanone 99 1-(4-benzylpiperazin-1-yl)-2-(2-(3-(methylamino)-1-(thiophen-2- yl)propoxy)phenyl)ethanone 100 1-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-(2-(3-(methylamino)-1- (thiophen-2-yl)propoxy)phenyl)ethanone 101 2-(2-(3-(methylamino)-1-(thiophen-2-yl)propoxy)phenyl)-1-(4- methylpiperazin-1-yl)ethanone 102 (4-Methyl-1,4-diazepan-1-yl)(2-(3-(methylamino)-1- phenylpropoxy)phenyl)methanone 103 (2-(3-(methylamino)-1-phenylpropoxy)phenyl)(4-phenethylpiperazin- 1-yl)methanone 104 1-Methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidine-4- carboxamide 105 1-benzyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidine-4- carboxamide 106 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1- phenethylpiperidine-4-carboxamide 107 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1-(thiophen-2- ylmethyl)piperidine-4-carboxamide 108 2-(4-(3-Hydroxyphenyl)piperidin-1-yl)-N-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)acetamide 109 3-(4-(3-hydroxyphenyl)piperidin-1-yl)-N-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)propanamide 110 N-((1-Benzylpiperidin-4-yl)methyl)-2-(3-(methylamino)-1- phenylpropoxy)aniline 111 1-benzyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)piperidin-4- amine 112 4-((4-(2-(3-(Methylamino)-1-(thiophen-2-yl)propoxy)benzyl)piperidin- 1-yl)methyl)benzonitrile 113 N-Methyl-3-(2-(1-methylpiperidin-4-yl)phenoxy)-3-phenylpropan-1- amine 114 N-methyl-3-phenyl-3-(2-(piperidin-4-yl)phenoxy)propan-1-amine 115 3-(2-(1-Benzylpiperidin-4-yl)phenoxy)-N-methyl-3-phenylpropan-1- amine 116 N-methyl-3-(2-(1-phenethylpiperidin-4-yl)phenoxy)-3-phenylpropan-1- amine 117 N-Ethyl-2-(3-(methylamino)-1-phenylpropoxy)-N-(1- phenethylpiperidin-4-yl)benzamide 118 N-Methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1- phenethylpiperidin-4-amine 119 1-benzyl-N-methyl-N-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidin-4-amine 120 N-Methyl-3-phenyl-3-(2-((3S,5R)-3,4,5-trimethylpiperazin-1- yl)phenoxy)propan-1-amine 121 1-benzyl-N-methyl-N-(2-(3-(methylamino)-1- phenylpropoxy)phenyl)piperidine-4-carboxamide 122 N-methyl-N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-1- phenethylpiperidine-4-carboxamide 123 N-(2-(3-(Methylamino)-1-phenylpropoxy)benzyl)-N-(1- phenethylpiperidin-4-yl)propionamide 124 N-(2-(3-(methylamino)-1-phenylpropoxy)phenyl)-N-(1- phenethylpiperidin-4-yl)propionamide 125 (R)-3-(2-(2-((S)-4,6-dimethyl-1,4-diazepan-1-yl)ethyl)phenoxy)-N- methyl-3-(thiophen-2-yl)propan-1-amine 126 (R)-3-(2-(2-((R)-4,6-dimethyl-1,4-diazepan-1-yl)ethyl)phenoxy)-N- methyl-3-(thiophen-2-yl)propan-1-amine

11. Process for the preparation of compounds of Formula (I) as defined in any one of claims 1 to 10, a) wherein X represents a bond, and wherein R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ and n have the meanings as defined in the preceding claims, said process comprises treating a compound of formula (IIa),

wherein Q represents chloro, bromo, iodo or triflate, with a suitable N- containing cyclic reagent of formula (III-1)

under Buchwald-Hartwig conditions;

or

b) wherein -X- represents -[C(RaRb)]p-, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R_4’, Y₁, Y₂ and n and p have the meanings as defined in the preceding claims, said process comprises treating a compound of formula (IIb)

wherein r represents 0 to 4, with a N-containing cyclic reagent of formula (III- 1)

under standard reductive amination conditions;

or

c) wherein -X- represents -[C(RaRb)]p-, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2 and n and p have the meanings as defined in the preceding claims, said process comprises treating a compound of formula (IIa),

wherein M represents a suitable organometallic group, preferably a boron or zinc reagent, and p has the meaning as defined in the preceding claims;

or d) wherein -X- represents -[CR_aR_b]_pC(O)[CH₂]_q- and q is 0, and wherein R_a, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and q have the meanings as defined in the preceding claims, said process comprises treating a compound of formula (IIc’)

wherein with a N-containing cyclic reagent of formula (III-1)

under conventional amidation conditions;

or

e) wherein -X- represents -[CR_aR_b]_pN(R_z)C(O)[CH₂]_q-, and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ , n, p and q have the meanings as defined in the preceding claims, said process comprises treating a compound of formula (VI’)

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, p, q and Rz have the meanings as defined in the preceding claims, with a N-containing cyclic reagent of formula (III-1)

under conventional alkylation conditions;

or

f) wherein -X- represents -[CR_aR_b]_pN(R_z)C(O)[CH₂]_q-, and wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂, n, p and q have the meanings as defined in the preceding claims, said process comprises treating an amino compound of formula (IId’)

wherein p and Rz have the meanings as defined in the preceding claims, with an acyl reagent of formula (III-3),

under amidation conditions, wherein Z represents OH or halogen and q has the meaning as defined in the preceding claims; or g) wherein -X- represents -[CRaRb]pN(Rz)C(O)[CH2]q-, p is 0, and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2 , n, p and q have the meanings as defined in the preceding claims, said process comprises reacting a compound of formula (IIa)

under Ullmann arylation conditions, wherein q and Rz have the meanings as defined in the preceding claims;

or

h) wherein n is 0, and wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁ and Y₂ have the meanings as defined in the preceding claims, said process comprises reacting a compound of formula (VIIa) wherein G is OH,

with an alkylating agent of formula (VIII)

or

ii) wherein n is 0, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the preceding claims, said process comprises reacting a compound of formula (VIIa) wherein G is OH,

with an agent of formula (VIII) in the presence of an azo compound,

wherein Z represents OH; or

j) wherein n is 0, and wherein R1, R2, R3, R3’, R4, R4’, X, Y1 and Y2 have the meanings as defined in the preceding claims, said process comprises reacting a compound of formula (VIIa) wherein G is halogen,

with an agent of formula (VIII) in the presence of a strong base,

wherein Z represents OH;

or

k) wherein n is 1, and wherein R₁, R₂, R₃, R_3’, R₄, R_4’, X, Y₁ and Y₂ have the meanings as defined in the preceding claims, said process comprises reacting a compound of formula (VIIb)

with an agent of formula (VIII),

wherein either Z represents OH and G represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, or alternatively Z represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate and G represents OH; or l) wherein -X- represents -[CRaRb]pN(Rz)[CH2]q- and wherein Ra, Rb, R1, R2, R3, R_3’, R₄, R_4’, Y₁, Y₂, n, p and q have the meanings as defined in the preceding claims, said process comprises treating an amino compound of formula (IId’)

wherein p and Rz have the meanings as defined in the preceding claims, with an aldehyde of formula (III-6),

wherein q’ represents 0, 1, 2, 3 or 4; or m) wherein -X- represents -[CRaRb]pN(Rz)[CH2]q- and wherein Ra, Rb, R1, R2, R3, R3’, R4, R4’, Y1, Y2, n, p and q have the meanings as defined in the preceding claims, said process comprises treating an amino compound of formula (IId’)

wherein p and Rz have the meanings as defined in the preceding claims, with an alkylating agent of formula (III-7),

12. Use of the compounds of Formula II, IIa, IIa-LG, IIb, IIb’, IIb-LG, IIb’-LG, IIc, IIc’, IIc-LG, IIc’-LG, IId, IId’, IId-LG, IId’-LG, III-1, III-2, III-2’, III-3, III-4, III-5, III-6, III- 7, IV, IVa, IVb, IVb’, IVc, IVc’, IVd, IVd’, IVf, Vfg V, VI, VI’, VII, VIIa, VIIb, VIII-A, VIII-LG or IX,

,

,

,

wherein R_a, R_b, R₁, R₂, R₃, R_3’, R₄, R_4’, Y₁, Y₂ , n, p, q, q’, r and R_z have the meanings as defined in the preceding claims, Q represents chloro, bromo, iodo or triflate, LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, have the meanings as defined in the description, M represents a suitable organometallic group, Z represents OH or halogen, and G is OH, halogen or a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I) as defined in any one of claims 1 to 10.

13. A pharmaceutical composition which comprises a compound of Formula (I) as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

14. A compound of Formula (I) as defined in any one of claims 1 to 10 for use as a medicament.

15. A compound of Formula (I) as defined in any one of claims 1 to 10 for use as a medicament; preferably for use as a medicament for the treatment of pain, especially medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia.