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1. WO2020157026 - DÉRIVÉS HYDROXYLÉS DE COMPOSÉS DE 1-OXA-4,9-DIAZASPIRO-UNDÉCANE AYANT UNE ACTIVITÉ MULTIMODALE CONTRE LA DOULEUR

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

HYDROXYLATED DERIVATIVES OF 1-OXA-4,9-DIAZASPIRO UNDECANE COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN

FIELD OF THE INVENTION

The present invention relates to compounds having dual pharmacological activity towards both the sigma ( s) receptor, and the µ-opioid receptor (MOR or mu-opioid receptor) and more particularly to hydroxylated derivatives of 1-oxa-4,9-diazaspiro undecane compounds 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. Treatment of chronic non-cancer pain. Lancet 377, 2226-2235 (2011)]. Pain affects a big portion of the population with an estimated prevalence of around 20% and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which lead to important productivity losses and socio-economic burden [Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 11, 770 (2011)]. 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.

As mentioned before, there are few available therapeutic classes for the treatment of pain, and opioids are among the most effective, especially when addressing severe pain states. They act through three different types of opioid receptors (mu, kappa and gamma) which are transmembrane G-protein coupled receptors (GPCRs). Still, the main analgesic action is attributed to the activation of the µ-opioid receptor (MOR). However, the general administration of MOR agonists is limited due to their important side effects, such as constipation, respiratory depression, tolerance, emesis and physical dependence [Meldrum, M.L. (Ed.). Opioids and Pain Relief: A Historical

Perspective. Progress in Pain Research and Management, Vol 25. IASP Press, Seattle, 2003]. Additionally, MOR agonists are not optimal for the treatment of chronic pain as indicated by the diminished effectiveness of morphine against chronic pain conditions. This is especially proven for the chronic pain conditions of neuropathic or inflammatory origin, in comparison to its high potency against acute pain. The finding that chronic pain can lead to MOR down-regulation may offer a molecular basis for the relative lack of efficacy of morphine in long-term treatment settings [Dickenson, A.H., Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur J Pain 9, 113-6 (2005)]. Moreover, prolonged treatment with morphine may result in tolerance to its analgesic effects, most likely due to treatment-induced MOR down-regulation, internalization and other regulatory mechanisms. As a consequence, long-term treatment can result in substantial increases in dosing in order to maintain a clinically satisfactory pain relief, but the narrow therapeutic window of MOR agonists finally results in unacceptable side effects and poor patient compliance.

The sigma-1 ( s1) receptor was discovered 35 years ago and initially assigned to a new subtype of the opioid family, but later on and based on the studies of the enantiomers of SKF-10,047, its independent nature was established. The first link of the s1 receptor to analgesia was established by Chien and Pasternak [Chien CC, Pasternak GW. Sigma antagonists potentiate opioid analgesia in rats. Neurosci. Lett. 190, 137-9 (1995)], who described it as an endogenous anti-opioid system, based on the finding that s1 receptor agonists counteracted opioid receptor mediated analgesia, while s1 receptor antagonists, such as haloperidol, potentiated it.

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. Sigma 1 receptor: A new therapeutic target for pain. Eur. J. Pharmacol, 716, 78-93 (2013)]. 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 comorbidities (i.e., anhedonia, a core symptom in depression) related to pain states.

Pain is multimodal in nature, since in nearly all pain states several mediators, signalling pathways and molecular mechanisms are implicated. Consequently, monomodal therapies fail to provide complete pain relief. Currently, combining existing therapies is a common clinical practice and many efforts are directed to assess the best combination of available drugs in clinical studies [Mao J, Gold MS, Backonja M. Combination drug therapy for chronic pain: a call for more clinical studies. J. Pain 12, 157-166 (2011)]. Hence, there is an urgent need for innovative therapeutics to address this unmet medical need.

As mentioned previously, opioids are among the most potent analgesics but they are also responsible for various adverse effects which seriously limit their use.

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

Thus, the technical problem can therefore be formulated as finding compounds that have an alternative or improved pharmacological activity in 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 combining in a single compound binding to two different receptors relevant for the treatment of pain. This was mainly achieved by providing the compounds according to the invention that bind both to the µ-opioid receptor and to the s1 receptor.

SUMMARY OF THE INVENTION

The main object of the invention is in one aspect directed to hydroxylated derivatives of 1-oxa-4,9-diazaspiro undecane compounds having a dual activity binding to the s1 receptor and the µ-opioid 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 dual ligands of the s1 receptor and the µ-opioid receptor it is a very preferred embodiment if the compound has a binding expressed as Ki which is preferably < 1000 nM for both receptors, more preferably < 500 nM, even more preferably < 100 nM.

More particularly the main aspect of the invention refers to a compound of general Formula (I),


wherein R1, R2, R3 and R3’ 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 some 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

The invention is directed to a family of structurally distinct to hydroxylated derivatives of 1-oxa-4,9-diazaspiro undecane compounds which have a dual pharmacological activity towards both the sigma ( s) receptor and the µ-opioid receptor, thus solving the above problem of identifying alternative or improved pain treatments by offering such dual compounds.

The invention is directed to compounds having a dual activity binding to the s1 receptor and the µ-opioid 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 dual ligands of the s1 receptor and the µ-opioid receptor it is a preferred embodiment if the compound has a binding expressed as Ki which is preferably < 1000 nM for both receptors, more preferably < 500 nM, even more preferably < 100 nM.

The applicant has surprisingly found that the problem of providing a new effective and alternative for treating pain and pain related disorders can be solved by using a multimodal balanced analgesic approach combining two different synergistic activities in a single drug (i.e., dual ligands which are bifunctional and bind to µ-opioid receptor and to s1 receptor), thereby enhancing the opioid analgesia through the s1 activation without increasing the undesirable side effects. This supports the therapeutic value of a dual MOR/ ^ s1 receptor compound whereby the s1 receptor binding component acts as an intrinsic adjuvant of the MOR binding component.

This solution offered the advantage that the two mechanisms complement each other in order to treat pain and chronic pain using lower and better tolerated doses needed based on the potentiation of analgesia but avoiding the adverse events of µ-opioid receptor agonists.

A dual compound that possess binding to both the µ-opioid receptor and to the s1 receptor shows a highly valuable therapeutic potential by achieving an outstanding

analgesia (enhanced in respect to the potency of the opioid component alone) with a reduced side-effect profile (safety margin increased compared to that of the opioid component alone) versus existing opioid therapies.

Advantageously, the dual compounds according to the present invention would show one or more the following functionalities: s1 receptor antagonism and µ-opioid receptor agonism. It has to be noted, though, that both functionalities“antagonism” and “agonism” are also sub-divided in their effect into subfunctionalities like partial agonism or inverse agonism. Accordingly, the functionalities of the dual compound should be considered within a relatively broad bandwidth.

An antagonist on one of the named receptors blocks or dampens agonist-mediated responses. Known subfunctionalities are neutral antagonists or inverse agonists.

An agonist on one of the named receptors increases the activity of the receptor above its basal level. Known subfunctionalities are full agonists, or partial agonists.

In addition, the two mechanisms complement each other since MOR agonists are only marginally effective in the treatment of neuropathic pain, while s1 receptor antagonists show outstanding effects in preclinical neuropathic pain models. Thus, the s1 receptor component adds unique analgesic actions in opioid-resistant pain. Finally, the dual approach has clear advantages over MOR agonists in the treatment of chronic pain as lower and better tolerated doses would be needed based on the potentiation of analgesia but not of the adverse events of MOR agonists.

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):

wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3- 6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

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.

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 embodiments and uses of“salt” being thus equivalent to“pharmaceutically acceptable salt”.

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


wherein R1, R2, R3 and R3’ 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.

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

wherein R1, R2, R3 and R3’ 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.

For clarity purposes, all groups and definitions described in the description and referring to compounds of general Formula (I), also apply to compounds of general Formula (I’’) and (I’’), as well as to all the intermediates of synthesis, when those groups are present in the mentioned general Markush formulae, since compounds of general (I’) and (I’’) are included in the general Formula (I).

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, C1-2-alkyl represents C1- or C2-alkyl, C1-3-alkyl represents C1-, C2- or C3-alkyl, C1-4-alkyl represents C1-, C2-, C3- or C4-alkyl, C1-5-alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl, C1-6-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl, C1-7-alkyl represents C1-, C2-, C3-, C4- , C5-, C6- or C7-alkyl, C1-8-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8- alkyl, C1-10-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C1-18-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 C1-4alkyl 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 octyne; or is C2-6-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C2-4-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), -NRcRc’, -SRc, -S(O)Rc, -S(O)2Rc, -ORc, -C(O)ORc, -CN, -C(O)NRcRc’, haloalkyl, haloalkoxy or -OC1-6 alkyl, being Rc represented by R11’ R13, R31, R32, (being Rc’ represented by R11’, R13’, R31’, R32’,) wherein R1 to R32’ are as defined in the description, and wherein when different radicals R1 to R32’ 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, if substituted, is substituted with one or more of

halogen (F, Cl, Br, I), -ORc, -CN,–SRc,-S(O)Rc, -S(O)2Rc, haloalkyl, haloalkoxy, -NRcRc’, or -OC1-6alkyl, being Rc represented by R11’ R13, R31, R32, (being Rc’ represented by R11’, R13’, R31’, R32’), wherein R1 to R32’ are as defined in the description, and wherein when different radicals R1 to R32’ 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 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 haloalkyl is understood in the context of this invention as halogen-substituted -OC1-4-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, C3-4-cycloalkyl represents C3- or C4-cycloalkyl, C3-5-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, C4-7-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl represents C5- or C6-cycloalkyl and C5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantly. 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, indanyl, 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphthyl or anthracenyl, preferably is phenyl.

A heterocyclyl radical or group (also called heterocyclyl hereinafter) is understood as meaning 5 to 18 membered mono or poly 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.

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 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.

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 5 to 18 membered ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is an aromatic 5 to 18 membered mono or polycyclic 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, oxetane, especially is benzodioxane, morpholine, tetrahydropyran, piperidine, oxopyrrolidine, oxetane and pyrrolidine.

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 oxetane, oxazepane, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, 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, tetrahydropyran, pyrazole, imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane, oxetane and pyrrolidine.

In the context of this invention oxopyrrolidine is understood as meaning pyrrolidin-2-one.

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

In the context of this invention 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 (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 alkylheterocyclyl is understood as meaning a heterocyclyl group (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 (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 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), -Rc ,-ORc, -CN, -NO2 , -NRcRc’, -C(O)ORc, NRcC(O)Rc’ , -C(O)NRcRc’ , -NRcS(O)2Rc’ , =O, -OCH2CH2ORc, -NRcC(O)NRc’Rc’’, -S(O)2NRcRc’, -NRcS(O)2NRc’Rc’’, haloalkyl, haloalkoxy, -SRc, -S(O)Rc, -S(O)2Rc or -C(CH3)ORc; NRcRc’, with Rc, Rc’ and Rc’’ 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-C1-6-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted -C(O)-C1-6-alkyl-group; a saturated or unsaturated, linear or branched, substituted or unsubstituted -C(O)-O-C1-6-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 Rc one of R11’ R14, R21 or R31, R32, (being Rc’ one of R11’, R14’, R21’ or R31’ or R32’; being Rc’’ one of R14’’ or R21’’), wherein R1 to R32’ are as defined in the description, and wherein when different radicals R1 to R32’ 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 alkylaryl, alkylcycloalkyl or alkylheterocyclyl) with one or more of halogen (F, Cl, Br, I), -Rc ,-ORc, -CN , -NO2 , -NRcRc’’’ , NRcC(O)Rc’, -NRcS(O)2Rc’ , =O, haloalkyl, haloalkoxy, or -C(CH3)ORc; -OC1-4alkyl being unsubstituted or substituted with one or more of ORc or halogen (F, Cl, I, Br), -CN, or -C1-4alkyl being unsubstituted or substituted with one or more of ORc or halogen (F, Cl, I, Br), being Rc one of R11, R14, R21 or R31, R32’, (being Rc’ one of R11’, R14’, R21’ or R31’ or R32; being Rc’’ one of R14’’ or R21’’), wherein R1 to R32’ are as defined in the description, and wherein when different radicals R1 to R32’ are present simultaneously in Formula I they may be identical or different.

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 (leading to a spiro

structure) and/or 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 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“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.

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 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 an 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.

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 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 more particular embodiment the compound according to the invention of general Formula (I)

is a compound wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R11’ halogen, -SR11’ -CN, haloalkyl and -NR11R11’;

wherein the alkyl, alkenyl and alkynyl in R1, if substituted, they are substituted with one or more substituents selected from–OR11’ halogen and -CN;

wherein R11 and R11’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

wherein the aryl or heterocyclyl in R2, if substituted, it is substituted with one or more substituents selected from–R21, -OR21, halogen, =O, -OCH2CH2OH, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,–haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2NR21’R21’’;

and wherein R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the alkyl, alkenyl and alkynyl in R3, if substituted, they are substituted with one or more substituents selected from–OR31, halogen and–CN;

wherein the cycloalkyl in R3 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R31, halogen, -SR31, -CN, haloalkyl and–NR31R31’;

and wherein R31 and R31’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the alkyl, alkenyl and alkynyl in R3’, if substituted, they are substituted with one or more substituents selected from–OR32, halogen and–CN;

wherein the cycloalkyl in R3’ if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R32, halogen, -SR32, -CN, haloalkyl and–NR32R32’;

and wherein R32 and R32’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted, is substituted with one or more substituent/s selected from –OR13, halogen, -CN and -NR13R13’;

wherein R13 and R13’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C2-6 alkynyl;

the aryl, heterocyclyl or cycloalkyl, also in 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;

wherein R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl;

These preferred 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 preferred embodiment of the invention according to general Formula (I), the compound is a compound of Formula (I’)


wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 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.

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

wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3- 6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R11, halogen, -SR11, -CN, haloalkyl and -NR11R11’;

wherein the alkyl, alkenyl and alkynyl in R1, if substituted, they are substituted with one or more substituents selected from–OR11, halogen and -CN;

wherein R11 and R11’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

wherein the aryl or heterocyclyl in R2, if substituted, it is substituted with one or more substituents selected from–R21, -OR21, halogen, =O, -OCH2CH2OH, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,–haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2NR21’R21’’;

and wherein R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the alkyl, alkenyl and alkynyl in R3, if substituted, they are substituted with one or more substituents selected from–OR31, halogen and–CN;

wherein the cycloalkyl in R3 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R31, halogen, -SR31, -CN, haloalkyl and–NR31R31’;

and wherein R31 and R31’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the alkyl, alkenyl and alkynyl in R3’, if substituted, they are substituted with one or more substituents selected from–OR32, halogen and–CN;

wherein the cycloalkyl in R3’ if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R32, halogen, -SR32, -CN, haloalkyl and–NR32R32’;

and wherein R32 and R32’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted, is substituted with one or more substituent/s selected from –OR13, halogen, -CN and -NR13R13’;

wherein R13 and R13’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C2-6 alkynyl;

the aryl, heterocyclyl or cycloalkyl, also in 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;

wherein R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 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 another preferred embodiment of the invention according to general Formula (I), the compound is a compound of Formula (I’’)

wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3- 6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 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.

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


wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3- 6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R11’ halogen, -SR11’ -CN, haloalkyl and -NR11R11’;

wherein the alkyl, alkenyl and alkynyl in R1, if substituted, they are substituted with one or more substituents selected from–OR11’ halogen and -CN;

wherein R11 and R11’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

wherein the aryl or heterocyclyl in R2, if substituted, it is substituted with one or more substituents selected from–R21, -OR21, halogen, =O, -OCH2CH2OH, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,–haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2NR21’R21’’;

and wherein R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the alkyl, alkenyl and alkynyl in R3, if substituted, they are substituted with one or more substituents selected from–OR31, halogen and–CN;

wherein the cycloalkyl in R3 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R31, halogen, -SR31, -CN, haloalkyl and–NR31R31’;

and wherein R31 and R31’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein the alkyl, alkenyl and alkynyl in R3’, if substituted, they are substituted with one or more substituents selected from–OR32, halogen and–CN;

wherein the cycloalkyl in R3’ if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R32, halogen, -SR32, -CN, haloalkyl and–NR32R32’;

and wherein R32 and R32’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted, is substituted with one or more substituent/s selected from –OR13, halogen, -CN and -NR13R13’;

wherein R13 and R13’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C2-6 alkynyl;

the aryl, heterocyclyl or cycloalkyl, also in 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;

wherein R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 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 of the invention is a compound of general Formula (I) wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3- 6 cycloalkyl and substituted or unsubstituted C4-7 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.

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

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 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.

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

R1 is selected from substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 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.

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

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic 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 of the invention is a compound of general Formula (I) wherein

R2 is substituted or unsubstituted monocyclic aryl;

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 of the invention is a compound of general Formula (I) wherein

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 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.

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

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 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.

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

R3 is 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 of the invention is a compound of general Formula (I) wherein

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 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.

In a further embodiment of the invention is a compound of general Formula (I) wherein R3’ is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 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.

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

R11 and R11’ are independently selected from hydrogen, substituted or unsubstituted C1- 6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

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

R11 and R11’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 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.

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

R11 and R11’ 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 of the invention is a compound of general Formula (I) wherein

R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

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

R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 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.

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

R21 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 a further embodiment of the invention is a compound of general Formula (I) wherein

R31 and R31’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

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

R31 and R31’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 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.

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

R32 and R32’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

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

R32 and R32’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 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.

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

R13 and R13’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and 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 further embodiment of the invention is a compound of general Formula (I) wherein

R13 and R13’ are independently selected from hydrogen and 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 of the invention is a compound of general Formula (I) wherein

R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 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 of the invention is a compound of general Formula (I) wherein

R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 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 of the invention is a compound of general Formula (I) wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 cycloalkyl;

wherein the cycloalkyl in R1 if substituted, it is substituted with one or more substituents selected from–R11’ halogen, -SR11’ -CN, haloalkyl and -NR11R11’;

wherein the alkyl in R1, if substituted, they are substituted with one or more substituents selected from–OR11’ halogen and -CN;

wherein R11 and R11’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 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.

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

R2 is substituted or unsubstituted monocyclic aryl;

wherein the aryl in R2, if substituted, it is substituted with one or more substituents selected from–R21, -OR21, halogen, =O, -OCH2CH2OH, -SR21, -S(O)R21, - S(O)2R21, -CN, haloalkyl, –haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, - NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2N R21’R21’’;

and wherein R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

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

R3 is selected from substituted or unsubstituted C1-6 alkyl;

wherein the alkyl in R3, if substituted, it is substituted with one or more substituents selected from–OR31, halogen and–CN;

and wherein R31 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

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

R3’ is selected from hydrogen and substituted or unsubstituted C1-6 alkyl;

wherein the alkyl in R3’, if substituted, it is substituted with one or more substituents selected from–OR32, halogen and–CN;

and wherein R32 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

In a further embodiment of the invention is a compound of general Formula (I) wherein the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted, is substituted with one or more substituent/s selected from –OR13, halogen, -CN and -NR13R13’;

wherein R13 and R13’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and 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 further embodiment of the invention is a compound of general Formula (I) wherein

the aryl, heterocyclyl or cycloalkyl, also in 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;

wherein R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 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 of the invention is a compound of general Formula (I) wherein R1 is selected from substituted or unsubstituted C1-6 alkyl and substituted or unsubstituted C3-6 cycloalkyl; preferably is selected from a substituted or unsubstituted group selected from methyl, ethyl, isopropyl and cyclopropyl;

wherein the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R11’ halogen, -SR11’ -CN, haloalkyl and -NR11R11’; preferably with one or two substituents selected from–R11, halogen, -SR11, -CN, haloalkyl and -NR11R11’; more preferably with one or two–

wherein the alkyl in R1, if substituted, it is substituted with one or more substituents selected from selected from–OR11, halogen, and -CN; preferably with one or two substituents selected from–OR11, halogen, and -CN;wherein R11 and R11’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl and unsubstituted C3-6 cycloalkyl; preferably R11 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 a further embodiment of the invention is a compound of general Formula (I) wherein

R2 is substituted or unsubstituted monocyclic aryl; preferably is substituted or unsubstituted phenyl;

wherein the aryl in R2, if substituted, it is substituted with one or more substituents selected from–R21, -OR21, halogen, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,– haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, - C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2NR21’R21’’; preferably with one or two substituents selected from–R21, -OR21, halogen, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,–haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21

and -NR21S(O)2NR21’R21’’; more preferably with one or two–R21, or halogen, more preferably with one or two hydrogen or fluorine;

and wherein R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl; preferably R21 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 a further embodiment of the invention is a compound of general Formula (I) wherein

R3 is substituted or unsubstituted C1-6 alkyl; preferably is selected from a substituted or unsubstituted group selected from methyl and ethyl;

wherein the alkyl in R3, if substituted, it is substituted with one or more substituents selected from–OR31, halogen and -CN; preferably with one or two substituents selected from–OR31, halogen and -CN;

and wherein R31 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

In a further embodiment of the invention is a compound of general Formula (I) wherein R3’ is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; preferably is selected from hydrogen and substituted or unsubstituted methyl;

wherein the alkyl, alkenyl and alkynyl in R3’, if substituted, they are substituted with one or more substituents selected from–OR32, halogen and–CN; preferably substituted with one or two substituents selected from–OR32, halogen and–CN;

and wherein R32 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 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.

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

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted, is substituted with one or more substituent/s selected from –OR13, halogen, -CN and -NR13R13’; preferably the alkyl, alkenyl or alkynyl if substituted, it is substituted with one or two substituent/s selected from–OR13, halogen, -CN and -NR13R13’;

wherein R13 and R13’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and 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 further embodiment of the invention is a compound of general Formula (I) wherein the aryl, heterocyclyl or cycloalkyl, also in 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;preferably the aryl, heterocyclyl or cycloalkyl, if substituted, it is substituted with one or two 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;

wherein R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 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 of the invention is a compound of general Formula (I) wherein

the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R11, halogen, -SR11, -CN, haloalkyl and -NR11R11’; preferably with one or two substituents selected from–R11, halogen, -SR11, -CN, haloalkyl and -NR11R11’; more preferably with one or two–R11; preferably R11 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 a further embodiment of the invention is a compound of general Formula (I) wherein

the alkyl in R1, if substituted, it is substituted with one or more substituents selected from selected from–OR11’ halogen, and -CN; preferably with one or two substituents selected from–OR11’ halogen, 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 of the invention is a compound of general Formula (I) wherein

the aryl in R2, if substituted, it is substituted with one or more substituents selected from –R21, -OR21, halogen, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,–haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2NR21’R21’’; preferably with one or two substituents selected from–R21, -OR21, halogen, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,–haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2NR21’R21’’; more preferably with one or two–R21 or halogen, more preferably with one or two hydrogen or fluorine;

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 of the invention is a compound of general Formula (I) wherein

the alkyl in R3, if substituted, it is substituted with one or more substituents selected from–OR31, halogen and -CN; preferably with one or two substituents selected from– OR31, halogen 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 of the invention is a compound of general Formula (I) wherein

the alkyl, alkenyl and alkynyl in R3’, if substituted, they are substituted with one or more substituents selected from–OR32, halogen and–CN; preferably substituted with one or two substituents selected from–OR32, halogen 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 of the invention is a compound of general Formula (I) wherein

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted, is substituted with one or more substituent/s selected from –OR13, halogen, -CN and -NR13R13’; preferably the alkyl, alkenyl or alkynyl if substituted, it is substituted with one or two substituent/s selected from–OR13, halogen, -CN 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 of the invention is a compound of general Formula (I) wherein

the aryl, heterocyclyl or cycloalkyl, also in 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;preferably the aryl, heterocyclyl or cycloalkyl, if substituted, it is substituted with one or two 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 a further embodiment of the invention is a compound of general Formula (I) wherein

R1 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl , substituted or unsubstituted C2-6 alkynyl , substituted or unsubstituted C3- 6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein

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, ethyl 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; more preferably the cycloalkyl is cyclopropyl;

and/or

R2 is selected from substituted or unsubstituted monocyclic aryl and substituted or unsubstituted monocyclic heterocyclyl;

wherein

the aryl is selected from phenyl, naphtyl, 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 oxazepane, 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;

and/or

R3 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein

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 ethyl;

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;

and/or

R3’ 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 C3-6 cycloalkyl and substituted or unsubstituted C4-7 alkylcycloalkyl;

wherein

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;

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;

and/or

R11 and R11’ are independently selected from hydrogen, substituted or unsubstituted C1- 6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

wherein

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;

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;

and/or

R21, R21’ and R21’’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

wherein

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;

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;

and/or

R31 and R31’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

wherein

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;

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;

and/or

R32 and R32’ are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl and substituted or unsubstituted C3-6 cycloalkyl;

wherein

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;

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;

and/or

R13 and R13’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C2-6 alkynyl;

wherein

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;

and/or

the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

and/or

R14, R14’ and R14’’ are independently selected from hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl;

wherein

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;

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;

and/or

the aryl is selected from phenyl, naphtyl, 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 oxazepane, 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;

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 R1 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, ethyl 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; more preferably the cycloalkyl is cyclopropyl;

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 R2 as defined in any of the embodiments of the present invention,

the aryl is selected from phenyl, naphtyl, 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 oxazepane, 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;

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; more preferably the C1-6 alkyl is methyl or ethyl;

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; 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; 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;

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;

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 R11 and R11’ 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;

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;

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 R21, R21’ and R21’’ 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;

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; 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 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 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;

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;

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; 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 R13 and R13’ 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;

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 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;

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;

and/or

the aryl is selected from phenyl, naphtyl, 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 oxazepane, 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, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole,

benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, indoline-2-one and quinazoline;

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

R1 is a substituted or unsubstituted group selected from methyl, ethyl, isopropyl and cyclopropyl.

In a further embodiment

R2 is a substituted or unsubstituted phenyl.

In a further embodiment

R3 is a substituted or unsubstituted group selected from methyl and ethyl.

In a further embodiment

R3’ is hydrogen or substituted or unsubstituted methyl.

In a further embodiment

R3 is a substituted or unsubstituted group selected from methyl and ethyl, while R3’ is hydrogen or substituted or unsubstituted methyl.

In a further embodiment

R3 is a substituted or unsubstituted group selected from methyl and ethyl, while R3’ is hydrogen.

In a further embodiment

R3 is substituted or unsubstituted methyl, while R3’ is hydrogen.

In a further embodiment

R3 is substituted or unsubstituted ethyl, while R3’ is hydrogen.

In a further embodiment

R3 and R3’ are both substituted or unsubstituted methyl.

In a further embodiment

R11 is hydrogen.

In a further embodiment

R21 is hydrogen.

In a further embodiment

the alkyl, alkenyl and alkynyl in R1, if substituted, they are substituted with one or more substituents selected from–OR11, halogen and -CN; preferably the alkyl, alkenyl and alkynyl in R1 is unsubstituted alkyl, alkenyl and alkynyl.

In a further embodiment

the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R11, halogen, -SR11, -CN, haloalkyl and -NR11R11’; preferably the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is substituted with– R11; more preferably the cycloalkyl in R1 if substituted, also in alkylcycloalkyl, it is unsubstituted cycloalkyl or unsubstituted alkylcycloalkyl.

In a further embodiment

the aryl or heterocyclyl in R2, if substituted, it is substituted with one or more substituents selected from–R21, -OR21, halogen, =O, -OCH2CH2OH, -SR21, -S(O)R21, -S(O)2R21, -CN, haloalkyl,–haloalkoxy, -NR21R21’, -NO2, -NR21C(O)R21’, -NR21SO2R21’, -C(O)OR21, -C(O)NR21R21’, -NR21C(O)NR21’R21’’, -S(O)2NR21R21’ and -NR21S(O)2NR21’R21’’; preferably the aryl or heterocyclyl in R2, if substituted, it is substituted with one or more substituents selected from–R21 and halogen; more

preferably the aryl or heterocyclyl in R2, if substituted, it is substituted with one or more halogen; even more preferably the aryl or heterocyclyl in R2, if substituted, it is substituted with one or two halogen;

In a further embodiment

the alkyl, alkenyl and alkynyl in R3, if substituted, they are substituted with one or more substituents selected from–OR31, halogen and–CN; preferably the alkyl, alkenyl and alkynyl in R3 is unsubstituted alkyl, alkenyl and alkynyl.

In a further embodiment

the cycloalkyl in R3 if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R31, halogen, -SR31, -CN, haloalkyl and–NR31R31’; preferably the cycloalkyl in R3 unsubstituted cycloalkyl or unsubstituted alkylcycloalkyl .

In a further embodiment

the alkyl, alkenyl and alkynyl in R3’, if substituted, they are substituted with one or more substituents selected from–OR32, halogen and–CN; preferably the cycloalkyl in R3’ unsubstituted.

In a further embodiment

the cycloalkyl in R3’ if substituted, also in alkylcycloalkyl, it is substituted with one or more substituents selected from–R32, halogen, -SR32, -CN, haloalkyl and–NR32R32’; preferably the cycloalkyl in R3’ is unsubstituted.

In a further embodiment

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted, is substituted with one or more substituent/s selected from –OR13, halogen, -CN and -NR13R13’; preferably the alkyl, alkenyl or alkynyl, the substitution of which has not been defined otherwise, it is unsubstituted.

In a further embodiment

the aryl, heterocyclyl or cycloalkyl, also in 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; preferably the aryl, heterocyclyl or cycloalkyl, also in alkylcycloalkyl, the substitution of which has not been defined otherwise, it is unsubstituted.

In a further embodiment

the halogen is fluorine, chlorine, iodine or bromine; preferably fluorine.

In an embodiment of the compound according to the invention of general Formula (I),

the halogen is fluorine, chlorine, iodine or bromine;

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.

As this invention is aimed at providing a compound or a chemically related series of compounds which act as dual ligands of the s1 receptor and the µ-opioid receptor it is a very preferred embodiment in which the compounds are selected which act as dual ligands of the s1 receptor and the µ-opioid receptor and especially compounds which have a binding expressed as Ki which is preferably < 1000 nM for both receptors, more preferably < 500 nM, 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 Formulae (I), (I’) or (I’’).

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.

In general the processes are described below in the experimental part. The starting materials are commercially available or can be prepared by conventional methods.

As a further general remark, the use of“comprising” and“comprises” as used herein, especially when defining the steps of a process is to be understood as also disclosing “consisting of” and“consists of” respectively etc. Thus, this also includes that the steps of the respective process are then to be also understood to be limited to the steps preceded by this“comprising” or“comprises” etc.

A preferred aspect of the invention is also a process for the production of a compound according to formula I,


wherein R1, R2, R3 and R3’ are as already defined in the description.

A particular embodiment is a process for the preparation of a compound of general formula I, wherein R3’ is H and R1, R2 and R3 are as already defined in the

description, by reacting a compound of formula (VII)

with a Grignard reagent of formula (IX),


wherein T represents chloro, bromo or iodo, in an aprotic solvent such as tetrahydrofuran, and R1, R2 and R3 are as already defined in the description, at a suitable temperature, preferably at room temperature.

Another particular embodiment of the invention is a process for the preparation of a compound of general formula I wherein R1, R2, R3 and R3’ are as already defined in the description, by reaction of a compound of formula (X)


with a compound of formula (VIIIa) or (VIIIb),

,

wherein LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, and wherein R2 is as already defined in the description.

A particular embodiment is a process for the preparation of a compound of general formula I, wherein R3’ is different from H and R1, R2 and R3 are as already defined in the description, by reaction of a compound of general formula I, wherein R3’ is H and R1, R2 and R3 are as already defined in the description, with a compound of formula (XIa) or (XIb) wherein R3’ is different from H,

,

and wherein LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, under alkylation or etherification conditions.

A particular embodiment is a process for the preparation of a compound of general formula I, wherein R3’ is H, R3 is methyl, and R1 and R2 and are as already defined in the description, by hydration of an olefine compound of formula (XVI)

wherein R1 and R2 and are as already defined in the description, under acidic media, such as trifluoroacetic acid, in a suitable solvent such as dichloromethane.

A particular embodiment is a process for the preparation of a compound of general formula I,

a) wherein R3’ is H and R1, R2 and R3 are as already defined in the description, by reacting a compound of formula (VII)

with a Grignard reagent of formula (IX),

wherein T represents chloro, bromo or iodo, in an aprotic solvent such as

tetrahydrofuran, and R1, R2 and R3 are as already defined in the description, at a suitable temperature, preferably at room temperature;

or

b) wherein R1, R2, R3 and R3’ are as already defined in the description, by reaction of a compound of formula (X)

with a compound of formula (VIIIa) or (VIIIb),

wherein LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, and wherein R2 is as already defined in the description;

or

c) wherein R3’ is different from H and R1, R2 and R3 are as already defined in the description, by reaction of a compound of general formula I, wherein R3’ is H and R1, R2 and R3 are as already defined in the description, with a compound of formula (XIa) or (XIb) wherein R3’ is different from H,


and wherein LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, under alkylation or etherification conditions;

or

d) wherein R3’ is H, R3 is methyl, and R1 and R2 and are as already defined in the description, by hydration of an olefin compound of formula (XVI)

wherein R1 and R2 and are as already defined in the description, under acidic media, such as trifluoroacetic acid, in a suitable solvent such as dichloromethane.

A particular embodiment there is the use of a compound of Formula (Ia)

,

wherein R1, R2 and R3 are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (Ib)

,

wherein R1, R2, R3 and R3’ are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (Ic)

,

wherein R1 and R2 are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (II)

,

wherein R2 is as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (IIP)

,

wherein P represents a suitable protecting group, preferably Boc, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (III)

,

wherein R2 is as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (IIIP)

,

wherein P represents a suitable protecting group, preferably Boc, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (IV)


wherein R1 is as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (V)

,

wherein R1 and R2 are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (VP)

,

wherein R1 is as already defined in the description and P represents a suitable protecting group, preferably Boc, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (VI)


,

wherein Z represents alkoxy or a leaving group such as chloro or bromo, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (VII)

,

wherein R1 and R2 are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (VIIP)


,

wherein R1 is as already defined in the description and P represents a suitable protecting group, preferably Boc, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (VIIH)

,

wherein R1 is as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (VIIIa)

wherein R2 is as already defined in the description and LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (VIIIb)

wherein R2 is as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (IX)

wherein R3 is as already defined in the description and T represents chloro, bromo or iodo, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (X)

wherein R1, R3 and R3’ are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XP)

,

wherein R1 and R3 are as already defined in the description and P represents a suitable protecting group, preferably Boc, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XH)

,

wherein R1 and R3 are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XIa),


wherein R3’ is as already defined in the description and LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XIb),

wherein R3’ is as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XIIP)

wherein R1, R3 and R3’ are as already defined in the description and P represents a suitable protecting group, preferably Boc, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XIIH)

,

wherein R1, R3 and R3’ are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XIII)

wherein W represents a leaving group such as chloro or bromo, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate and Q represents methyl or benzyl, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XIV)

,

wherein R1 and R2 are as already defined in the description, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate and Q represents methyl or benzyl, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XIVP)

,

wherein R1 is as already defined in the description, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, P represents a suitable protecting group, preferably Boc and Q represents methyl or benzyl, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XV)

,

wherein R1 and R2 are as already defined in the description and Q represents methyl or benzyl, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XVP)

,

wherein R1 is as already defined in the description, P represents a suitable protecting group, preferably Boc and Q represents methyl or benzyl, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XVI)

,

wherein R1 and R2 are as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XVIP)

,

wherein R1 is as already defined in the description and P represents a suitable protecting group, preferably Boc, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (XbH)

,

wherein R1 is as already defined in the description, for the preparation of a compound of Formula (I).

A particular embodiment there is the use of a compound of Formula (Ia), (Ib), (Ic), (II), (IIP), (III), (IIIP), (IV), (V), (VP), (VI), (VII), (VIIP), (VIIH), (VIIIa), (VIIIb), (IX), (X), (XP), (XH), (XIa), (XIb), (XIIH), (XIIP), (XIII), (XIV), (XIVP), (XV), (XVP), (XVI), (XVIP) or (XbH)

wherein R1, R2, R3 and R3’ are as already defined in the description, P represents a suitable protecting group, preferably Boc, Z represents alkoxy or a leaving group such as chloro or bromo, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, W represents a leaving group such as chloro or bromo, and Q represents methyl or benzyl, for the preparation of a compound 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 formulas I, I’, or 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.

As a general remark, the use of “comprising” and“comprises” as used herein, especially when defining the contents of a medicament or a pharmaceutical formulation is to be understood as also disclosing“consisting of” and“consists of” respectively etc. Thus, this also includes that the contents of the respective medicament or pharmaceutical formulation are then to be also understood to be limited to the exact contents preceded by this“comprising” or“comprises” etc.

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, gelatine, 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 appropriate unit

dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.

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

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

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

Another aspect of the invention refers to 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 a compound of the invention according as described above according to general formulas I, I’, or 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 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 present invention.

General Experimental Part (Methods and Equipment of the synthesis and analysis)

Two different general methods have been developed for obtaining the compounds of the invention, as described below in Schemes 1 and 2.

A 4 to 5 step process is described in Scheme 1 for the preparation of compounds of general formula (I).

wherein R1, R2, R3 and R3’ have the meanings as defined above for a compound of formula (I), Z represents alkoxy or a leaving group such as chloro or bromo, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, T represents chloro, bromo or iodo and P represents a suitable protecting group (preferably Boc).

The 4 to 5 step-process is carried out as described below:

Step 1: A compound of formula (III) is prepared by treating a compound of formula (II) with a suitable methyl-transfer reagent such as trimethylsulfoxonium iodide or trimethylsulfonium iodide, in a suitable aprotic solvent such as dimethylsulfoxide or 1,2-dimethoxyethane, and in the presence of a strong base such as sodium hydride or potassium tert-butoxide, at a suitable temperature, preferably comprised between 0 ºC and 60 ºC.

Alternatively, the preparation of a compound of formula (III) from a compound of formula (II) can be carried out in 2 steps by performing a Wittig olefination followed by epoxidation of the resulting olefin, using conventional procedures described in the literature. As a way of example, the Wittig reaction is carried out by treating a compound of formula (II) with methylenetriphenylphosphorane (prepared in situ from methyltriphenylphosphonium bromide and a strong base such as butyllithium), in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, preferably comprised between -78 ºC and room temperature; and the epoxidation reaction is carried out by treating the olefin obtained in the Wittig reaction with a suitable oxidizing agent, such as hydrogen peroxide or an alkyl hydroperoxide in the presence of a metal catalyst, or preferably using a peroxyacid such as meta-chloroperoxybenzoic acid in a suitable solvent such as dichloromethane or chloroform.

Step 2: A compound of formula (V) is prepared by reacting a compound of formula (III) with an amine of formula (IV), in a suitable solvent such as an alcohol, preferably ethanol-water mixtures, at a suitable temperature comprised between room temperature and the reflux temperature, preferably at room temperature.

Step 3: A compound of formula (VII) is prepared by reacting a compound of formula (V) with an acylating agent of formula (VI). When Z is a leaving group such as chloro or

bromo, the reaction is carried out in a suitable solvent, such as dichloromethane or tetrahydrofuran; in the presence of an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as K2CO3; and at a suitable temperature, preferably comprised between 0 ºC and room temperature. Alternatively, when Z is alkoxy, the reaction is carried out in a suitable solvent, such as ethanol, at a suitable temperature, preferably heating.

Step 4: A compound of formula (Ia), where R3’ is H, is prepared by reacting a compound of formula (VII) with a Grignard reagent of formula (IX), in an aprotic solvent such as tetrahydrofuran, at a suitable temperature, preferably at room temperature.

Step 5: Finally, a compound of formula (Ib), where R3’ is different from H, or its precursor of formula (XIIP) can be prepared from a compound of formula (Ia) or its precursor of formula (XP), respectively, by reaction with a compound of formula (XIa) or (XIb) under alkylation or etherification conditions. The reaction with an alkylating agent of formula (XIa), preferably an alkyl halide or dialkyl sulfate, is carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide, in the presence of a strong base such as NaH, at a suitable temperature, preferably at room temperature. The etherification reaction between a hydroxy compound of formula (Ia) and an alcohol of formula (XIb) can be carried out in the presence of a strong acid such as HCl, in a suitable solvent, preferably using alcohol (XIb) as reagent and solvent. Alternatively, the group (CH2)2R2 can be incorporated in the last step of the synthesis by reaction of a compound of formula (XH) or (XIIH) with a compound of formula (VIIIa) or (VIIIb), as shown in Scheme 1. A compound of formula (XH) or (XIIH) is obtained by deprotection of a compound of formula (XP) or (XIIP), respectively, wherein P represents a suitable protecting group, preferably Boc (tert-butoxycarbonyl). When the protecting group is Boc, the deprotection can be conducted by adding a solution of an acid such as HCl, in a suitable solvent such as diethyl ether or 1,4-dioxane, or preferably with trifluoroacetic acid in dichloromethane. A compound of formula (XP) is prepared from a compound of formula (IIP) following the same sequence described for the synthesis of compounds of formula (Ia).

The alkylation reaction between a compound of formula (XH) or (XIIH) (or a suitable salt such as trifluoroacetate or hydrochloride) and a compound of formula (VIIIa) is carried out in a suitable solvent, such as acetonitrile, dichloromethane, 1,4-dioxane or dimethylformamide, preferably in acetonitrile; in the presence of an inorganic base such as K2CO3 or Cs2CO3, or an organic base such as triethylamine or diisopropylethylamine, preferably K2CO3; 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. Additionally, an activating agent such as NaI can be used.

The reductive amination reaction between a compound of formula (XH) or (XIIH) and a compound of formula (VIIIb) is carried out in the presence of a reductive reagent, preferably sodium triacetoxyborohydride, in a suitable solvent, preferably tetrahydrofuran, dichloroethane or dichloromethane, optionally in the presence of an acid such as acetic acid or a base such as triethylamine.

The compounds of general formula (I) wherein R3 is methyl and R3’ is hydrogen (compounds of formula Ic) can be alternatively prepared starting from a compound of formula (V), as described in Scheme 2:

Scheme 2

wherein R1 and R2 have the meanings as defined above for a compound of formula (I), W represents a leaving group such as chloro or bromo, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, P represents a suitable protecting group (preferably Boc), and Q represents methyl or benzyl.

A compound of formula (XIV) is prepared by reacting a compound of formula (V) with an acylating agent of formula (XIII). The acylation reaction is carried out in a suitable solvent, such as dichloromethane or tetrahydrofuran; in the presence of an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as K2CO3; and at a suitable temperature, preferably comprised between -10 ºC and room temperature.

In turn, a compound of formula (XIV) is converted into a compound of formula (XV) by intramolecular cyclization, followed by an elimination reaction to render a compound of formula (XVI). The cyclization reaction is carried out in a suitable solvent, such as tetrahydrofuran; in the presence of a strong base such as potassium tert-butoxide or sodium hydride; and at a suitable temperature, comprised between -78 ºC and room temperature, preferably cooling. The elimination reaction is carried out under similar reaction conditions, in the presence of a base, such as potassium tert-butoxide, in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, preferably at room temperature. Alternatively, the cyclization and elimination reactions can be carried out in a“one-pot” manner, by treating a compound of formula (XIV) with potassium tert-butoxide, initially at -78 ºC and then warming-up to room temperature.

Finally, a compound of formula (Ic) is obtained by hydration of an olefin compound of formula (XVI) under acidic media, such as trifluoroacetic acid, in a suitable solvent such as dichloromethane.

Alternatively, the group (CH2)2R2 can be incorporated in the last step of the synthesis by reaction of a precursor compound of formula (XbH) with a compound of formula (VIIIa) or (VIIIb), as shown in Scheme 2, under the reaction conditions described above in Scheme 1. A compound of formula (XbH) is obtained by simultaneous deprotection and hydration of an olefin compound of formula (XVIP), wherein P represents a suitable protecting group, preferably Boc (tert-butoxycarbonyl). The reaction is carried out under the same conditions described for the preparation of a compound of formula (Ic) from a compound of formula (XVI). In turn, a compound of formula (XVIP) is prepared from a compound of formula (VP) following the same sequence described in Scheme 2 for the synthesis of compounds of formula (Ic).

The compounds of general formula (II), (IIP), (IV), (VI), (VIIIa), (VIIIb), (IX), (XIa), (XIb) and (XIII) 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 demethylation of a methoxy group to yield an hydroxy group, the reduction of a nitro group to yield an amino group, the acylation of an amino group to yield an acylamino group, the conversion of an amino group into an ureido group and the conversion of an ester to an amide.

Examples

The following abbreviations are used in the examples:

ACN: acetonitrile

aq.: aqueous

Boc: tert-butoxycarbonyl

DCM: dichloromethane

DMSO: dimethylsulfoxide

EtOAc: ethyl acetate

EtOH: ethanol

EX: example

h: hour/s

HPLC: high performance liquid chromatography

INT: intermediate

MS: mass spectrometry

Min.: minutes

Quant: quantitative

Ret.: retention

r.t.: room temperature

Sat: saturated

Sol.: solution

TEA: triethylamine

TFA: TFA

THF: tetrahydrofuran

Wt: weight

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

Method A

Column: Xbridge C18 XP 30 x 4.6 mm, 2.5um

Temperature:40ºC

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 aprox.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)---1min---(0:100)

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

Synthesis of Intermediates

INT 1: tert-Butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate.


To a suspension of trimethylsulfoxonium iodide (24.3 g, 110 mmol) and NaH (4.4 g, 60 wt% in mineral oil, 110 mmol) in DMSO (140 mL), a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100 mmol) in DMSO (140 mL) was added dropwise. The reaction mixture was stirred at r.t. for 30 min and then heated at 50 ºC for 1 h. After cooling to r.t., ice was slowly added, and the reaction mixture was extracted three times with EtOAc. The organic phases were combined, washed with water, dried over MgSO4 and concentrated under vacuum to give the title compound (17.6 g, 82% yield) as a white solid.

INT 2A: tert-Butyl 4-hydroxy-4-((methylamino)methyl)piperidine-1-carboxylate.


To a solution of INT 1 (0.50 g, 2.34 mmol) in a mixture of EtOH-water 5.5:1 v/v (14 mL), methylamine (4.1 mL, 40 wt% solution in water, 47 mmol) was added. The reaction mixture was stirred at r.t. overnight in a sealed tube. The solvent was removed under vacuum to give the title compound (0.534 g, 93% yield) as a white solid.

This method was used for the preparation of INT 2B-2D using suitable starting materials:

INT 3A: tert-Butyl 4-ethyl-2,3-dioxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate.

To a solution of INT 2B (1.0 g, 3.87 mmol) in EtOH (50 mL), cooled at 0 ºC, a solution of diethyl oxalate (1.57 mL, 11.6 mmol) in EtOH (10 mL) was added dropwise and the mixture was heated to reflux for 72 h. The solvent was concentrated to dryness and the residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (0.402 g, 33% yield).

INT 3B: tert-Butyl 4-cyclopropyl-2,3-dioxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate.

To a solution of INT 2D (0.5 g, 1.85 mmol) and 4-dimethylaminopyridine (11 mg, 0.092 mmol) in DCM (20 mL), cooled at 0 ºC, TEA (0.77 mL, 5.55 mmol) was added. After stirring for 10 min at 0 ºC, oxalyl chloride (0.25 mL, 2.2 mmol) was added dropwise. The reaction mixture was stirred at 0 ºC for 1 h and then at r.t. for 48 h. Cold water was added, the phases were separated and the aq. phase was extracted with DCM. The combined organic phases were washed with 1 M HCl aq. sol., dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient gradient DCM to MeOH:DCM (1:4) to give the title compound (0.263 g, 44% yield).

Synthesis of Examples.

Example 1: 2-Hydroxy-2,4-dimethyl-9-phenethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.

Step 1. tert-Butyl 4-((2-chloro-3-methoxy-N-methylpropanamido)methyl)-4-hydroxypiperidine-1-carboxylate. To a solution of INT 2A (2 g, 8.19 mmol) in a mixture of THF (101 mL) and TEA (5.7 mL, 40.9 mmol), cooled at 0 ºC, a solution of 2-chloro-3-methoxypropanoyl chloride (1.93 g, 12.3 mmol) in THF (5.9 mL) was added, and the reaction mixture was stirred at r.t. for 1 h. Then, NaHCO3 sat. sol. and EtOAc were added, the phases were separated and the aq. phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give the title compound (3.12 g, overweight, quant. yield assumed) as a crude product that was used in the next step without further purification.

Step 2. tert-Butyl 2-(methoxymethyl)-4-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. To a solution of the product obtained in Step 1 (2.9 g, 8.18 mmol) in dry THF (15 mL), cooled at -78 ºC under a N2 atmosphere, potassium tert-butoxide solution (1 M in THF, 9.8 mL, 9.8 mmol) was added dropwise and the reaction mixture was stirred at -78 ºC for 30 min. Then, NaHCO3 sat. sol. was added, 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 under vacuum. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (1.69 g, 63% yield).

Step 3. tert-Butyl 4-methyl-2-methylene-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. Potassium tert-butoxide solution (1 M in THF, 3.34 mL, 3.34 mmol) was added to a solution of the product obtained in Step 2 (0.519 g, 1.58 mmol) in dry THF (23 mL), previously cooled at -78 ºC. Then, the reaction mixture was stirred at r.t for 2 h. NaHCO3 sat. sol. was added and the aq. phase was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated under

vacuum. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (139 mg, 29% yield).

Step 4. 2-Hydroxy-2,4-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, trifluoroacetate salt. To a solution of the product obtained in Step 3 (139 mg, 0.47 mmol) in DCM (6.6 mL), TFA (0.36 mL, 4.7 mmol) was added and the reaction mixture was stirred at r.t for 3 h. The solvent was evaporated to dryness to give the title compound as a crude product (impurified with Boc-deprotected Step 3) that was used in the following step without further purification.

Step 5. Title compound. A mixture of the crude product obtained in Step 4, (2-bromoethyl)benzene (0.076 mL, 0.56 mmol), K2CO3 (0.324 g, 2.34 mmol) in ACN (3.9 mL) was heated at 80 ºC overnight in a sealed tube. Water and EtOAc were added, the phases were separated and the aq. phase was again extracted with EtOAc. The organic phases were combined, 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 give the title compound (23 mg, 15% combined yield for Steps 4 and 5).

HPLC retention time (method A): 2.72 min; MS: 319.2 (M+H).

Example 2: 9-(3-Fluorophenethyl)-2-hydroxy-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.


Step 1. tert-Butyl 4-((3-(benzyloxy)-2-bromo-N-isopropylpropanamido)methyl)-4-hydroxypiperidine-1-carboxylate. To a solution of INT 2C (4.0 g, 14.7 mmol) in a mixture of DCM (163 mL) and TEA (4.91 mL, 35.2 mmol), cooled at 0 ºC, a solution of 3-(benzyloxy)-2-bromopropanoyl chloride (6.11 g, 22.03 mmol) in DCM (163 mL) was added, and the reaction mixture was stirred at 0 ºC for 2 h. Then, NaHCO3 sat. sol. was added and it was extracted with DCM. The combined organic extracts were washed

with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (6.06 g, 80% yield).

Step 2. tert-Butyl 4-isopropyl-2-methylene-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. To a solution of the product obtained in Step 1 (6.06 g, 11.8 mmol) in dry THF (197 mL), cooled to -78 ºC, potassium tert-butoxide solution (1 M in THF, 13 mL, 13 mmol) was added and the reaction mixture was stirred at -78 ºC for 30 min and then at -30 ºC for 30 min. Additional potassium tert-butoxide solution (1 M in THF, 13 mL, 13 mmol) was added and the reaction mixture was stirred at r.t. overnight. NH4Cl sat. sol. was added and the aq. phase was extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (2.5 g, 65% yield).

Step 3. 2-Hydroxy-4-isopropyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, trifluoroacetate salt. Following the experimental procedure described in Step 4 of Example 1, starting from the product obtained in Step 2 (0.2 g, 0.62 mmol), the title compound was obtained.

Step 4. Title compound. Following the experimental procedure described in Step 5 of Example 1, starting from the product obtained in Step 4 and a suitable alkylating agent, the title compound was obtained (127 mg, 57% combined yield for Steps 3 and 4).

HPLC retention time (method A): 3.46 min; MS: 365.2 (M+H).

Example 3. 4-Ethyl-9-(3-fluorophenethyl)-2-hydroxy-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.

Step 1. tert-Butyl 4-ethyl-2-hydroxy-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. To a solution of INT 3A (1.5 g, 4.8 mmol) in dry THF (0.7 mL), methylmagnesium bromide solution (3.4 M in THF, 2.1 mL, 7.2 mmol) was added dropwise and the reaction mixture was stirred at r.t. for 1 h. Then, NH4Cl sat. sol. was added and the aq. phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, filtered and concentrated to dryness to give the title compound (1.61 g, quant. yield), as a crude product that was used in the next step without further purification.

Step 2. 4-Ethyl-2-hydroxy-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, trifluoroacetate salt. Following the experimental procedure described in Step 4 of Example 1, starting from the product obtained in Step 1 (0.5 g, 1.52 mmol), the title compound was obtained (918 mg, overweight, quant. yield assumed).

Step 3. Title compound. Following the experimental procedure described in Step 5 of Example 1, starting from the product obtained in Step 2 (0.76 mmol) and a suitable alkylating agent, the title compound was obtained (115 mg, 43% yield).

HPLC retention time (method B): 3.63 min; MS: 351.1 (M+H).

This method was used for the preparation of examples 4-6 using suitable starting materials:



Example 7: 9-(2,5-Difluorophenethyl)-2,4-diethyl-2-hydroxy-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.

Step 1. 4-Ethyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,3-dione, trifluoroacetate salt. Following the experimental procedure described in Step 4 of Example 1, starting from INT 3A (0.4 g, 1.3 mmol), the title compound was obtained (774 mg, overweight, quant. yield assumed).

Step 2. 9-(2,5-Difluorophenethyl)-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,3-dione. Following the experimental procedure described in Step 5 of Example 1, starting from the product obtained in Step 1 (1.18 mmol) and a suitable alkylating agent, the title compound was obtained (26 mg, 6% yield).

Step 3. Title compound. Following the experimental procedure described in Step 1 of Example 3, starting from the product obtained in Step 2 (26 mg, 0.07 mmol) and ethylmagnesium bromide, the title compound was obtained (8.7 mg, 31% yield).

HPLC retention time (method B): 4.23 min; MS: 383.1 (M+H).

Example 8: 9-(2,5-Difluorophenethyl)-4-ethyl-2-methoxy-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.

Step 1. tert-Butyl 4-ethyl-2-methoxy-2-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. To a solution of the product obtained in Step 1 of Example 3 (100 mg, 0.304 mmol) in dry THF (5 mL), NaH (18 mg, 60 wt% in mineral oil, 0.46 mmol) was added and the reaction mixture was stirred at r.t. for 30 min. Then, iodomethane (0.028 mL, 0.46 mmol) was added and the reaction mixture was stirred at r.t. overnight. Water was added and it was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford the title compound (84 mg, 80% yield).

Step 2. 4-Ethyl-2-methoxy-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, trifluoroacetate salt. Following the experimental procedure described in Step 4 of Example 1, starting from the product obtained in Step 1 (84 mg, 0.24 mmol), the title compound was obtained (quant. yield assumed).

Step 3. Title compound. Following the experimental procedure described in Step 5 of Example 1, starting from the product obtained in Step 2 and a suitable alkylating agent, the title compound was obtained (7.9 mg, 15% yield).

HPLC retention time (method B): 4.59 min; MS: 383.1 (M+H).

Table of Examples with binding to the µ-opioid Receptor and the ^ s1 -Receptor:

BIOLOGICAL ACTIVITY

Pharmacological study

Human s1 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.

Human m-opioid receptor radioligand assay

Transfected CHO-K1 cell membranes (20 mg) were incubated with 1 nM of [3H]-DAMGO in assay buffer containing Tris-HCl 50 mM, MgCl25 mM at pH 7.4. NBS (non-specific binding) was measured by adding 10 mM Naloxone. The binding of the test compound was measured at five different concentrations. Plates were incubated at 27 °C for 60 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 (pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail.

Results:

As this invention is aimed at providing a compound or a chemically related series of compounds which act as dual ligands of the s1 receptor and the µ-opioid receptor it is a very preferred embodiment in which the compounds are selected which act as dual ligands of the s1 receptor and the µ-opioid receptor and especially compounds which have a binding expressed as Ki which is preferably < 1000 nM for both receptors, more preferably < 500 nM, even more preferably < 100 nM.

The following scale has been adopted for representing the binding to the the s1 receptor and the µ-opioid receptor expressed as Ki:

+ Both Ki-µ and Ki- s1 >= 500 nM

++ One Ki <500 nM while the other Ki is >=500 nM

+++ Both Ki-µ and Ki- s1 < 500 nM

All compounds prepared in the present application exhibit binding to the s1 receptor and the µ-opioid receptor, in particular the following binding results are shown: