WO2020089263A1

WO2020089263A1 - Optionally nitrogenated isoquinolin-1(2h)-ones and 1h-isochromen- 1-ones for treating pain and pain related conditions

Info

Publication number: WO2020089263A1
Application number: PCT/EP2019/079588
Authority: WO
Inventors: Carmen ALMANSA-ROSALES; Antonio-David RODRIGUEZ-GARRIDO; Ramon Merce-Vidal; Ute Christmann
Original assignee: Esteve Pharmaceuticals, S.A.
Priority date: 2018-10-31
Filing date: 2019-10-30
Publication date: 2020-05-07

Abstract

The present invention relates to new compounds that show pharmacological activity towards the subunit α28 of voltage-gated calcium channels (VGCC), especially the α28 1 subunit of voltage-gated calcium channels or dual activity towards the subunit α28 of voltage-gated calcium channels (VGCC), especially the α28-1 subunit of voltage-gated calcium channels, and the μ-opiod receptor (MOR or mu-opioid). The invention is also related to the process for the preparation of said compounds as well as to compositions comprising them, and to their use as medicaments.

Description

OPTIONALLY NITROGENATED ISOQUINOLIN-1 (2H)-ONES AND 1 H-ISOCHROMEN- 1 -ONES FOR TREATING PAIN AND

PAIN RELATED CONDITIONS

FIELD OF THE INVENTION

5 The present invention relates to new compounds that show pharmacological activity

towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d- 1 subunit of voltage-gated calcium channels.

More particularly, the present invention relates to optionally nitrogenated isoquinolin- 1 (2/-/)-ones and 1 /-/-isochromen-1-ones having this pharmacological activity, to

10 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

15 available treatments provide in many cases only modest improvements, leaving many

patients unrelieved (Turk, D.C., Wilson, H.D., Cahana, A.; 201 1 ; Lancet ; 377; 2226- 2235). Pain affects a big portion of the population with an estimated prevalence of 20 %

and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as

20 depression, anxiety and insomnia, which lead to important productivity losses and socio- economical burden (Goldberg, D.S., McGee, S.J.; 201 1 ; BMC Public Health ; 1 1 ; 770).

Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of

25 secondary effects that preclude their use, especially in chronic settings.

Voltage-gated calcium channels (VGCC) are required for many key functions in the body.

Different subtypes of voltage-gated calcium channels have been described (Zamponi et al., Pharmacol. Rev. 2015 67:821-70). The VGCC are assembled through interactions of different subunits, namely oti (Ca_vai), b (Ca_vp) a₂d (Ca_va₂6) and g (Ca_vy). The oti

30 subunits are the key porous forming units of the channel complex, being responsible for

the Ca²⁺ conduction and generation of Ca²⁺ influx. The a₂d, b, and g subunits are auxiliary, although very important for the regulation of the channel, since they increase the expression of the oti subunits in the plasma membrane as well as modulate their function, resulting in functional diversity in different cell types. Based on their

35 physiological and pharmacological properties, VGCC can be subdivided into low voltage- activated T-type (Ca_v3.1 , Ca_v3.2, and Ca_v3.3), and high voltage-activated L- (Ca_v1.1 through Ca_v1 .4), N-(Ca_v2.2), P/Q-(Ca_v2.1 ), and R-(Ca_v2.3) types, depending on the channel forming Cava subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1 ) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo, Neurotherapeutics. 2009 6:679-92; Zamponi et al., 2015 supra ; Neumaier et al., Prog. Neurobiol. 2015 129:1 -36.). A large body of data has clearly indicated that VGCC are implicated in mediating various disease states including pain processing. Drugs interacting with the different calcium channel subtypes and subunits have been developed. Current therapeutic agents include drugs targeting L-type Ca_v1 .2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca_v3) channels are the target of ethosuximide, widely used in absence epilepsy. Ziconotide, a peptide blocker of N-type (Ca_v2.2) calcium channels, has been approved as a treatment of intractable pain. (Perret and Luo, 2009, supra, Vink and Alewood, Br J Pharmacol. 2012 167:970-89.).

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

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

The Ca_vot₂5-1 subunit (and the Ca_va₂5-2, but not Ca_vot₂5-3 and Ca_vot₂5-4, subunits) is the binding site for gabapentin which has anti-allodynic/ hyperalgesic properties in patients and animal models. Because injury-induced Ca_vot₂5-1 expression correlates with neuropathic pain development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability, injury-induced Ca_vot₂5-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn. Intrathecal antisense oligonucleotides against the Ca_vot₂5-1 subunit can block nerve injury-induced Ca_vot₂5-1 upregulation and prevent the onset of allodynia and reserve established allodynia.

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

Thus, the present application, relates to the advantages of having activity for the a,₂d-1 subunit of voltage-gated calcium channels to treat chronic pain.

In this way, the present invention relates to compounds having a mechanism of action (blocker of the a,₂d subunit, in particular the a,₂d-1 subunit, of voltage-gated calcium channels) which implies a better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin).

Accordingly, there is still a need to find compounds that have an alternative or improved pharmacological activity in the treatment of pain, being both effective and showing the desired selectivity, and having good“drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion. The inventors have found a series of compounds that show pharmacological activity towards the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel, resulting in an innovative, effective and alternative solution for the treatment of pain.

In view of the existing results of the currently available therapies and clinical practices, the present invention offers a solution relevant for the treatment of pain. This was mainly achieved by providing the compounds according to the invention that bind to the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel.

SUMMARY OF THE INVENTION

The present invention discloses novel compounds with pharmacological activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage-gated calcium channels and to their use in therapy, in particular for the treatment of pain and pain related disorders.

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

wherein Ri, R₂, R3, R₄, R₄·, W, Wi, W₂, W3, W₄, W_5, n and m are as defined below in the detailed description. A further aspect of the invention refers to the processes for preparation of compounds of formula (I).

A still further aspect of the invention refers to the use of intermediate compounds for the preparation of a compound of formula (I). It is also an aspect of the invention a pharmaceutical composition comprising a compound of formula (I).

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

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a family of compounds, in particular, to optionally nitrogenated isoquinolin-1 (2/-/)-ones and 1 /-/-isochromen-1-ones which show a pharmacological activity towards the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel thus, solving the above problem of identifying alternative or improved pain treatments by offering such compounds.

The applicant has surprisingly found that the problem of providing a new effective and alternative solution for treating pain and pain related disorders can be solved by using an analgesic approach using compounds binding to the a₂d subunit, in particular the a₂d- 1 subunit, of the voltage-gated calcium channel. In a first aspect, the present invention is directed to a compound of formula (I):

wherein

Ri is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted alkyl-heterocyclyl, and -ORr; wherein

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

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

R₃ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C₂-6 alkenyl, substituted or unsubstituted C₂-6 alkynyl, and =0; alternatively, R₄ and R₄· may be attached to the same carbon atom and form, together with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl;

W is nitrogen or carbon;

W₁, W₂, W₃ and W₄ are independently selected from the group consisting of nitrogen and carbon; wherein if one of W₁, W₂, W₃ or W₄ is nitrogen the others are carbon;

W₅ is -NR₅ or -0-; wherein R₅ is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; m is 0, 1 or 2; and n is 0, 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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 or solvate thereof.

For the sake of clarity the expression“a compound according to formula (I), wherein R₁, R2, R3, R₄, R_4', R5, W, W1, W2, W3, W₄, W_5, n and m are as defined below in the detailed description” would (just like the expression“a compound of formula (I) as defined in any one of claims 1 to 7 found in the claims) refer to“a compound according to formula (I)”, wherein the definitions of the respective substituents R1 etc. (also from the cited claims) are applied.

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

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

Alkenyl is understood as meaning straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one unsaturation, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -CH=CH-CH₃. The alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in the context of this invention alkenyl is C_2-6-alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C_2-4-alkenyl, like ethylene, propylene, or butylenes.

Alkynyl is understood as meaning a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one carbon-carbon triple bond, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -C^C-CHs (1 - propynyl). Preferably alkynyl in the context of this invention is C_2-6-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C_2-4-alkynyl like ethyne, propyne or butyene.

In connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl and O-alkyl - unless defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen, -OR’, -SR’, -SOR’, -SO₂R’, , -CN, -COR’, -COOR’, -NR’R”, - CONR’R”, haloalkyl, haloalkoxy or -OC_1-6 alkyl wherein each of the R’ and R” groups is independently selected from the group consisting of hydrogen, OH, NO₂, NH₂, SH, CN, halogen, -COH, -C(0)-alkyl, -COOH and C_1-6 alkyl.

In a particular embodiment of the invention, the alkyl, alkenyl or alkynyl as defined in R₁- R₅ if substituted, is substituted with one or more substituent/s selected from -OR’, halogen, -CN, haloalkyl, haloalkoxy and -NR’R”; wherein R, R’ and R” are independently selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C_2-6 alkynyl; More than one replacement on the same molecule and also on the same carbon atom is possible with the same or different substituents. This includes for example 3 hydrogens being replaced on the same C atom, as in the case of CF₃, or at different places of the same molecule, as in the case of e.g. -CH(OH)-CH=CH-CHCl2.

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

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

In the context of this invention cycloalkyl is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted. Preferred cycloalkyls are C3-4-cycloalkyl representing C3- or C4-cycloalkyl, C3-5-cycloalkyl representing C3-, C4- or C5-cycloalkyl, C3-6-cycloalkyl representing C3-, C4-, C5- or C6-cycloalkyl, C3-7- cycloalkyl representing C3-, C4-, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl representing C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl representing C4- or C5- cycloalkyl, C4-6-cycloalkyl representing C4-, C5- or C6-cycloalkyl, C4-7-cycloalkyl representing C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl representing C5- or C6- cycloalkyl and C5-7-cycloalkyl representing C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl. Preferably in the context of this invention cycloalkyl is C3-8-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C3-7-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C3-6-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl. Aryl is understood as meaning 6 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphthyl or anthracenyl, more preferably the aryl is phenyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(leading to a spiro structure) and/or with =0.

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 =0.

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 =0.

A ring system is a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with“joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings. The term “leaving group” means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-), mesylate, nosylate or triflate.

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

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

These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with 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 it is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid. The compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid.

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

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

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

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

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

Unless otherwise defined, all the groups above mentioned that can be substituted or unsubstituted may be substituted at one or more available positions by one or more suitable groups such as OR’, =0, SR’, SOR’, SO2R’, OSO2R’, OSO3R’, NO2, NHR’, N(R’)₂, =N-R’, N(R’)COR’, N(COR’)₂, N(R’)S0₂R’, N(R’)C(=NR’)N(R’)R’, N₃, CN, halogen, COR’, COOR’, OCOR’, OCOOR’, OCONHR’, OCON(R’)₂, CONHR’, CON(R’)₂, CON(R’)OR’, CON(R’)S0₂R’, PO(OR’)₂, PO(OR’)R’, PO(OR’)(N(R’)R’), C1-12 alkyl, C3-10 cycloalkyl, C_2-12 alkenyl, C_2-12 alkynyl, aryl, and heterocyclic group, wherein each of the R’ groups is independently selected from the group consisting of hydrogen, OH, NO_2, NH₂, SH, CN, halogen, COH, COalkyl, COOH, C_1-12 alkyl, C_3-10 cycloalkyl, C_2-12 alkenyl, C_2-12 alkynyl, aryl and heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list.

In a particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W is nitrogen;

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

In a particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein all W₁, W₂, W₃ and W₄ are carbon;

In another particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein one of W₁, W₂, W₃ or W₄ is nitrogen and the others are carbon;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a more particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W₁, is nitrogen and W₂, W₃ or W₄ are carbon; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein both, W and Wi are nitrogen and W₂, W₃ and W₄ are carbon;

In a particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein Ri is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted alkyl-heterocyclyl, and -ORr; wherein

Rr is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein R₁ is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl, and -ORr; wherein

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

In a preferred embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein Ri is selected from the group consisting of hydrogen, halogen, preferably Br, and -ORr; wherein

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

In a particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein R₂ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a more particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein R₂ is selected from the group consisting of hydrogen, and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, more preferably C1-3 alkyl, even more preferably propyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In a more particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein R₃ is selected from the group consisting of hydrogen, and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl, more preferably Ci_-3 alkyl, even more preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein R₄ and R₄· are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C₂-6 alkenyl, substituted or unsubstituted C₂-6 alkynyl, and =0; alternatively, R₄ and R₄· may be attached to the same carbon atom and form, together with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a more particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein R₄ and R₄· are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, preferably unsubstituted C_1-6 alkyl, more preferably C_1-3 alkyl, even more preferably methyl and - C(O); optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W₅ is -O- or -NR₅; wherein

R₅ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W₅ is -NR₅; wherein

In a preferred embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W is nitrogen and W₅ is NR₅; wherein R₅ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W is nitrogen, Wi, W₂, W₃ and W₄ are carbon and W₅ is -NR₅; wherein

In a more preferred embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W is nitrogen, W₁, W₂, W₃ and W₄ are carbon and W₅ is -NR₅; wherein

In another particular embodiment of the invention, the compound of formula (I) according to the invention is a compound wherein W is nitrogen, W₁, W₂, W₃ and W₄ are carbon and W₅ is -0-; wherein optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

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

the cycloalkyl is C_3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C_3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C_3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and/or

the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; and/or

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

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in Rr, R₂, R₃, R₄ or R₄· 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, and 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene, and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment of the invention m and n are 1 ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

Ri is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted alkyl-heterocyclyl, and -ORr; wherein

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

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

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

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C₂-6 alkenyl, substituted or unsubstituted C₂-6 alkynyl, and =0; alternatively, R₄ and R₄· may be attached to the same carbon atom and form, together with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl; and/or

W is nitrogen or carbon; and/or

Wi, W₂, W3 and W₄ are independently selected from the group consisting of nitrogen and carbon; wherein if one of W₁, W₂, W₃ or W₄ is nitrogen the others are carbon;

W₅ is -NR₅ or -0-; wherein

R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; and/or m is 0, 1 or 2; and/or n is 0, 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

Ri is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, substituted or unsubstituted Ci-₆ alkyl, and -ORr; wherein

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

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

R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted C1-6 alkyl, preferably unsubstituted C1-6 alkyl; and/or

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, preferably unsubstituted C1-6 alkyl, and =0; and/or

W is nitrogen; and/or

W₁, W₂, W₃ and W₄ are independently selected from the group consisting of nitrogen and carbon; wherein if one of W₁, W₂, W₃ or W₄ is nitrogen the others are carbon; and/or

W₅ is -NR₅ or -0-; wherein

R5 is selected from the group consisting of hydrogen and substituted or unsubstituted C1-6 alkyl, preferably unsubstituted C1-6 alkyl; and/or m is 1 or 2; and/or n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

W is nitrogen; and/or

W₁, W₂, W₃ and W₄ are carbon; and/or

W₅ is -NR₅ or -0-; wherein R₅ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and/or m is 1 or 2; and/or n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and/or

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, preferably unsubstituted C_1-6 alkyl, and =0; and/or

W is nitrogen; and/or

W₁, W₂, W₃ and W₄ are carbon; and/or

W₅ is -NR₅; wherein

R₅ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and/or m is 1 or 2; and/or n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₁ is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, substituted or unsubstituted C_1-6 alkyl, and -ORr; wherein

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

R₂ is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and/or R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted C1-6 alkyl, preferably unsubstituted C1-6 alkyl; and/or

W is nitrogen; and/or

W1, W₂, W₃ and W₄ are carbon; and/or

W₅ is -0-; wherein and/or m is 1 or 2; and/or n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

W is nitrogen; and/or one of W₁, W₂, W₃ or W₄ is nitrogen the others are carbon; preferably Wi is nitrogen and the others, W₂, W₃ and W₄, are carbon;

and/or

W₅ is -O- or -NR₅; wherein

W is nitrogen; and/or one of W₁, W₂, W₃ or W₄ is nitrogen the others are carbon; preferably W₁ is nitrogen and the others, W₂, W₃ and W₄, are carbon;

and/or

W₅ is -0-; and/or m is 1 or 2; and/or n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

W is nitrogen; and/or one of W1 , W2, W3 or W₄ is nitrogen the others are carbon; preferably Wi is nitrogen and the others, W2, W3 and W₄, are carbon;

and/or

W₅ is -NR₅; wherein

Ri is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted alkyl-heterocyclyl, and -ORr; wherein

Rr is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and R₂ is selected from the group consisting of substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; and

R3 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; and

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, and =0; alternatively, R₄ and R₄· may be attached to the same carbon atom and form, together with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl; and

W is nitrogen or carbon; and

W1 , W2, W3 and W₄ are independently selected from the group consisting of nitrogen and carbon; wherein if one of W1 , W₂, W3 or W₄ is nitrogen the others are carbon;

W₅ is -NR₅ or -0-; wherein

R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; and m is 0, 1 or 2; and n is 0, 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted C1-6 alkyl, preferably unsubstituted C1-6 alkyl; and

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, preferably unsubstituted C1-6 alkyl, and =0; and

W is nitrogen; and Wi, W₂, W3 and W₄ are independently selected from the group consisting of nitrogen and carbon; wherein if one of W₁, W₂, W₃ or W₄ is nitrogen the others are carbon; and

W₅ is -NR₅ or -0-; wherein

R5 is selected from the group consisting of hydrogen and substituted or unsubstituted C1-6 alkyl, preferably unsubstituted C1-6 alkyl; and m is 1 or 2; and n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

R₂ is selected from the group consisting of substituted or unsubstituted Ci-₆ alkyl, preferably unsubstituted Ci-₆ alkyl; and R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, preferably unsubstituted C_1-6 alkyl, and =0; and

W is nitrogen; and

W₁, W₂, W₃ and W₄ are carbon; and

W₅ is -NR₅ or -0-; wherein

R₅ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and m is 1 or 2; and n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another more preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein R₁ is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, substituted or unsubstituted C_1-6 alkyl, and -ORr; wherein

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

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

R₃ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-6 alkyl; and

W is nitrogen; and

W₁, W₂, W₃ and W₄ are carbon; and

W₅ is -NR₅; wherein

W is nitrogen; and

W₁, W₂, W₃ and W₄ are carbon; and W₅ is -0-; wherein and m is 1 or 2; and n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, preferably unsubstituted C_1-6 alkyl, and =0; and W is nitrogen; and one of Wi, W₂, W₃ or W₄ is nitrogen the others are carbon; preferably Wi is nitrogen and the others, W₂, W₃ and W₄, are carbon;

and

W₅ is -O- or -NR₅; wherein

W is nitrogen; and one of W₁, W₂, W₃ or W₄ is nitrogen the others are carbon; preferably Wi is nitrogen and the others, W₂, W₃ and W₄, are carbon;

and

W₅ is -0-; and m is 1 or 2; and n is 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₁ is selected from the group consisting of hydrogen, halogen, preferably Cl, F or Br, substituted or unsubstituted C_1-6 alkyl, and -ORr; wherein Rr is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl; and

and

W₅ is -NR₅; wherein

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

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

[1 ] 3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-2-methylisoquinolin-1 (2H)-one;

[2] 3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-7-methoxy-2-methylisoquinolin- 1 (2H)-one;

[3] 3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-6-methoxy-2-methylisoquinolin- 1 (2H)-one;

[4] 2-Ethyl-7-methoxy-3-[1 -(2-oxopiperazin-1 -yl)butyl]isoquinolin-1 (2H)-one;

[5] 2-Methyl-3-[1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl]isoquinolin-1 (2H)-one;

[6] 6-Methoxy-2-methyl-3-[1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl]isoquinolin-1 (2H)- one;

[7] 7-Methoxy-2-methyl-3-[1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl]isoquinolin-1 (2H)- one;

[8] 3-{1 -[(3R,5S)-3,5-Dimethylpiperazin-1 -yl]butyl}-1 H-isochromen-1 -one;

[9] 7-Bromo-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H-isochromen-1 -one;

[10] 6-Bromo-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H-isochromen-1 -one;

[1 1 ] 7-(1 -(4-Methyl-1 ,4-diazepan-1 -yl)butyl)-5H-pyrano[4,3-b]pyridin-5-one;

[12] 3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-2-ethylisoquinolin-1 (2H)-one;

[13] (R)-6-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)isoquinolin-1 (2H)- one;

[14] (S)-6-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)isoquinolin-1 (2H)- one;

[15] (R)-7-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)isoquinolin-1 (2H)- one; [16] (S)-7-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)isoquinolin-1 (2H)- one;

[17] 7-(1 -(4-Methyl-1 ,4-diazepan-1 -yl)butyl)-1 ,6-naphthyridin-5(6H)-one; and

[18] 6-Ethyl-7-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 ,6-naphthyridin-5(6H)-one; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another aspect, the invention refers to a process for the preparation of a compound of formula (I) as defined above.

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

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

The compounds of formula (I) can be obtained by following the method described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure.

The compounds of formula (I) may be prepared by a one to three step process as described in Scheme 1 . The reactions steps are shown in Scheme 1 below in more detail:

Scheme 1

wherein R₁, R₂, R₃, R₄, R₄·, Rs, W, W₁, W₂, W₃, W₄, W₅, m and n have the meanings as defined in claim 1 , Aik represents and alkyl group and X represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate).

In this sense, in another aspect, the invention refers to a process for the preparation of a compound of formula (I) wherein W₅ is -O- (la):

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

with a compound of formula (VI):

wherein Ri, R₂, R₃, R₄, R₄·, Rs, W, Wi, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated above for a compound of formula (I) and X is a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate.

In a particular embodiment, a compound of formula (la) can be prepared by treating a compound of formula (V) with a suitable acid derivative of formula (VI) in the presence of a Pd catalyst, such as Pd(PPh3)₄ and an organometallic reagent such as ZnCI₂ or Cul and a suitable base, such as triethylamine, in a suitable solvent, such as dimethylformamide or ethanol, at a suitable temperature, such as heating.

A compound of formula (V) as mentioned above can be prepared by a three component coupling of an amine of formula (II)

(II).

aldehyde of formula (III)

R₂CHO

(III)

and an acetylene equivalent such as calcium carbide (IV)

in the presence of a copper reagent, such as CuCI, in a suitable solvent, such as dimethylsulfoxide, at a suitable temperature, preferably heating;

wherein Ri, R₂, R₃, R₄, R₄ , W, W₁, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated above.

In another particular embodiment, the invention refers to a process for the preparation of a compound of formula (I) wherein W₅ is -O- (la):

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

with a compound of formula (II):

wherein Ri, R₂, R₃, R₄, R₄·, Rs, W, Wi, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated above for a compound of formula (I) and X is a leaving group.

In a more particular embodiment, a compound of formula (la) can be prepared by reacting a compound of formula (XV) with a suitable amine of formula (II), in a suitable solvent, such as acetonitrile or dimethylformamide, optionally in the presence of a base such as triethylamine, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating. Alternatively, the reactions can be carried out under microwave heating and optionally using an activating agent, such as sodium iodide or potassium iodide.

In another particular embodiment, the invention refers to a process for the preparation of a compound of formula (XV)

(XV) said method comprising reacting a compound of formula (XIV)

with a suitable halogenating agent, such as bromine in the presence of a suitable solvent, such as acetic acid, at a suitable temperature, preferably heating; wherein R₁, R₂, W, W₁, W₂, W₃, and W₄ have the same meaning as indicated above and X represents a leaving group, such as a halogen atom. In another particular embodiment, the invention refers to a process for the preparation of a compound of formula (XIV) as described above comprising: reacting a compound of formula (VI)

with an alkyne of formula (XIII)

wherein Ri, R₂, W, Wi, W₂, W3 and W₄ have the same meaning as indicated above and X is a leaving group. In a preferred embodiment, the process for the preparation of compound of formula (XIV) is performed using the conditions described above for the preparation of compounds of formula (la) from compounds of formula (V) and (VI).

In another embodiment, the invention refers to a process for the preparation of a compound of formula (I) wherein W₅ is -NR₅- (lb):

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

with a compound of formula (XII):

wherein Ri, R₂, R₃, R₄, R₄·, Rs, W, Wi, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated above for a compound of formula (I) and Me is methyl.

In a more particular embodiment, a compound of formula (lb) can be prepared by coupling of a compound of formula (XI) with an orto-methylamide of formula (XII), in the presence of a base, such as butyllithium, in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, such as room temperature.

In another particular embodiment, the invention refers to a process for the preparation of a compound of formula (XI) as described above comprising: reacting a compound of formula (X)

with L/,O-Dimethylhydroxylamine hydrochloride in the presence of a suitable coupling agent, such as the mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1- hydroxybenzotriazole, in the presence of a base such as /V,/V-diisopropylethylamine, in a suitable solvent, such as dichloromethane, at a suitable temperature, preferably at room temperature.

In a particular embodiment, a compound of formula (X) can be prepared by hydrolysis of a compound of formula (IX) as described above with a base such as sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature, such as heating.

In another particular embodiment, the invention refers to a process for the preparation of a compound of formula (IX) as described above comprising: reacting a compound of formula (VIII)

with an amine of formula (II)

wherein Ri, R₂, R₃, R₄, R₄·, W, m and n have the same meaning as indicated above, X represents a leaving group and Aik is an alkyl group and Me is methyl.

In a preferred embodiment, the process for the preparation of the compound of formula (IX) is performed in the presence of a base such as triethylamine, K2CO₃ or N,N- diisopropylethylamine, in a suitable solvent, such as acetonitrile, at a suitable temperature, such as room temperature.

said process comprising: treating a compound of formula (la) as described above with a compound of formula (VII)

NH2R5

(VII) wherein R₁, R₂, R₃, R₄, R₄·, Rs, W, W₁, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated indicated before.

In addition, certain compounds of the present invention can also be obtained by functional group interconversion over compounds of formula (I) or any of the intermediates shown in Scheme 1. For example, a compound in which R₅ is H may be converted to a compound in which R₅ is alkyl by alkylation with an alkyl iodide in the presence of a base, such as sodium hydride in a suitable solvent such as dimethylformamide, at a suitable temperature, such as room temperature.

The compounds of formula (II), (III), (IV), (VI), (VII), (VIII), (XII) and (XIII) used in the methods disclosed above are commercially available or can be synthesized following common procedures described in the literature and exemplified in the synthesis of some intermediates.

In some of the processes described above it may be necessary to protect the reactive or labile groups present with suitable protecting groups, such as for example Boc (tert- butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups, and common silyl protecting groups for the protection of the hydroxyl group. The procedures for the introduction and removal of these protecting groups are well known in the art and can be found thoroughly described in the literature.

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

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

(XIV) (XV) wherein Ri, R₂, R₃, R₄, R₄·, Rs, W, W₁, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated indicated before, Aik is an alkyl group and X is a leaving group, for the manufacture of a compound of formula (I) according to the invention.

Turning to another aspect, the invention also relates to the therapeutic use of the compounds of general formula (I). As mentioned above, compounds of general formula (I) show a strong affinity to the subunit a2d and more preferably to the a2d-1 subunit of voltage-gated calcium channels and can behave as agonists, antagonists, inverse agonists, partial antagonists or partial agonists thereof. Therefore, compounds of general formula (I) are useful as medicaments. Another aspect of the invention refers to a pharmaceutical composition which comprises a compound according to the invention as described above according to formula (I) or a pharmaceutically acceptable salt thereof, prodrug, solvate or steroisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The present invention thus provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, prodrug, solvate or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.

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

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

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

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts. Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.

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

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

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

Another aspect of the invention refers to a compound of formula I, or a pharmaceutically acceptable salt or isomer thereof, for use in the treatment or prophylaxis of pain. Preferably, the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, 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 or prevention a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Among the pain syndromes that can be treated or prevented are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia. The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.

EXAMPLES

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

The following abbreviations are used:

Anh: Anhydrous

Aq: Aqueous

Boc: tert- Butyloxycarbonyl

Bu: Butyl

Bz: Benzoyl

DIPEA: /V,/V-Diisopropylethylamine

DMF: Dimethylformamide

EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

EtNhh: Ethylamine

EtOAc: Ethyl acetate

EtOH: Ethanol

ESI: Electrospray ionization

Ex: Example

h: Hour/s

HPLC: High-performance liquid chromatography

HOBt: 1-Hydroxybenzotriazole

INT: Intermediate

MeOH: Methanol

MS: Mass spectrometry

Min: Minutes

NBS: /V-Bromosuccinimide

PPh₃: Triphenylphosphine

Ret: Retention time

rt: Room temperature

tert\ Tertiary

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran The following methods were used to generate the HPLC-MS data:

Method A: Column Luna C18 (2) 5 pm, 2.0x50 mm; flow rate: 0.30 mL/min; A: CH3CN:MeOH (1 :1 ); B: water; C: 100 mM ammonium acetate pH 7; gradient A:B:C: 3 min in 10:85:5 + from 10:85:5 to 95:0:5 in 6 min + 6 min in 95:0:5.

Method B: Column: SunFire C18, 3.5 pm, 2.1 x100 mm; flow rate: 0.30 mL/min; A: CHsCN:MeOH (1 :1 ); B: water; C: 100 mM ammonium acetate pH 7; gradient: 5 min in 10:85:5 + from 10:85:5 to 95:0:5 in 15 min + 10 min in 95:0:5.

Method C: Column Aquity UPLC BEH C18 2.1 x 50 mm, 1.7 pm, flow rate 0.61 mL/min; A: NH₄HCO₃ 10 mM, B: CH₃CN, C: MeOH + 0.1 % formic acid; gradient 0.3 min 98% A, 98%A to 0:95:5 A:B:C in 2.7 min; 0:95:5 A:B:C to 100% B in 0.1 min; isocratic 2 min 100% B.

Method D: Column Acquity UPLC BEH C18 2.1 x50 mm, 1.7 pm; flow rate 0.60 mL/min; A: AcONH₄ 10mM; B: CH3CN; Gradient: 0.2 min in 90% A, 90% A to 5% A in 3.3 min, isocratic 0.5 min 5% A.

Intermediate A1. tert-Butyl (2S,6/?)-4-{1 -[methoxy(methyl)amino]-1 -oxopentan-2- yl}-2,6-dimethylpiperazine-1 -carboxylate.

a) Ethyl 2-[(3S,5/?)-3,5-dimethylpiperazin-1 -yl]pentanoate.

DIPEA (5.96 mL, 35.06 mmol) and (2R,6S)-2,6-dimethylpiperazine (4.00 g, 35.06 mmol) were added to a solution of ethyl 2-bromopentanoate (5.42 mL, 31.89 mmol) in CH3CN (40 mL) cooled at 0 °C. The reaction was allowed to reach rt and was stirred for 19 h. The solvent was concentrated off and the residue was diluted with CH2CI2_. The organic layer was washed with H2O, dried over anh Na2S0₄, filtered and concentrated to afford the title product (9.20 g, colorless oil, 1 19% weight) which was used without further purification.

HPLC (Method A): Ret, 8.44 min; ESL-MS m/z, 243 (M+H). b) tert-Butyl (2S,6/?)-4-(1 -ethoxy-1 -oxopentan-2-yl)-2,6-dimethylpiperazine-1 - carboxylate.

B0C2O (3.84 g, 17.6 mmol) was added to a solution of the compound obtained in step a (16 mmol, crude material from previous reaction) and DIPEA (4 ml.) in CH2CI2 (25 ml.) cooled at 0 °C. The mixture was stirred at low temperature for 10 min and at room temperature for 2 days. The reaction was diluted with CH2CI2 and was washed with H2O. The organic layer was dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (4% MeOH/ChhCh) to afford the title product (5.90 g, colorless oil, 100% yield).

HPLC (Method A): Ret, 12.06 min; ESP-MS m/z, 343 (M+H).

c) 2-[(3S,5/?)-4-(tert-Butoxycarbonyl)-3,5-dimethylpiperazin-1 -yl]pentanoic acid.

NaOH (10 ml_, 6 M aq) was added to a solution of of the compound obtained in step b (5.90 g, 17.27 mmol) in EtOH (25 ml_). The mixture was heated at 60 °C for 2 h. The solvent was concentrated off and the residue was diluted with CH2CI2 and was acidified with HCI (10% aq). The organic layer was dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (5% MeOH/ChbCh) to afford the title product (4.03 g, colorless oil, 74% yield).

HPLC (Method A): Ret, 9.66 min; ESP-MS m/z, 315 (M+H).

d) Title compound.

L/,O-Dimethylhydroxylamine hydrochloride (0.44 g, 4.55 mmol), DIPEA (1 .78 mL, 10.50 mmol), EDCI (0.87 g, 4.55 mmol) and HOBt (0.92 g, 4.55 mmol) were added to a solution of of the compound obtained in step c (1 .10 g, 3.50 mmol) in CH2CI2 (15 mL) and the mixture was stirred at rt for 22 h. The reaction was diluted with CH2CI2 and washed with NaOH (10% aq, 10 mL) and H2O. The organic layer was dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (2% MeOH/CH2Cl2) to afford the title product (0.83 g, colorless oil, 66% yield).

HPLC (Method A): Ret, 1 1.42 min; ESP-MS m/z, 358 (M+H).

This method was used for the preparation of intermediates A2-A3 using suitable starting materials:

Intermediate B1. A/,2-Dimethylbenzamide.

Oxalyl chloride (1.41 ml_, 16.64 mmol) and DMF (3 drops) were added to a solution of 2- methylbenzoic acid (2.06 g, 15.13 mmol) in CH2CI2 (30 ml.) cooled at 0 °C. The mixture was stirred at low temperature for 5 min and at rt for 1 h. The reaction was cooled at -15 °C and methylamine (5.60 ml_, 33% weight in EtOH, 45.39 mmol) was added. After 15 min the mixture was diluted with CH2CI2 and was poured into brine (50. The phases were separated and the organic layer was dried over anh Na2S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (40% EtOAc/hexanes) to afford the title product (1.90 g, white solid, 84% yield).

HPLC (Method A): Ret, 6.48 min; ESF-MS m/z, 150 (M+H).

This method was used for the preparation of intermediates B2-B4 using suitable starting materials:

Intermediate C1. 1 -(1 -Hexyn-3-yl)-4-methyl-1 ,4-diazepane.

A mixture of 4-methyl-1 ,4-diazepane (1.14 g, 10 mmol), calcium carbide (1.60 g, 25 mmol), butyraldehyde (2.16 g, 3 mmol), CuCI (0.099 g, 0.1 mmol) and water (0.54 ml_, 3 mmol) in DMSO (6 ml.) was stirred at 100 °C under N₂ for 4 h. The resulting mixture was filtered to remove the solid, and the liquor was extracted with EtOAc and washed with brine. The resulting organic phase was dried over anh Na₂S0₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM:MeOH) to afford the title product (0.7 g, pale yellow oil, 36% yield). HPLC (Method C): Ret, 1.40 min; ESP-MS m/z, 195 (M+H).

Example 1 : 3-{1 -[(3S,5/?)-3,5-Dimethylpiperazin-1 -yl]butyl}-2-methylisoquinolin- 1(2H)-one.

a) ferf-Butyl (2S,6/?)-2,6-dimethyl-4-[1 -(2-methyl-1 -oxo-1 ,2-dihydroisoquinolin-3- yl)butyl]piperazine-1 -carboxylate.

n-BuLi (2.5 M solution in hexanes, 1.60 ml_, 4.01 mmol) was added dropwise to a solution of /V,2-dimethylbenzamide (0.29 g, 1.91 mmol) in THF (10 ml.) cooled at -30 °C, while the mixture became dark orange. After 30 min a solution of INT A1 (0.82 g, 2.29 mmol) in THF (8 ml.) was transferred via canula and stirring continued for 1 h. After this time, HCI (10% aq, 5 mL) was added and the reaction was allowed to reach rt. The solvent was concentrated off and the residue was diluted with EtOAc and washed with brine. The organic layer was dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (25®35% EtOAc/hexanes) to afford the title product [0.37 g, colorless oil, 73% purity (the mixture contains 24% of unconsumed INT A1 )].

HPLC (Method A): Ret, 1 1.82 min; ESP-MS m/z, 428 (M+H).

b) Title compound.

TFA (4 mL, 52.22 mmol) was added to a solution of the compound obtained in step a (0.36 g, 0.84 mmol, purity 73%) in CH2CI2 (30 mL), and the mixture was stirred at rt for

1 h. The reaction was diluted with CH2CI2 and was poured into NaHCC>3 sat aq solution. The phases were separated and the organic layer was washed with brine, dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (95:5:1 CH2Cl2:MeOH:NH₄OH) to afford the title product [54 mg, white foam, 8% yield (two steps)].

HPLC (Method B): Ret, 15.12 min; ESP-MS m/z, 328 (M+H).

This method was used for the preparation of Ex 2 using suitable starting materials:

Example 3: 3-{1 -[(3S,5/?)-3,5-Dimethylpiperazin-1 -yl]butyl}-6-methoxy-2- methylisoquinolin-1 (2H)-one.

a) ferf-Butyl (2S,6/?)-4-{1 -[5-methoxy-2-(methylcarbamoyl)phenyl]-2-oxohexan-3- yl}-2,6-dimethylpiperazine-1 -carboxylate. The title product was obtained following the procedure described in Example 1 , step a and using Intermediate A1 and Intermediate B3 as starting materials.

HPLC (Method A): Ret, 1 1.42 min; ESP-MS m/z, 476 (M+H).

b) Title compound.

HCI (2.25 M aqueous solution, 1.0 ml.) was added to a solution of the compound obtained in step a (62 mg, 0.13 mmol) in MeOH (5 ml.) and the mixture was heated under reflux for 3 h. The reaction was allowed to reach rt and volatiles were removed. The crude residue was purified by flash chromatography on silica gel (12% MeOH/ChbCh) followed by semipreparative HPLC to afford the title product (white foam, 39 mg, 83% yield).

HPLC (Method B): Ret, 15.46 min; ESP-MS m/z, 358 (M+H).

This method was used for the preparation of Ex 4-7 using suitable starting materials:

Example 8: 3-{1 -[(3/?,5S)-3,5-Dimethylpiperazin-1 -yl]butyl}-1H-isochromen-1 -one.

a) Butyl-1 H-isochromen-1 -one.

A mixture of hex-1 -yne (1 .85 ml_, 16.12 mmol), 2-iodobenzoic acid (2.00 g, 8.06 mmol), Cul (76 mg, 0.40 mmol), PPhi₃ (0.21 g, 0.81 mmol), Pd (5% on carbon, 0.34 g, 0.16 mmol) and EtsN (5.60 ml_, 40.30 mmol) in EtOH (50 ml.) was heated under reflux for 4.5 h. It was allowed to reach rt and filtered through a pad of Celite (rinsed with 50 ml. of EtOAc). Volatiles were removed in the presence of silica gel and the residue was purified by column chromatography on silica gel (2% EtOAc/hexanes) to afford the title product (0.71 g, pale yellow oil, 43% yield).

HPLC (Method A): Ret, 10.75 min; ESP-MS m/z, 203 (M+H).

b) 3-(1 -Bromobutyl)-1 H-isochromen-1 -one.

NBS (0.60 g, 3.37 mmol) and (BzO)₂ (4 mg, 0.01 mmol) were added to a solution of butyl- 1 /-/-isochromen-1 -one (0.60 g, 2.93 mmol) in CHC (30 ml.) and the mixture was heated under reflux for 4.5 h. The reaction was allowed to reach rt and it was poured into water (50 ml_). The aqueous layer was extracted with CH2CI2 (2 x 30 ml.) and the combined organic layers were dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (5% EtOAc/hexanes) to afford the title product (0.39 g, yellow oil, 48% yield).

HPLC (Method A): Ret, 10.88 min; ESP-MS m/z, 281/283 (M+H).

c) Title compound.

A solution of (2R,6S)-2,6-dimethylpiperazine (0.48 g, 4.20 mmol) and 3-(1 -bromobutyl)- 1 /-/-isochromen-1 -one (0.40 g, 1.40 mmol) in CH₃CN (15 mL) was heated at 50 °C for 15 h. The reaction mixture was allowed to reach rt and it was poured into water (40 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL) and the organic layer was dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (95:5:1 CH2Cl2:MeOH:NH₄OH) to afford the title product (0.36 g, pale yellow oil, 82% yield).

HPLC (Method B): Ret, 15.42 min; ESP-MS m/z, 315 (M+H).

Example 9: 7-Bromo-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H-isochromen-1 - one.

A mixture of 1-(1-hexyn-3-yl)-4-methyl-1 ,4-diazepane (Int C1 , 984 mg, 4.88 mmol), 5- bromo-2-iodobenzoic acid (1.45 g, 4.43 mmol), ZnCh (604 mg, 4.43 mmol), Pd(PPh3)4 (256 mg, 0.22 mmol), and EίbN (1.85 ml_, 13.3 mmol) in DMF (12 ml.) was stirred under argon at 80 °C for 3 h. The mixture was allowed to reach rt and was treated with water and extracted with EtOAc. The organic phase was evaporated in the presence of silica gel and the residue was purified by column chromatography on silica gel (DCM/MeOH) to afford the title compound (0.70 g, pale yellow oil, 42% yield).

HPLC (Method C): Ret, 2.07 min; ESP-MS m/z, 393 (M+H).

This method was used for the preparation of Ex 10-1 1 using suitable starting materials:

Example 12: 3-{1 -[(3S,5/?)-3,5-Dimethylpiperazin-1 -yl]butyl}-2-ethylisoquinolin- 1(2H)-one.

a) 2-{3-[(3S,5/?)-3,5-Dimethylpiperazin-1 -yl]-2-oxohexyl}-/V-ethylbenzamide.

EtNhh (2 M solution in MeOH, 4.25 ml.) was added to a solution of the compound obtained in Ex 8 (0.27 g, 0.85 mmol) in EtOH (5 ml.) and the mixture was heated under reflux for 3 days. The reaction was allowed to reach rt and volatiles were removed, rendering a yellow oil that was used in the next step without further purification.

HPLC (Method A): Ret, 8.71 min; ESP-MS m/z, 360 (M+H).

b) Title compound.

The title product was obtained following the procedure described in Example 3, step b, and using the compound obtained in step a as starting material (0.060 g, white solid, 21% yield).

HPLC (Method B): Ret, 16.22 min; ESP-MS m/z, 342 (M+H).

This method was used for the preparation of Ex 13-18 using suitable starting materials:

Example 17: 7-(1 -(4-Methyl-1 ,4-diazepan-1 -yl)butyl)-1 ,6-naphthyridin-5(6H)-one.

A solution of 7-(1-(4-methyl-1 ,4-diazepan-1-yl)butyl)-5H-pyrano[4,3-b]pyridin-5-one (Ex 1 1 , 50 mg, 0.16 mmol) in NH₃ ( M solution in MeOH, 2 mL) was heated for 1 h at 120 °C under microwave irradiation. The reaction was allowed to reach rt and volatiles were removed. The crude product thus obtained, was purified by column chromatography to afford the title product (35 mg, cream solid, 70% yield).

HPLC (Method C): Ret, 1.21 min; ESP-MS m/z, 315 (M+H).

Example 18: 6-Ethyl-7-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 ,6-naphthyridin- 5(6H)-one.

To a solution of 7-(1-(4-methyl-1 ,4-diazepan-1-yl)butyl)-1 ,6-naphthyridin-5(6H)-one (Ex 17, 73 mg, 0.22 mmol) in DMF (4 mL), sodium hydride (60% in mineral oil, 18 mg, 0.45 mmol) was added and the mixture was stirred under argon at 0 °C for 30 min. lodoethane (38 mg, 0.24 mmol) was added and the mixture was stirred overnight at rt. The reaction mixture was treated with water and extracted with EtOAc. The organic layer was dried over anh Na₂S0₄, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel to afford the title compound (3 mg, 4% yield).

HPLC (Method C): Ret, 1.45 min; ESP-MS m/z, 343 (M+H).

Examples of biological activity

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

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

In a preferred embodiment, compounds showing a binding expressed as K, which is K_ί(a₂d-1) >= 5000 nM, show a inhibition, measured as percentage of inhibition, between 1 % and 50%.

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

Human a2d-1 enriched membranes (2.5 pg) were incubated with 15 nM of radiolabeled [3H]-Gabapentin in assay buffer containing Hepes-KOH 10 mM, pH 7.4.

NSB (non specific binding) was measured by adding 10 pM pregabalin. The binding of the test compound was measured at five different concentrations. After 60 min incubation at 27 °C, binding reaction was terminated by filtering through Multiscreen GF/C (Millipore) presoaked in 0.5 % polyethyleneimine in Vacuum Manifold Station, followed by 3 washes with ice-cold filtration buffer containing 50 mM Tris-HCI, pH 7.4.

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

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

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

+ Kΐ(a₂d-1) >= 5000 nM

++ 500nM <= K_ί(a₂d-1) <5000 nM

+++ K_ί(a₂d-1) <500 nM

Preferably, when K,(a₂d-1 ) >= 5000 nM, the following scale has been adopted for representing the binding to the a₂d-1 subunit of voltage-gated calcium channels: + K_ί(a₂d-1) >= 5000 nM or inhibition ranges between 1 % and 50 %

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

Claims

1 . A compound of formula (I):

wherein

R₃ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; R₄ and R_4’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, and =0; alternatively, R₄ and R₄· may be attached to the same carbon atom and form, together with the carbon atom to which they are attached, a substituted or unsubstituted cycloalkyl;

W is nitrogen or carbon;

W₅ is NR₅ or O; wherein

R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; m is 0, 1 or 2; and n is 0, 1 or 2; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

2. Compound according to claim 1 , wherein W is nitrogen.

3. Compound according to any one of claims 1 or 2 wherein Wi is nitrogen.

4. Compound according to any one of claims 1 or 2 wherein W₁, W₂, W₃ and W₄ are carbon.

5. Compound according to any one of claims 1 to 4, wherein W₅ is NR₅; wherein R5 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl.

6. Compound according to any one of claims 1 to 4, wherein W₅ is O.

7. Compound according to claim 1 wherein said compound is selected from the group consisting of

[1 ] 3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-2-methylisoquinolin-

1 (2H)-one;

[2] 3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-7-methoxy-2- methylisoquinolin-1 (2/-/)-one;

[3] 3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-6-methoxy-2- methylisoquinolin-1 (2/-/)-one;

^ 2-Ethyl-7-methoxy-3-[1 -(2-oxopiperazin-1 -yl)butyl]isoquinolin-

1 (2H)-one; r₍-, 2-Methyl-3-[1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl]isoquinolin-1 (2 H)-

\P\

one;

6-Methoxy-2-methyl-3-[1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl]isoquinolin-1 (2/-/)-one;

7-Methoxy-2-methyl-3-[1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl]isoquinolin-1 (2/-/)-one;

3-{1 -[(3R,5S)-3,5-Dimethylpiperazin-1 -yl]butyl}-1 /-/-isochromen-1 - one;

7-Bromo-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H-isochromen-1 - one;

6-Bromo-3-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 H-isochromen-1 -

[10]

one; 7-(1 -(4-Methyl-1 ,4-diazepan-1 -yl)butyl)-5H-pyrano[4,3-b]pyridin-5-

[1 1 ]

one;

3-{1 -[(3S,5R)-3,5-Dimethylpiperazin-1 -yl]butyl}-2-ethylisoquinolin- 1 (2H)-one;

(R)-6-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 -

[13]

yl)butyl)isoquinolin-1 (2H)-one;

(S)-6-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl)isoquinolin-1 (2H)-one;

(R)-7-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 -

[15]

yl)butyl)isoquinolin-1 (2H)-one;

(S)-7-Bromo-2-methyl-3-(1 -(4-methyl-1 ,4-diazepan-1 - yl)butyl)isoquinolin-1 (2H)-one;

7-(1 -(4-Methyl-1 ,4-diazepan-1 -yl)butyl)-1 ,6-naphthyridin-5(6H)-one;

[17]

and

6-Ethyl-7-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)-1 ,6-naphthyridin- 5(6H)-one.

8. Process for the preparation of a compound of formula (I) according to claim 1 wherein W₅ is -O- (la):

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

with a compound of formula (VI):

wherein Ri, R₂, R₃, R₄, R₄·, W, Wi, W₂, W3, W₄, W₅, m and n have the same meaning as indicated indicated in any one of claims 1 to 7 and X is a leaving group.

9. Process for the preparation of a compound of formula (I) according to claim 1 wherein W₅ is -O- (la):

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

with a compound of formula (II):

wherein Ri, R₂, R₃, R₄, R₄·, W, Wi, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated indicated in any one of claims 1 to 7 and X is a leaving group.

10. Process for the preparation of a compound of formula (I) according to claim 1 wherein W₅ is -NR₅- (lb):

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

with a compound of formula (XII):

wherein Ri, R₂, R₃, R₄, R₄·, W, W₁, W₂, W₃, W₄, W₅, m and n have the same meaning as indicated indicated in any one of claims 1 to 7 and Me is methyl. 1 1. Process for the preparation of a compound of formula (I) according to claim 1 wherein W₅ is -NR₅- (lb):

said process comprising treating a compound of formula (I) wherein W₅ is -O- with a compound of formula (VII) NH₂R_S

(VII) wherein Ri, R₂, R3, R₄, R₄·, Rs, W, Wi, W₂, W₃, W , W₅, m and n have the same meaning as indicated indicated in any one of claims 1 to 7 and.

12. Use of a compound selected from

(XIV) (XV) wherein

wherein R₁, R₂, R₃, R₄, R₄·, Rs, W, Wi, W₂, W₃, W , W₅, m and n have the same meaning as indicated indicated in any one of claims 1 to 7, Aik is an alkyl group, Me is methyl and X is a leaving group, for the manufacture of a compound according to claim 1.

13. Compound according to any of claims 1 to 7 for use as a medicament. 14. A compound according to any of claims 1 to 7, for use in the treatment and/or prophylaxis of diseases and/or disorders mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels.

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

16. A pharmaceutical composition comprising a compound of general formula (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.