WO2020016315A1 - Dérivés de dihydroindazole fusionnés ayant une activité multimodale contre la douleur - Google Patents

Dérivés de dihydroindazole fusionnés ayant une activité multimodale contre la douleur Download PDF

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WO2020016315A1
WO2020016315A1 PCT/EP2019/069277 EP2019069277W WO2020016315A1 WO 2020016315 A1 WO2020016315 A1 WO 2020016315A1 EP 2019069277 W EP2019069277 W EP 2019069277W WO 2020016315 A1 WO2020016315 A1 WO 2020016315A1
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thieno
dihydro
indazol
methanone
substituted
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PCT/EP2019/069277
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José-Luís DÍAZ-FERNÁNDEZ
Lourdes GARRIGA-SANAHUJA
Monica Garcia-Lopez
Sergi RODRIGUEZ-ESCRICH
Carmen ALMANSA-ROSALES
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Esteve Pharmaceuticals, S.A.
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Publication of WO2020016315A1 publication Critical patent/WO2020016315A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to compounds having pharmacological activity towards the a 2 d subunit of the voltage-gated calcium channel.
  • the present invention also relates to compounds having dual pharmacological activity towards both the a 2 d subunit of the voltage-gated calcium channel, and the sigma-1 (s1 ) receptor.
  • the present invention relates to fused dihydroindazole derivatives having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • opioid agonists opioid agonists
  • calcium channel blockers and antidepressants
  • antidepressants but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.
  • Voltage-gated calcium channels are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et a I . , Pharmacol Rev. 2015, 67, 821 -70).
  • the VGCC are assembled through interactions of different subunits, namely oti (Ca v oti), b (Ca v p) a 2 d (Ca v a 2 3) and g (Ca v y).
  • the o i subunits are the key porous forming units of the channel complex, being responsible for the Ca 2+ conduction and generation of Ca 2+ influx.
  • VGCC can be subdivided into low voltage-activated T-type (Ca v 3.1 , Ca v 3.2, and Ca v 3.3), and high voltage-activated L- (Ca v 1 .1 through Ca v 1 .4), N-(Ca v 2.2), P/Q-(Ca v 2.1 ), and R-(Ca v 2.3) types, depending on the channel forming Cava subunits.
  • Current therapeutic agents include drugs targeting L-type Ca v 1 .2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension.
  • T-type (Ca v 3) channels are the target of ethosuximide, widely used in absence epilepsy.
  • Ziconotide a peptide blocker of N-type (Ca v 2.2) 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 v 1 and Ca v 2 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.
  • a d subunit which 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 a2d subunits have now been cloned.
  • a 2 d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution.
  • the a 2 d-2 and a 2 d-3 subunits were subsequently cloned from brain.
  • the most recently identified subunit, a 2 d-4 is largely nonneuronal.
  • the human a 2 d-4 protein sequence shares 30, 32 and 61 % identity with the human a 2 d-1 , a 2 d-2 and a 2 d-3 subunits, respectively.
  • the gene structure of all a 2 d subunits is similar. All a 2 d 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 v ot 2 5-1 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 v ot 2 5-1 , but not Ca v ot 2 5-2, subunit upregulation in the spinal dorsal horn, and DRG (dorsal root ganglia) after nerve injury that correlates with neuropathic pain development.
  • the Ca v ot 2 5-1 subunit (and the Ca v ot 2 5-2, but not Ca v ot 2 5-3 and Ca v ot 2 5-4, subunits) is the binding site for gabapentin which has anti-allodynic/ hyperalgesic properties in patients and animal models.
  • injury-induced Ca v ot 2 5-1 expression correlates with neuropathic pain development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability
  • injury-induced Ca v ot 2 5-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn.
  • Intrathecal antisense oligonucleotides against the Ca v ot 2 5-1 subunit can block nerve injury-induced Ca v ot 2 5-1 upregulation and prevent the onset of allodynia and reserve established allodynia.
  • the 0, 2 6 subunits of VGCC form the binding site for gabapentin and pregabalin, which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations.
  • the binding of gabapentin and pregabalin to the Ca v ot 2 5 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).
  • the sigma-1 (s1 ) receptor was discovered 40 years ago and initially assigned to a new subtype of the opioid family. This receptor is expressed both in the endoplasmic reticulum and in the plasma membrane and plays an important role in the regulation of intracellular calcium concentration. A signaling pathway associated with the activation of the s1 receptor has not been described, although it is believed that it has an amplification function of activation of intracellular cascades. In this sense, the s1 receptor regulates and modulates the activity of numerous voltage-dependent ion channels, including Ca2+-, K+-, Na+, CI-, SK, and NMDA channels and the IP3 receptor.
  • s1 receptor is linked to analgesia, since s1 receptor agonists counteract opioid receptor mediated analgesia, while s1 receptor antagonists, such as haloperidol, potentiated it (Chien CC, Pasternak GW. Neurosci. Lett. 1995, 190, 137- 9).
  • capsaicin did not induce mechanical hypersensitivity, both phases of formalin-induced pain were reduced, and cold and mechanical hypersensitivity were strongly attenuated after partial sciatic nerve ligation or after treatment with paclitaxel, which are models of neuropathic pain. Many of these actions were confirmed by the use of s1 receptor antagonists and led to the advancement of one compound, S1 RA, into clinical trials for the treatment of different pain states.
  • Compound S1 RA exerted a substantial reduction of neuropathic pain and anhedonic state following nerve injury (i.e., neuropathic pain conditions) and, as demonstrated in an operant self- administration model, the nerve-injured mice, but not sham-operated mice, acquired the operant responding to obtain it (presumably to get pain relief), indicating that s1 receptor antagonism relieves neuropathic pain and also address some of the comorbidities (i.e., anhedonia, a core symptom in depression) related to pain states (Romero et al. BrJ Pharmacol. 2012, 166, 2289-306).
  • Polypharmacology is a phenomenon in which a drug binds multiple rather than a single target with significant affinity.
  • the effect of polypharmacology on therapy can be positive (effective therapy) and/or negative (side effects). Positive and/or negative effects can be caused by binding to the same or different subsets of targets; binding to some targets may have no effect.
  • Multi-component drugs or multi-targeting drugs can overcome toxicity and other side effects associated with high doses of single drugs by countering biological compensation, allowing reduced dosage of each compound or accessing context-specific multitarget mechanisms. Because multitarget mechanisms require their targets to be available for coordinated action, one would expect synergies to occur in a narrower range of cellular phenotypes given differential expression of the drug targets than would the activities of single agents.
  • multi-targeting drugs may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive pain. Because they actually make use of biological complexity, multi-targeting (or multi-component drugs) approaches are among the most promising avenues toward treating multifactorial diseases such as pain (Gilron et al., Lancet Neurol. 2013, 12, 1084-95).
  • positive synergistic interaction for several compounds, including analgesics has been described (Schroder et al., J Pharmacol Exp Ther. 201 1 , 337, 312-20. Erratum in: J Pharmacol Exp Ther. 2012, 342, 232; Zhang et al., Cell Death Dis. 2014, 5:e1 138; Gilron et al., 2013, supra).
  • An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008, supra).
  • the s1 receptor as well as the a2d1 subunit modulate intracellular calcium concentration and the activity of voltage-dependent calcium channels.
  • the present application also relates to the advantages of having dual activity, for the a 2 d-1 subunit of voltage-gated calcium channels and the s1 receptor, in the same molecule to treat chronic pain.
  • the inventors have found a multitude of compounds that show a primary pharmacological activity towards the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel, and compounds that show dual pharmacological activity towards both the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel and the s1 receptor resulting in an innovative, effective, complementary and alternative solution for the treatment of pain.
  • the present invention offers a solution by developing compounds binding to a single target or by combining in a single compound binding to two different targets relevant for the treatment of pain. This was mainly achieved by providing the compounds according to the invention that bind to the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel, or both to the s1 receptor and to the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel.
  • the inventors have found a series of compounds, encompassed by formula (I), that show pharmacological activity towards the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel. Also, the inventors have found that some of these compounds have a dual pharmacological activity towards both the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel and the s1 receptor, thus solving the above problem of identifying alternative or improved pain treatments by offering such compounds.
  • the main object of the invention is directed to a compound having binding capacicy to the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel.
  • This compound can be used in the treatment of pain.
  • Another object of the invention is directed to a compound having a dual activity binding to the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel and the s ⁇ receptor. This compound can be used in the treatment of pain.
  • the invention is directed in a main aspect to a compound 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).
  • composition comprising a compound of formula (I).
  • the invention is directed to a family of compounds, in particular, to fused dihydroindazole derivatives which show primary pharmacological activity towards the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel.
  • the invention also refers to compounds having a dual pharmacological activity towards both the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel and the s1 receptor and to their use in the treatment of pain and related disorders.
  • 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 binding to the a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel or a multimodal analgesic approach combining two activities in a single drug (i.e., dual ligands which are bifunctional and bind to s1 receptor and to a 2 d subunit, in particular the a 2 d-1 subunit, of the voltage-gated calcium channel).
  • the present invention also relates to the advantages of having dual activity, for the a 2 d-1 subunit of voltage-gated calcium channels and the s1 receptor, in the same molecule to treat pain, i.e. binding to two different targets relevant for the treatment of pain.
  • a dual compound that possess binding to both the s1 receptor and to the a 2 d subunit of the voltage-gated calcium channel shows a highly valuable therapeutic potential by achieving an outstanding analgesia.
  • a further advantage of using designed multiple ligands is a lower risk of drug-drug interactions compared to cocktails or multi-component drugs, thus involving simpler pharmacokinetics and less variability among patients. Additionally, this approach may improve patient compliance and broaden the therapeutic application in relation to monomechanistic drugs, by addressing more complex aetiologies.
  • the present invention is directed to a compound of formula (I):
  • Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted C 2-6 alkenyl, 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; R 2 IS selected from substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstit
  • R5, R5' or R 5 are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH 2 ] n -NR”R’”; wherein
  • R’, R” and R’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl- heterocyclyl;
  • R3 and R3' are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted haloalkyl; wherein n is 0, 1 or 2; R 6 is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl;group A is a diamine selected from
  • a and b are independently selected from 0, 1 and 2;
  • R ? and R 7' are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A’, R 7 and R 7 ⁇ taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group; Rs and Rs ⁇ are hydrogen; and m is 1 , 2, 3 or 4; preferably m is 2;
  • X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q-> and -0-, wherein
  • R 4 , R 4' , R 4” and R 4 are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; p is 0, 1 , 2 or 3; and q is 0, 1 , 2 or 3; and
  • W is selected from S and O; 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 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.
  • 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.
  • 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. -CH 3 and -CH 2 -CH 3 .
  • 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-s-alkyl represents C1 -, C2-, C3-, C4-, or C5-alkyl
  • Ci- 6 -alkyl represents C1 -, C2-, C3-, C4-, C5- or C6-alkyl.
  • 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.
  • aryl 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.
  • 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.
  • the alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl).
  • alkenyl is C2-6-alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C2- 4 -alkenyl, like ethylene, propylene, or butylenes.
  • Alkynyl is understood as meaning 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).
  • alkynyl in the context of this invention is C2-6-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C2- 4 -alkynyl like ethyne, propyne or butyene.
  • alkyl also in aryl-alkyl, alkyl-heterocyclyl or alkyl-cycloalkyl, alkyl- aryl
  • 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’, -OR’, -CN, -COR’, -COOR’, -NR’R”, -CONR’R”, haloalkyl, haloalkoxy or -OC1-6 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, -COalkyl, -COOH and C1-6 alkyl.
  • the alkyl, alkenyl or alkynyl as defined in Ri-Rir 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 Ci- 6 alkyl, unsubstituted C2-6 alkenyl, and unsubstituted C2-6 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 CF 3 , or at different places of the same molecule, as in the case of e.g. -CH(OH)-CH CH-CHCl2.
  • 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, -CHC , -CHF2, -CCI3, -CF3 and -CH2-CHCI2.
  • 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 -CH 2 CI, -CH 2 F, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CHCb, -CHF 2 , and -CF3.
  • 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.
  • 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.
  • 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, C 4-6 -cycloalkyl,
  • Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl.
  • 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.
  • Examples include non-aromatic heterocyclyls such as tetrahyd ropy ran, oxazepane, morpholine, piperidine, pyrrolidine as well as heteroaryls such as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, thiazole, benzothiazole, indole, benzotriazole, carbazole and quinazoline.
  • non-aromatic heterocyclyls such as tetrahyd ropy ran, oxazepane, morpholine, piperidine, pyrrolidine as well as heteroaryls such as furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine
  • 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 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, thi
  • 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, tetrahyd ropy ran, morpholine, indoline, oxopyrrolidine, benzodioxane, especially is piperazine, benzodioxane, morpholine, tetrahydr
  • 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.
  • 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.
  • said heterocyclyl is a substituted mono or bicyclic heterocyclyl ring system.
  • 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 ox
  • 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.
  • alkyl-aryl or aryl-alkyl 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.
  • aryl-alkyl is understood as meaning an aryl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups.
  • alkyl-heterocyclyl or heterocyclyl-alkyl is understood as meaning an heterocyclyl 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.
  • alkyl-heterocyclyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups.
  • alkyl-cycloalkyl or cycloalkyl-alkyl is understood as meaning an cycloalkyl 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.
  • alkyl-cycloalkyl is understood as meaning a cycloalkyl group (see above) being connected to another atom through 1 to 4 (-Chh) groups.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 this are 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”.
  • 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.
  • 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 NH 4 , 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.
  • 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.
  • 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.
  • 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).
  • the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon or of a nitrogen by 15 N-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.
  • 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.
  • the compound of formula (I) or (I’) according to the invention is a compound wherein
  • R 2 is selected from substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted aryl, preferably phenyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [Chhj n - C(0)-R5; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, -OR5, -C(O), -C(0)R5, -NO
  • R5, R5' or R 5 are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH2] n -NR”R’”; wherein
  • R’, R” and R’ are independently selected from hydrogen, halogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted C2- 6 alkenyl, and substituted or unsubstituted C2- 6 alkynyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl-heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound according to the invention of formula (I) or (I’) is a compound wherein
  • R2 IS selected from substituted or unsubstituted C2- 6 alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [Chhl n -C(0)-Rs; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen and substituted or unsubstituted C1-6 alkyl, preferably substituted or unsubstituted C1- 3 alkyl; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, preferably substituted or unsubstituted C1
  • R 5 , R 5' or R 5 are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, preferably unsubstituted C 1-3 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl- alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, preferably C 1-3 alkyl-phenyl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH 2 ] n -NR”R’”; wherein
  • R’, R” and R’ are independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, preferably unsubstituted C 1-3 alkyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl-heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the compound of the invention according to formula (I) is a compound, wherein in R 5 , Rs and Rs- 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 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,
  • the aryl is selected from phenyl, naphtyl, and anthracenyl; preferably is napthyl and phenyl; 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 compound of the invention according to formula (I) is a compound, wherein in R’, R” and R’” as defined in any of the embodiments of the present invention, the C alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and 2-methylpropyl; 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,
  • the aryl is selected from phenyl, naphtyl, and anthracenyl; preferably is napthyl and phenyl; 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 compound according to the invention of formula (I) or (G) is a compound wherein group
  • 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 compound according to the invention of formula (I) or (G) is a compound wherein group
  • a and b are independently selected from 1 and 2; preferably a and b 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.
  • the compound according to the invention of formula (I) or (G) is a compound wherein in group
  • Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl;
  • R 3 and R 3' are independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; wherein n is 0, 1 or 2;
  • R ? and R 7' are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, R 7 and R 7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl, preferably a substituted or unsubstituted N-containing heterocyclyl group; a and b are independently selected from 1 and 2; preferably, a and b are 1 ; and
  • X is selected from a bond and -[C(R4R4')] P -, wherein
  • R 4 and R 4' are independently selected from hydrogen and substituted or unsubstituted C 1-6 alkyl; and p is 0, 1 , 2 or 3; 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 compound according to the invention of formula (I) or (I’) is a compound wherein in group
  • Ri is selected from hydrogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl;
  • R ? and R 7' are hydrogen
  • X is selected from a bond and -[C(R4R4')] P -, wherein
  • R 4 and R 4' are independently selected from hydrogen and substituted or unsubstituted C 1-6 alkyl; and p is 0, 1 , 2 or 3; n is 0; and a and b 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.
  • the compound according to the invention of formula (I) or (G) is a compound wherein W is selected from S and O, preferably W is -S; 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 compound according to the invention of formula (I) or (G) is a compound wherein
  • R 6 is selected from hydrogen, halogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl; preferably Re is selected from hydrogen, halogen and substituted or unsubstituted C 1-6 alkyl, more preferably, R 6 is hydrogen or halogen; 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 compound according to the invention of formula (I) or (G) is a compound wherein
  • X is selected from a bond, -[C(R4R4')] P - and -O- , wherein
  • R 4 and R 4' are independently selected from hydrogen and substituted or unsubstituted C 1-6 alkyl; preferably R 4 and R 4' , are hydrogen and p is 0, 1 , 2 or 3; 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 compound according to the invention of formula (I) or (G) is a compound wherein
  • Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; preferably C1-3 alkyl-cycloalkyl, substituted or unsubstituted aryl; preferably phenyl, substituted or unsubstituted alkyl-aryl, preferably C1-3 alkyl-phenyl, and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a
  • the compound according to the invention of formula (I) is a compound wherein
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, preferably substituted or unsubstituted C1-3 alkyl; substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; preferably C1-3 alkyl-cycloalkyl, preferably C1-3 alkyl-cyclopropyl; substituted or unsubstituted aryl; preferably phenyl, substituted or unsubstituted alkyl-aryl, preferably C1-3 alkyl-phenyl and substituted or unsubstituted heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • the aryl as defined in R1 if substituted, is substituted with one or more substituent/s selected from C1-6 alkyl and -O Rn , wherein
  • R11 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl.
  • Rn is unsubstituted C1-6 alkyl, preferably C1-3 alkyl, more preferably methyl.
  • the C 1-6 alkyl as defined in R 1 if substituted, is substituted with one or more substituent/s selected from unsubstituted C 1-6 alkyl, preferably unsubstituted C 1-3 alkyl, more preferably methyl, or unsubstituted C 2-6 alkenyl and unsubstituted C 2-6 alkynyl.
  • the compound according to the invention of formula (I) is a compound wherein
  • -X-R 1 is substituted or unsubstituted C 1-6 alkyl-Ri, preferably unsubstituted C 1-3 alkyl- R 1 , wherein
  • R 1 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl; preferably, R 1 is selected from hydrogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted alkyl-cycloalkyl; preferably C 1-3 alkyl -cyclopropyl, substituted or unsubstituted aryl; preferably phenyl, and substituted or unsubstituted alkyl-aryl, preferably C 1-3 alkyl-phenyl;
  • R 4 and R 4' are hydrogen; and p is 0, 1 or 2;
  • stereoisomers 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 compound according to the invention of formula (I) is a compound wherein
  • R 3 and R 3' are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl, preferably unsubstituted C 1-3 alkyl; wherein n is 0 or 1 ; 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 compound of the invention according to formula (I) is a compound, wherein
  • Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl; and/or
  • R 2 is selected from substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [Chhln -C(0)-R5; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably C1-3 alkyl, substituted or unsubstituted heterocyclyl; substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, -OR5, -
  • R 5 , R 5' or R 5 are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH 2 ] n -NR”R’”; wherein R’, R” and R’” are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, and substituted or unsubstituted C 2-6 alkynyl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted alkyl- heterocycl
  • R3 and R3' are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkyl-aryl; preferably C1- 3 alkyl-aryl and substituted or unsubstituted haloalkyl; wherein n is 0, 1 or 2; and/or
  • Re is selected from hydrogen, halogen and substituted or unsubstituted C1-6 alkyl; and/or group A is a diamine selected from wherein a and b are independently selected from 0, 1 and 2; and
  • R ? and R 7' are independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A’, R 7 and R 7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group, preferably a N-containing heterocyclyl group; and/or
  • X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q- > and -0-, wherein
  • R 4 , R 4' , R 4” and R 4” are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3; and/or
  • W is selected from S and 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.
  • the compound of the invention according to formula (I) is a compound, wherein R 2 is as represented in formula (G)
  • Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl; and/or
  • R 2 is selected from substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; and [CH 2 ]n -C(0)-Rs; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen and substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, preferably substituted or
  • aryl group when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl, OR5, NO2, NR5R5', C1-3 alkyl-aryl, CN, -NR 5 C(0)- [CH 2 ]n-NR 5 R 5” , -C(0)NR 5 -[CH 2 ]n-NR 5' R 5” , -NR 5 C(0)R 5 ⁇ , -C(0)NR 5 R 5 ⁇ , -
  • NR 5 [CH2]n-NR 5' R5 substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is not piperidine, preferably said heterocyclyl is an aromatic heterocyclyl;
  • R 5 , R 5' or R 5 are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH2] n -NR”R’”; wherein
  • R’, R” and R’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; substituted or unsubstituted alkyl- aryl, and substituted or unsubstituted alkyl-heterocyclyl; and/or R3 and R3' are independently selected from hydrogen, halogen, and substituted or unsubstituted C1-6 alkyl; wherein n is 0, 1 or 2;
  • Re is selected from hydrogen, halogen and substituted or unsubstituted C1-6 alkyl; and/or group A is a diamine selected from
  • a and b are independently selected from 0, 1 and 2;
  • R ? and R 7' are independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A, R 7 and R 7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group, preferably a N-containing heterocyclyl group; and/or
  • X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q- > and -0-, wherein R 4 , R 4' , R 4” and R 4 - are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3; and/or W is selected from S and 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.
  • the compound of the invention according to formula (I) is a compound, wherein R 2 is as represented in formula (I
  • Ri is selected from hydrogen, halogen, substituted or unsubstituted Ci- 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl; and
  • R 2 is selected from substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl- heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, and [CH 2 ] n -C(0)-R5; wherein when the cycloalkyl group is substituted the substituents are selected from the group consisting of halogen and substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl; when the heterocyclyl group is substituted the substituents are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, preferably substituted
  • NR 5 [CH2]n-NR 5' R5 substituted or unsubstituted alkyl-heterocyclyl, and substituted or unsubstituted heterocyclyl wherein said heterocyclyl is not piperidine, preferably said heterocyclyl is an aromatic heterocyclyl;
  • R 5 , R 5' or R 5 are independently selected from hydrogen, -OR’, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-alkoxy, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted aryl, substituted or unsubstituted N-containing heterocyclyl, COR’, and [CH2] n -NR”R’”; wherein
  • R’, R” and R’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; substituted or unsubstituted alkyl- aryl, and substituted or unsubstituted alkyl-heterocyclyl; and
  • R 3 and R 3' are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl; wherein n is 0, 1 or 2;
  • Re is selected from hydrogen, halogen and substituted or unsubstituted C 1-6 alkyl; and group A is a diamine selected from
  • a and b are independently selected from 0, 1 and 2;
  • R ? and R 7' are independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted alkyl-aryl; and substituted or unsubstituted haloalkyl; alternatively, in group A’, R 7 and R 7' taken together with the carbon atom to which they are attached form a substituted or unsubstituted heterocyclyl group, preferably a N-containing heterocyclyl group; and
  • X is selected from a bond, -[C(R4R4')] -, -[C(R4R4')] C(0)[C(R4”R4 )]q- > and -0-, wherein
  • R 4 , R 4' , R 4” and R 4” are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3; and
  • W is selected from S and 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.
  • the compound of the invention according to formula (I) is a compound, wherein R 2 is as represented in formula (G)
  • Ri is selected from substituted or unsubstituted C alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted alkyl-aryl, and substituted or unsubstituted heterocyclyl; and
  • R 2 is selected from substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyl-heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl and [Chhl n -C(0)-Rs; wherein when the aryl group is substituted the substituents are selected from the group consisting of halogen, substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-3 alkyl, OR5, NO2, NR5R5', C1-3 alkyl-aryl, CN, -NR 5 C(0)-[CH2] n - NR 5 R 5” , -C(0)NR 5 -[CH 2 ] n -NR
  • R’, R” and R’ are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; substituted or unsubstituted alkyl- aryl, and substituted or unsubstituted alkyl-heterocyclyl; and R 6 is hydrogen; and group A is
  • R ? and R7' are independently hydrogen; and n is 0 and X is a bond, and
  • W is S; 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 compound according to formula (I) is a compound, wherein in R 4 , R 4 ⁇ , R 4 - and R 4 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.
  • the compound according to formula (I) is a compound, wherein in R 6 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; 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 compound is a compound, wherein in R 3 and R 3 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;
  • 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 haloalkyl is selected from -CH2CI, -CH2F, -CHCb, -CHF2, -CCI3, -CF3, and -CH2-CHCI2; and/or
  • the aryl is selected from phenyl, naphtyl, and anthracenyl; preferably is napthyl and phenyl; 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 compound is a compound, wherein in R 7 and R 7 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 haloalkyl is selected from -CH 2 CI, -CH 2 F, -CHC , -CHF 2 , -CCI 3 , -CF 3 and -CH2-CHCI2; and/or
  • the aryl is selected from phenyl, naphtyl, or anthracenyl; preferably is napthyl and phenyl; 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 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 haloalkyl is selected from -CH 2 CI, -CH 2 F, -CHCI 2 , -CHF 2 , -CCI 3 , -CF 3 and -CH2-CHCI2; more preferably the haloalkyl is -CHF2 or -CF3; 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; more preferably the cycloalkyl is cyclopropyl; 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,
  • the aryl is selected from phenyl, naphtyl, or anthracenyl; preferably is napthyl and phenyl; 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 compound is a compound, wherein in R 5 , Rs ⁇ and Rs- as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C alkyl; more preferably, the Ci- 6 alkyl is 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 C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne, and isobutyne;
  • -C(0)0R 3 or -S(0) 2 0R 3' are preferably -C(0)0H and -S(0) 2 0H; 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 halogen is fluorine, bromine or chlorine.
  • 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 compound of formula (I) is selected from:
  • 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.
  • 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 methods 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.
  • Method A represents a first process for synthesizing compounds according to formula t - ln this sense, in another aspect, the invention refers to a process for the preparation of a compound of formula (I)
  • Ri, R 2 , R3, R3', R 6 , W, X, n and A have the same meaning as indicated before and Z is selected from O-alkyl, OH, Cl, N(OMe)Me and H. In a particular embodiment of the method according to the invention, Z is selected from OH and Cl.
  • a compound of formula V, where Z represents O-alkyl can be prepared by treating a compound of formula II with a suitable hydrazine of formula III, as shown in Scheme 1 , in the presence of a suitable solvent, such as ethanol, at a suitable temperature, preferably heating.
  • a compound of formula V, where Z represents OH can be prepared by reacting a compound of formula V, where Z represents O-alkyl, in basic media, such as sodium hydroxide in the presence of a suitable solvent, such as water, at a suitable temperature, between room temperature and 100 °C and optionally under microwave heating.
  • basic media such as sodium hydroxide
  • a suitable solvent such as water
  • a compound of formula V, where Z represents OH may be converted to a compound of formula V, where Z represents a chlorine atom, using thionyl chloride, in a suitable solvent, such as pyridine, at a suitable temperature, such as room temperature
  • a compound of formula (I) can be prepared by treating a compound of formula V with an amine of formula VII.
  • the reaction is carried out using a suitable coupling reagent such as N- (3-dimethylaminopropyl)-/V'-ethylcarbodiimide (EDO), dicyclohexylcarbodiimide (DCC), /V-[(dimethylamino)-1 H- 1 ,2,3-triazolo-[4,5-fc>] pyridin-1 -ylmethylene]-/V- methylmethanaminium hexafluorophosphate N- oxide (HATU) or /V,/V,/V',/V'-tetramethyl- 0-(1H- benzotriazol-1 -yl)uronium hexafluorophosphate (HBTU), optionally in the presence of 1 -hydroxybenzotriazole, optionally in the presence of an organic base such as /V-methylmorpholine or /V,/V-diisopropylethylamine, in a suitable coupling rea
  • the reaction is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran, ethyl acetate or ethyl acetate-water mixtures; in the presence of an organic base such as triethylamine or /V,/V-diisopropylethylamine or an inorganic base such as K2CO 3 ; and at a suitable temperature, preferably comprised between 0 °C and room temperature.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or ethyl acetate-water mixtures
  • an organic base such as triethylamine or /V,/V-diisopropylethylamine or an inorganic base such as K2CO 3
  • a suitable temperature preferably comprised between 0 °C and room temperature.
  • an activating agent such as 4-dimethylaminopyridine can be used.
  • a compound of formula V, where Z represents hydrogen can be prepared by reduction of a compound of formula V, where Z represents N(OMe)Me, using a suitable reagent, such as didisobutylaluminiumhydride in the presence of a suitable solvent, such as tetrahydrofuran at a suitable temperature, such as between -10 °C and room temperature.
  • a suitable reagent such as didisobutylaluminiumhydride
  • a suitable solvent such as tetrahydrofuran at a suitable temperature, such as between -10 °C and room temperature.
  • a compound of formula V, where Z represents hydrogen can be prepared using a two-step procedure that involves conversion of a compound of formula V, where Z represents OH, to a compound of formula V where Z represents N(OMe)Me, which is then reduced.
  • Z represents hydrogen
  • a compound of formula V, where Z represents N(OMe)Me can be prepared by treating a compound of formula V, where Z represents OH, with N,O-dimethylhydroxylamine using a suitable coupling reagent such as /V-(3-dimethylaminopropyl)-/V'- ethylcarbodiimide (EDO), dicyclohexylcarbodiimide (DCC), /V-[(dimethylamino)-1 /-/- 1 ,2,3-triazolo-[4,5-fc>]pyridin-1 -ylmethylene]-/V-methylmethanaminium
  • a suitable coupling reagent such as /V-(3-dimethylaminopropyl)-/V'- ethylcarbodiimide (EDO), dicyclohexylcarbodiimide (DCC), /V-[(dimethylamino)-1 /-/- 1 ,2,3
  • HATU hexafluorophosphate N- oxide
  • HBTU hexafluorophosphate N- oxide
  • 1 - hydroxybenzotriazole optionally in the presence of 1 - hydroxybenzotriazole
  • an organic base such as N- methylmorpholine or L/,/V-diisopropylethylamine
  • a suitable solvent such as dichloromethane or dimethylformamide
  • a compound of formula V, where Z represents hydrogen can be prepared by reduction of a compound of formula V, where Z represents N(OMe)Me using a suitable reagent, such as lithiumaluminium hydride in the presence of a suitable solvent, such as tetrahydrofuran at a suitable temperature, such as 0 °C.
  • a suitable reagent such as lithiumaluminium hydride
  • a suitable solvent such as tetrahydrofuran at a suitable temperature, such as 0 °C.
  • the compound of the invention can be produced according to the process explained below.
  • a process for the preparation of a compound of formula (I) wherein Ri, R 2 , R 3 , R 3' , R 6 , W, X, n and A have the same meaning as indicated before, said process comprising a) treating a compound of formula (VII)
  • Ri, R 2 , R 3 , R 3' , R 6 , W, X, n and A have the same meaning as indicated before; and Z is OH or O-alkyl; and b) treating the compound obtained in step a) with a compound of formula XI R 2 G
  • a compound of formula II (see Scheme 1 ) can be reacted with hydrazine in the presence of a suitable solvent, such as ethanol, at a suitable temperature, preferably hetating, to give a compound of formula VIII, which, using the same reaction sequence and conditions that lead from V to I, wherein Z is OH or chlorine, may produce a compound of formula XII (see Scheme 1 ).
  • a compound of formula XII may be then converted to a compound of formula I by reaction with a compound of formula XI.
  • G may be an halogen atom, such as bromo and the reaction of XII with XI is carried out in the presence of a copper salt such as Cul and a base such as N,N'- dimethyl-1 ,2-cyclohexanediamine in a suitable solvent such as toluene, at a suitable temperature, such as heating.
  • a copper salt such as Cul
  • a base such as N,N'- dimethyl-1 ,2-cyclohexanediamine
  • G may also be a B(OH) 2 group and the reaction of XII with XI is carried out in the presence of a copper salt, such as Cu(OAC) 2 , in a suitable solvent, such as dichloromethane, at a suitable temperature, such as room temperature.
  • G is a leaving group and the alkylation reaction may be carried out under alkylation conditions, in a suitable solvent, such as dimethylacetamide, isopropanol, ethanol or acetonitrile; optionally in the presence of an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as K 2 C03 or Cs 2 C03; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor.
  • a suitable solvent such as dimethylacetamide, isopropanol, ethanol or acetonitrile
  • an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as K 2 C03 or Cs 2 C03
  • the reactions can be carried out in a microwave reactor.
  • the compounds of formula II may be prepared, as described in Scheme 2, by reacting a compound of formula XIII with a compound of formula XIV, where Z is O-alkyl, in the presence of a base such as lithiumhexamethyldisilazane in a suitable solvent such as tetrahydrofuran at a suitable temperature, such as room temperature.
  • a base such as lithiumhexamethyldisilazane
  • a suitable solvent such as tetrahydrofuran
  • the invention refers to the use of a compound selected from
  • R 2 and R 6 have the same meaning as indicated above and Z is O-alkyl, OH; H or Cl for the manufacture of a compound as described above according to formula (I).
  • Certain compounds of the present invention can also be obtained starting from other compounds of formula (I) by appropriate conversion reactions of functional groups, in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions. These conversions may also be applied to any intermediate of the synthesis as depicted in Schemes 1 and 2.
  • an halogen may be converted to a cyano group by reaction with zinc cyanide in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably under heating.
  • An halogen atom may be converted to an amino derivative by using standard Buchwald coupling conditions, for instance in the presence of a suitable catalyst, such as Pd 2 (dba) 3 , a suitable base, such as NaOtBu and a suitable phosphine, such as X- Phos, in a suitable solvent, such as dioxane.
  • a suitable catalyst such as Pd 2 (dba) 3
  • a suitable base such as NaOtBu
  • a suitable phosphine such as X- Phos
  • a cyano or ester group may be hydrolyzed to a carboxylic acid using sodium hydroxide in a suitable solvent, such as methanol.
  • An amino group may be alkylated using the alkylation conditions described above or using reductive amination conditions, by treatment with a reducing agent such as sodium triacetoxyborohydride in the presence of a suitable solvent, such as dichloroethane and optionally heating using microwave irradiation.
  • a nitro group may be reduced to an amino group using for example Fe in a suitable solvent such as acetic acid, at a suitable temperature, such as heating.
  • An amino group may be acylated using a suitable acylating agent, such as an acyl chloride, in a suitable solvent such as dichloromethane, in the presence of a base such as triethylamine.
  • An alkoxy group may be converted into a hydroxyl group using a Lewis acid, such as boron tribromide in the presence of a suitable solvent, such as dichloromethane.
  • a Lewis acid such as boron tribromide
  • a suitable solvent such as dichloromethane
  • An hydrogen atom present in any of the aromatic rings of a compound of formula I may be converted to an halogen atom by treatment with a suitable halogenating agent, such as bromine, in the presence of a suitable solvent, such as acetic acid.
  • 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.
  • Boc tert - butoxycarbonyl
  • Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl
  • common silyl protecting groups for the protection of the hydroxyl group.
  • 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.
  • the resolution step can be carried out at a previous stage, using any suitable intermediate.
  • 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.
  • compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
  • 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.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 offormula I, ora pharmaceutically acceptable salt or isomer thereof, for use in the treatment or prophylaxis of pain.
  • 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.
  • 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.
  • a compound as above defined or a pharmaceutical composition thereof is administered 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.
  • 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.
  • DIPEA N,N-Diisopropylethylamine
  • EDC-HCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • EtOAc Ethyl acetate Et 2 0: Diethyl ether EtOH: Ethanol h: Hour/s
  • HATU (1-[Bis(dimethylamino)methylene]-1 /-/-1 ,2,3-triazolo[4,5-5]pyridinium 3-oxid hexafluorophosphate)
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • Step b 6-Oxaspiro[4.5]decan-9-one.
  • step a To a solution of the compound obtained in step a (444 mg, 2.84 mmol), 4- methylmorpholine 4-oxide (666 mg, 5.68 mmol) in anhydrous DCM (10 ml_), molecular sieves 4 A was added and the mixture was stirred at rt for 30 min. Tetrapropylammonium perruthenate (30 mg, 0.085 mmol) was added portion wise and the mixture was stirred at room temperature overnight. The reaction mixture was filtrated through celite, washed with DCM and solvent was removed under vacuum to give the title compound (390 mg, Yield: 89%).
  • Step c tert- butyl 2-(6-oxaspiro[4.5]decan-9-yl)hydrazinecarboxylate.
  • tert- butyl hydrazinecarboxylate 368 mg, 2.79 mmol
  • Solvent was removed under vacuum and AcOH (6.6 ml_)
  • sodium cianoborohydride (175 mg, 2.79 mmol) were added and the reaction mixture was stirred at rt overnight.
  • the mixture was basified to pH:7 with NaOH 6N and the product was extracted with DCM.
  • the combined organic layers were dried over Na 2 S0 4, filtered and concentrated under vacuum to give the title compound (526 mg, Yield: 77%).
  • Step d 6-Oxaspiro[4.5]decan-9-ylhydrazine hydrochloride.
  • Step a tert- butyl 3-(methyl(phenethyl)amino)piperidine-1-carboxylate.
  • step a To a solution of the compound obtained in step a (22 mg, 0.068 mmol) in DCM (2 ml_), TFA was added (101 mI_, 1.34 mmol) and the mixture was stirred at rt overnight. NaHC03 sat sol was added and the crude product was extracted with DCM. The combined organic layers were joined and dried over Na2S04, filtered and concentrated to dryness to give the title compound (13 mg, Yield: 89%).
  • Example 1 (1 -(4-Ethoxyphenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4- ethylpiperazin-1 -yl)methanone.
  • Step a Ethyl 2-oxo-2-(4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-5-yl)acetate.
  • Step b Ethyl 1 -(4-ethoxyphenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylate.
  • step a To a solution of the compound obtained in step a (165 mg, 0.62 mmol) in EtOH (2 ml.) under Ar atmosphere, (4-ethoxyphenyl)hydrazine hydrochloride (128 mg, 0.68 mmol) was added portion wise and the reaction was heated at 65 °C for 3 h. The crude mixture was evaporated under vacuum and the crude product was purified by flash chromatography, silica gel, gradient CH to CH:EtOAc (9:1 ) to give the title compound (207 mg, Yield: 91 %).
  • Step c 1-(4-Ethoxyphenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylic acid.
  • step c To a solution of the compound obtained in step c (177 mg, 0.52 mmol) in anhydrous DCM (10 ml.) under Ar atmosphere, EDC-HCI (199 mg, 1.04 mmol), HOBt (159 mg, 1.04 mmol) and TEA (362 mI_, 2.60 mmol) were added and the reaction was stirred at rt for 10 min. Then, 1-ethylpiperazine (99 mI_, 0.78 mmol) was added drop wise and the reaction was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with H2O. The organic layer was dried over Na 2 S0 4 , filtered and concentrated under vacuum to give the title compound (220 mg, Yield: 92%).
  • Example 36 was obtained using intermediate 1.
  • Example 117 (4-Methylpiperazin-1 -yl)(1 -(piperidin-4-yl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone.
  • Step a Ethyl 1-(1-(fe/f-butoxycarbonyl)piperidin-4-yl)-4,5-dihydro-1 /-/-thieno[2,3- g]indazole-3-carboxylate.
  • Step b 1 -(1 -(fe/f-Butoxycarbonyl)piperidin-4-yl)-4, 5-dihydro- 1 /-/-thieno[2,3-g]indazole- 3-carboxylic acid.
  • Step c tert- Butyl 4-(3-(4-methylpiperazine-1-carbonyl)-4,5-dihydro-1 /-/-thieno[2,3- g]indazol-1 -yl)piperidine-1 -carboxylate.
  • step c To a solution of the compound obtained in step c (50 mg, 0.103 mmol) in DCM (3 ml_), TFA (244 mI_, 3.3 mmol) was added and the reaction mixture was stirred at rt overnight. Aqueous NaHCC>3 sat sol was added and the mixture was extracted with DCM. The organic layers were joined and dried over Na2S0 4 , filtered and concentrated to dryness to give the title compound (30 mg, Yield: 76%).
  • Example 121 (4-Methylpiperazin-1 -yl)(1 -(1 -phenethylpiperidin-4-yl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)methanone.
  • Step a Ethyl 1-(piperidin-4-yl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylate.
  • Step b Ethyl 1-(1-phenethylpiperidin-4-yl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylate.
  • Step c 1 -(1 -Phenethylpiperidin-4-yl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylic acid.
  • step b Starting from the compound obtained in step b (38.4 mg, 0.088 mmol) and following the procedure described in step c of Example 1 , the title compound was obtained (33 mg, Yield: 26%).
  • Example 123 (4-Aminopiperidin-1 -yl)(1 -phenyl-4, 5-dihydro-1H-thieno[2, 3- g]indazol-3-yl)methanone.
  • Step a Ethyl 1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylate.
  • Step b 1 -Phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylic acid.
  • Step c tert- Butyl (1-(1 -phenyl-4, 5-dihydro-1 /-/-thieno[2, 3-g]indazole-3- carbonyl)piperidin-4-yl)carbamate.
  • step d Starting from the compound obtained in step b (282 mg, 0.95 mmol) and following the procedure described in step d of Example 1 , the title compound was obtained (112 mg, Yield: 93 %). Step d. Title compound.
  • step c Starting from the compound obtained in step c (1 12 mg, 0.233 mmol)) and following the procedure described in step d of Example 117, the title compound was obtained (90 mg, Yield: 93%).
  • Example 134 /V-(2-Aminoethyl)-1 -phenyl-4, 5-dihydro-1H-thieno[2,3-g]indazole-3- carboxamide.
  • Step a tert- Butyl (2-(1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)ethyl)carbamate.
  • step b Starting from the compound obtained in step b (2.0 g, 12.3 mmol) of example 123 and following the experimental procedure described in step d of Example 1 , the title compound was obtained (2.9 g, Yield: 98%).
  • Step b Title compound. Starting from the compound obtained in step a (3.4 g, 7.7 mmol) and following the experimental procedure described in step d of Example 1 17, the title compound was obtained (2.6 g, Yield: 99%).
  • Example 134 Starting from the compound obtained in Example 134 (100 mg, 0.295 mmol) dissolved in DCE (10 ml_); formaldehyde (22.2 mI_, 0.27 mmol) and NaBH(OAc) 3 (188 mg, 0.89 mmol) were added and the mixture was heated under MW irradiation (150 W) at 120 °C for 5 min. Aqueous NaHCC>3 sat sol was added and the crude product was extracted with DCM. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (90:10) to give the title compound (75 mg, Yield: 69%).
  • Step a tert- Butyl (2-(1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)ethyl)carbamate.
  • Example 134 The compound obtained in Example 134 (200 mg, 0.59 mmol) dissolved in anhydrous DCM (5 ml.) under Ar atmosphere was treated with BOC2O (129 mg, 0.59 mmol) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was washed with water, aqueous NaHCC>3 sat sol, NaCI and the crude product was extracted with DCM. The combined organic layers were dried over Na 2 S0 4 and filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient CH to CH/EtOAc (70:30) to give the title compound (235 mg, Yield: 91 %).
  • Step b tert- Butyl methyl(2-(/V-methyl-1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)ethyl)carbamate.
  • step a To a solution of the compound obtained in step a (175 mg, 0.4 mmol) in anhydrous DMF (10 ml_), NaH (60% dispersion oil, 24 mg, 0.6 mmol) was added portion wise at 0 °C. Then, iodomethane (1 13 mg, 0.8 mmol) was added and the reaction mixture was heated at 65 °C overnight. The reaction mixture was diluted with aqueous NaHCC>3 sat sol and the crude product was extracted with EtOAc/hhO (1 :1 ). The combined organic layers were dried over Mg 2 S0 4 , filtered and concentrated. The solvent was removed under vacuum and the crude product was purified by flash chromatography, silica gel, gradient CH to CH/EtOAc (75:25) to give the title compound (100 mg, Yield: 54%).
  • step b Starting from the compound obtained in step b (100 mg, 0.21 mmol) and following the experimental procedure described in step d of Example 134, the title compound was obtained (74.7 mg, Yield: 95 %).
  • Step a tert- Butyl methyl(2-(1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)ethyl)carbamate.
  • step a Starting from the compound obtained in step a (245 mg, 0.54 mmol) and following the experimental procedure described in step d of Example 134, the title compound was obtained (189 mg, Yield: 99%).
  • Example 139 /V-Benzyl-N-(2-(methylamino)ethyl)-1 -phenyl-4, 5-dihydro-1 H- thieno[2,3-g]indazole-3 -carboxamide.
  • Step a tert- Butyl (2-(/V-benzyl-1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)ethyl)carbamate.
  • Step b tert- Butyl (2-(/V-benzyl-1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)ethyl)(methyl)carbamate.
  • step a Starting from the compound obtained in step a (90 mg, 0.14 mmol) and following the experimental procedure described in step b of Exemple 136, the title compound was obtained (67 mg, Yield: 77 %). Step c. Title compound.
  • Example 140 (4-Ethylpiperazin-1 -yl)(1 -phenyl-4, 5-dihydro-1H-furo[2,3-g]indazol- 3-yl)methanone.
  • Step a Ethyl 2-oxo-2-(4-oxo-4,5,6,7-tetrahydrobenzofuran-5-yl)acetate.
  • Step b Ethyl 1 -phenyl-4, 5-dihydro-1 /-/-furo[2,3-g]indazole-3-carboxylate.
  • the title compound was obtained (90 mg, Yield:42 %).
  • Step c. 1 -Phenyl-4, 5-dihydro-1 /-/-furo[2,3-g]indazole-3-carboxylic acid
  • step b Starting from the compound obtained in step b (90 mg, 0.29 mmol) and following the experimental procedure described in step c of Example 1 , the title compound was obtained (75 mg, Yield:92 %).
  • step c Starting from the compound obtained in step c (75 mg, 0.27 mmol) and following the experimental procedure described in step d of Example 1 , the title compound was obtained ( mg, Yield:42 %).
  • Example 141 (1 -(4-Amino-2-chlorophenyl)-4,5-dihydro-1H-thieno[2,3-g]indazol- 3-yl)(4-methylpiperazin-1 -yl)methanone.
  • Step a Ethyl 1-(2-chloro-4-nitrophenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylate.
  • Step b 1-(2-Chloro-4-nitrophenyl)-4,5-dihydro-1/-/-thieno[2,3-g]indazole-3-carboxylic acid.
  • step a To a solution of the compound obtained in step a (1.1 g, 2.72 mmol) in MeOH (15 ml_), a solution of LiOH (290 mg, 12.1 mmol) in water (8 ml.) was added. The reaction mixture was stirred at rt overnight. DCM was added and the aqueous layer was acidified to pH: 2 with 2 N HCI. The aqueous phase was extracted with DCM and the combined organic layers were dried over Na2S0 4 , filtered and concentrated under vacuum, to give the title compound (970 mg, Yield: 95%).
  • Step c (1 -(2-Chloro-4-nitrophenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1 -yl)methanone.
  • step b Starting from the compound obtained in step b (450 mg, 1.2 mmol) and following the procedure described in step d of Example 1 , the title compound was obtained (540 mg, Yield: 98%).
  • step c To a solution of the compound obtained in step c (100 mg, 0.218 mmol) in H 2 0:AcOH (1 :3, 2.7 ml_), Fe (61 mg, 1.09 mmol) was added and the mixture was heated at 50 °C for 1.5 h. The reaction mixture was filtrated and the filtrate was diluted with water and the mixture extracted with DCM. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (88:12) to give the title compound (86 mg, Yield: 81%).
  • Example 144 /V-(3-Chloro-4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1H- thieno[2,3-g]indazol-1 -yl)phenyl)acetamide.
  • Example 141 To a solution of the Example 141 (230 mg, 0.537 mmol) in anhydrous DCM (20 ml.) under Ar atmosphere, TEA (281 mI_, 1.6 mmol) was added and the mixture was stirred at rt for 15 min. Then, acetyl chloride (57 mI_, 0.81 mmol) was added drop wise and the mixture was stirred at rt overnight.
  • the crude product was diluted with aqueous NaHCCh sat sol and the product was extracted with DCM and washed with water. The combined organic layers were dried over Na2S0 4 , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM/MeOH (90:10) to give the title compound (105 mg, Yield: 42%).
  • MLM- 3043 To a solution of the Example 141 (230 mg, 0.537 mmol) in anhydrous DCM (20 ml.) under Ar atmosphere
  • Example 148 and 149 were obtained as by-products of the acetylation reaction.
  • Example 150 1 -Methyl-/V-(4-(3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)phenyl)-1 H-pyrazole-3 -carboxamide.
  • Example 64 Starting from the compound obtained in Example 64 (40 mg, 0.1 mmol) and following the method described in Example 144, but using 1 -methyl-1 H-pyrazole-3-carbonyl chloride instead of acetyl chloride the title compound was obtained (8.1 mg, Yield 15%).
  • Example 16 /V-Methyl-/V-(2-(methylamino)ethyl)-4-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)benzamide.
  • Step a 4-(3-(Ethoxycarbonyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazol-1-yl)benzoic acid.
  • the title compound was obtained (1 g, Yield 69%).
  • Step b Ethyl 1 -(4-((2-((ferf- butoxycarbonyl)(methyl)amino)ethyl)(methyl)carbamoyl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carboxylate.
  • the title compound was obtained (182 mg, Yield 99%).
  • step b Starting from the compound obtained in step b (221 mg, 0.41 mmol) and following the method described in step b of Example 141 , the title compound was obtained (209 mg, Yield: quantitative).
  • Step d tert- Butyl methyl(2-(N-methyl-4-(3-(4-methylpiperazine-1-carbonyl)-4,5- dihydro-1 /-/-thieno[2,3-g]indazol-1 -yl)benzamido)ethyl)carbamate.
  • step d Starting from the compound obtained in step d (26 mg, 0.043 mmol) and following the method described in step d of Example 117, the title compound was obtained (12.5 mg, Yield: 58%).
  • Example. 167 (4-Ethylpiperazin-1 -yl)(1 -(4-(2-morpholinoethoxy)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone.
  • Step a Ethyl 1-(4-methoxyphenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylate.
  • Step b 1-(4-Hydroxyphenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylic acid.
  • step a To a solution of the compound obtained in step a (161 mg, 0.454 mmol) in DCM (1.5 ml.) cooled at - 40 0 C, BBr3 (1 M in DCM, 9 ml_, 9 mmol) was added and the mixture was stirred at - 40 °C for 2 h. The reaction mixture was allowed to reach rt and then was diluted with aqueous NaHCC>3 sat sol until neutral pH. The aqueous phase was extracted with DCM and the combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under vacuum, to give the title compound (142 mg, Yield: 99%).
  • Step c (4-Ethylpiperazin-1-yl)(1-(4-hydroxyphenyl)-4,5-dihydro-1 /-/-thieno[2,3- g]indazol-3-yl)methanone.
  • step b Starting from the compound obtained in step b (70 mg, 0.224 mmol) and following the method described in step d of Example 1 , the title compound was obtained (65 mg, Yield 71 %).
  • step c To a solution of the compound obtained in step c (65 mg, 0.16 mmol) and Cs 2 CC> 3 (129 mg, 0.395 mmol) in anhydrous ACN (4 ml_), 4-(2-chloroethyl)morpholine hydrochloride (59 mg, 0.32 mmol) was added and the mixture was heated at 80 °C overnight. The reaction mixture was concentrated under vacuum, diluted with aqueous NaHCC>3 sat sol and the crude product was extracted with EtOAc. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (90:10) to give the title compound (32 mg, Yield: 38%).
  • Example 169 (1 -(4-(Methyl(2-(methylamino)ethyl)amino)phenyl)-4,5-dihydro-1H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone.
  • Example 59 A solution of the Example 59 (100 mg, 0.219 mmol) in anhydrous dioxane (10 mL) was added to a closed tube charged with Pd 2 (dba) 3 (10 mg, 0.011 mmol), NaOtBu (104.1 mg, 0.743 mmol), X-Phos (10.4 mg, 0.022 mmol) and /V ⁇ /V ⁇ dimethylethane-1 ,2- diamine (25.6 mI_, 0.240 mmol) under Ar atmosphere. The mixture was heated at 110 °C for 4 h, filtered through celite and washed with DCM. Solvent was removed under vacuum and the crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (80:20) to give the title compound (40 mg, Yield: 39%).
  • Example. 170 W-Ethyl-/V-((1 -phenethylpiperidin-3-yl)methyl)-1 -phenyl-4, 5- dihydro-1 H-thieno[2,3-g]indazole-3-carboxamide.
  • Step a tert- Butyl 3-((N-ethyl-1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)methyl)piperidine-1-carboxylate.
  • Step b /V-Ethyl-1 -phenyl-/V-(piperidin-3-ylmethyl)-4,5-dihydro-1 /-/-thieno[2,3- g]indazole-3-carboxamide.
  • step b To a solution of the product obtained in step b (52 mg, 0.124 mmol), DIPEA (33 mI_, 0.187 mmol) in ACN (2 ml_), (2-bromoethyl)benzene (15 mI_, 0.106 mmol) was added and the reaction mixture was heated under MW irradiation (150 W) at 120 °C for 30 min. The solvent was removed under vacuum and the crude product was dissolved in EtOAc and aqueous NaHCC>3 sat sol.
  • Example 17 (3-(Methyl(phenethyl)amino)piperidin-1 -yl)(1 -phenyl-4, 5-dihydro- 1H-thieno[2,3-g]indazol-3-yl)methanone.
  • the title compound was obtained (4 mg, Yield: 14%).
  • Example 172 W-Methyl-/V-((1 -phenethylpiperidin-3-yl)methyl)-1 -phenyl-4, 5- dihydro-1 H-thieno[2,3-g]indazole-3 -carboxamide.
  • Step a tert- Butyl 3-((N-methyl-1 -phenyl-4, 5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxamido)methyl)piperidine-1 -carboxylate.
  • step b of example 134 50 mg, 0.169 mmol
  • step d of Example 1 the title compound was obtained (85 mg, Yield: 99%).
  • Step b /V-Methyl-1 -phenyl-/V-(piperidin-3-ylmethyl)-4,5-dihydro-1 H- thieno[2,3- g]indazole-3-carboxamide.
  • step a Starting from the product obtained in step a (85 mg, 0.168 mmol) and following the experimental procedure described in step d of Example 117, the title compound was obtained (67 mg, Yield: 99%).
  • step b Starting from the product obtained in step b (78 mg, 0.192 mmol) and following the experimental procedure described in step e of Example 170, the title compound was obtained (1 1 mg, Yield: 12%).
  • Example 17 /V-(4-(7-Bromo-3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)phenyl)acetamide.
  • Step a 2-Bromo-6,7-dihydrobenzo[t)]thiophen-4(5/-/)-one.
  • Step b Ethyl 2-(2-bromo-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-5-yl)-2- oxoacetate.
  • step a Starting from the product obtained in step a (1.0 g, 4.33 mmol) and following the experimental procedure described in step a of Example 1 , the title compound was obtained (1.3 g, Yield: 91%).
  • Step c Ethyl 1-(4-acetamidophenyl)-7-bromo-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylate.
  • step b Starting from the product obtained in step b (1.3 g, 3.94 mmol) and following the experimental procedure described in step b of Example 1 , the title compound was obtained (780 mg, Yield: 43%).
  • Step d 1 -(4-Acetamidophenyl)-7-bromo-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylic acid.
  • the title compound was obtained (120 mg, Yield: 68%).
  • Step e /V-(4-(7-Bromo-3-(4-methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H- thieno[2,3- g]indazol-1 -yl)phenyl)acetamide.
  • step d Starting from the product obtained in step d (250 mg, 0.578 mmol) and following the experimental procedure described in step d of Example 1 , the title compound was obtained (70 mg, Yield: 23%).
  • Example 174 (4-Methylpiperazin-1 -yl)(1 -(2-morpholinoethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)methanone.
  • Step a Ethyl 1 -(2-hydroxyethyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylate.
  • Step b Ethyl 1 -(2-((methylsulfonyl)oxy)ethyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylate.
  • step b To a solution of the compound obtained in step b (51 mg, 0.138 mmol), morpholine (10 mg, 0.115 mmol) and K 2 CC> 3 (31.7 mg, 0.230 mmol) were added and the reaction mixture was stirred at 80 °C overnight. The mixture was added drop wise into cold water and it was extracted with EtOAc. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (90:10) to give the title compound, (26 mg, Yield: 64%).
  • Step d 1-(2-Morpholinoethyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylic acid.
  • step c Starting from the product obtained in step c (26 mg, 0.073 mmol) and following the experimental procedure described in step c of Example 1 , the title compound was obtained (19 mg, Yield: 77%).
  • step d Starting from the product obtained in step d (19 mg, 0.056 mmol) and following the experimental procedure described in step d of Example 1 , the title compound was obtained (21 mg, Yield: 90%).
  • Example 178 1 -(4,6-Dimethyl-1 ,4-diazepan-1 -yl)-2-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)ethanone.
  • Step a Ethyl 4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylate.
  • Step b 4,5-Dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylic acid.
  • step a Starting from the product obtained in step a (4.48 g, 18 mmol) and following the experimental procedure described in step c of Example 1 , the title compound was obtained (525 mg, Yield: 13%).
  • Step c (4,5-Dihydro-1 /-/-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone.
  • step b Starting from the product obtained in step b (565 mg, 2.56 mmol) and following the experimental procedure described in step d of Example 1 , the title compound was obtained (525 mg, Yield: 37%).
  • Step d 1 -(4,6-Dimethyl-1 ,4-diazepan-1 -yl)-2-(3-(4-methylpiperazine-1 -carbonyl)-4,5- dihydro-1 /-/-thieno[2,3-g]indazol-1 -yl)ethanone.
  • step c To a solution of the product obtained in step c (320 mg, 1.058 mmol), intermediate 4 (260 mg, 1.27 mmol) in anhydrous DMA (15 ml.) and CS2CO3 (689.6 mg, 2.1 1 mmol) were added and the mixture was heated at 100 °C for 2 h. The solvent was removed under vacuum, and the residue was dissolved in EtOAc and washed with water. The combined organic layers were dried over Na2S0 4 , filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (80:20) to give the title compound (95 mg, Yield: 20%).
  • Example 179 6-(3-(4-(Cyclopropylmethyl)piperazine-1 -carbonyl)-4,5-dihydro-1H- thieno[2,3-g]indazol-1 -yl)isobenzofuran-1 (3H)-one.
  • Step a (4-(Cyclopropylmethyl)piperazin-1 -yl)(4,5-dihydro-1 /-/-thieno[2,3-g]indazol-3- yl)methanone.
  • step a A solution of the product obtained in step a (80 mg, 0.234 mmol), 6- bromoisobenzofuran-1 (3/-/)-one (60 mg, 0.28 mmol), (1 R,2R)-N 1 ,N 2 - dimethylcyclohexane-1 ,2-diamine (6.65 mg, 0.047 mmol), K2CO3 (64.6 mg, 0.47 mmol) and Cul (2.25 mg, 0.012 mmol) in toluene (1 ml.) under atmosphere of Ar, was heated under MW irradiation (150 W) at 130 °C for 2 h.
  • Example 18 (1 -(4-(Methylamino)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1 -yl)methanone.
  • Step a Ethyl 4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylate.
  • step a of example 1 500 mg, 1.98 mmol
  • step b of example 1 the title compound was obtained (533 mg, Yield: 81 %).
  • Step b Ethyl 1-(4-(methylamino)phenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3- carboxylate.
  • step a 50 mg, 0.2 mmol
  • step b the title compound was obtained (53 mg, Yield: 74%).
  • Step c 1 -(4-(Methylamino)phenyl)-4,5-dihydro-1 /-/-thieno[2,3-g]indazole-3-carboxylic acid.
  • the title compound was obtained (48 mg, Yield: 49%).
  • step c Starting from the product obtained in step c (24 mg, 0.075 mmol) and following the experimental procedure described in step 2 of example 1 , the title compound was obtained (5.5 mg, Yield: 20%).
  • Human a,2d-1 enriched membranes (2.5 pg) were incubated with 15 nM of radiolabeled [3H]-Gabapentin in assay buffer containing Hepes-KOH 10mM, pH 7.4.
  • NSB non specific binding
  • the binding of the test compound was measured at either one concentration (% inhibition at 1 mM or 10 mM) or five different concentrations to determine affinity values (K,).
  • 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 scintillation cocktail (30 mI_) were added to each well before radioactivity reading. Readings were performed in a Trilux 1450 Microbeta radioactive counter (Perkin Elmer).
  • transfected HEK-293 membranes and [ 3 H](+)-pentazocine (Perkin Elmer, NET-1056), as the radioligand, were used.
  • the assay was carried out with 7 pg of membrane suspension, 5 nM of [ 3 H](+)-pentazocine in either absence or presence of either buffer or 10 mM Haloperidol for total and non-specific binding, respectively.
  • Binding buffer contained Tris-HCI 50 mM at pH 8. Plates were incubated at 37 °C for 120 min.
  • reaction mix was then transferred to Multiscreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris- HCL (pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail.
  • this invention is aimed at providing a compound or a chemically related series of compounds which act as ligands of the a 2 d subunit of voltage-gated calcium channels or as dual ligands of the a 2 d subunit of voltage-gated calcium channels and the s1 receptor it is a very preferred embodiment in which the compounds are selected which act as single ligands of the a 2 d subunit of voltage-gated calcium channels or as dual ligands of the a 2 d subunit of voltage-gated calcium channels and the s1 receptor and especially compounds which have a binding expressed as K, responding to the following scales:
  • K, (s1 ) is preferably ⁇ 1000 nM and more preferably ⁇ 500 nM.
  • K ⁇ (a 2 d-1 ) is preferably ⁇ 10000 nM, more preferably ⁇ 5000 nM, even more preferably
  • the following scale has been adopted for representing the binding to s1 receptor expressed as K,:

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Abstract

La présente invention concerne des dérivés de dihydroindazole fusionnés ayant une activité pharmacologique vis-à-vis de la sous-unité α2δ, en particulier de la sous-unité α2δ, du canal calcique dépendant de la tension. L'invention concerne également des composés ayant une activité pharmacologique double envers à la fois la sous-unité α2δ, en particulier la sous-unité α2δ, du canal calcique dépendant de la tension et du récepteur δ1. La présente invention concerne en outre des procédés de préparation de ces composés, des compositions pharmaceutiques les comprenant, ainsi que leur utilisation thérapeutique, en particulier pour le traitement de la douleur.
PCT/EP2019/069277 2018-07-20 2019-07-17 Dérivés de dihydroindazole fusionnés ayant une activité multimodale contre la douleur WO2020016315A1 (fr)

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