WO2019121670A1

WO2019121670A1 - 4,5-dihydro-1h-thieno[2,3-g]indazolyl derivatives having multimodal activity against pain

Info

Publication number: WO2019121670A1
Application number: PCT/EP2018/085479
Authority: WO
Inventors: Lourdes GARRIGA-SANAHUJA; Rosalía PASCUAL-RAMON; Carmen ALMANSA-ROSALES; José-Luís DÍAZ-FERNÁNDEZ
Original assignee: Esteve Pharmaceuticals, S.A.
Priority date: 2017-12-20
Filing date: 2018-12-18
Publication date: 2019-06-27

Abstract

wherein the meanings for the various substituents are as disclosed in the description, having dual pharmacological activity towards both the α2δ subunit, in particular the α2δ-1 subunit, of the voltage-gated calcium channel and the μ-opioid receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

Description

4,5-DIHYDRO-1 H-THIENO[2,3-G]INDAZOLYL DERIVATIVES HAVING

MULTIMODAL ACTIVITY AGAINST PAIN

FIELD OF THE INVENTION

The present invention relates to compounds having dual pharmacological activity towards both the a₂d subunit of the voltage-gated calcium channel, and the m-opioid receptor (MOR or mu-opioid receptor), and more particularly to 4,5-Dihydro-1 H- thieno[2,3-g]indazolyl derivatives having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

BACKGROUND OF THE INVENTION

The adequate management of pain constitutes an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved (Turk, D.C., Wilson, H.D., Cahana, A.; 201 1 ; Lancet ; 377; 2226- 2235). Pain affects a big portion of the population with an estimated prevalence of 20 % and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which lead to important productivity losses and socio- economical burden (Goldberg, D.S., McGee, S.J.; 201 1 ; BMC Public Health ; 1 1 ; 770). Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.

Voltage-gated calcium channels (VGCC) are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et al., Pharmacol. Rev. 2015 67:821 -70). The VGCC are assembled through interactions of different subunits, namely oti (Ca_vai), b (Ca_vp) a₂d (Ca_va₂3) and g (Ca_vy). The oti subunits are the key porous forming units of the channel complex, being responsible for the Ca²⁺ conduction and generation of Ca²⁺ influx. The a₂d, b, and g subunits are auxiliary, although very important for the regulation of the channel, since they increase the expression of the oti subunits in the plasma membrane as well as modulate their function, resulting in functional diversity in different cell types. Based on their physiological and pharmacological properties, VGCC can be subdivided into low voltage- activated T-type (Ca_v3.1 , Ca_v3.2, and Ca_v3.3), and high voltage-activated L- (Ca_v1 .1 through Ca_v1 .4), N-(Ca_v2.2), P/Q-(Ca_v2.1 ), and R-(Ca_v2.3) types, depending on the channel forming Cava subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1 ) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo, Neurotherapeutics. 2009 6:679-92; Zamponi et al., 2015 supra ; Neumaier et al., Prog. Neurobiol. 2015 129:1 -36.). A large body of data has clearly indicated that VGCC are implicated in mediating various disease states including pain processing. Drugs interacting with the different calcium channel subtypes and subunits have been developed. Current therapeutic agents include drugs targeting L-type Ca_v1 .2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca_v3) channels are the target of ethosuximide, widely used in absence epilepsy. Ziconotide, a peptide blocker of N-type (Ca_v2.2) calcium channels, has been approved as a treatment of intractable pain. (Perret and Luo, 2009, supra, Vink and Alewood, Br J Pharmacol. 2012 167:970-89.).

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

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

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

As mentioned above, the 0,₂6 subunits of VGCC form the binding site for gabapentin and pregabalin, which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations. The binding of gabapentin and pregabalin to the Ca_vot₂5 subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management. Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009, supra, Vink and Alewood, 2012, supra, Zamponi et al., 2015, supra).

As mentioned before, there are few available therapeutic classes for the treatment of pain, and opioids are among the most effective, especially when addressing severe pain states. They act through three different types of opioid receptors (mu, kappa and gamma) which are transmembrane G-protein coupled receptors (GPCRs). Still, the main analgesic action is attributed to the activation of the m-opioid receptor (MOR). However, the general administration of MOR agonists is limited due to their important side effects, such as constipation, respiratory depression, tolerance, emesis and physical dependence [Meldrum, M.L. (Ed.). Opioids and Pain Relief: A Historical Perspective. Progress in Pain Research and Management, Vol 25. IASP Press, Seattle, 2003]. Additionally, MOR agonists are not optimal for the treatment of chronic pain as indicated by the diminished effectiveness of morphine against chronic pain conditions. This is especially proven for the chronic pain conditions of neuropathic or inflammatory origin, in comparison to its high potency against acute pain. The finding that chronic pain can lead to MOR down-regulation may offer a molecular basis for the relative lack of efficacy of morphine in long-term treatment settings [Dickenson, A.H., Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur J Pain 9, 1 13-6 (2005)]. Moreover, prolonged treatment with morphine may result in tolerance to its analgesic effects, most likely due to treatment-induced MOR down-regulation, internalization and other regulatory mechanisms. As a consequence, long-term treatment can result in substantial increases in dosing in order to maintain a clinically satisfactory pain relief, but the narrow therapeutic window of MOR agonists finally results in unacceptable side effects and poor patient compliance.

Polypharmacology is a phenomenon in which a drug binds multiple rather than a single target with significant affinity. The effect of polypharmacology on therapy can be positive (effective therapy) and/or negative (side effects). Positive and/or negative effects can be caused by binding to the same or different subsets of targets; binding to some targets may have no effect. Multi-component drugs or multi-targeting drugs can overcome toxicity and other side effects associated with high doses of single drugs by countering biological compensation, allowing reduced dosage of each compound or accessing context-specific multitarget mechanisms. Because multitarget mechanisms require their targets to be available for coordinated action, one would expect synergies to occur in a narrower range of cellular phenotypes given differential expression of the drug targets than would the activities of single agents. In fact, it has been experimentally demonstrated that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities, such selectivity is achieved through differential expression of the drugs’ targets in cell types associated with therapeutic, but not toxic, effects (Lehar et al., Nat Biotechnol 2009; 27: 659-666.).

In the case of chronic pain, which is a multifactorial disease, multi-targeting drugs may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive pain. Because they actually make use of biological complexity, multi- targeting (or multi-component drugs) approaches are among the most promising avenues toward treating multifactorial diseases such as pain (Gilron et al., Lancet Neurol. 2013 Nov;12(1 1 ):1084-95.). In fact, 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). Given the significant differences in pharmacokinetics, metabolisms and bioavailability, reformulation of drug combinations (multi-component drugs) is challenging. Further, two drugs that are generally safe when dosed individually cannot be assumed to be safe in combination. In addition to the possibility of adverse drug-drug interactions, if the theory of network pharmacology indicates that an effect on phenotype may derive from hitting multiple targets, then that combined phenotypic perturbation may be efficacious or deleterious. The major challenge to both drug combination strategies is the regulatory requirement for each individual drug to be shown to be safe as an individual agent and in combination (Hopkins, Nat Chem Biol. 2008; 4:682-90.).

An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008, supra).

Thus, the present application, relates to the advantages of having dual activity, for m- receptor and the a₂d-1 subunit of voltage-gated calcium channels, in the same molecule to treat chronic pain.

In this way, the present invention relates to compounds having a complementary dual mechanism of action (m-receptor agonist and blocker of the a₂d subunit, in particular the a₂d-1 subunit, of voltage-gated calcium channels) which implies a better profile of tolerability than the strong opioids (morphine, oxycodone, fentanyl etc) and/or better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin).

Pain is multimodal in nature, since in nearly all pain states several mediators, signaling pathways and molecular mechanisms are implicated. Consequently, monomodal therapies fail to provide complete pain relief. Currently, combining existing therapies is a common clinical practice and many efforts are directed to assess the best combination of available drugs in clinical studies (Mao, J., Gold, M.S., Backonja, M.; 201 1 ; J. Pain; 12; 157-166). Accordingly, there is still a need to find compounds that have an alternative or improved pharmacological activity in the treatment of pain, being both effective and showing the desired selectivity, and having good“drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion. The inventors have found a series of compounds showing dual pharmacological activity towards both the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel, and the m-opioid receptor (MOR or mu-opioid receptor) resulting in an innovative, effective and alternative solution for the treatment of pain.

In view of the existing results of the currently available therapies and clinical practices, the present invention offers a solution 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 both to the m-opioid receptor and to the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel.

SUMMARY OF THE INVENTION

The inventors have found a series of compounds, encompassed by formula (I), that show a dual pharmacological activity towards both the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel, and the m-opioid receptor thus solving the above problem of identifying alternative or improved pain treatments by offering such dual compounds.

The main object of the invention is directed to a compound having a dual activity binding to the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel and the m-opioid 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),

wherein Ri, Rr R₂, Rs, R6, W₃, W₄, X, Y and A are as defined below in the detailed description. A further aspect of the invention refers to the processes for preparation of compounds of formula (I).

A still further aspect of the invention refers to the use of intermediate compounds for the preparation of a compound of formula (I).

It is also an aspect of the invention a pharmaceutical composition comprising a compound of formula (I).

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

DETAILED DESCRIPTION OF THE INVENTION The invention is directed to a family of compounds which have a dual pharmacological activity towards both the a₂d subunit, in particular the a₂d-1 subunit, of the voltage-gated calcium channel, and the m-opioid 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 for treating pain and pain related disorders can be solved by using a multimodal balanced analgesic approach combining two different synergistic activities in a single drug (i.e., dual ligands which are bifunctional and bind to m-opioid receptor and to a2d subunit, in particular the a2d-1 subunit, of the voltage-gated calcium channel), thereby enhancing through the a2d blockade without increasing the undesirable side effects. This supports the therapeutic value of a dual agent, whereby the a2d binding component acts as an intrinsic adjuvant of the MOR binding component.

A dual compound that possess binding to both the m-opioid receptor and to the a2d subunit of the voltage-gated calcium channel shows a highly valuable therapeutic potential by achieving an outstanding analgesia (enhanced in respect to the potency of the opioid component alone) with a reduced side-effect profile (safety margin increased compared to that of the opioid component alone) versus existing opioid therapies.

Advantageously, the dual compounds according to the present invention would in addition show one or more the following functionalities: blockade of the a2d subunit, in particular the a2d-1 subunit, of the voltage-gated calcium channel and m-opioid receptor agonism

It has to be noted, though, that functionalities“antagonism” and“agonism” are also sub- divided in their effect into subfunctionalities like partial agonism or inverse agonism. Accordingly, the functionalities of the compound should be considered within a relatively broad bandwidth.

An antagonist blocks or dampens agonist-mediated responses. Known subfunctionalities are neutral antagonists or inverse agonists.

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

In addition, the two mechanisms complement each other since MOR agonists are only marginally effective in the treatment of neuropathic pain, while the blockers of the a2d subunit, in particular the a2d-1 subunit, of voltage-gated calcium channels show outstanding effects in preclinical neuropathic pain models. Thus, the a2d component, in particular the a2d-1 component, adds unique analgesic actions in opioid-resistant pain. Finally, the dual approach has clear advantages over MOR agonists in the treatment of chronic pain as lower and better tolerated doses would be needed based on the potentiation of analgesia but not of the adverse events of MOR agonists. A further advantage of using designed multiple ligands is a lower risk of drug-drug interactions compared to cocktails or multi-component drugs, thus involving simpler pharmacokinetics and less variability among patients. Additionally, this approach may improve patient compliance and broaden the therapeutic application in relation to monomechanistic drugs, by addressing more complex aetiologies.

In a first aspect, the present invention is directed to a compound of formula (I):

wherein one of W3 and W₄ is S and the other is C;

Y is -C(O)-, -[C(RaRa')]n-, -CRa(CN)- or -CR_a(CONRa'Ra ")-. wherein each R_a, R_a· and R_a” 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; and n is 0, 1 , 2 or 3;

X is selected from a bond, -[C(RbRb )] -, -[C(RbRb )] C(0)[C(Rb"Rb )]q-_> substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl-C(O) and substituted or unsubstituted aryl- alkyl, wherein each R_b, R_b·, R_b- and R_b- are independently selected from hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C2-6 alkynyl; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3;

Group A is a substituted or unsubstituted 4 to 10 membered mono or bicyclic heterocyclyl containing one nitrogen atom and optionally a second heteroatom selected from N and O, wherein A is attached to Y through a nitrogen atom; each R1 and Rr 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-cycloalkyl; N R4R4', C(0)OR₄ and substituted or unsubstituted haloalkyl; wherein each R₄ and R_4' are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and C(0)OR₄·; wherein R_{4 "} is substituted or unsubstituted C_1-6 alkyl;

R₅ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6alkenyl, substituted or unsubstituted C_2-6 alkynyl, CN, -C(0)OR₃ and -S(0)₂0R_3' ; wherein each R₃ and Ry are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₆ 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;

R₂ is a group of the following formula:

wherein m is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 , 2 or 3;

Wi is selected from C and N; each Rg, Rg·, Rg- and Rg- are independently selected from hydrogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a carbonyl group; each R10, Rio·, R10” and Rio- are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, R10, Rio· and/or Rio ·, R10- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, Rio and Rio· and/or Rio- and Rio- taken together with the carbon atom to which they are attached may form a carbonyl group;

R₇ is selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aromatic heterocyclyl;

Rs is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C₂- e alkynyl;

Rs· is selected from hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C₂- e alkynyl; alternatively, R₇ and Rs taken together with -N(Rs')-[CH₂]_t- atoms to which they are attached form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In another embodiment, these compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt or solvate thereof.

For the sake of clarity the expression“a compound according to formula (I), wherein R₁, Rr R₂, Rs, R₆, W₃, W₄, X, Y and A are as defined herein in the detailed description” would (just like the expression“a compound of formula (I) as defined in any one of claims 1 to 8 found in the claims) refer to“a compound according to formula (I)”, wherein the definitions of the respective substituents R₁ etc. (also from the cited claims) are applied. For clarity purposes, all groups and definitions described in the present description and referring to compounds of formula (I), also apply to all intermediates of synthesis.

In addition, and for clarity purposes, it should further be understood that naturally if t is 0, the nitrogen is still present in R₂.

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

Alkenyl is understood as meaning straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one unsaturation, and which is attached to the rest of the molecule by a single bond. It may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -CH=CH-CH₃. The alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in the context of this invention alkenyl is 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). Preferably 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. In connection with alkyl (also in aryl-alkyl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl and O-alkyl - unless defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen, -OR’, -SR’, -SOR’, -SO₂R’, -OR’, -CN, -COR’, -COOR’, -NR’R”, -CONR’R”, haloalkyl, haloalkoxy or -OC_1-6 alkyl wherein each of the R’ and R” groups is independently selected from the group consisting of hydrogen, OH, NO₂, NH₂, SH, CN, halogen, -COH, -COalkyl, -COOH and C_1-6 alkyl.

In a particular embodiment of the invention, the alkyl, alkenyl or alkynyl as defined in R₁- R_10” if substituted, is substituted with one or more substituent/s selected from -OR’, halogen, -CN, haloalkyl, haloalkoxy and -NR’R”; wherein R, R’ and R” are independently selected from hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C_2-6 alkynyl;

More than one replacement on the same molecule and also on the same carbon atom is possible with the same or different substituents. This includes for example 3 hydrogens being replaced on the same C atom, as in the case of CF₃, or at different places of the same molecule, as in the case of e.g. -CH(OH)-CH=CH-CHCl2.

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

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

In the context of this invention cycloalkyl is understood as meaning saturated and unsaturated (but not aromatic) cyclic hydrocarbons (without a heteroatom in the ring), which can be unsubstituted or once or several times substituted. Preferred cycloalkyls are C3-4-cycloalkyl representing C3- or C4-cycloalkyl, C3-5-cycloalkyl representing C3-, C4- or C5-cycloalkyl, C3-6-cycloalkyl representing C3-, C4-, C5- or C6-cycloalkyl, C3-7- cycloalkyl representing C3-, C4-, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl representing C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl representing C4- or C5- cycloalkyl, C4-6-cycloalkyl representing C4-, C5- or C6-cycloalkyl, C4-7-cycloalkyl representing C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl representing C5- or C6- cycloalkyl and C5-7-cycloalkyl representing C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl. Preferably in the context of this invention cycloalkyl is C3-8-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C3-7-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C3-6-cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl.

Aryl is understood as meaning 6 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphthyl or anthracenyl, more preferably the aryl is phenyl.

A heterocyclyl radical or group (also called heterocyclyl hereinafter) is understood as meaning 4 to 18, preferably 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 tetrahydropyran, 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.

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

the non-aromatic heterocyclyl is a 4 to 18, preferably 5 to 18, membered mono or polycyclic heterocyclic ring system of one or more rings of which at least one ring - with this (or these) ring(s) then not being aromatic - contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two rings of which one or both rings - with this one or two rings then not being aromatic - contain/s one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably it is selected from oxazepam, pyrrolidine, piperidine, piperazine, tetrahydropyran, morpholine, indoline, oxopyrrolidine, benzodioxane, especially is piperazine, benzodioxane, morpholine, tetrahydropyran, piperidine, oxopyrrolidine and pyrrolidine.

Preferably, in the context of this invention heterocyclyl is defined as a 4 to 18 membered mono or polycyclic heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. Preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. More preferably, it is a 5 to 10 membered mono or bicyclic heterocyclyl ring system containing one nitrogen atom and optionally a second heteroatom selected from nitrogen and oxygen. In another preferred embodiment of the invention, said heterocyclyl is a substituted mono or bicyclic heterocyclyl ring system. Preferred examples of heterocyclyls include oxazepam, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, tetrahydroisoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole and quinazoline, especially is pyridine, piperazine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyran, pyrazole, imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane and pyrrolidine. In the context of this invention oxopyrrolidine is understood as meaning pyrrolidin-2-one.

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

In the context of this invention 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. Preferably aryl-alkyl is understood as meaning an aryl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups.

In the context of this invention alkylheterocyclyl 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. Preferably alkylheterocyclyl is understood as meaning an heterocyclyl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups.

In the context of this invention alkylcycloalkyl 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. Preferably alkylcycloalkyl is understood as meaning a cycloalkyl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups.

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

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

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

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

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”.

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

These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH₄, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.

Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals. By this it is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

The compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid.

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

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

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

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

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

All the groups above mentioned that can be substituted or unsubstituted may be substituted at one or more available positions by one or more suitable groups such as OR’, =0, SR’, SOR’, S0₂R’, OS0₂R’, OSOSR’, N0₂, NHR’, N(R’)₂, =N-R’, N(R’)COR’, N(COR’)₂, N(R’)S0₂R’, N(R’)C(=NR’)N(R’)R’, N₃, CN, halogen, COR’, COOR’, OCOR’, OCOOR’, OCONHR’, OCON(R’)₂, CONHR’, CON(R’)₂, CON(R’)OR\ C0N(R’)S0₂R\ PO(OR’)₂, PO(OR’)R’, PO(OR’)(N(R’)R’), CI-I₂ alkyl, C3-10 cycloalkyl, C₂-i₂ alkenyl, C₂-i₂ alkynyl, aryl, and heterocyclic group, wherein each of the R’ groups is independently selected from the group consisting of hydrogen, OH, N0_2, NH₂, SH, CN, halogen, COH, COalkyl, COOH , CM₂ alkyl, C3-10 cycloalkyl, C_2-i2 alkenyl, C_2-i2 alkynyl, aryl and heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list.

In a particular embodiment of the invention, the compound of formula (I) is a compound wherein

W3 is S and W₄ is C;

Y is -C(O)-, -[C(RaRa')]n-, -CRa(CN)- or -CR_a(CONRa'Ra ")-. wherein each R_a, R_a· and R_a” 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; and n is 0, 1 , 2 or 3;

X is selected from a bond, -[C(RbRb )] -, -[C(RbRb )] C(0)[C(Rb"Rb )]q-_> substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl-C(O), substituted or unsubstituted aryl- alkyl, wherein each R_b, R_b·, R_b- and R_b- 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; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3;

Group A is a substituted or unsubstituted 5 to 10 membered mono or bicyclic heterocyclyl containing one nitrogen atom and optionally a second heteroatom selected from N and O, wherein A is attached to Y through a nitrogen atom; each R1 and Rr 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-cycloalkyl; NR₄R_4', C(0)0R₄ and substituted or unsubstituted haloalkyl; wherein each R₄ and R_4' are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and C(0)0R₄·; wherein R_{4 "} is substituted or unsubstituted C_1-6 alkyl.

R₅ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6alkenyl, substituted or unsubstituted C_2-6 alkynyl, CN, -C(0)0R₃ and -S(0)₂0R_3' ; wherein each R₃ and R₃· are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₆ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl (tert-butyl), substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl,

R₂ is a group of the following formula

wherein m is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 , 2 or 3;

Wi is selected from C or N; each Rg, Rg·, Rg- and Rg- are independently selected from hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-₆ alkynyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a carbonyl group; each R10, Rio·, R10” and Rio- are independently selected from hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C2-₆ alkenyl and substituted or unsubstituted C2-₆ alkynyl; alternatively, R1₀, R-io· and/or Rio ·, R-io- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, R1₀ and R-io· and/or Rio- and R-io- taken together with the carbon atom to which they are attached may form a carbonyl group;

Rs is selected from hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C2-₆ alkenyl and substituted or unsubstituted C2- e alkynyl;

Rs· is selected from hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C2-₆ alkenyl and substituted or unsubstituted C2- e alkynyl; alternatively, R₇ and Rs taken together with -N(Rs )-[CH2]t- atoms to which they are attached form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

Y is -C(O)-, -[C(R_aR_a )]_n-, -CR_a(CN)- or -CR_a(CONR_a R_a )-, wherein each R_a, R_a· and R_a- 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; and n 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.

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

Y is -C(O)-, -[C(R_aR_a )]_n-, -CR_a(CN)- or -CR_a(CONR_a R_a )-, wherein each R_a, R_a· and R_a- are hydrogen, n is 0, 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

X is selected from a bond, -[C(RbRb )]_P-, -[C(RbRb )]_PC(0)[C(Rb"Rb )]_q-, unsubstituted aryl, preferably phenyl, unsubstituted aryl-C(O), preferably phenyl-C(O) and unsubstituted aryl-alkyl, preferably phenyl-alkyl, and wherein each Rb, Rb·, Rb- and Rb- are hydrogen, and p is 0, 1 or 2; q is 0, 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

-X-R₂ is selected from -[C(RbRb)]_P-R2, -[C(RbRb)]_PC(0)[C(Rb"Rb )]_q-R2, -aryl-R_2, preferably -phenyl-R₂ and -aryl-C(0)-R₂, preferably -phenyl-C(0)-R₂, -aryl-alkyl-R₂, preferably -phenyl-alkyl-R₂, wherein each Rb, Rb·, Rb- and Rb- are hydrogen; and p is 0, 1 or 2; q is 0, 1 or 2; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another particular embodiment of the invention, the compound according to the invention of formula (I) is a compound wherein group A is selected from:

wherein b is 0, 1 or 2; and

W₂ is selected from O, C and N; each R1 and Rr 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-cycloalkyl; NR4R4', - C(0)0R₄- and substituted or unsubstituted haloalkyl; wherein each R₄ and R_4' are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and -C(0)OR₄·-; wherein R_{4 "} is substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein when W₂ is N and R₁ or Rr is NR₄R_4'; then NR₄R_4' is not atacthed to W₂. In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein each R₁ and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR₄R_4', and substituted or unsubstituted haloalkyl; wherein each R₄ and R₄· are independently selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment, the alkyl, alkenyl or alkynyl, also in alkyl-cycloalkyl and haloalkyl defined in R1 or Rr, if substituted, is substituted with one or more substituent/s selected from -O R51 , halogen, and -NRsiRsr; wherein each of R51 or R₅r is independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl. In a more preferred embodiment, each of R51 orR₅r is selected from hydrogen and unsubstituted C1-6 alkyl, more preferably methyl.

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

wherein b is 1 or 2;

W₂ is N; and each R₁ and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, unsubstituted alkyl-cycloalkyl; preferably alkyl-cyclopropyl, and substituted or unsubstituted haloalkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein group A is

wherein b is 1 ;

W₂ is N; and each R1 and Rr are independently selected from hydrogen, halogen, preferably fluor, substituted or unsubstituted C1-6 alkyl, preferably methyl, substituted or unsubstituted alkyl-cycloalkyl; preferably alkyl-cyclopropyl, and substituted or unsubstituted haloalkyl; preferably -CH₂F, -CH₂-CH₂F, -CH₂-CHF₂, or -CHF₂. optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a more preferred embodiment, the compound according to the invention of formula (I) is a compound wherein group A is

wherein b is 1 ; W₂ is N;

R1 is hydrogen; and Rr is substituted or unsubstituted Ci-6 alkyl, and wherein Rr is directly attached to W₂.

each Ri and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C alkyl; and substituted or unsubstituted haloalkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

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

In a particular embodiment of the invention, the compound according to the invention of formula (I) is a compound wherein R₂ is a group of the following formula

wherein m is 1 ; r is 1 ; t is 0 or 1 ; Wi is C or N; each Rg, Rg·, Rg- and Rg- are hydrogen; each Rio, Rio·, Rio- and Rio- are hydrogen;

R7 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aromatic heterocyclyl; Re is selected from hydrogen and substituted or unsubstituted C1-6 alkyl;

Re· is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; or

R7 and Re taken together with -N(R8')-[CH2]_t- atoms to which they are attached form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another particular embodiment, the compound according to the invention of formula (I) is a compound wherein R₂ is a group of the following formula:

wherein m is 1 ; r is 1 ; t is 0;

Wi is C; each Rg, Rg·, Rg- and Rg- are hydrogen; each R10, Rio·, Rio- and Rio- are hydrogen;

R₇ is substituted or unsubstituted aryl; preferably phenyl;

Rs is substituted or unsubstituted C1-₆ alkyl; preferably methyl, and Rs· is substituted or unsubstituted C1-₆ alkyl; preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another particular embodiment, the compound according to the invention of formula (I) is a compound wherein R₂ is a group of the following formula

(R2) wherein m is 1 ; r is 1 ; t is 0;

Wi is N; each Rg, Rg·, Rg- and Rg- are hydrogen; each Rio, Rio·, Rio” and Rio- are hydrogen;

R₇ is substituted or unsubstituted aryl; preferably phenyl;

Rs is substituted or unsubstituted C_1-6 alkyl; preferably methyl, and

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

In a particular embodiment, the compound according to the invention of formula (I) is a compound wherein R₇ is selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl, preferably phenyl, and substituted or unsubstituted aromatic heterocyclyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another particular embodiment, the alkyl, aryl and aromatic heterocyclyl as defined in R₇, if substituted, is substituted with one or more substituent/s selected from -OR₇₁ and halogen, wherein

R₇₁ is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl. In a more preferred embodiment, R₇₁ is selected from hydrogen and unsubstituted C_1-6 alkyl, preferably C_1-3 alkyl, more preferably methyl. In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein R₇ is C_1-6 alkyl; more preferably C_1-3 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein R₇ is substituted or unsubstituted aryl; more preferably, R₇ is 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.

In a particular embodiment, the aryl as defined in R₇, if substituted, is substituted with one or more substituent/s selected from -OR₇I and halogen, preferably fluor, wherein

R₇I is selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl. In a more preferred embodiment, R₇I is selected from hydrogen and unsubstituted C_1-6 alkyl, preferably C_1-3 alkyl, more preferably methyl.

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

In a particular embodiment, the C_1-6 alkyl as defined in Re, if substituted, is substituted with one or more substituent/s selected from substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-3 alkyl, and halogen, preferably fluor. In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein Re· is selected from hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment, the C_1-6 alkyl as defined in Re·, if substituted, is substituted with one or more substituent/s selected from substituted or unsubstituted C_1-6 alkyl, preferably unsubstituted C_1-3 alkyl, and halogen, preferably fluor.

In a preferred embodiment, the compound according to the invention of formula (I) is a compound wherein R₇ and Rs taken together with -N(Rs')-[CH₂]_t- atoms to which they are attached may form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; more preferably said heterocyclyl is an unsubstituted heterocyclyl fused with an unsubstituted aryl group; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a more preferred embodiment, the compound according to the invention of formula (I) is a compound wherein R₇ and Rs taken together with -N(Rs')-[CH₂]_t- atoms to which are attached is

wherein Wi and Rs· are as defined above, preferably Wi is N and Rs· is Ci-6 alkyl, preferably methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a particular embodiment, the compound according to the invention of formula (I) is a compound wherein when Wi is N then X is not a bond. In another preferred embodiment, the compound of the invention according to formula (I) is a compound, wherein: one of W₃ and W₄ is S and the other is C; preferably, W₃ is S and W₄ is C;

and/or Y is -C(O)-, -[C(RaRa')]n-, -CRa(CN)- or -CRa(CONRa'Ra' ')-, wherein each R_a, R_a· and R_a- are hydrogen and n is 0, 1 or 2; and/or

X is selected from a bond, -[C(RbRb )]_P-, -[C(RbRb )]_PC(0)[C(Rb”Rb )]q-_> unsubstituted aryl, preferably phenyl, unsubstituted aryl-C(O), preferably phenyl-C(O) and unsubstituted aryl-alkyl, preferably phenyl-alkyl, and wherein each R_b, R_b·, R_b- and R_b- are hydrogen, p is 0, 1 or 2; q is 0, 1 or 2; and/or group A is selected from:

wherein b is 0, 1 or 2; and

W₂ is selected from O, C and N; each R1 and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR4R4', -C(0)OR₄- and substituted or unsubstituted haloalkyl; wherein each R₄ and R_4' are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl and -C(0)OR₄·-; wherein R_{4 "} is substituted or unsubstituted C_1-6 alkyl; and/or

R₅ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, CN, - C(0)0R3 and -S(0)20R3· ; wherein each R₃ and R_3' are hydrogen; and/or

R₆ is selected from hydrogen, halogen and substituted or unsubstituted C_1-6 alkyl; and/or

R2 IS:

wherein m is 1 ; r is 1 ; t is 0 or 1 ;

Wi is C or N; each Rg, Rg·, Rg- and Rg- are hydrogen; each R10, Rio·, R10” and Rio- are hydrogen; R7 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, preferably phenyl, and substituted or unsubstituted aromatic heterocyclyl;

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

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

R7 and Re taken together with -N(R8')-[CH2]_t- atoms to which they are attached may form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

W3 is S and W₄ is C;

and/or

Y is -C(O)-, -[C(RaRa')]n-, -CRa(CN)- or -CR_a(CONRa'Ra ")-. wherein each R_a, R_a· and R_a- are hydrogen and n is 0, 1 or 2; and/or

wherein b is 0, 1 or 2; and

W2 is selected from O, C and N; each Ri and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR₄R_4', -C(0)0R₄- and substituted or unsubstituted haloalkyl; wherein each R4 and R4' are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl and -C(0)0R₄·-; wherein R4" is substituted or unsubstituted C1-6 alkyl; and/or

R5 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, CN, - C(0)0R3 and -S(0)20R3· ; wherein each R3 and R3' are hydrogen; and/or

R₆ is selected from hydrogen, halogen and substituted or unsubstituted C1-6 alkyl; and/or

R2 IS:

R7 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, preferably phenyl, and substituted or unsubstituted aromatic heterocyclyl;

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

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

R7 and Re taken together with -N(R8')-[CH2]_t- atoms to which they are attached may form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R_a, R_a and R_a- as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl 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.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R_b, R_b·, R_b- and R_b- 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

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in Ri and Rr 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 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or

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

the haloalkyl is selected from -CH₂CI, -CH₂F, -CHC , -CHF₂, -CCI₃, -CF₃ and -CH2-CHCI2; more preferably the haloalkyl is -CHF2 or -CF3;

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

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₄and R₄ 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 C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or

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

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₅ as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C1-6 alkyl; more preferably, the Ci-₆ alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2- methylpropyl; and/or

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

and/or

-C(0)0R₃ or -S(0)₂0R_3' are preferably -C(0)0H and -S(0)₂0H; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₆ as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C1-6 alkyl; more preferably, the Ci-₆ alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2- methylpropyl; and/or

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₇ as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C1-6 alkyl; more preferably, the C1-6 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2- methylpropyl; and/or

the aryl is selected from phenyl, naphtyl, or anthracenyl; preferably is napthyl and phenyl; and/or

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

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in Re and Re· as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C1-6 alkyl; more preferably, the Ci-₆ alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2- methylpropyl; and/or

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in Rg, Rg·, Rg- and Rg- as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C_1-6 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 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R1₀, R-io·, R-io- and Rio- as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C_1-6 alkyl; more preferably, the C_1-6 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2- methylpropyl; and/or

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R_a, R_a and R_a- as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₄and R₄ 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; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₅ as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C_1-6 alkyl; more preferably, the C_1-6 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2- methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R₆ 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 preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein in R-io, R-io·, R-io- and Rio” as defined in any of the embodiments of the present invention, the alkyl is preferably selected from C alkyl; more preferably, the C alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl and 2-methylpropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein one of W₃ and W₄ is S and the other is C;

and

Y is -C(O)-, -[C(RaRa')]n-, -CRa(CN)- or -CR_a(CONRa'Ra ")-. wherein each R_a, R_a· and R_a- are hydrogen and n is 0, 1 or 2; and

X is selected from a bond, -[C(RbRb )]_P-, -[C(RbRb )]_PC(0)[C(Rb”Rb )]q-_> unsubstituted aryl, preferably phenyl, unsubstituted aryl-C(O), preferably phenyl-C(O) and unsubstituted aryl-alkyl, preferably phenyl-alkyl, and wherein each Rb, Rb·, Rb- and Rb- are hydrogen; p is 0, 1 or 2; q is 0, 1 or 2; and group A is selected from:

wherein b is 0, 1 or 2; and

W₂ is selected from O, C and N; each Ri and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR₄R_4', -C(0)0R₄- and substituted or unsubstituted haloalkyl; and wherein each R₄ and R_4' are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, , and -C(0)0R₄·-; wherein R_{4 "} is substituted or unsubstituted C_1-6 alkyl;

R₅ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, CN, - C(0)0R3; -S(0)20R3· ; wherein each R₃ and R_3' are hydrogen,

R₆ is selected from hydrogen, halogen and substituted or unsubstituted C_1-6 alkyl; and

R₂ is a group of the following formula:

m is 1 ; r is 1 ; t is 0 or 1 ;

Wi is C or N; each Rg, Rg·, Rg- and Rg- are hydrogen; each R10, Rio·, R10” and Rio- are hydrogen;

R₇ is selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl, preferably phenyl, and substituted or unsubstituted aromatic heterocyclyl;

Re is selected from hydrogen and substituted or unsubstituted C_1-6 alkyl;

Re’ is selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; or

R₇ and Re taken together with -N(R_8')-[CH₂]_t- atoms to which they are attached may form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

W₃ is S and W₄ is C;

and

Y is -C(O)-, -[C(R_aR_a )]_n-, -CR_a(CN)- or -CR_a(CONR_a R_a )-, wherein each R_a, R_a· and R_a- are hydrogen and n is 0, 1 or 2; and X is selected from a bond, -[C(RbRb )]_P-, -[C(RbRb )]_PC(0)[C(Rb"Rb )]_q-, unsubstituted aryl, preferably phenyl, unsubstituted aryl-C(O), preferably phenyl-C(O) and unsubstituted aryl-alkyl, preferably phenyl-alkyl, and wherein each Rb, Rb·, Rb- and Rb- are hydrogen; p is 0, 1 or 2; q is 0, 1 or 2; and group A is selected from:

wherein b is 0, 1 or 2; and

W₂ is selected from O, C and N; each Ri and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR4R4', -C(0)OR₄- and substituted or unsubstituted haloalkyl; and wherein each R4 and R4' are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, , and -C(0)OR₄·-; wherein R4" is substituted or unsubstituted C1-6 alkyl;

R5 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, CN, - C(0)OR3; -S(0)₂0R_3' ; wherein each R₃ and Ry are hydrogen,

R₆ is selected from hydrogen, halogen and substituted or unsubstituted C1-6 alkyl; and

R2 is a group of the following formula:

m is 1 ; r is 1 ; t is 0 or 1 ;

Wi is C or N; each Rg, Rg·, Rg- and Rg- are hydrogen; each Rio, Rio·, Rio” and Rio- are hydrogen;

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

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

R7 and Re taken together with -N(R8')-[CH2]_t- atoms to which they are attached may form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to formula (I) the compound is a compound, wherein

W3 is S and W₄ is C;

and

Y is -C(O)-, -[C(R_aRa )]n-, -CR_a(CN)- or -CR_a(CONR_a R_a )-, wherein each R_a, R_a· and R_a- are hydrogen and n is 0, 1 or 2; and X is selected from a bond, -[C(RbRb )]_P-, -[C(RbRb )]_PC(0)[C(Rb”Rb )]q-_> phenyl, preferably phenyl-C(O) and phenyl-alkyl, and wherein each R_b, R_b·, R_b- and R_b- are hydrogen, p is 0, 1 or 2; q is 0, 1 or 2; and group A is:

wherein b is 0, 1 or 2; and

W₂ is selected from O, C and N; and each R1 and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR4R4', -C(0)OR₄- and substituted or unsubstituted haloalkyl; wherein each R₄ and R₄· are independently selected from hydrogen, substituted or unsubstituted C_1-6 alkyl, , and -C(0)0R_4”-; wherein R₄- is substituted or unsubstituted C_1-6 alkyl; and R₅ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, CN, - C(0)0R3 and -S(0)20R3· ; wherein each R₃ and R_3' are hydrogen; and

R₆ is selected from hydrogen and substituted or unsubstituted C_1-6 alkyl; and

R₂ is a group of the following formula

wherein m is 1 ; r is 1 ; t is 0 or 1 ;

R₇ is selected from substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl, preferably phenyl, and substituted or unsubstituted aromatic heterocyclyl; Re is selected from hydrogen and substituted or unsubstituted Ci-₆ alkyl;

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

W₃ is S and W₄ is C; and

Y is -C(O)-; and

X is selected from a bond and -[C(R_bR_b )]_P-, wherein each R_b, R_b· are hydrogen and p is 1 or 2; and group A is:

wherein b is 1 and W₂ is N; each R1 and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR4R4', -C(0)0R₄- and substituted or unsubstituted haloalkyl; and each R₄ and R₄· are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, , and -C(0)0R_4”-; wherein R₄- is substituted or unsubstituted Ci-₆ alkyl; and

R5 is selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, CN, - C(0)0R₃ and -S(0)₂0R₃· ; wherein each R3 and R3' are hydrogen; and

R₆ is selected from hydrogen and substituted or unsubstituted C1-6 alkyl; and

R2 is a group of the following formula

wherein m is 1 ; r is 1 ; t is 0;

Wi is C; each Rg, Rg·, Rg- and Rg- are hydrogen; each R10, Rio·, R10” and Rio- are hydrogen;

R7 is substituted or unsubstituted aryl, preferably phenyl;

Re is selected from hydrogen and substituted or unsubstituted Ci-₆ alkyl; and

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

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

[1] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[2] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(morpholino)methanone;

[3] (1-((1s,4s)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[4] tert-butyl 4-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)-1 ,4-diazepane-1-carboxylate;

[5] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1-yl)methanone;

[6] (1-((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((3S,5R)-3,5-dimethylpiperazin-1-yl)methanone;

[7] (1-((1 r,4r)-4-(dimethylamino)-4-(3-hydroxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[8] (1-((1s,4s)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[9] (1-((1s,4s)-4-(dimethylamino)-4-(4-fluorophenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone; [10] (1-((1s,4s)-4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[11] (1-((1s,4s)-4-(dimethylamino)-4-(4-methoxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[12] (1-((1 r,4r)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[13] (1-((1 r,4r)-4-(dimethylamino)-4-(4-fluorophenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[14] (1-((1 r,4r)-4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[15] (1-((1s,4s)-4-(dimethylamino)-4-(3-hydroxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[16] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-ethylpiperazin-1-yl)methanone;

[17] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(piperidin-1-yl)methanone;

[18] (1-((1 r,4r)-4-(methylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[19] (1-((1s,4s)-4-(dimethylamino)-4-(2-methoxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[20] (S)-tert-butyl 4-(1-((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)-3-methylpiperazine-1-carboxylate;

[21] (R)-tert-butyl 4-(1-((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)-3-methylpiperazine-1-carboxylate;

[22] (1-((1s,4s)-4-(methylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[23] (1-((1 r,4r)-4-(dimethylamino)-4-(4-methoxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone; [24] tert-butyl 5-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 H)-carboxylate;

[25] tert-butyl 6-(1-((1 r,4r)-4-(dimethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate;

[26] (1-((1 r,4r)-4-((dimethylannino)nnethyl)-4-(3-nnethoxyphenyl)cyclohexyl)-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-nnethylpiperazin-1-yl)nnethanone;

[27] (1-((1s,4s)-4-((dimethylamino)nnethyl)-4-(3-nnethoxyphenyl)cyclohexyl)-4, 5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-nnethylpiperazin-1-yl)nnethanone;

[28] tert-butyl 4-(1-((1 r,4r)-4-(dimethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)-6,6-difluoro-1 ,4-diazepane-1-carboxylate;

[29] (1-((1 r,4R)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((R)-3-(hydroxymethyl)-4-nnethylpiperazin-1-yl)nnethanone;

[30] (1-((1 r,4S)-4-(dimethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((S)-3-(hydroxynnethyl)-4-nnethylpiperazin-1-yl)nnethanone;

[31] tert-butyl 2-(difluoromethyl)-4-(1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)piperazine-1-carboxylate;

[32] (4-(cyclopropylmethyl)piperazin-1-yl)(1-((1 r,4r)-4-(dinnethylannino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[33] (4,6-dimethyl-1 ,4-diazepan-1-yl)(1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)nnethanone;

[34] (4,7-dimethyl-1 ,4-diazepan-1-yl)(1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)nnethanone;

[35] (1-((1 r,4S)-4-(dimethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((S)-3-(dinnethylannino)piperidin-1-yl)nnethanone;

[36] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)nnethanone;

[37] (1-(4-(4-(dimethylannino)-4-(3-hydroxyphenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1-yl)nnethanone; [38] (1-(4-(4-(dimethylamino)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[39] (1-(3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[40] tert-butyl (1-(1-(4-(4-(dimethylamino)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)pyrrolidin-3-yl)(methyl)carbamate;

[41] (1-(4-(4-(dimethylamino)-4-ethylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[42] (1-(4-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '-yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[43] (1-(4-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[44] (1-(4-(4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[45] (1-(4-(4-(methylamino)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[46] (1-(4-(4-(3-hydroxyphenyl)-4-(methylamino)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[47] (1-(3-(4-(methylamino)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[48] (1-(3-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '-yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[49] (1-(3-(4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[50] (1-(3-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[51] (1-(4-(4-((dimethylamino)methyl)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone; [52] (1-(4-(3-(dimethylamino)-3-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[53] (1-(3-(4-((dimethylamino)methyl)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[54] (1-(3-(4-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-1-yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[55] (1-(4-(4-(dimethylamino)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1-yl)methanone;

[56] (1-(3-(4-(dimethylamino)-4-(pyridin-2-yl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[57] (1-(3-(4-(dimethylamino)-4-(pyridin-2-yl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[58] (1-(4-(4-(dimethylamino)-4-(pyridin-2-yl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[59] (1-(4-(4-(dimethylamino)-4-(4-methoxyphenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[60] (1-(4-(4-(dimethylamino)-4-(2-methoxyphenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[61] (1-(4-(4-(dimethylamino)-4-(3-fluorophenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[62] (1-(4-(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[63] (1-(3-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)methyl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[64] (1-(4-((4-(dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[65] (1-(3-((4-(dimethylamino)-4-phenylpiperidin-1-yl)methyl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone; [66] (1-(4-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)methyl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[67] (4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)(3-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[68] (4-(dimethylamino)-4-phenylpiperidin-1-yl)(4-(3-(4-methylpiperazine-1-carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[69] (4-(dimethylamino)-4-phenylpiperidin-1-yl)(3-(3-(4-methylpiperazine-1-carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[70] (2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '-yl)(4-(3-(4- methylpiperazine-1-carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1- yl)phenyl)methanone;

[71] (2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '-yl)(3-(3-(4- methylpiperazine-1-carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1- yl)phenyl)methanone;

[72] (4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)(4-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[73] (4-(methylamino)-4-phenylpiperidin-1-yl)(4-(3-(4-methylpiperazine-1-carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[74] (4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)(4-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[75] (4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)(3-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[76] (4-(methylamino)-4-phenylpiperidin-1-yl)(3-(3-(4-methylpiperazine-1-carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[77] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-1 H-thieno[2,3-g]indazol-3-yl)(4- methylpiperazin-1-yl)methanone;

[78] (7-Bromo-1-((1 r,4r)-4-(dimethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[79] 1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1-carbonyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazole-7-carbonitrile; [80] 1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1 -carbonyl)-

4,5-dihydro-1 H-thieno[2,3-g]indazole-7-carboxylic acid;

[81] 1-((1 r,4r)-4-(dimethylannino)-4-phenylcyclohexyl)-3-(4-nnethylpiperazine-1-carbonyl)-

4.5-dihydro-1 H-thieno[2,3-g]indazole-7-sulfonic acid;

[82] (1-((1 r,4r)-4-((2-fluoroethyl)nnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-nnethylpiperazin-1-yl)nnethanone;

[83] (1-((1 r,4r)-4-((2,2-difluoroethyl)(nnethyl)annino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-nnethylpiperazin-1-yl)nnethanone;

[84] (1-((1 r,4r)-4-((2,2-difluoroethyl)(nnethyl)annino)-4-phenylcyclohexyl)-1 H-thieno[2,3- g]indazol-3-yl)(4-nnethylpiperazin-1-yl)nnethanone;

[85] (1 ,4-diazepan-1-yl)(1-((1 r,4r)-4-(dimethylannino)-4-phenylcyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)methanone;

[86] (1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(piperazin-1-yl)nnethanone;

[87] (1-((1 r,4S)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((S)-2-nnethylpiperazin-1-yl)nnethanone;

[88] (1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)nnethanone;

[89] (1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(2,6-diazaspiro[3.4]octan-6-yl)nnethanone;

[90] (6,6-difluoro-1 ,4-diazepan-1-yl)(1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)-

4.5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[91] (3-(difluoromethyl)piperazin-1-yl)(1-((1 r,4r)-4-(dinnethylannino)-4-phenylcyclohexyl)-

4.5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)nnethanone;

[92] (1-(4-(4-(dinnethylannino)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(3-(nnethylannino)pyrrolidin-1-yl)nnethanone;

[93] (1-((1 r,4R)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((R)-2-nnethylpiperazin-1-yl)nnethanone; [94] (7-bromo-1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(piperazin-1-yl)methanone;

[95] (1-((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((R)-3-(hydroxymethyl)piperazin-1-yl)methanone;

[96] (1-((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((S)-3-(hydroxymethyl)piperazin-1-yl)methanone;

[97] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-(2-fluoroethyl)piperazin-1-yl)methanone;

[98] (4-(2,2-difluoroethyl)piperazin-1-yl)(1-((1 r,4r)-4-(dimethylannino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[99] (2-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H-thieno[2,3- g]indazol-3-yl)(4-ethylpiperazin-1-yl)methanone;

[100] (2-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H-thieno[2,3- g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1-yl)methanone;

[101] (2-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[102] 2-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)-2-(4-methylpiperazin-1-yl)acetonitrile;

[103] 2-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;

[104] (1 r,4r)-4-(8-(tert-butyl)-3-((4-methylpiperazin-1-yl)methyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)-N,N-dimethyl-1-phenylcyclohexanamine;

[105] N,N-dimethyl-1-(4-(3-((4-methylpiperazin-1-yl)methyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-1-yl)phenyl)-4-phenylpiperidin-4-amine;

[106] (1 r,4r)-N,N-dimethyl-4-(3-((4-methylpiperazin-1-yl)methyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)-1-phenylcyclohexanamine;

[107] (1-((4-(dimethylamino)-4-phenylcyclohexyl)methyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone; [108] (1-(2-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[109] (1-(2-(4-(3-hydroxyphenyl)-4-(methylamino)piperidin-1-yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 10] (1-(2-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 1 1] (1-(2-(4-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-1-yl)ethyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 12] (1-(2-(4-(methylamino)-4-phenylpiperidin-1-yl)ethyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 13] (2-(2-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)ethyl)-4,5-dihydro-2H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 14] (1-(2-(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1-yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 15] (1-(2-(4-(dimethylamino)-4-(3-fluorophenyl)piperidin-1-yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 16] (1-(2-(4-((dimethylamino)methyl)-4-phenylpiperidin-1-yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 17] (1-(2-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[1 18] 1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)-2-(3-(4-methylpiperazine-1-carbonyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[1 19] 1-(4-(dimethylamino)-4-(3-fluorophenyl)piperidin-1-yl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[120] 1-(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1-yl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[121] 1-(4-(dimethylamino)-4-(4-methoxyphenyl)piperidin-1-yl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone; [122] 1-(4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[123] 1-(4-((dimethylamino)methyl)-4-phenylpiperidin-1-yl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[124] 1-(4-(dimethylamino)-4-(2-methoxyphenyl)piperidin-1-yl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[125] 1-(4-(diethylamino)-4-phenylpiperidin-1-yl)-2-(3-(4-methylpiperazine-1-carbonyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[126] 1-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone;

[127] 1-(4-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-(3-(4- methylpiperazine-1-carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone; tert-butyl 4-(1-((1 r,4r)-4-(dimethylannino)-4-(4-nnethoxyphenyl)cyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)piperazine-1-carboxylate; tert-butyl (1-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)azetidin-3-yl)(methyl)carbamate;

((S)-4-benzyl-3-methylpiperazin-1-yl)(1-((1 r,4S)-4-(dinnethylannino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)nnethanone;

((R)-4-benzyl-3-methylpiperazin-1-yl)(1-((1 r,4R)-4-(dimethylannino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

(1-((1 r,4R)-4-(dinnethylannino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((R)-3-methylpiperazin-1-yl)nnethanone;

(1-((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)((S)-3-methylpiperazin-1-yl)methanone; 1-tert-butyl 2-methyl 4-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-

[134]

dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)piperazine-1 ,2-dicarboxylate;

(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-1 ,4-

[136] dihydrothieno[3',2':4,5]cyclopenta[1 ,2-c]pyrazol-3-yl)(4-methylpiperazin-1- yl)methanone;

(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-1 ,4-

[137] dihydrothieno[2',3':4,5]cyclopenta[1 ,2-c]pyrazol-3-yl)(4-methylpiperazin-1- yl)methanone; tert-butyl ((S)-1-(1-((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-

[138]

thieno[2,3-g]indazole-3-carbonyl)piperidin-3-yl)carbamate;

(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[3,2-

[139]

g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[140] (1-((1 r,4r)-4-(dimethylamino)-4-(4-methoxyphenyl)cyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(piperazin-1-yl)methanone;

[141] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(3-(methylamino)azetidin-1-yl)methanone;

[142] 4-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazole-3-carbonyl)piperazine-2-carboxylic acid;

[143] methyl 4-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)piperazine-2-carboxylate;

[144] (R)-4-(1-((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazole-3-carbonyl)-2-(hydroxymethyl)piperazine-1 -carboxylic acid;

[145] ((S)-3-aminopiperidin-1-yl)(1-((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[146] N-((1s,4s)-4-(dimethylamino)-4-phenylcyclohexyl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)acetamide; [147] N-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-2-(3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)acetannide;

[148] (1-(2-(4-(dimethylamino)-4-(4-methoxyphenyl)piperidin-1-yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[149] (1-(2-(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1-yl)ethyl)-1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[150] (1-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(3-(dimethylamino)azetidin-1-yl)methanone; and

[151] 1-(4-(Methylamino)-4-phenylpiperidin-1-yl)-2-(3-(4-methylpiperazine-1-carbonyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)ethanone, 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. A preferred aspect of the invention is also a process for obtaining a compound of formula (I) as described above. Several procedures have been developed for obtaining all the compounds of the invention, and the procedures will be explained below in methods A- C.

The obtained reaction products may, if desired, be purified by conventional methods, such as crystallization and chromatography. Where the processes described below for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. One preferred pharmaceutically acceptable form of a compound of the invention is the crystalline form, including such form in pharmaceutical composition. In the case of salts and also solvates of the compounds of the invention the additional ionic and solvent moieties must also be non-toxic. The compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms. The compounds of formula (I) can be obtained by following the 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

Method A represents a first process for synthesizing compounds according to formula

In this sense, in another aspect, the invention refers to a process for the preparation of a compound of formula (I)

said process comprising treating a compound of formula (VII)

with a compound of formula (V):

(V)

wherein

Ri, Rr, R₂, R₅, R6, W₃, W₄, X, Y and A have the same meaning as indicated before and Z is selected from OH, Cl, N(OMe)Me and H.

In a particular embodiment of the method according to the invention, W₃ is S and W₄ is C.

In a particular embodiment of the method according to the invention, Z is selected from OH and Cl.

In a particular embodiment of the method according to the invention, the compound of formula (la) wherein Y= -C(O)-, can be prepared by treating a compound of formula V, where Z represents OH or a chlorine atom, with an amine of formula VII (see Scheme 1 )·

When Z is OH, the reaction is carried out using a suitable coupling reagent such as N- (3-dimethylaminopropyl)-/V'-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), /V-[(dimethylamino)-1 H- 1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-/V- methylmethanaminium hexafluorophosphate N- oxide (HATU) or L/,L/,L/',L/'-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 solvent such as dichloromethane or dimethylformamide, and at a suitable temperature, preferably at room temperature. In another particular embodiment, when Z is a chlorine atom, 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 K₂CO₃; and at a suitable temperature, preferably comprised between 0 °C and room temperature. Additionally, an activating agent such as 4-dimethylaminopyridine can be used.

In another particular embodiment, a compound of formula (lb) wherein Y=-[C(R_aR_a )]_n, more particularly wherein Y=CH₂, can be prepared by reduction of a compound of formula (la) using a suitable reagent, such as alane in the presence of a suitable solvent, such as tetrahydrofuran at a suitable temperature, such as between -10 °C and room temperature. In another particular embodiment of the method according to the invention, a compound of formula (lc) wherein Y= -CR_aR_a (CN)-, in particular -CH2(CN)-, can be prepared by reaction between a compound of formula V, where Z represents hydrogen, and an amine of formula VII in the presence of potassium cyanide, using a suitable solvent, such as mixtures of hhCbMeOH at a suitable temperature, such as room temperature.

In a particular embodiment of the method according to the invention, a compound of formula (Id) wherein Y= -CR_a(CONR_a R_a”)-, more particularly Y=CH2-(CONH2), can be prepared by hydrolisis of a compound of formula (lc) wherein Y=-CH2(CN)-, using a suitable reagent, such as sodium hydroxide and hydrogen peroxide in the presence of a suitable solvent, such as mixtures of MeOH:DMSO at a suitable temperature, such as room temperature.

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.

Alternatively, 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 V, where Z represents hydrogen, can be prepared by reduction of a compound of formula V, where Z represents O-alkyl, 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.

Alternatively, 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. The following conditions apply: 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-b] pyridin-1 -ylmethylene]-/V-methylmethanaminium

hexafluorophosphate N- oxide (HATU) or /V,/V,/V',/V'-tetramethyl-0-( //-/-benzotriazol-1- yl)uronium hexafluorophosphate (HBTU), optionally in the presence of 1- hydroxybenzotriazole, optionally in the presence of an organic base such as N- methylmorpholine or /V,/V-diisopropylethylamine, in a suitable solvent such as dichloromethane or dimethylformamide, and at a suitable temperature, preferably at room temperature.

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.

The reactions steps are shown in Scheme 1 below in more detail:

Scheme 1 METHOD B

As it is shown in Sheme 1 , alternatively, the compound of the invention can be produced according to the process explained below. Thus, in another aspect of the present invention relates to a process for the preparation of a compound of formula (I)

wherein Ri, Rr, R₂, Rs, R6, W₃, W₄, X, Y and A have the same meaning as indicated before, said process comprising a) treating a compound of formula (VII)

with a compound of formula (VIII):

wherein

R1, Rr, R₂, Rs, R6, W3, W₄, X, Y 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

R₂-X-G

(XI) wherein R₂, and X have the same meaning as indicated before; and G is

B(OH)2 when X is aryl, and G is a leaving group when X is alkylene.

In a particular embodiment of the method according to the invention, W₃ is S and W₄ is C. Depending on the nature of X, different meanings of G and different reaction conditions apply:

When X is aryl, G is 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. When X is alkylene, 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 K2CO₃ or CS2CO₃; 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.

As an alternative procedure, these reaction conditions with a compound of formula XI may be applied to compounds of formula VIII, wherein Z represents O-alkyl or OH, to give, respectively, compounds of formula V, wherein Z represents O-alkyl or OH. METHOD C

Method C represents a third process for synthesizing compounds according to formula

(I).

Thus, in another aspect, the invention refers to a process for the preparation of a compound of formula (I)

wherein Ri, Rr, R₂, Rs, R6, W₃, W₄, X, and A have the same meaning as as indicated before and Y represents -C(O)- said process comprising: a) treating a compound of formula (XIV)

with a compound of formul

b) treating the compound obtained in step a) with R2H; wherein Z is O-alkyl, OH or a leaving group (LG).

In a particular embodiment of the method according to the invention, W3 is S and W₄ is C. A compound of formula XIV may be transformed to a compound of formula XVI as despeicted in Scheme 2 using the conditions described above for the preparation of compound of formula I wherein Y= -C(O)-.

Scheme 2

A compound of formula XVI, where M represents OH, may be converted to a compound of formula XVII, where M represents a leaving group, such as chlorine. The reaction may be carried out using thionyl chloride in a suitable solvent, such as dichloromethane, at a suitable temperature, such as room temperature.

The compound of formula I, wherein Y represents -C(O)- may be obtained by reaction of a compound of formula XVII with a suitable reagent of formula XVIII using alkylation conditions such as the described above.

The compounds of formula II may be prepared, as described in Scheme 3, by reacting a compound of formula XIX with a compound of formula XX, 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.

Scheme 3 The compounds of formula III, VII, XI, XIII, XVIII, XIX and XX used in the methods and schemes disclosed above are commercially available or can be synthesized following common procedures described in the literature and exemplified in the synthesis of some intermediates.

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

wherein R₂, Rs, R₆, W₃, W₄ and X have the same meaning as indicated above and Z is O-alkyl, OH; H or Cl for the manufacture of a compound a compound according to the invention as described above according to formula (I). In a particular embodiment of the invention, W₃ is S and W₄ is C.

Certain compounds of the present invention can also be obtained starting from other compounds of formula (I) by appropriate conversion reactions of functional groups, in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions. As a way of example, some of these conversions include the reduction of a double bond from a tetrahydropyridine to a piperidine derivative or the reductive amination of an amino group with an aldehyde or ketone, or alternatively the reaction of an amino group with an alkylating agent, to prepare a further substituted amino group.

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

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

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

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

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

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

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

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

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

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

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

Another aspect of the invention refers to a compound of formula I, or a pharmaceutically acceptable salt or isomer thereof, for use in the treatment or prophylaxis of pain. Preferably, the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia. This may include mechanical allodynia or thermal hyperalgesia.

Another aspect of the invention refers to the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of pain. In a preferred embodiment the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, also preferably including mechanical allodynia or thermal hyperalgesia.

Another aspect of this invention relates to a method of treating or preventing pain which method comprises administering to a patient in need of such a treatment or prevention a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Among the pain syndromes that can be treated or prevented are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia.

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

EXAMPLES

The following abbreviations are used in the intermediates and examples: ACN: Acetonitrile

Anh: Anhydrous Aq: Aqueous

BOC2O: Di-tert-butyl dicarbonate tBuOH: tert-Butanol Cone: Concentrated DCE: Dichloroethane DCM: Dichloromethane

DDQ: 4,5-Dichloro-3,6-dioxocyclohexa-1 ,4-diene-1 ,2-dicarbonitrile DEA: Diethylamine

DIPEA: N,N-Diisopropylethylamine

DMA: Dimethylacetamide

DMAP: 4-Dimethylaminopyridine

DMF: Dimethylformamide EDC-HCI: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

EtOAc: Ethyl acetate Et₂0: Diethyl ether EtOH: Ethanol h: Hour/s HATU: (1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate)

HFIP: Hexafluoroisopropanol

HOBt: Hydroxybenzotriazole HPLC: High-performance liquid chromatography

HRMS: High-resolution mass spectrometry MeOH: Methanol MS: Mass spectrometry Min: Minutes

Quant: Quantitative Rt: Retention time rt: Room temperature Sat: Saturated TFA: T rifluoroacetic acid

THF: Tetrahydrofuran TEA: EtsN, Triethylamine TOSMIC: Toluenesulfonylmethyl isocyanide Wt: Weight

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

Method A: Column Acquity UPLC BEH C18 2.1x50 mm, 1.7 mm; flow rate 0.61 mL/min; A: NH4HCO3 10 mM; B: ACN; Gradient: 0.3 min 98% A, 98% to 5% A in 2.52 min, isocratic 5%_> A 1.02 min. Method B: Column Zodiac C18 50x4.6 mm 3 pm; flow rate 0.6 mL/min; A: 0.1 % formic acid in water; B: ACN; Gradient 95% to 50% A in 3 min, 50% to 5%_> A in 2 min isocratic 5% A 2 min.

Method C: Column Acquity UPLC BEH C18 2.1x50 mm, 1.1 pm; flow rate 0.80 mL/min; A: NH4HCO3 10 mM; B: ACN; Gradient: 0.3 min 90% A, 90% to 5% A in 2.7 min, isocratic 5% A 0.7 min. Method D: Column Aquity UPLC BEH C18 2.1 x 50 mm, 1.7 pm, flow rate 0.61 mL/min; A: NH4HCO3 10 mM, B: ACN, C: MeOH + 0.1% formic acid; gradient 0.3 min 98% A, 98% A to 0:95:5 A:B:C in 2.7 min; 0:95:5 A:B:C to 100%o B in 0.1 min; isocratic 2 min 100% B. Method E: Column Acquity UPLC BEH C18 2.1x50 mm, 1.7 pm; flow rate 0.61 mL/min; A: NH4HCO3 10 mM pH 10.6; B: ACN; Gradient: 0.3 min 98%_> A, 98%_> to 0%_> A in 2.7 min, isocratic 0%_> A 2 min.

Method F: Column Acquity UPLC BEH C18 2.1x50 mm, 1.7 pm; flow rate 0.5 mL/min; A: NH4HCO3 10mM; B: ACN; Gradient: 90%_> A to 5%_> A in 4 min, 1 min in 5%_> A, 5%_> A to 90%_> A in 0.1 min, 1.9 min in 90%_> A

Method G: Column Acquity UPLC BEH C18 2.1x50 mm, 1.7 pm; flow rate 0.80 mL/min; A: ACONH4 10 mM; B: ACN; Gradient: 0.3 min 90%_> A, 90%_> to 5%_> A in 2.7 min, isocratic 5%o A 0.7 min.

Synthesis of Intermediates

Intermediate 1. (1 r,4r)-4-Hydrazinyl-N,N-dimethyl-1-phenylcyclohexanamine

trihydrochloride.

Step a. 8-(Dimethylamino)-1 ,4-dioxaspiro[4.5]decane-8-carbonitrile.

To a stirred solution of fe/f-butyl 4-oxopiperidine-1-carboxylate (300 g, 1.51 mol) in EtOH (1200 ml.) and H2O (600 ml.) at rt, dimethylamine (40% Wt in H2O, 1700 mL, 15 mol) was added drop wise followed by the addition of KCN (244 g, 3.7 mol). The reaction mixture was stirred for 4 days at rt and extracted with DCM. The combined organic layers were washed with H2O and sat aq NaCI, dried over anh Na₂S0₄, filtered and evaporated to dryness to give the title compound (350 g, Yield: 89%).

Step b. N,N-Dimethyl-8-phenyl-1 ,4-dioxaspiro[4.5]decan-8-amine. To a stirred solution of the compound obtained in step a) (95 g 0.45 mol) in THF (100 ml.) freshly prepared Grignard solution of bromophenyl (245.64 g, 1 .36 mol) was added dropwise at 0 °C. The reaction mixture was stirred at rt for 18 h and then quenched with sat aq NH4CI, extracted with EtOAc and washed with sat aq NaCI. The combined organic layers were dried over anh Na2S0₄, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography silica gel, gradient CHC o CHC iMeOH (9:1 ) to give the title compound (70 g, Yield: 59%).

Step c. 4-(Dimethylamino)-4-phenylcyclohexanone.

To a stirred solution of the compound obtained in step b) (70 g, 0.27 mol) in MeOH (50 ml_), cone. HCI (350 ml.) was added drop wise at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction was diluted with H2O and washed with EtOAc. The aqueous layer was basified with NaOH 8 N and the product was extracted with CHCI3. The combined organic layers were washed with H2O and sat aq NaCI and dried over anh Na₂S0₄, filtered and evaporated to dryness to give the title compound (40 g, Yield: 68%).

Step d. tert-Butyl 2-(4-(dimethylamino)-4-phenylcyclohexyl)hydrazinecarboxylate.

To a stirred solution of the compound obtained in step c) (40 g, 0.184 mol) in MeOH (100 ml_), tert-butyl hydrazinecarboxylate (36.49 g, 276.49 mmol) in MeOH (400 ml.) and acetic acid (0.52 ml_, 9.22 mmol) was added at 0 °C. Then NaCNBHs (23.29 g, 0.37 mol) was added portion wise at 0 °C and the reaction mixture was stirred at rt for 16 h. The reaction mixture was evaporated and diluted with DCM, washed with H2O and sat aq NaCI. The combined organic layers were dried over anh Na₂S0_4, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (95:5) to give the title compound (17.5 g, Yield: 28 % yield).

Step e. di-tert-Butyl 1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)hydrazine-1 ,2- dicarboxylate.

To a stirred solution of the compound obtained in step d) (17.5 g, 52.39 mmol) in anhydrous DCM (200 ml_), TEA (20.92 g, 157.17 mmol) and B0C2O (13.70 ml_, 62.86 mmol) were added at 0 °C and the reaction mixture was stirred for 16 h at rt. The reaction mixture was poured into ice cold H2O and extracted with DCM. The combined organic layer were dried over anh Na₂S0₄, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography, silica gel, gradient Hexane to Hexane:EtOAc (7:3) to give the title compound (6.0 g, Yield: 26%).

Step f. Title compound.

To a stirred solution of the compound obtained in step e) (2.5 g, 5.96 mmol), in MeOH (25 ml_), cone. HCI (1.08 g, 29.83 mmol) was added dropwise at 0 °C. The reaction mixture was allowed to stir at rt for 16 h. The mixture was evaporated, co-distilled with toluene (3x 50 ml.) and dried under vacuum to give the title compound. (1.75 g, Yield: 89%).

Intemediate 2. (1 s,4s)-4-(Dimethylamino)-4-phenylcyclohexyl 4- methylbenzenesulfonate.

Step a. 4-(Dimethylamino)-4-phenylcyclohexanol.

To a solution of the compound obtained in step c) of Intermediate 1 (7.5 g, 34.6 mmol) in MeOH (75 ml_), sodium borohydride (3.9 g, 9.1 mmol) was added portion wise at 0 °C. The reaction mixture was stirred at rt for 2 h. Sat aq NH₄CI was added dropwise at 0 °C and the product was extracted with DCM. The combined organic layers were dried over anh Na₂S0_4, filtered and evaporated under vacuum to give the title compound (6.5 g, Yield: 86 %). Step b. Title compound.

To a solution of the compound obtained in step a) (6.5 g; 29.7 mmol) in anh DCM (100 ml_), TEA (8.4 ml_, 60.3 mmol) was added dropwise at rt and the reaction mixture was cooled to 0 °C. Then DMAP (0.2 g, 1.6 mmol) and p-toluensulfonyl chloride (6.22 g, 32.6 mmol) were added at 0 °C and the reaction mixture was stirred at rt for 48 h. The reaction mixture was neutralized with sat aq NaHCCh and the product was extracted with DCM. The combined organic layers were washed with H2O and sat aq NaCI, dried over anh Na₂S0_4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography silica gel, gradient petroleum ether to petroleum ethenEtOAc (70:30), to give the title compound (3.4 g, Yield: 31 %).

Intemediate 3. ((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)methyl 4- methylbenzenesulfonate.

Step a. (1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexanecarbonitrile.

To a solution of the compound obtained in step c) of Intermediate 1 (30 g, 138.2 mmol) in anhydrous THF (1200 mL), TOSMIC (40.4 g, 207.4 mmol) in THF (900 ml.) was added drop wise at 0 °C. Then, MeOH (8.84 g, 276.4 mmol) and KO‘Bu (46.5 g, 414.7 mmol) were added at 0 °C. The reaction mixture was stirred at 0 °C for 45 min and at rt for 16 h. The mixture was extracted with EtOAc, washed with FhO and sat aqueous NaCI. The combined organic layers were dried over anh Na2S0_4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography neutral alumina, gradient petroleum ether to petroleum ethenEtOAc (96:4), to give the title compound (1 r,4r, 7.5 g, Yield: 24%) and its (1 s,4s)-isomer (7.0g, Yield: 22%).

Step b. (1 r,4r)-Methyl 4-(dimethylamino)-4-phenylcyclohexanecarboxylate.

To a solution of the compound obtained in step a) (3 g, 13.1 mmol) in MeOH (30 mL), TMSCI (33.6 ml, 263.1 mmol) was added at rt. The reaction mixture was stirred at rt for 20 h. Then sat aq NaHCOs was added dropwise at 0 °C, and the product was extracted with DCM and washed with sat aq NaCI (1x 10 mL). The organic layer was dried over any Na2S0₄, filtered and evaporated under reduced pressure to give the title compound (2.9 g, Yield: 85%). Step c. ((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)methanol. To a solution of the compound obtained in step b) (3 g, 1 1.5 mmol) in THF (50 ml_), LiAII-U (655 mg, 17.2 mmol) was added portion wise at 0 °C and the mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc (60 ml.) and then sat aq Na₂S0₄ was added dropwise at 0 °C. The organic layer was washed with sat aq NaCI and dried over anh Na₂S0_4, filtered, and evaporated under vacuum to give the title compound (2.5 g, Yield: 93%).

Step d. Title compound.

To a stirred solution of the compound obtained in step c) (2.5 g, 10.7 mmol) in anhydrous DCM (30 ml_), TEA (4.5 ml_, 32.2 mmol) and DMAP (130 mg, 1.1 mmol) were added at 0 °C. Then p-toluensulfonyl chloride (2.45 g, 12.9 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with H2O (30 ml.) and extracted with DCM. . The organic layer was washed with sat aq NaCI, dried over anh Na₂S0_4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography silica gel, gradient DCM to DCM:MeOH (95:5), to give the title compound (2.3 g, Yield: 56%).

Intermediate 4. 2-(4-(Dimethylamino)-4-phenylcyclohexyl)ethyl 4- methylbenzenesulfonate.

Step a. Methyl 2-(4-(dimethylamino)-4-phenylcyclohexylidene)acetate. To a stirred solution of 4-(dimethylamino)-4-phenylcyclohexanone (500 mg, 2.3 mmol) in DMF (12 ml_), methyl 2-(dimethoxyphosphoryl)acetate (628.5 mg, 3.4 mmol) and potassium 2-methylpropan-2-olate (387.3 mg, 3.4 mmol) were added and the mixture was heated at 60 °C for 4 h. Some ice was added and the product was extracted with Et2<D. The organic layer were combined and dried over anh Na₂S0₄ and the solvent was removed under vacuum to give the title compound (617.4 mg, Yield: 96%).

Step b. 2-(4-(Dimethylamino)-4-phenylcyclohexylidene)ethanol. To a stirred solution of LiAlhU (1 M in Et₂0, 4.78 mL, 4.8 mmol) cooled at -70 ⁰ C, the compound obtained in step a) (261.1 mg, 0.95 mmol) in Et₂0 (6 mL) was added and the mixture was stirred at -70 °C for 2 h. The reaction was quenched with ice and the product was extracted with EtOAc and Et₂0. The combined organic layers were dried over anh Na₂S0_4, and the solvent was removed under vacuum to give the title compound (211.5 mg, Yield: 90%).

Step c. 2-(4-(Dimethylamino)-4-phenylcyclohexyl)ethanol.

A solution of the compound obtained in step b) in MeOH (10 mL), was reacted in a continuous flow hydrogenation reactor (Thales Nano H-Cube) using a catalyst cartridge (Pd/C 5%, 30 mm, 25 °C, 30 bars of H₂, 1 mL/ min flow rate). The collected fractions were evaporated under reduced pressure to give the title compound (1 11.5 mg, Yield: 89%).

Step d. Title compound.

A solution of the compound obtained in step c) (11 1.5 mg, 0.45 mmol) in anhDCM (6 mL), TEA (90 mί, 0.63 mmol) and DMAP (3.6 mg, 0.03 mmol) were added and the mixture was cooled at 0 °C. p-Toluenesulfonyl chloride (103.1 mg, 0.54 mmol) was added and reaction mixture was allowed to reach rt and was stirred for 4 h. The reaction was quenched with water and the product was extracted with DCM. The combined organic layers were dried over anh Na₂S0_4, and the solvent was removed under vacuum, to give the title compound (107mg, Yield: 59%).

Synthesis of Examples

Example 1. (1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone. Step a. Ethyl 2-oxo-2-(4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-5-yl)acetate. To a solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (3 g, 19.71 mmol) in anh THF (60 ml.) under argon atmosphere, lithium bis(trimethylsilyl)amide (1 M in THF, 29.56 ml_, 29.56 mmol) was added dropwise at rt. Then diethyl oxalate (4.28 ml_, 31.53 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction crude was diluted with EtOAc and washed with H2O. The aqueous layer was acidified to pH:2 with 2 N HCI and extracted with EtOAc. The combined organic layers were dried over anh Na₂S0₄ and concentrated to dryness to give the title compound (4.40 g, Yield: 89%).

Step b. Ethyl 1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carboxylate.

To a solution of the compound obtained in step a) (1 .1 g, 4.36 mmol) in EtOH (35 ml.) under argon atmosphere, Intermediate 1 (1 .12 g, 3.54 mmol) was added portion wise and the reaction was heated at 65 °C for 2.5 h. The mixture was cooled at room temperature and a solid precipitated. The solid was filtered and washed with EtOH to give the title compound (1.59 g, Yield: 96%).

Step c. 1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazole-3-carboxylic acid.

To a solution of the compound obtained in step b) (1.5 g, 3.4 mmol) in EtOH (15 ml.) under argon atmosphere, NaOH (680 mg, 17 mmol) was added and the reaction was heated at 85 °C for 3 h. The reaction was quenched with HCI (2 M in Et₂0, 8.5 ml.) and solvents were evaporated under vacuum. The crude product was dissolved in DCM:water (1 :1 , 40 ml.) and the remaining solid was filtered, washed with water and dried under vacuum, to give the title compound (1.44 g, Yield: 85%).

Step d. Title compound.

To a solution of the compound obtained in step c) (1 .23 g, 2.9 mmol) in anh DCM:DMF (1 :1 , 10 ml.) under argon atmosphere, EDC-HCI (1 .1 14 g, 5.81 mmol), HOBt (890.01 mg, 5.81 mmol) and TEA (1.21 ml_, 8.72 mmol) were added and the reaction was stirred at rt for 10 min. Then 1 -methylpiperazine (0.483 ml_, 4.36 mmol) was added dropwise and the reaction was stirred at rt overnight. Solvents were evaporated under vacuum and the crude product was dissolved in DCM and washed with H2O. The organic layer was dried over anh Na2S0₄, filtered and concentrated to dryness to give the title compound (1 .035 g, Yield: 71 %).

HPLC-MS (D): Rt, 1.93 min; ESI+-MS m/z: 504.2 This method was used for the preparation of Examples 2-76 using suitable starting materials and intermediates.

Examples X:

Example 77. (1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-1 H-thieno[2,3-g]indazol- 3-yl)(4-methylpiperazin-1 -yl)methanone. To a solution of the compound obtained in Example 1 (150 mg, 0.3 mmol) in anhydrous dioxane (5 ml.) under argon atmosphere, DDQ (135.2 mg, 0.6 mmol) was added and the reaction mixture was heated at 100 °C for 1 h. More DDQ was added (67.6 mg, 0.3 mmol) and the reaction mixture was heated at 100 °C for 1 .5 h. After cooling to rt the solvent was removed under vacuum. EtOAc was added and the organic layer was washed with Na2C03 and brine, dried over anh Na2S0₄ and the solvent was removed. The crude product was purified by flash chromatography silica gel, gradient DCM to MeOH, to give the title compound (8 mg, Yield: 5%).

HPLC-MS (D): Rt, 1.99 min; ESI+-MS m/z: (502.3)

Example 78. (7-Bromo-1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone.

Step a. 2-bromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one.

To a solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (1.5 g, 9.85 mmol) in AcOH: H2O (20 ml_, 1 :1 ), bromine (1.57 g, 9.85 mmol) was added dropwise at 0 °C. After 20 min, the reaction mixture was warmed at rt and stirred for 18 h. The reaction was quenched at 0 °C by addition of 1 M NaOH until basic pH. The precipitated formed was collected by filtration, washed with water and dried in a vacuum oven at 50 °C to give the title compound (2.08 g, Yield: 91%). Step b. Ethyl 2-(2-bromo-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-5-yl)-2-oxoacetate.

Starting from the compound obtained in step a) (300 mg, 1.29 mmol) and following the experimental procedure described in step a) of Example 1 , the title compound was obtained (425.8 mg, Yield: quantitative).

Step c. Ethyl 7-bromo-1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carboxylate.

Starting from the compound obtained in step b) (425.8 mg, 1.29 mmol) and following the experimental procedure described in step b) of Example 1 , the title compound was obtained (607.0 mg, Yield: 89 %).

Step d. 7-Bromo-1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carboxylic acid.

Starting from the compound obtained in step c) (607.0 mg, 1.15 mmol) and following the experimental procedure described in step c) of Example 1 , the title compound was obtained (574.7 mg, Yield: quantitative).

Step e. Title compound.

Starting from the compound obtained in step d) (291.4 mg, 0.582 mmols) and following the experimental procedure described in step d) of Example 1 , the title compound was obtained (309.0 mg, Yield: 91%).

HPLC-MS (D): Rt, 2.28 min; ESI+-MS m/z: 582.1 )

Example 79. 1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-7-carbonitrile.

To a solution of the compound obtained in Example 78 (50 mg, 0.09 mmol) in anhydrous DMF (1 ml.) under argon atmosphere, Zn(CN)₂ (10.1 mg, 0.09 mmol) and Pd(PPh3)4 (9.92 mg, 0.02 mmol) were added and the reaction mixture was heated under microwave irradiation (100 °C, 150 W, 45 min). The reaction was quenched with 2 N HCI and extracted with EtOAc. The organic layer was dried with anh Na₂S0₄ and the solvent was removed under vacuum. The crude product was purified by flash chromatography silica gel, gradient DCM to MeOH, to give the title compound (10 mg, Yield: 22%).

HPLC-MS (D): Rt, 2.28 min; ESI+-MS m/z: 470.2 (M-45)

Example 80. 1-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-7-carboxylic acid.

To a solution of the compound obtained in Example 79 (27 mg, 0.05 mmol) in EtOH (0.5 ml_), NaOH (2.5 M, 0.41 ml_, 1.02 mmol) and H2O2 (30%, 78 mI_, 0.77 mmol) were added and the mixture was stirred at 90 °C for 16 h. The solvent was removed under vacuum and the crude product was purified by flash chromatography C18, gradient NH₄HCC>₃ (10 mM) to ACN to give the title compound (6 mg, Yield: 22%). HPLC-MS (D): Rt, 1.22 min; ESI+-MS m/z: 548.2

Example 81. 1-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-7-sulfonic acid.

To a solution of the compound obtained in Example 1 (62.5 mg, 0.12 mmol) in anhydrous DCM (2 ml_), sulphuric acid (48.7 mg, 0.5 mmol) and acetic anhydride (152 mg, 1.5 mmol) were added drop wise at -10 °C. The mixture was stirred at rt for 16 h. The solvent was removed under vacuum and the crude product was purified by flash chromatography, silica gel gradient DCM to DCM:MeOH (85:15), to give the title compound (68.3 mg, Yield: 94%).

HPLC-MS (D): Rt, 1.93 min; ESI+-MS m/z: 504.2

Example 82. (1-((1 r,4r)-4-((2-Fluoroethyl)methylamino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone.

A solution of the compound obtained in Example 18 (60 mg, 0.123 mmol) in ACN (5 ml_), 2-methoxyethyl trifluoromethanesulfonate (255.0 mg, 1.23 mmol) and TEA (37.2 mg, 0.368 mmol) were added and the reaction mixture was heated at 100 °C overnight. The solvent was removed under vacuum and EtOAc was added. The organic layer was washed with NaHCC>3_, dried over anh Na₂S0₄ and filtered. The solvent was removed to dryness and the crude product was purified by flash chromatography, gradient DCM to MeOH (1% NH₃), to give the title compound (2 mg, Yield: 3%).

HPLC-MS (D): Rt, 2.26 min; ESI+-MS m/z: 536.3

This method was used for the preparation of Example 83 using suitable starting materials:

Example 84. (1 -((1 r,4r)-4-((2,2-Difluoroethyl)(methyl)amino)-4-phenylcyclohexyl)-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone.

Starting from the compound obtained in Example 83 (86.2 mg, 0.155 mmol) and following the experimental procedure described in Example 77 the title compound was obtained (6 mg, Yield: 7%).

HPLC-MS (D): Rt, 2.46 min; ESI+-MS m/z: 552.3

Example 85. (1 ,4-Diazepan-1 -yl)(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone.

To a solution of the compound obtained in Example 4 (200 mg, 0.33 mmol) in anh DCM (2.7 ml_), TFA (345 mI_) was added drop wise at 0 °C and the reaction mixture was stirred overnight at rt. The mixture was neutralised with 20% aq NaOH, diluted with DCM and washed with sat aq NaCI. The organic layer was dried over anh Na₂S0₄, filtered and evaporated to dryness, to give the title compound (45 mg, Yield: 27%).

HPLC-MS (D): Rt, 1.77 min; ESI+-MS m/z: 504.2 This method was used for the preparation of Examples 86-96 using suitable starting materials:

Example 97. (1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-(2-fluoroethyl)piperazin-1-yl)methanone.

A sealed tube was charged with a solution of the compound obtained in Example 86 (40 mg, 0.082 mmol) in anh ACN (2 ml_). DIPEA (20.9 mI_, 0.12 mmol) and 1-fluoro-2- iodoethane (22.9 mI_, 0.1 mmol) were added drop wise and the reaction mixture was irradiated under microwaves (120 °C, 150 W, 1 h). The reaction mixture was diluted with DCM and washed with H2O. The organic layer was dried over anh Na₂S0₄, filtered and evaporated under vacuum. The crude product was purified by flash chromatography silica gel, gradient DCM to DCM:MeOH (98:2), to give the title compound (20 mg, Yield: 45%).

HPLC-MS (D): Rt, 2.08 min; ESI+-MS m/z: 536.3

This method was used for the preparation of Example 98 using suitable starting materials:

Example 99. (2-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H- thieno[2,3-g]indazol-3-yl)(4-ethylpiperazin-1-yl)methanone.

Step a. Ethyl 2-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H- thieno[3,2-e]isoindole-3-carboxylate. To a solution of the compound obtained in step b) of Example 1 (320 mg, 1.16 mmol) in DMA (1.5 ml.) under argon atmosphere, Intermediate 2 (519 mg, 1.392 mmol) and CS2CO3 (567 mg, 1.74 mmol) were added and the reaction was heated at 100 °C for 2 h. The crude mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over anh Na₂S0₄, filtered and concentrated to dryness. The crude product was purified by flash chromatography silica gel, gradient DCM to DCM:MeOH (8:2), to give the title compound (80.4 mg, Yield: 15%).

Step b. 2-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H-thieno[3,2- e]isoindole-3-carboxylic acid.

Starting from the product obtained in step a) (80 mg, 0.179 mmol) and following the experimental procedure described in step c) of Example 1 , the title compound was obtained (55 mg, Yield: 72%).

Step c. Title compound.

Starting from the product obtained in step b) (55 mg, 0.128 mmol) and following the experimental procedure described in step d) of Example 1 , the title compound was obtained (57 mg, Yield: 87%).

HPLC-MS (E): Rt, 2.66 min; ESI+-MS m/z: 473.2

This method was used for the preparation of Examples 100-101 using suitable starting materials:

Example 102. 2-(1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)-2-(4-methylpiperazin-1-yl)acetonitrile. Step a. 1-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-N-methoxy-N-methyl-4,5- dihydro-1 H-thieno[2,3-g]indazole-3-carboxamide.

Starting from the compound obtained in step c) of Example 1 (180 mg, 0.427 mmols) and following the experimental procedure described in step d) of the same example, the title compound was obtained (172.63 mg, Yield: 87%). Step b. 1-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazole-3-carbaldehyde.

To a solution of the compound obtained in step a) (66 mg, 0.142 mmols) in anh THF (2ml_) cooled at 0 °C, LiAII-U (1 M in THF, 0.17 ml_, 0.17 mmols) was added drop wise and the mixture was stirred for 30 min. The reaction was quenched with 10 % HCI and the mixture was neutralized with aq NaHCCh sat solution and extracted with EtOAc. The organic layer was dried over anh Na2S0₄, filtered and concentrated to dryness, to give the title compound (53.6 mg, Yield: 93%).

Step c. Title compound. To a solution of the compound obtained in step b) (73 mg, 0.18 mmol) in hhCbMeOH (1 :1 , 8 ml_), Na2S2C>3 (17.1 mg, 0.09 mmol) was added and the mixture was stirred vigorously at rt for 2 h. Methylpiperazine (18.02 mg, 0.18 mmol) was added, the mixture was stirred for 1 h and then KCN (23.4 mg, 0.36 mmol) was added and the mixture was stirred for 48 h more. MeOH was removed under vacuum and the crude product was extracted with EtOAc, washed with sat NaCI and water. The organic layer was dried over anh Na₂S0₄, filtered and concentrated to dryness to obtain the title compound (77.0 mg, Yield: 93%).

HPLC-MS (D): Rt, 2.28 min; ESI+-MS m/z: 470.2 (M-45)

Example 103. 2-(1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide.

To a solution of the compound obtained in Example 102 (48 mg, 0.093 mmol) in MeOH/DMSO (3:1.5, 4.5 ml_), NaOH (2.5 M, 74 mI_, 0.187 mmol) and H₂0₂ (30%, 48 mI_, 0.466 mmol) were added and the mixture was stirred at rt for 30 min. Solvents were removed under vacuum and the residue was extracted with EtOAc). The organic layer was washed with H2O, dried over anh Na₂S0₄ and filtered. The solvent was removed under vacuum to give the title compound (49.62 mg, Yield: quantitative).

HPLC-MS (D): Rt, 1.7 min; ESI+-MS m/z: 533.2

Example 104. (1 r,4r)-4-(8-(tert-Butyl)-3-((4-methylpiperazin-1 -yl)methyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-1-yl)-N,N-dimethyl-1-phenylcyclohexanamine. To a stirred solution of the compound obtained in Example 103 (48.0 mg, 0.090 mmol) in HhOdBuOH (1.6 ml_, 1 :1 ), TFA (0.689 ml_, 9.01 mmol) was added and the mixture was heated at 100 °C for 6 days. The solvent was removed under vacuum, EtOAc (5 ml.) was added and the organic layer was washed with NaHCC>3 aq sat sol. The organic layer was dried over anh Na₂S0₄ and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (30:70), to give the title compound. (10 mg, Yield: 20%).

HPLC-MS (D): Rt, 2.75 min; ESI+-MS m/z: 546.2

Example 105. N,N-Dimethyl-1-(4-(3-((4-methylpiperazin-1-yl)methyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)-4-phenylpiperidin-4-amine.

Step a. Aluminium trihydride.

A vigorously stirred solution of LiAIH₄ (1 M in THF, 25 ml_, 25 mmol) was cooled at -78 °C. Sulfuric acid (666.3 mI; 12.5 mmol) was added drop wise and the mixture was stirred at -78 °C for 1.5 h. The mixture was used in the next step.

Step b. Title compound.

To a stirred solution of freshly prepared alane in step a) (1.7 ml_, 1.7 mmols), Example 38 (195.5 mg, 0.337 mmols) was added at 0 °C and the mixture was stirred at 0 °C for 1.5 h. The reaction mixture was quenched by drop wise addition of water (5ml_) and the mixture was extracted with EtOAc. The combined organic layers were dried over anh Na₂S0₄, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography AI₂O₃, using gradient DCM to DCM:MeOH (7:3), to give the title compound (108 mg, Yield: 57%). HPLC-MS (A): Rt, 2.41 min; ESI+-MS m/z: 567.3

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

Example. 107 (1-((4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone.

Step a. Ethyl 4,5-dihydro-1 H-thieno[2,3-g]indazole-3-carboxylate.

To a solution of the compound obtained in step a) of Example 1 (1.0 g, 3.96 mmol) in EtOH (15 ml.) under argon atmosphere, hydrazine hydrate (218.27 mg, 4.36 mmol) was added drop wise. Following the experimental procedure described in step c) of Example 1 , the title compound was obtained (955.2 mg, Yield: 97%).

Step b. 4,5-Dihydro-1 H-thieno[2,3-g]indazole-3-carboxylic acid.

Starting from the product obtained in step a) (955.2 mg, 3,85 mmol) and following the experimental procedure described in step c) of Example 1 , the title compound was obtained (727 mg, Yield: 86%).

Step c. (4,5-Dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone. Starting from the product obtained in step b) (167 mg, 0.67 mmol) and following the experimental procedure described in step d) of Example 1 , the title compound was obtained (126 mg, Yield: 63%).

Step d. Title compound.

To a solution of the compound obtained in step c) (60 mg, 0.2 mmol) in DMA (2 ml_), Intermediate 2 (99.2 mg, 0.24 mmol) and CS2CO3 (97 mg, 0.3 mmol) were added, and the mixture was heated at 100 °C for 2 h. The solvent was removed under vacuum and EtOAc was added. The organic layer was washed with water and brine and dried over anh Na₂S0₄and the solvent was removed under vacuum. The crude product was purified by flash chromatography S1O2, using gradient DCM to MeOH, to give the title compound (31 mg, Yield: 30%).

HPLC-MS (C): Rt, 2.33 min; ESI+-MS m/z: 518.1

Example 108. (1 -(2-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)ethyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone.

Alkylation of the product obtained in step c) of Example 106 (84 mg, 0.278 mmol) with intermediate 4 and following the experimental procedure described in step d) of the same example, provided the title compound (38.1 mg, Yield: 26%).

HPLC-MS (D): Rt, 1.97 min; ESI+-MS m/z: 532.3.

Example 109. (1 -(2-(4-(3-Hydroxyphenyl)-4-(methylamino)piperidin-1 -yl)ethyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone.

Step a. Ethyl 1 -(2-hydroxyethyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-3-carboxylate.

To a solution of the compound obtained in step a) of Example 1 (8 g, 32.89 mmol) in HFIP (55 ml.) under argon atmosphere, 2-hydrazinylethanol (3.34 ml_, 49.35 mmol) was added drop wise and the reaction was stirred at rt for 1 .5 h. The solid product was filtered, washed with HFIP and dried under vacuum to give the title compound (8 g, Yield: 83%).

Step b. 1 -(2-Hydroxyethyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-3-carboxylic acid.

Starting from the product obtained in step a) (5.87 g, 20.08 mmol) and following the experimental procedure described in step c) of Example 1 , the title compound was obtained (4.35 g, Yield: 82%).

Step c. (1 -(2-Hydroxyethyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin- 1 -yl)methanone.

Starting from the product obtained in step b) (1.5 g, 5.67 mmol) and following the experimental procedure described in step d) of Example 1 , the title compound was obtained (830 mg, Yield: 42%).

Step d. (1 -(2-Chloroethyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin- 1 -yl)methanone.

To a solution of the compound obtained in step c) (155 mg, 0.447 mmol) in anh DCM (25 ml.) under argon atmosphere, thionyl chloride (99.8 mI_, 1 .34 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at rt overnight. The crude mixture was diluted with DCM and washed with H2O. The organic layer was dried over anh Na₂S0₄, filtered and concentrated to dryness to give the title compound (152 mg, Yield: 93%).

Step e. Title compound.

A sealed tube was charged with the compound obtained in step d) (80 mg, 0.219 mmol), DMF (2 ml_), DIPEA (190 mI_, 1 .096 mmol), Kl (36.9 mg, 0.219 mmol) and 3-(4- (methylamino)piperidin-4-yl)phenol (76.9 mg, 0.373 mmol). The reaction mixture was irradiated under microwaves at 150 W for 2 h at 100 °C. EtOAc was added and the mixture was washed three times with H2O. The organic layer was dried over Na₂S0₄ filtered and evaporated under vacuum. The crude product was purified by flash chromatography silica gel, gradient DCM to DCM:MeOH (85:15), to give the title compound (33 mg, Yield: 28%).

HPLC-MS (D): Rt, 1.53 min; ESI+-MS m/z: 535.1

This method was used for the preparation of Examples 109-1 16 using suitable starting materials:

Example 118. 1 -(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)-2-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)ethanone.

Step a. 2-Chloro-1-(4-(dimethylamino)-4-phenylpiperidin-1-yl)ethanone.

To a solution of N,N-dimethyl-4-phenylpiperidin-4-amine (491 mg, 1.771 mmol) in anh DCM (30 ml_), 2-chloroacetyl chloride (200 mg, 1.771 mmol) and TEA (0.44 ml_, 3.19 mmol) were added at 0 °C. The mixture was stirred for 3 h and the solvent was removed under vacuum. The crude product was purified by flash chromatography AI2O3, gradient cyclohexane to AcOEt, to give the title compound (256.3 mg, Yield: 62%).

Step b. Title compound.

To a solution of the compound obtained in step a) in DMA (15 ml_), the product obtained in step c) (147.0 mg, 0.486 mmol) of Example 106 was added. Following the experimental procedure described in step d) of the same example, the title compound was obtained (60.5 mg, Yield: 23%).

HPLC-MS (D): Rt, 1.81 min; ESI+-MS m/z: 547.3

This method was used for the preparation of Examples 117-127 using suitable starting materials:

Following the experimental procedure described in Example 1 , and using suitable starting materials, the compounds of Examples 128-140 were prepared.

Following the experimental procedure described in Example 85 and using suitable starting materials, the compounds of Examples 141-146 were prepared.

Following the experimental procedure described in Example 118 and using suitable starting materials, the compounds of Examples 147-148 were prepared.

Following the experimental procedure described in Example 109 and using suitable starting materials, the compounds of Examples 149-150 were prepared.

Example 151. (1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(3-(dimethylamino)azetidin-1 -yl)methanone.

A sealed MW tube was charged with Example 142 (30 mg, 0.061 mmol) dissolved in DCE (2 ml_), formaldehyde (17 mI, 0.613 mmol) and NaBH(OAc)₃ (39 mg, 0.184mmol) were added and the reaction mixture was irradiated at MW at 150 W for 5 min at 120 °C. The reaction mixture was dissolved in DCM and washed three times with H2O. The organic layer was dried over Na2S0₄ filtered and evaporated under vacuum to give the title compound (32 mg, Yield: quant).

HPLC-MS (D): Rt, 2.03 min; ESI+-MS m/z: 549.3.

Example 152. 1 -(4-(Methylamino)-4-phenylpiperidin-1 -yl)-2-(3-(4-methylpiperazine- 1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)ethanone.

Following the experimental procedure described in Example 77, and using suitable starting materials, the title compound was prepared.

HPLC-MS (G): Rt, 2.23 min; ESI+-MS m/z: 532.7.

PHARMACOLOGICAL STUDY

Human a2d-1 subunit of Cav2.2 calcium channel assay

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) was measured by adding 10 mM pregabalin. The binding of the test compound was measured at five different concentrations. After 60 min incubation at 27 °C, binding reaction was terminated by filtering through Multiscreen GF/C (Millipore) presoaked in 0.5 % polyethyleneimine in Vacuum Manifold Station, followed by 3 washes with ice-cold filtration buffer containing 50 mM Tris-HCI, pH 7.4. Filter plates were dried at 60 °C for 1 h and scintillation cocktail (30 mI_) were added to each well before radioactivity reading. Readings were performed in a Trilux 1450 Microbeta radioactive counter (Perkin Elmer).

Human u-opioid receptor radioligand assay

Transfected CHO-K1 cell membranes (20 pg) were incubated with [³H]-DAMGO (1 nM) in assay buffer containing Tris-HCI 50 mM, MgCI₂ 5 mM at pH 7.4. NBS (non-specific binding) was measured by adding 10 mM Naloxone. The binding of the test compound was measured at five different concentrations. Plates were incubated at 27 °C for 60 min. After the incubation period, the reaction mixture was then transferred to Multiscreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris-HCI (pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail.

Results:

This invention is aimed at providing a series of compounds which act as dual ligands of the a₂d subunit of voltage-gated calcium channels and the m-opioid receptor it is a very preferred embodiment in which the compounds are selected which act as dual ligands of the a₂d subunit of voltage-gated calcium channels and the m-opioid receptor and especially compounds which have a binding expressed as K, responding to the following scales:

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

K,(m) is preferably < 1000 nM, more preferably < 500 nM, even more preferably < 100 nM.

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

+ Kΐ(a₂d-1) >= 5000 nM ++ 500nM <= K_ί(a₂d-1) <5000 nM

+++ K_ί(a₂d-1) <500 nM

The following scale has been adopted for representing the binding to m-opioid receptor expressed as K,: + Ki (m) >= 500 nM

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

+++ K_ΐ(m) < 100 nM

All compounds prepared in the present application exhibit binding to the a2d-1 subunit of voltage-gated calcium channels and the m-opioid receptor, in particular the following binding results are shown:

Claims

1. A compound of formula (I):

wherein one of W₃ and W₄ is S and the other is C;

X is selected from a bond, -[C(RbRb )] -, -[C(RbRb )] C(0)[C(Rb"Rb )]q-_> substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl-C(O), substituted or unsubstituted aryl- alkyl, wherein each R_b, R_b·, R_b- and R_b- 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; and p is 0, 1 , 2 or 3; q is 0, 1 , 2 or 3;

Group A is a substituted or unsubstituted 4 to 10 membered mono or bicyclic heterocyclyl containing one nitrogen atom and optionally a second heteroatom selected from N and O, wherein A is attached to Y through a nitrogen atom; each Ri and Rr are independently 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 alkyl-cycloalkyl; NR₄R_4', C(0)0R₄ and substituted or unsubstituted haloalkyl; wherein each R₄ and R_4' are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and C(0)OR₄·; wherein R_{4 "} is substituted or unsubstituted C_1-6 alkyl.

R₅ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6alkenyl, substituted or unsubstituted C_2-6 alkynyl, CN, -C(0)OR₃ and -S(0)₂0R_3' ; wherein each R₃ and Ry are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; R₆ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl (tert-butyl), substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl,

R₂ is a group of the following formula

(R2) wherein m is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 , 2 or 3;

Wi is selected from C or N; each Rg, Rg·, Rg- and Rg- are independently selected from hydrogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a carbonyl group; each R10, Rio·, R10” and R10- are independently selected from hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C2-₆ alkenyl and substituted or unsubstituted C2-₆ alkynyl; alternatively, R1₀, R-io· and/or Rio ·, R-io- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, R1₀ and R-io· and/or Rio- and Rio- taken together with the carbon atom to which they are attached may form a carbonyl group;

R7 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aromatic heterocyclyl;

Rs is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2- e alkynyl; Rs· is selected from hydrogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2- e alkynyl; alternatively, R7 and Rs taken together with -N(Rs )-[CH2]_t- atoms to which they are attached form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; wherein the compound of formula (I) is optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

2. Compound according to claim 1 wherein

W3 is S and W₄ is C;

Y is -C(O)-, -[C(RaRa')]n-, -CRa(CN)- or -CR_a(CONRa'Ra ")-. wherein each R_a, R_a· and R_a” 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; and n is 0, 1 , 2 or 3;

Group A is a substituted or unsubstituted 5 to 10 membered mono or bicyclic heterocyclyl containing one nitrogen atom and optionally a second heteroatom selected from N and O, wherein A is attached to Y through a nitrogen atom; each Ri and Rr are independently 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 alkyl-cycloalkyl; NR₄R_4', C(0)0R₄ and substituted or unsubstituted haloalkyl; wherein each R₄ and R_4' are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, and C(0)0R₄·; wherein R_{4 "} is substituted or unsubstituted C_1-6 alkyl.

R₅ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6alkenyl, substituted or unsubstituted C_2-6 alkynyl, CN, -C(0)0R₃ and -S(0)₂0R_3' ; wherein each R₃ and R_3' are independently selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; R₆ is selected from hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl (tert-butyl), substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl,

R₂ is a group of the following formula

wherein m is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 , 2 or 3; Wi is selected from C or N; each Rg, Rg·, Rg- and Rg- are independently selected from hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-₆ alkynyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, Rg and Rg· and/or Rg- and Rg- taken together with the carbon atom to which they are attached may form a carbonyl group; each R10, Rio·, R10” and Rio- are independently selected from hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C2-₆ alkenyl and substituted or unsubstituted C2-₆ alkynyl; alternatively, R1₀, R-io· and/or Rio ·, R-io- taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, R1₀ and R-io· and/or Rio- and R-io- taken together with the carbon atom to which they are attached may form a carbonyl group;

Rs· is selected from hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C2-₆ alkenyl and substituted or unsubstituted C2- e alkynyl; alternatively, R₇ and Rs taken together with -N(Rs )-[CH2]t- atoms to which they are attached form a substituted or unsubstituted heterocyclyl optionally fused with a substituted or unsubstituted aryl group; 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.

3. Compound according to claim 1 or 2 wherein group A is selected from:

wherein b is 0, 1 or 2; W₂ is selected from O, C and N; wherein each R1 and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted alkyl-cycloalkyl; N R4R4', C(0)OR₄ and substituted or unsubstituted haloalkyl; wherein each R4 and R4' are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, and C(0)OR4·; wherein R4" is substituted or unsubstituted C1-6 alkyl.

4. Compound according to claim 3, wherein A is

wherein b is 1 or 2;

W₂ is N; wherein each Ri and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted alkyl-cycloalkyl; and substituted or unsubstituted haloalkyl.

5. Compound according to claim 4, wherein b is 1 ;

W₂ is N; Ri is hydrogen and Rr is substituted or unsubstituted Ci-₆ alkyl, and wherein Rr is directly attached to W₂.

6. Compound according to any one of claims 1 to 5, wherein each Ri and Rr are independently selected from hydrogen, halogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted alkyl-cycloalkyl; NR₄R_4', and substituted or unsubstituted haloalkyl; wherein each R4 and R4' are independently selected from hydrogen and substituted or unsubstituted C1-6 alkyl.

7. Compound according to any one of claims 1 to 6, wherein R₂ is a group of the following formula:

(R₂) wherein m is 1 ; r is 1 ; t is 0; Wi is C; each Rg, Rg·, Rg- and Rg- are hydrogen; each Rio, Rio·, Rio” and Rio- are hydrogen;

R7 is substituted or unsubstituted aryl;

Rs is substituted or unsubstituted C1-6 alkyl; and Rs· is substituted or unsubstituted C1-6 alkyl. 8. Compound according to any one of claims 1 to 7, wherein said compound is selected from:

[1] (1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[2] (1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(morpholino)methanone;

[3] (1 -((1 s,4s)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[4] tert-butyl 4-(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazole-3-carbonyl)-1 ,4-diazepane-1 -carboxylate;

[5] (1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1 -yl)methanone;

[6] (1 -((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((3S,5R)-3,5-dimethylpiperazin-1 -yl)methanone;

[7] (1 -((1 r,4r)-4-(dimethylamino)-4-(3-hydroxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone; [8] (1 -((1 s,4s)-4-(dimethylamino)-4-(3-fluorophenyl)cyclohexyl)-4, 5-dihydro- 1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[9] (1 -((1 s,4s)-4-(dimethylamino)-4-(4-fluorophenyl)cyclohexyl)-4, 5-dihydro- 1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[10] (1-((1s,4s)-4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[11] (1-((1s,4s)-4-(dimethylamino)-4-(4-methoxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[14] (1-((1 r,4r)-4-(dimethylamino)-4-(3-methoxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[15] (1-((1s,4s)-4-(dimethylamino)-4-(3-hydroxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[19] (1-((1s,4s)-4-(dimethylamino)-4-(2-methoxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[20] (S)-tert-butyl 4-(1 -((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)-3-methylpiperazine-1- carboxylate; [21] (R)-tert-butyl 4-(1-((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)-3-methylpiperazine-1- carboxylate;

[22] (1 -((1 s,4s)-4-(methylamino)-4-phenylcyclohexyl)-4, 5-dihydro- 1 H-thieno[2,3- g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[23] (1 -((1 r,4r)-4-(dimethylamino)-4-(4-methoxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[24] tert-butyl 5-(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-

1 H-thieno[2,3-g]indazole-3-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1 H)- carboxylate;

[25] tert-butyl 6-(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-

1 H-thieno[2,3-g]indazole-3-carbonyl)-2,6-diazaspiro[3.4]octane-2- carboxylate;

[26] (1 -((1 r,4r)-4-((dimethylamino)methyl)-4-(3-methoxyphenyl)cyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[27] (1 -((1 s,4s)-4-((dimethylamino)methyl)-4-(3-methoxyphenyl)cyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[28] tert-butyl 4-(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-

1 H-thieno[2,3-g]indazole-3-carbonyl)-6,6-difluoro-1 ,4-diazepane-1 - carboxylate;

[29] (1 -((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((R)-3-(hydroxymethyl)-4-methylpiperazin-1- yl)methanone;

[30] (1 -((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((S)-3-(hydroxymethyl)-4-methylpiperazin-1- yl)methanone;

[31] tert-butyl 2-(difluoromethyl)-4-(1-((1 r,4r)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-3- carbonyl)piperazine-1 -carboxylate; [32] (4-(cyclopropylmethyl)piperazin-1 -yl)(1 -((1 r,4r)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[33] (4,6-dimethyl-1 ,4-diazepan-1 -yl)(1 -((1 r,4r)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[34] (4,7-dimethyl-1 ,4-diazepan-1 -yl)(1 -((1 r,4r)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[35] (1 -((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((S)-3-(dimethylamino)piperidin-1-yl)methanone;

[36] (1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)methanone;

[37] (1 -(4-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1 - yl)methanone;

[38] (1 -(4-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[39] (1 -(3-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[40] tert-butyl (1 -(1 -(4-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)pyrrolidin-3- yl)(methyl)carbamate;

[41] (1-(4-(4-(dimethylamino)-4-ethylpiperidin-1-yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[42] (1 -(4-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '- yl)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1- yl)methanone;

[43] (1 -(4-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone; [44] (1 -(4-(4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[45] (1 -(4-(4-(methylamino)-4-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[46] (1 -(4-(4-(3-hydroxyphenyl)-4-(methylamino)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[47] (1 -(3-(4-(methylamino)-4-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[48] (1 -(3-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '- yl)phenyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1- yl)methanone;

[49] (1 -(3-(4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[50] (1 -(3-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[51] (1-(4-(4-((dimethylamino)methyl)-4-phenylpiperidin-1-yl)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[52] (1 -(4-(3-(dimethylamino)-3-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[53] (1 -(3-(4-((dimethylamino)methyl)-4-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[54] (1 -(3-(4-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-1 -yl)phenyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[55] (1 -(4-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1-yl)methanone;

[56] (1-(3-(4-(dimethylamino)-4-(pyridin-2-yl)piperidin-1-yl)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone; [57] (1-(3-(4-(dimethylamino)-4-(pyndin-2-yl)piperidin-1-yl)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[58] (1-(4-(4-(dimethylamino)-4-(pyridin-2-yl)piperidin-1-yl)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[59] (1 -(4-(4-(dimethylamino)-4-(4-methoxyphenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[60] (1 -(4-(4-(dimethylamino)-4-(2-methoxyphenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[61] (1-(4-(4-(dimethylamino)-4-(3-fluorophenyl)piperidin-1-yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[62] (1 -(4-(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1 -yl)phenyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[63] (1 -(3-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)phenyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[64] (1 -(4-((4-(dimethylamino)-4-phenylpiperidin-1 -yl)methyl)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[65] (1 -(3-((4-(dimethylamino)-4-phenylpiperidin-1 -yl)methyl)phenyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[66] (1 -(4-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)phenyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[67] (4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)(3-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)phenyl)methanone;

[68] (4-(dimethylamino)-4-phenylpiperidin-1 -yl)(4-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[69] (4-(dimethylamino)-4-phenylpiperidin-1 -yl)(3-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone; [70] (2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '-yl)(4-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)phenyl)methanone;

[71] (2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1 ,4'-piperidin]-1 '-yl)(3-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)phenyl)methanone;

[72] (4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)(4-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)phenyl)methanone;

[73] (4-(methylamino)-4-phenylpiperidin-1 -yl)(4-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[74] (4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)(4-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)phenyl)methanone;

[75] (4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)(3-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)phenyl)methanone;

[76] (4-(methylamino)-4-phenylpiperidin-1 -yl)(3-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1-yl)phenyl)methanone;

[77] (1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-1 H-thieno[2,3-g]indazol-3- yl)(4-methylpiperazin-1-yl)methanone;

[78] (7-Bromo-1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[79] 1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-7-carbonitrile;

[80] 1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-7-carboxylic acid; [81] 1-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-3-(4-methylpiperazine-1- carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazole-7-sulfonic acid;

[82] (1 -((1 r,4r)-4-((2-Fluoroethyl)methylamino)-4-phenylcyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[83] (1 -((1 r,4r)-4-((2,2-difluoroethyl)(methyl)amino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[84] (1 -((1 r,4r)-4-((2,2-Difluoroethyl)(methyl)amino)-4-phenylcyclohexyl)-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[85] (1 ,4-Diazepan-1 -yl)(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[86] (1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(piperazin-1-yl)methanone;

[87] (1 -((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((S)-2-methylpiperazin-1-yl)methanone;

[88] (1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)methanone;

[89] (1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone;

[90] (6,6-difluoro-1 ,4-diazepan-1 -yl)(1 -((1 r,4r)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[91] (3-(difluoromethyl)piperazin-1-yl)(1-((1 r,4r)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[92] (1 -(4-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)phenyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(3-(methylamino)pyrrolidin-1-yl)methanone;

[93] (1 -((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((R)-2-methylpiperazin-1-yl)methanone; [94] (7-bromo-1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(piperazin-1-yl)methanone;

[95] (1 -((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((R)-3-(hydroxymethyl)piperazin-1-yl)methanone;

[96] (1 -((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)((S)-3-(hydroxymethyl)piperazin-1-yl)methanone;

[97] (1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-(2-fluoroethyl)piperazin-1-yl)methanone;

[98] (4-(2,2-difluoroethyl)piperazin-1 -yl)(1 -((1 r,4r)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[99] (2-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H- thieno[2,3-g]indazol-3-yl)(4-ethylpiperazin-1-yl)methanone;

[100] (2-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-2H-thieno[2,3- g]indazol-3-yl)(4-methyl-1 ,4-diazepan-1 -yl)methanone;

[102] 2-(1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)-2-(4-methylpiperazin-1-yl)acetonitrile;

[103] 2-(1 -((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;

[104] (1 r,4r)-4-(8-(tert-Butyl)-3-((4-methylpiperazin-1 -yl)methyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)-N,N-dimethyl-1-phenylcyclohexanamine;

[105] N,N-Dimethyl-1-(4-(3-((4-methylpiperazin-1-yl)methyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1-yl)phenyl)-4-phenylpiperidin-4-amine;

[106] (1 r,4r)-N,N-dimethyl-4-(3-((4-methylpiperazin-1-yl)methyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-1 -yl)-1 -phenylcyclohexanamine; [107] (1 -((4-(Dimethylamino)-4-phenylcyclohexyl)methyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[108] (1 -(2-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[109] (1 -(2-(4-(3-Hydroxyphenyl)-4-(methylamino)piperidin-1 -y I )eth y I )-4 , 5-d i hyd ro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 10] (1 -(2-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)ethyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 11] (1 -(2-(4-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-1 -yl)ethyl)- 4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 12] (1 -(2-(4-(methylamino)-4-phenylpiperidin-1 -yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 13] (2-(2-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)ethyl)-4,5- dihydro-2H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 14] (1 -(2-(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1 -yl)ethyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 15] (1 -(2-(4-(dimethylamino)-4-(3-fluorophenyl)piperidin-1 -yl)ethyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 16] (1 -(2-(4-((dimethylamino)methyl)-4-phenylpiperidin-1 -yl)ethyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 17] (1 -(2-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)ethyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone;

[1 18] 1 -(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)-2-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)ethanone;

[1 19] 1 -(4-(dimethylamino)-4-(3-fluorophenyl)piperidin-1-yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone; [120] 1 -(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1-yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone;

[121] 1 -(4-(dimethylamino)-4-(4-methoxyphenyl)piperidin-1 -yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone;

[122] 1 -(4-(dimethylamino)-4-(3-methoxyphenyl)piperidin-1 -yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone;

[123] 1 -(4-((dimethylamino)methyl)-4-phenylpiperidin-1 -yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone;

[124] 1 -(4-(dimethylamino)-4-(2-methoxyphenyl)piperidin-1 -yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone;

[125] 1 -(4-(diethylamino)-4-phenylpiperidin-1 -yl)-2-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)ethanone;

[126] 1 -(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone;

[127] 1 -(4-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-(3-(4- methylpiperazine-1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 - yl)ethanone; tert-butyl 4-(1 -((1 r,4r)-4-(dimethylamino)-4-(4-methoxyphenyl)cyclohexyl)-

[128]

4,5-dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)piperazine-1 -carboxylate; tert-butyl (1 -(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazole-3-carbonyl)azetidin-3-yl)(methyl)carbamate; ((S)-4-benzyl-3-methylpiperazin-1 -yl)(1 -((1 r,4S)-4-(dimethylamino)-4-

[130]

phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

((R)-4-benzyl-3-methylpiperazin-1 -yl)(1 -((1 r,4R)-4-(dimethylamino)-4-

[131 ]

phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

(1 -((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-

[132]

thieno[2,3-g]indazol-3-yl)((R)-3-methylpiperazin-1 -yl)methanone;

(1 -((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-

[133]

thieno[2,3-g]indazol-3-yl)((S)-3-methylpiperazin-1 -yl)methanone;

1 -tert-butyl 2-methyl 4-(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5- dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)piperazine-1 ,2-dicarboxylate;

(R)-tert-butyl 4-(1 -(4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-

[136] thieno[2,3-g]indazole-3-carbonyl)-2-(hydroxymethyl)piperazine-1 - carboxylate;

(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-1 ,4-

[137] dihydrothieno[3',2':4,5]cyclopenta[1 ,2-c]pyrazol-3-yl)(4-methylpiperazin-1 - yl)methanone;

(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-1 ,4-

[138] dihydrothieno[2',3':4,5]cyclopenta[1 ,2-c]pyrazol-3-yl)(4-methylpiperazin-1 - yl)methanone; tert-butyl ((S)-1 -(1 -((1 r,4S)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-

[139]

dihydro-1 H-thieno[2,3-g]indazole-3-carbonyl)piperidin-3-yl)carbamate;

(1 -((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[3,2-

[140]

g]indazol-3-yl)(4-methylpiperazin-1 -yl)methanone; [141] (1-((1 r,4r)-4-(dimethylamino)-4-(4-methoxyphenyl)cyclohexyl)-4,5-dihydro- 1 H-thieno[2,3-g]indazol-3-yl)(piperazin-1 -yl)methanone;

[142] (1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3- g]indazol-3-yl)(3-(methylamino)azetidin-1-yl)methanone;

[143] 4-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)piperazine-2-carboxylic acid;

[144] methyl 4-(1-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)piperazine-2-carboxylate;

[145] (R)-4-(1-((1 r,4R)-4-(dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazole-3-carbonyl)-2-(hydroxymethyl)piperazine-1 -carboxylic acid;

[146] ((S)-3-aminopiperidin-1-yl)(1-((1 r,4S)-4-(dimethylamino)-4- phenylcyclohexyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-3-yl)methanone;

[147] N-((1s,4s)-4-(dimethylamino)-4-phenylcyclohexyl)-2-(3-(4-methylpiperazine- 1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)acetamide;

[148] N-((1 r,4r)-4-(dimethylamino)-4-phenylcyclohexyl)-2-(3-(4-methylpiperazine- 1 -carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)acetamide;

[149] (1-(2-(4-(dimethylamino)-4-(4-methoxyphenyl)piperidin-1-yl)ethyl)-4,5- dihydro-1 H-thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[150] (1 -(2-(4-(dimethylamino)-4-(4-fluorophenyl)piperidin-1 -yl)ethyl)-1 H- thieno[2,3-g]indazol-3-yl)(4-methylpiperazin-1-yl)methanone;

[151] (1-((1 r,4r)-4-(Dimethylamino)-4-phenylcyclohexyl)-4,5-dihydro-1 H- thieno[2,3-g]indazol-3-yl)(3-(dimethylamino)azetidin-1-yl)methanone; and

[152] 1 -(4-(Methylamino)-4-phenylpiperidin-1 -yl)-2-(3-(4-methylpiperazine-1 - carbonyl)-4,5-dihydro-1 H-thieno[2,3-g]indazol-1 -yl)ethanone.

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

wherein R₁, Rr, R₂, Rs, R6, W₃, W₄, X, Y and A have the same meaning as indicated in any one of claims 1 to 7, said process comprising treating a compound of formula (VII)

with a compound of formula (V):

wherein

Ri, Rr, R₂, R₅, R6, W₃, W₄, X, Y and A have the same meaning as indicated in any one of claims 1 to 7; and Z is selected from OH, Cl, N(OMe)Me and H.

10. Process according to claim 9, wherein W₃ is S and W₄ is C.

1 1. Process according to any one of claims 9 or 10 wherein Z is OH or Cl. 12. Process for the preparation of a compound of formula (I) according to claim 1 :

wherein Ri, Rr, R₂, Rs, R₆, W₃, W₄, X, Y and A have the same meaning as indicated in any one of claims 1 to 7, said process comprising a) treating a compound of formula (VII)

with a compound of formula (VIII):

wherein Ri, Rr, R₂, R₅, R6, W₃, W₄, X, Y and A have the same meaning as indicated in any one of claims 1 to 7; and Z is OH or O-alkyl; and b) treating the compound obtained in step a) with a compound of formula XI g R₂ X^~G

(XI) wherein R₂, and X have the same meaning as indicated in any one of claims 1 to 7; and G is B(OH)₂ when X is aryl, and G is a leaving group when X is0 alkylene.

13. Process according to claim 12, wherein W₃ is S and W₄ is C.

14. Process for the preparation of a compound of formula (I) according to claim 1

wherein R₁, Rr, R₂, R₅, R6, W₃, W₄, X and A have the same meaning as indicated in any one of claims 1 to 7 and Y represents -C(O)-, said process comprising: 0

a) treating a compound of formula (XIV)

(XIV) with a compound of formula (VII)

b) treating the compound obtained in step a) with R2H; wherein Z is O-alkyl, OH or a leaving group.

15. Process according to claim 14, wherein W₃ is S and W₄ is C.

16. Use of a compound selected from

wherein R₂, Rs, R₆, W₃, W₄, and X have the same meaning as indicated in any one of claims 1 to 7 and Z is O-alkyl, OH; H or Cl for the manufacture of a compound according to claim 1.

17. A pharmaceutical composition which comprises a compound of formula (I) as defined in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

18. A compound as defined in any of claims 1 to 8 or a pharmaceutical salt thereof for use in therapy.

19. A compound as defined in any of claims 1 to 8 or a pharmaceutical salt thereof for use in the treatment or prophylaxis of pain, specially medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia.