WO2020089397A1

WO2020089397A1 - Substituted quinazolin-4(3h)-one derivatives having multimodal activity against pain

Info

Publication number: WO2020089397A1
Application number: PCT/EP2019/079842
Authority: WO
Inventors: Jose Luis Diaz-Fernandez; Carmen ALMANSA-ROSALES; Ariadna FERNANDEZ-DONIS
Original assignee: Esteve Pharmaceuticals, S.A.
Priority date: 2018-10-31
Filing date: 2019-10-31
Publication date: 2020-05-07

Abstract

The present invention relates to substituted quinazolin-4(3H)-one derivatives having dual pharmacological activity towards both the α2subunit, in particular the α2-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

SUBSTITUTED QUINAZOLIN-4(3H)-ONE 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 substituted quinazolin- 4(3/-/)-one 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.; 2011 ; 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 leads 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_voti), b (Ca_vp) a₂d (Ca_va₂6) and g (Ca_vy). The o i 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 post-translationally cleaved and then linked by disulfide bonds. Four genes encoding a2d subunits have now been cloned. a₂d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution. The a₂d-2 and a₂d-3 subunits were subsequently cloned from brain. The most recently identified subunit, a₂d-4, is largely non-neuronal. 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_vot₂5-1 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_vot₂5-1 , but not Ca_vot₂5-2, 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 a,2d subunits of VGCC form the binding site for gabapentin and pregabalin, which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations. The binding of gabapentin and pregabalin to the Ca_vot₂5 subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management. Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009, supra, Vink and Alewood, 2012, supra, Zamponi et al., 2015, supra).

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 delta) 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- receptorand 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 authors of the present invention, have found a series of compounds that show 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) 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

In this invention a family of structurally distinct substituted quinazolin-4(3/-/)-one derivatives, encompassed by formula (I), 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, was identified 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 for use in the treatment of pain.

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

wherein Ri, R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11”, X, W1, m, r and t are as defined below in the detailed description.

A further object of the invention refers to the processes for preparation of compounds of general formula (I).

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

Finally, it is an object of the invention the use of compound as a medicament and more particularly for the treatment of pain and pain related conditions.

DETAILED DESCRIPTION OF THE INVENTION

In this invention a family of structurally distinct substituted quinazolin-4(3/-/)-one derivatives, encompassed by formula (I), 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 was identified, 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, for use in the treatment of pain.

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

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

Preferably, when K, (m) > 500 nM, the following scale has been adopted for representing the binding to the m -receptor:

+ Ki (m) > 500 nM or inhibition ranges between 1 % and 50 %.

K_ί(a₂d-1 ) is preferably < 10000 nM, more preferably < 5000 nM, even more preferably < 500 nM or even more preferably < 100 nM. Preferably, when K_ί(a₂d-1 ) > 5000 nM, the following scale has been adopted for representing the binding to the a,2d-1 subunit of voltage-gated calcium channels:

+ K_ί(a₂d-1) > 5000 nM or inhibition ranges between 1 % and 50 %

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. It is also seen as a way of improving the R&D output obtained using the“one drug-one target” approach, which has been questioned over the last years [Bornot A, Bauer U, Brown A, Firth M, Hellawell C, Engkvist O. Systematic Exploration of Dual-Acting Modulators from a Combined Medicinal Chemistry and Biology Perspective. J. Med. Chem, 56, 1 197-1210 (2013)].

In its broader aspect, the present invention is directed to compounds of general Formula (I):

wherein

X is selected from the group consisting of a bond, -[C(R_aRb)]_P-, -[CH2]_P-0-[CH2]_q, - [CH₂]_PC(0)[CH₂]q-, -[CH₂]_PC(0)N(R_z)[CH₂]q-, -[CH₂]_PN(R_z)C(0)[CH₂]q- and -

[CH₂]_PN(R_z)[CH₂]q-;

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

C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R_a and R_b, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;

R_z is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(0)-Ci-₆ alkyl; p is 0, 1 , 2, 3, 4 or 5; q is 0, 1 , 2, 3, 4 or 5; Wi is Nitrogen or CR_wi; m is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 or 2;

R_wi is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; additionally, when m and r are 1 , Rwi and one of R10, R10’, R10” or R10’” may form a double bond;

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

R2 is selected from the group consisting of -R21, -OR21, -NO2, halogen, -NR21R21’, - NR₂IC(0)R₂I \ -NR_2iS(0)₂R2i\ -S(0)₂NR_2iR2i\ - NR_2iC(0)NR2i’R_2i”, -SR21 , -S(0)R_2i, -S(0)2R2i, -CN, haloalkyl, haloalkoxy, -C(0)OR2i, -C(0)NR2iR2i’, -OCH2CH2OR21, - NR_2iS(0)₂NR2i’R2i” and -C(CH₃)₂OR₂I ; wherein R21, R21’ and R21” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; R₃ is selected from the group consisting of

wherein,

W₃ is nitrogen or -CH-; n is 1 or 2; v is 1 or 2;

R₅, Rs’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₅ and R₅’ and/or R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl group;

R₆, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R₇ and R₇’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; R₄ is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

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

Re’ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; alternatively, Re and Re’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclyl;

Rg is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted alkylheterocyclyl;

R10, R10’, R10” and R10’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₁₀ and R₁₀’ and/or R₁₀” and R₁₀’” taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, R₁₀ and R₁₀’ and/or R₁₀” and R₁₀’” taken together with the carbon atom to which they are attached form a carbonyl group;

R₁₁, R₁₁’, R₁₁” and R₁₁’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, Rn and Rn’ and/or Rn” and Rn’” taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; These compounds according to the invention are optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In a particular embodiment, the following proviso applies: when X is -[CH₂]pC(0)N(Rz)[CH₂]q- or -[CH₂]pN(Rz)[CH₂]q- and q is 0, then \N^ is -CRwi;

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

wherein X is selected from the group consisting of a bond, -[C(R_aRb)]_P-, -[CH2]_P-0-[CH2]_q, - [CH₂]_PC(0)[CH₂]q-, -[CH₂]_PC(0)N(R_z)[CH₂]q-, -[CH₂]_PN(R_z)C(0)[CH₂]q- and -

[CH₂]_PN(R_z)[CH₂]q-;

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

R_b is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R_a and R_b, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;

R_z is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(0)-Ci-₆ alkyl; p is 0, 1 , 2, 3, 4 or 5; q is 0, 1 , 2, 3, 4 or 5;

Wi is Nitrogen or CR_wi; m is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 or 2;

R_wi is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; additionally, when m and r are 1 , Rwi and one of R10, R-io’, R10” or R10’” may form a double bond;

Ri is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6alkynyl; wherein the alkyl, alkenyl or alkynyl defined in R₁, if substituted, is substituted with one or more substituent/s selected from the group consisting of -OR₁₂, halogen, -CN, haloalkyl, haloalkoxy and -NR₁₂R₁₂’; wherein R₁₂ and R₁₂’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R2 is selected from the group consisting of -R21, -OR21, -NO2, halogen, -NR21R21’, - NR_2IC(0)R_2I’, -NR_2iS(0)₂R2i’, -S(0)₂NR_2iR2i’, - NR2iC(0)NR_2i’R_2i”, -SR21 , -S(0)R_2i, -S(0)2R2i, -CN, haloalkyl, haloalkoxy, -C(0)OR2i, -C(0)NR2iR2i’, -OCH2CH2OR21, - NR_2iS(0)₂NR2i’R2i” and -C(CH3)20R2i; wherein R₂₁, R₂₁’ and R₂₁” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R₃ is selected from the group consisting of

wherein, W₃ is nitrogen or -CH-; n is 1 or 2; v is 1 or 2;

R₅, R₅’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen, halogen substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₅ and R₅’ and/or R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl group;

R6, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R₇ and R₇’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; wherein the alkyl, alkenyl or alkynyl defined in R₇ or R₇’, if substituted, is substituted with one or more substituent/s selected from the group consisting of -OR7i, halogen, -CN, haloalkyl, haloalkoxy and -NR₇₁R₇₁’; wherein R₇₁ and R₇₁’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₄ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; wherein the alkyl, alkenyl or alkynyl defined in R₄, if substituted, is substituted with one or more substituent/s selected from the group consisting of -OR₄-i, halogen, -CN, haloalkyl, haloalkoxy and -NR₄I R₄-T; wherein R₄I and R₄-T are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

Re is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl,; wherein the alkyl, alkenyl or alkynyl defined in Re, if substituted, is substituted with one or more substituent/s selected from the group consisting of - ORsi, halogen, -CN, haloalkyl, haloalkoxy and -NReiRsi’; wherein the cycloalkyl defined in Re, also in alkylcycloalkyl, if substituted, is substituted with one or more substituent/s selected from the group consisting of =0, halogen, -Rei, -ORei, -NO2, -NReiRei’, -NReiC(0)Rei’, -NReiS(0)2Rei’, -S(0)2NReiRei’, - NReiC(0)NRei’Rei”, -SRei , -S(0)Rei, -S(0)2Rei, -CN, haloalkyl, haloalkoxy, -C(0)0Rei, -C(0)NReiRei’, - OCH2CH2OR81, -NR_8iS(0)2NR8i’Rei” and -C(CHe)20R8i; wherein Rei, R₈₁’ and Rei” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

Re’ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; wherein the alkyl, alkenyl or alkynyl defined in Re’, if substituted, is substituted with one or more substituent/s selected from the group consisting of -ORs₂, halogen, -CN, haloalkyl, haloalkoxy and -NR₈₂R₈₂’; the cyclolakyl defined in Re’, also in alkylcycloalkyl, if substituted, is substituted with one or more substituent/s selected from the group consisting of =0, halogen, -R₃₂, -ORs2, -NO2, -NR82R82’, -NR82C(0)Rs2’, - NR₈₂S(0)₂R82’, -S(0)2NR82R82’, - NR82C(0)NRe2 R82”, -SR82 , -S(0)R82, - S(0)2Re2, -CN, haloalkyl, haloalkoxy, -C(0)0Rs2, -C(0)NR82Rs2’, - OCH2CH2OR82, - N R82S (O )2 N R82’ R82’’ and -C(CH₃)20R82; wherein R₃₂, R₈₂’ and R₈₂” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; alternatively, Re and Re’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclyl; wherein the heterocyclyl, as defined in Re-Re’, if substituted, is substituted with one or more substituent/s selected from the group consisting of =0, halogen, -R8₃, -ORs₃, -NO2, -NR83R83’, -NR8₃C(0)R8₃’, -NR8₃S(0)2R83’, - S(0)2NR83R83’, - NR83C(0)NR83’R83”, SR83 , -S(0)R83, -S(0)2R83,— CN, haloalkyl, haloalkoxy, -C(0)0Rs3, -C(0)NR83R83’, -OCH2CH2OR83, - NR83S(0)2NR83’R83’’ and -C(CH₃)₂OR₈₃; wherein R₃₃, R₈₃’ and Rs₃” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

Rg is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted alkylheterocyclyl; wherein the alkyl, alkenyl or alkynyl defined in Rg, if substituted, is substituted with one or more substituent/s selected from the group consisting of -ORg-i, halogen, -CN, haloalkyl, haloalkoxy and -NR₉₁R₉₁’; the cycloalkyl, aryl or heterocyclyl, also in alkylcycloalkyl, alkylaryl or alkylheterocyclyl, as defined in Rg, if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, -R₉₁, -OR₉₁, -NO₂, -NR₉₁R₉₁’, -NRgiC(0)Rgi’, - NRgiS(0)₂R_9i’, -S(0)₂NR_9iRgi’, -NRgiC(0)NRgi’Rgi”, -SR₉₁ , -S(0)Rgi, -S(0)₂R_9i,— CN, haloalkyl, haloalkoxy, -C(0)0Rgi, -0C(0)Rgi, -C(0)NRgiRgi’, -OCH₂CH₂OR₉₁, - NRgiS(0)₂NR_9i’R_9i” and -C(CH3)20Rgi; wherein R₉₁, Rgi’and R₉₁” are independently selected from the group consisting of the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl;

R₁₀, R₁₀’, R₁₀” and R₁₀’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₁₀ and R₁₀’ and/or R₁₀” and R₁₀’” taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; alternatively, R₁₀ and R₁₀’ and/or R₁₀” and R₁₀’” taken together with the carbon atom to which they are attached form a carbonyl group;

R₁₁, R₁₁’, R₁₁” and R₁₁’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, Rn and Rn’ and/or Rn” and Rn’” taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl;

the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from the group consisting of -OR-₁₃, halogen, -CN, haloalkyl, haloalkoxy and -NR₁₃R₁₃’; wherein R₁₃ and R₁₃’ are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, and unsubstituted C₂- e alkynyl; the aryl, heterocyclyl or cycloalkyl, also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from the group consisting of halogen, -R-u, -OR₁₄, - NO2, -NR14R14’, -NRI₄C(0)RI₄’, -NRi4S(0)2Ri4’, -S(0)₂NRi₄Ri4’, - NRi₄C(0)NRi₄’Ri4”, -SRi4 , -S(0)Ri4, -S(0)2Ri4, -CN, haloalkyl, haloalkoxy, -C(0)0Ri4, -C(0)NRi4Ri4’, - OCH2CH2OR14, -NRi₄S(0)₂NRi4’Ri4” and -C(CH3)20R-i4; wherein R-u, R-u’ and R₁₄” are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl, unsubstituted C_2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl;

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

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

O^’) wherein R₂, R₄, Rs, Rs’, Re’, Re”, R7, Rs, Rs’, R9, R10, X, W1, W3, t and v are as defined below in the detailed description, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

d") wherein Ri , R₂, R₄, Rs, Rs’, Rs”, Rs’”, R7, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, X, Wi, W3, m, r and t are as defined below in the detailed description. optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

For clarity purposes, all groups and definitions described in the present description and referring to compounds of general Formula (I), also apply to compounds of general Markush Formulae (I’), (I^”), (I³’) or (IZ), (where applicable), and to all intermediate of synthesis, when those groups are present in the mentioned general Markush formulae, since compounds of general Markush Formulae (I’), (I^”), (I³’) or (IZ), are included within the scope of the larger definition of general Markush Formula (I).

For clarity purposes, the general Markush Formula (I)

is equivalent to

wherein only -C(RioR-io’)- and -C(Rio”R-io”’)- are included into the brackets, and m and r mean the number of times that -C(RioRio’)- and -C(Rio”Rio”’)- are repeated, respectively. The same would apply, when applicable, to general Markush Formulae (G), (I”) and (I³’), and to all intermediates of synthesis. In addition, and for clarity purposes, it should further be understood that naturally if m is 0, the adjacent groups Wi and -C(RnRn’)- are still present. This is also applicable to all intermediates of synthesis. Further, and for clarity purposes, it should further be understood that naturally if r is 0, the adjacent groups Wi and -C(Rn”Rn”’)- are still present. This is also applicable to all intermediates of synthesis.

Further, and for clarity purposes, it should further be understood that naturally if t is 0, the adjacent groups -NReRs’ and the cycle are still present. This is also applicable to all intermediates of synthesis.

For clarity purposes, reference is also made to the following statements below in the definitions of substitutions on alkyl etc. or aryl etc. that“wherein when different radicals Ri to R91” are present simultaneously in Formula (I) they may be identical or different”. This statement is reflected in the below general Formula (I³’) being derived from and falling into general Formulae (I) or (IZ),

wherein Ri , R₂, R3, Rs, Rs’, Rg, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, m, r and t are as defined in the description. In addition, Rio_a and Rio_a’ are added. As said above, this statement is thus reflected in that R10 and R10’ are or could be different from R-io_a and Rioa’ or not. The same would be applicable mutatis mutandis for general Formulas like general Formula (I) as well as the other general Formulas (G), (I”) and (IZ) above and to all intermediates of synthesis.

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

In the context of this invention, alkyl is understood as meaning saturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses e.g. -CH3 and -CH2-CH3. In these radicals, 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, Ci-6-alkyl represents C1 -, C2-, C3-, C4-, C5- or C6-alkyl, Ci-7-alkyl represents C1 -, C2-, C3-, C4- , C5-, C6- or C7-alkyl, Ci-s-alkyl represents C1 -, C2-, C3-, C4-, C5-, C6-, C7- or C8- alkyl, Ci-10-alkyl represents C1 -, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and Ci-ie-alkyl represents C1 -, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C1 1 -, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. The alkyl radicals are preferably methyl, ethyl, propyl, methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, pentyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1 - methylpentyl, if substituted also CHF2, CF3 or CH2OH etc. Preferably alkyl is understood in the context of this invention as Ci-salkyl like methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; preferably is Ci-₆alkyl like methyl, ethyl, propyl, butyl, pentyl, or hexyl; more preferably is Ci-₄alkyl like methyl, ethyl, propyl or butyl.

Alkenyl is understood as meaning unsaturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -CH=CH-CH3. The alkenyl radicals are preferably vinyl (ethenyl), allyl (2-propenyl). Preferably in the context of this invention alkenyl is C2-io-alkenyl or C2-8-alkenyl like ethylene, propylene, butylene, pentylene, hexylene, heptylene or octylene; or is C2-6- alkenyl like ethylene, propylene, butylene, pentylene, or hexylene; or is C2-₄-alkenyl, like ethylene, propylene, or butylenes.

Alkynyl is understood as meaning unsaturated, linear or branched hydrocarbons, which may be unsubstituted or substituted once or several times. It encompasses groups like e.g. -( C-CH₃ (1 -propinyl). Preferably alkynyl in the context of this invention is C2-10- alkynyl or C2-8-alkynyl like ethyne, propyne, butyene, pentyne, hexyne, heptyne, or octyne; or is C2-6-alkynyl like ethyne, propyne, butyene, pentyne, or hexyne; or is C2-4- alkynyl like ethyne, propyne, butyene, pentyne, or hexyne.

In connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl and O-alkyl - unless defined otherwise - the term substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical on a carbon atom by halogen (F, Cl, Br, I), -NRkRk·, -SRk, -S(0)Rk, -S(0)2Rk, -ORk, - C(0)Rk, -C(0)0Rk, -CN, -C(0)NRkRk·, haloalkyl, haloalkoxy, being Rk represented by R11, R13, R41, R71 , Rei, RS2 or Rgi, (being R_k· represented by Rn’, R13’, R41’, R71’, Rei’, R82’ or Rgi’; wherein R1 to Rgi”and R_z and R_a and R_b are as defined in the description, and wherein when different radicals R1 to Rgr and R_z and R_a and R_b are present simultaneously in Formula I they may be identical or different.

Most preferably in connection with alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl, substituted is understood in the context of this invention that any alkyl (also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl), alkenyl, alkynyl or O-alkyl which is substituted with one or more of halogen (F, Cl, Br, I), -NR_kR_k·, -OR_k, -CN, -SR_k, haloalkyl, haloalkoxy, being R_k represented by Rn_, R1_3, R41, R71 , Rei , RS2 or Rgi , (being R_k· represented by Rn’, R13’, R41’, R71’, Rei’, R82’ or Rgi’_; wherein wherein R1 to Rgi” and R_z and R_a and R_b are as defined in the description, and wherein when different radicals R1 to Rgr· and R_z and R_a and R_b are present simultaneously in Formula I they may be identical or different.

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

In the context of this invention haloalkyl is understood as meaning an alkyl being substituted once or several times by a halogen (selected from F, Cl, Br, I). It encompasses e.g. -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, -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, -OCHC , -OCHF2, -OCCI3, -OCF3 and - OCH2-CHCI2. Preferably haloalkoxy is understood in the context of this invention as halogen-substituted -OCi-4-alkyl representing halogen substituted C1-, C2-, C3- or C4- alkoxy. The halogen-substituted 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. Furthermore, C3-4- cycloalkyl represents C3- or C4-cycloalkyl, C3-5-cycloalkyl represents C3-, C4- or C5- cycloalkyl, C3-6-cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl, C3-7-cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl represents C3-, C4-, C5- , C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl represents C4- or C5-cycloalkyl, C4-6- cycloalkyl represents C4-, C5- or C6-cycloalkyl, C4-7-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl represents C5- or C6-cycloalkyl and C5-7-cycloalkyl represents C5-, C6- or C7-cycloalkyl. Examples are cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl. Preferably in the context of this invention cycloalkyl is C3-8cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or is C3-7cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or is C3-6cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, especially cyclopentyl or cyclohexyl.

Aryl is understood as meaning 5 to 18 membered mono or polycyclic ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, 9H- fluorenyl or anthracenyl radicals, which can be unsubstituted or once or several times substituted. Most preferably aryl is understood in the context of this invention as phenyl, naphthyl or anthracenyl, preferably is phenyl.

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

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

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

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

Preferably in the context of this invention heterocyclyl is defined as a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring. Preferably it is a 5 to 18 membered mono or polycyclic heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring.

Preferred examples of heterocyclyls include oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, , benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, 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, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyran, pyrazole, imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane, azetidine and pyrrolidine.

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

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

In general, such a heterocyclyl may contain between 3 and 32 atoms in the rings (preferably 4 to 20 atoms in the rings, or most preferably 5 to 18 atoms in the rings). Thus, a heterocyclyl may contain between 3 and 12 atoms in the ring (preferably 4 to 10 atoms in the ring, or 5 to 8 atoms in the ring, or 5 to 6 atoms in the ring) in case of a heterocyclyl of one ring. Such a heterocyclyl may also contain between 5 and 22 atoms in both rings together (preferably 6 to 16 atoms in both rings together, or 7 to 12 atoms in both rings together or 8 to 10 atoms in both rings together) in case of a heterocyclyl of two rings. Such a heterocyclyl may also contain between 7 and 32 atoms in the 3 rings together (preferably 10 to 22 atoms in the three rings together, or 12 to 20 atoms in the three rings together or 10 to 18 atoms in the three rings together) in case of a heterocyclyl of three rings. Each ring of the ring system, independently of each other, can be saturated or unsaturated.

In the context of this invention, a cyclic amide is defined as a subgroup of a heterocyclyl (as defined above) formed through the cyclization of a carbon sequence, containing at least the sequence

-N-C(0)-C->

forming part of the cycle. Said cyclic amide may optionally be fused to a ring system. Preferably the cyclic amide is an“indoline-2-one”. A cyclic amide may be substituted or unsubstituted as defined for heterocyclyl above.

In the context of this invention, a cyclic urea is defined as a subgroup of a heterocyclyl (as defined above) formed through the cyclization of a carbon sequence containing at least the sequence

5-N-C(0)-N- ^ ^ forming part of the cycle. Said cyclic urea may optionally be fused to a ring system. Preferably the cyclic urea is“1 H-benzo[d]imidazol-2(3H)-one”. A cyclic urea may be substituted or unsubstituted as defined for heterocyclyl above.

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

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

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

In the context of this invention alkylcycloalkyl is understood as meaning an cycloalkyl group being connected to another atom through a Ci-₆-alkyl (see above) which may be branched or linear and is unsubstituted or substituted once or several times. Preferably alkylcycloalkyl is understood as meaning a cycloalkyl group (see above) being connected to another atom through 1 to 4 (-CH2-) groups. Most preferably alkylcycloalkyl is -Chh-cyclopropyl. More preferably, the“alkyl” in alkycycloalkyl is an unsubstitued alkyl. Preferably, the aryl is a monocyclic aryl. More preferably the aryl is a 5, 6 or 7 membered monocyclic aryl. Even more preferably the aryl is a 5 or 6 membered monocyclic aryl.

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

Preferably, the non-aromatic heterocyclyl is a monocyclic non-aromatic heterocyclyl. More preferably the non-aromatic heterocyclyl is a 4, 5, 6 or 7 membered monocyclic non-aromatic heterocyclyl. Even more preferably the non-aromatic heterocyclyl is a 5 or 6 membered monocyclic non-aromatic heterocyclyl.

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

In connection with aryl (including alkyl-aryl), cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkyl-heterocyclyl), substituted is understood - unless defined otherwise - as meaning substitution of the ring-system of the aryl or alkyl-aryl, cycloalkyl or alkyl-cycloalkyl; heterocyclyl or alkyl-heterocyclyl with one or more of halogen (F, Cl, Br, I), -R_k ,-OR_k, -CN, -N0₂ , -NR_kR_k·, -C(0)OR_k, NR_kC(0)R_k· , -C(0)NR_kR_k· , - NR_kS(0)₂R_k· , =0, -OCH₂CH₂OH, -NR_kC(0)NR_k R_k”, -S(0)₂NR_kR_k·, -NR_kS(0)₂NR_k R_k”, haloalkyl, haloalkoxy, -SR_k, -S(0)R_k, -S(0)₂R_k or C(CH3)OR_k, or substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, with R_k, R_k and R_k- independently being either H or a saturated or unsaturated, linear or branched, substituted or unsubstituted Ci-₆-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted Ci-₆-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted -O-Ci-₆-alkyl (alkoxy); a saturated or unsaturated, linear or branched, substituted or unsubstituted - S-Ci-₆-alkyl; a saturated or unsaturated, linear or branched, substituted or unsubstituted -C(0)-Ci-₆-alkyl-group; a saturated or unsaturated, linear or branched, substituted or unsubstituted -C(0)-0-Ci-₆-alkyl-group; a substituted or unsubstituted aryl or alkyl-aryl; a substituted or unsubstituted cycloalkyl or alkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl or alkyl-heterocyclyl, being R_k one of RM, Rei_, Rs_2, Rs₃ or Rgi_, (being Rk’ one of RM’, Rei’, 82’, R83’ or Rgi’, being Rk” one of RM”, Rei”, R82”, R83” or Rgi” wherein R₁ to R₉₁” and R_z and R_a and R_b are as defined in the description, and wherein when different radicals R₁ to R₉₁” and R_z and R_a and R_b are present simultaneously in Formula I they may be identical or different.

Most preferably in connection with aryl (including alkyl-aryl), cycloalkyl (including alkyl- cycloalkyl), or heterocyclyl (including alkyl-heterocyclyl), substituted is understood in the context of this invention that any aryl, cycloalkyl and heterocyclyl which is substituted is substituted (also in an alyklaryl, alkylcycloalkyl or alkylheterocyclyl) with one or more of halogen (F, Cl, Br, I), -Rk ,-ORk, -CN , -NO2 , -NRkRk” , NRkC(0)Rk·, - NRkS(0)2Rk· , -S(0)2NRkRk·, -NRkC(0)NRk Rk", haloalkyl, haloalkoxy, -SRk , -S(0)Rk or S(0)₂R_k, or substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, being R_k one of RM, Rei_, Rs2_, Rs3 or Rgi, (being Rk· one of RM’, Rei’, R82’, R83’ or Rgi’_; being Rk- one of RM”, Rei”, R82”, R83” or Rgi”; wherein R₁ to Rgi”and R_z and R_a and R_b are as defined in the description, and wherein when different radicals R₁ to R91” and R_z and R_a and R_b are present simultaneously in Formula I they may be identical or different.

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

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

Moreover, in connection with cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl-heterocyclyl), substituted is also understood - unless defined otherwise - as meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl, non- aromatic heterocyclyl or non aromatic alkyl-heterocyclyl is spirosubstituted or substituted with =0. Moreover, in connection with cycloalkyl (including alkyl-cycloalkyl), or heterocyclyl (including alkylheterocyclyl) namely non-aromatic heterocyclyl (including non-aromatic alkyl-heterocyclyl), substituted is also understood - unless defined otherwise - as meaning substitution of the ring-system of the cycloalkyl or alkyl-cycloalkyl, non- aromatic heterocyclyl or non aromatic alkyl-heterocyclyl with =0.

A ring system is an organic system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with“joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings.

The term“polycyclic ring system” means that the ring system is made of two or more rings joined by sharing at least one atom.

The term“leaving group” means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-) or mesylate.

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

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

Please note that“or a corresponding salt thereof does also mean“or a corresponding pharmaceutically acceptable salt thereof”. This does apply to all below described embodiments and uses of“salt” being thus equivalent to“pharmaceutically acceptable salt”. These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH₄, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.

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

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

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

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

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

Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon or of a nitrogen by ¹⁵N-enriched nitrogen are within the scope of this invention. This would especially also apply to the provisos described above so that any mentioning of hydrogen or any Ή” in a formula would also cover deuterium or tritium.

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

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein X is selected from the group consisting of a bond, -[C(R_aRb)]_P-, -[C(R_aRb)]_P-0- [C(R_cRd)]q, -[C(R_aRb)]pC(0)[C(R_cRd)]q-, -[C(R_aR_b)]pC(0)N(R_z)[C(R_cRd)]q- or - [C(R_aRb)]pN(R_z)C(0)[C(RcRd)]q- and-[C(R_aRb)]pN(R_z)[C(RcRd)]q-;

R_zis selected from the group consisting of hydrogen, substituted or unsubstituted C1-₆ alkyl, substituted or unsubstituted C2-₆ alkenyl, substituted or unsubstituted C2-₆ alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(0)-Ci-₆ alkyl;

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

R_b is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R_a and R_b, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl;

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

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

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein X is selected from the group consisting of a bond, -[C(R_aRb)]_P-, -[CH2]_P-0-[CH2]_q, - [CH₂]_PC(0)[CH₂]q- and -[CH₂]_PN(R_z)[CH₂]_q-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

-X-Wi is selected from the group consisting of a -Wi, -[C(R_aR_b)] -Wi, -[CH₂] -0-[CH₂]_q- Wi, -[CH₂]_PC(0)[CH₂]_q-Wi, -[CH₂]_PC(0)N(R_z)[CH₂]_q-Wi, -[CH₂]_PN(R_z)C(0)[CH₂]_q-Wi and -[CH₂]_PN(R_z)[CH₂]_q-Wi; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at 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-Wi is selected from the group consisting of a -Wi, -[C(R_aR_b)] -Wi, -[CH₂] -0-[CH₂]_q- Wi, -[CH₂]_PC(0)[CH₂]_q-Wi and -[CH₂]_PN(R_z)[CH₂]_q-Wi; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein

R_a is selected from the group consisting of 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.

Rb is selected from the group consisting of 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.

R_z is selected from the group consisting of 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. In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein

R_wi is selected from the group consisting of 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.

R1 is substituted or unsubstituted C1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R2 is selected from the group consisting of -R21, halogen, -CN, -C(0)0R_2i and - C(0)NR_2I R_2I’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein

R₄ is selected from the group consisting of 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.

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

R₅, R₅’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen and halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R6, Re’_, Re” and Re’” are independently selected from the group consisting of 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.

R₇ and R₇’ are independently selected from the group consisting of 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.

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

Rs 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.

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

Re’ is selected from the group consisting of hydrogen and substituted or unsubstituted C 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.

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

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

R11 , Ri i’, R11” and Rn’” are independently selected from the group consisting of hydrogen, halogen and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₁₂ and R₁₂’ are independently selected from the group consisting of 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.

R₁₃ and R₁₃’ are independently selected from the group consisting of hydrogen and unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

R₂₁, R₂₁’ and R₂₁” are independently selected from the group consisting of 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.

R₄₁ and R₄₁’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₇₁ and R₇₁’ are independently selected from the group consisting of 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.

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

R₈₂, R₈₂’ and R₈₂” are independently selected from the group consisting of 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.

R_S2 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.

R₈₃, R₈₃’ and R_S3” are independently selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In a further embodiment the compound according to the invention of general Formula (I) is a compound wherein R_S3 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.

R₉₁, R₉₁’ and R₉₁” are independently selected from the group consisting of the group consisting of 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 another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R₁, if substituted, is substituted with one or more substituent/s selected from the group consisting of -OR₁₂, halogen, -CN, haloalkyl, haloalkoxy and -NR12R12’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R₄, if substituted, is substituted with one or more substituent/s selected from the group consisting of -OR₄-i, halogen, -CN, haloalkyl, haloalkoxy and -NR_4I R₄-T; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R₇ or R₇’, if substituted, is substituted with one or more substituent/s selected from the group consisting of -OR_7I , halogen, -CN, haloalkyl, haloalkoxy and -NR_7I R₇-T; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in R₇ or R₇’, if substituted, is substituted with one or more halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in Re, if substituted, is substituted with one or more substituent/s selected from the group consisting of -ORsi, halogen, -CN, haloalkyl, haloalkoxy and -NRe-iRs-T; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the cycloalkyl defined in Rs, also in alkylcycloalkyl, if substituted, is substituted with one or more substituent/s selected from the group consisting of =0, halogen, -Rsi, -ORsi, - NO2, -NRsiRsi’, -NR₈IC(0)R₈I’, -NReiS(0)2R8i’, -S(0)2NR8iRsi’, - NR8iC(0)NR8i’Rsi”, -SRsi , -S(0)Rsi, -S(0)2R8i, -CN, haloalkyl, haloalkoxy, -C(0)ORsi, -C(0)NRsiR8i’, - OCH2CH2OR81, -NR_8iS(0)₂NR8i’R8i” and -C(CH₃)20R8i; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in Re’, if substituted, is substituted with one or more substituent/s selected from the group consisting of -ORs2, halogen, -CN, haloalkyl, haloalkoxy and -NR82R82’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in Re’, if substituted, is substituted with one or more substituent/s selected from the group consisting of -ORs2 and halogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the cyclolakyl defined in Re’, also in alkylcycloalkyl, if substituted, is substituted with one or more substituent/s selected from the group consisting of =0, halogen, -Rs2, - OR82, -NO2, -NR82R82’, -NR82C(0)R82’, -NR82S(0)2R82’, -S(0)2NR82R82’,

NR82C(0)NR82’R82”, -SRS2 , -S(0)Rs2, -S(0)2Rs2, -CN, haloalkyl, haloalkoxy, - C(0)0R₈₂, -C(0)NR₈₂R82’, -OCH2CH2OR82, -NR₈₂S(0)₂NR₈₂’R82” and -C(CH₃)₂OR82; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein wherein the heterocyclyl, as defined in Re-Rs’, if substituted, is substituted with one or more substituent/s selected from the group consisting of =0, halogen, -Re3, -ORs3, - NO2, -NR83R83’, -NR83C(0)R83’, - N R83S (O )₂ Re3’ , -S(0)2NR83R83’, - NR83C(0)NR83’R83”, -SRS3 , -S(0)RS3, -S(0)2RS3, -CN, haloalkyl, haloalkoxy, -C(0)0Rs3, -C(0)NR₈₃R83’, - OCH2CH2OR83, -NR83S(0)2NR83’R83” 3nd -C(CH3)20R83; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein wherein the heterocyclyl, as defined in Re-Re’, if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen and -OR83; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl defined in Rg, if substituted, is substituted with one or more substituent/s selected from the group consisting of -OR91, halogen, -CN, haloalkyl, haloalkoxy and -NRg-iRg-T; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the cycloalkyl, aryl or heterocyclyl, also in alkylcycloalkyl, alkylaryl or alkylheterocyclyl, as defined in Rg, if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, -R91, -OR91, -NO2, -NR91R91’, -NRgiC(0)R9i’, - NRgiS(0)2R9i’, -S(0)2NRgiR9i’, -NR9iC(0)NR9i’R9i”, -SR91 , -S(0)Rgi, -S(0)2R9i,— CN, haloalkyl, haloalkoxy, -C(0)0Rgi, -0C(0)Rgi, -C(0)NRgiR9i’, -OCH2CH2OR91, - NR9iS(0)2NR9i’Rgi” and -C(CH3)20Rgi; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the cycloalkyl, aryl or heterocyclyl, also in alkylcycloalkyl, alkylaryl or alkylheterocyclyl, as defined in Rg, if substituted, is substituted with one or more substituent/s selected from the group consisting of halogen, -OR91 and -OC(0)Rgi ; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the alkyl, alkenyl or alkynyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from the group consisting of -OR-₁₃, halogen, -CN, haloalkyl, haloalkoxy and -NR₁₃R₁₃’; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the compound according to the according to the invention of general Formula (I) is a compound wherein the aryl, heterocyclyl or cycloalkyl, also in alkylaryl, alkylheterocyclyl or alkylcycloalkyl, if substituted and the substitution has not been defined otherwise, it is substituted with one or more substituent/s selected from the group consisting of halogen, -R-u, -OR₁₄, - NO2, -NR14R14’, -NRI₄C(0)RI₄’, -NRi4S(0)2Ri4’, -S(0)₂NRi₄Ri4’, - NRi₄C(0)NRi4’Ri₄”, -SRi4 , -S(0)Ri4, -S(0)2Ri4, -CN, haloalkyl, haloalkoxy, -C(0)0Ri4, -C(0)NRi4Ri4’, - OCH2CH2OR14, -NRi₄S(0)₂NRi4’Ri4” and -C(CH3)20Ri4; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

[CH₂] N(R_z)[CH₂]q-; preferably X is selected from the group consisting of a bond, - [C(R_aRb)]p-, -[CH₂]_P-0-[CH₂]q, -[CH₂]_PC(0)[CH₂]q- and -[CH₂]_PN(R_z)[CH₂]_q-; more preferably selected from a bond, -CH₂-, -C(O)-, -O- and -NH-; and/or R_a is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R_a is hydrogen; and/or R_b is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R_b is hydrogen; and/or

R_a and R_b, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted cycloalkyl; and/or

R_z is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(0)-Ci-₆ alkyl; preferably R_z is hydrogen; and/or p is 0, 1 , 2, 3, 4 or 5; preferably p is 0 or 1 ; and/or q is 0, 1 , 2, 3, 4 or 5;preferably q is 0; and/or

Wi is Nitrogen or CR_wi; and/or m is 0, 1 or 2; preferably m is 0 or 1 ; and/or r is 0, 1 or 2; preferably r is 0 or 1 ; and/or t is 0, 1 or 2; preferably t is 0 or 1 ; and/or R_wi is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;preferably R_wi is hydrogen and/or when m and r are 1 , Rwi and one of R10, R10’, R10” or R10’” may form a double bond; and/or

R1 is selected from the group consisting of substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R1 is substituted or unsubstituted C1-6 alkyl; more preferably R1 is substituted or unsubstituted propyl; and/or

R2 is selected from the group consisting of -R21, -OR21, -NO2, halogen, -NR21R21’, - NR₂IC(0)R₂I’, -NR_2iS(0)₂R2i’, -S(0)₂NR_2iR2i’, - NR2iC(0)NR_2i’R_2i”, -SR21 , -S(0)R_2i, -S(0)2R2i, -CN, haloalkyl, haloalkoxy, -C(0)OR2i, -C(0)NR2iR2i’, -OCH2CH2OR21, - NR_2iS(0)₂NR2i’R2i” and -C(CH3)20R2i; preferably R2 is selected from the group consisting of -R21, halogen, -CN, -C(0)OR2i and -C(0)NR2iR2i’; more preferably R2 is selected from the group consisting of hydrogen, fluorine, -CN, -C(0)OH and -C(0)NH₂; and/or

R3 is selected from the group consisting of

and/or

R₄ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₄ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably R₄ is selected from hydrogen and a substituted or unsubstituted group selected from methyl, ethyl and propyl; and/or

R₅, R₅’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R5, R5’, Rs” and R5’” are independently selected from the group consisting of hydrogen and halogen; more preferably, R₅, Rs’_, Rs” and Rs’” are independently selected from the group consisting of hydrogen and fluorine; or

Rs and R₅’ and/or R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl group; and/or

R₆, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R6, Re’, Re” and Re’” are independently selected from the group consisting of hydrogen and substituted or unsubstituted Ci-₆ alkyl; more preferably R₆, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen and substituted or unsubstituted methyl; and/or

R₇ and R₇’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₇ and R₇’ are independently selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably preferably R₇ and R₇’ are independently selected from the group consisting of hydrogen and a substituted or unsubstitutedgroup selected from methyl and ethyl; and/or

Re is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; preferably Rs is substituted or unsubstituted C_1-6 alkyl; more Rs is a substituted or unsubstituted group selected from methyl and ethyl; and/or

Rs’ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; preferably Rs’ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably Rs’ is selected from the group consisting of hydrogen and a substituted or unsubstituted group selected from methyl and ethyl;

or Re and Re’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclyl; preferably Re and Re’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted azetidinyl; and/or

Rg is selected from the group consisting of substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted alkylheterocyclyl; preferably Rg is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylaryl; more preferably Rg is selected from the group consisting of substituted or unsubstituted ethyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted thiophenyl and substituted or unsubstituted benzyl; and/or

R10, R10’, R10” and R10’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₁₀, R₁₀’, R₁₀” and R10’” are all hydrogen; or

R₁₀ and R₁₀’ and/or R₁₀” and R₁₀’” taken together with the carbon atom to which they are attached may form a substituted or unsubstituted cycloalkyl; or

R₁₀ and R₁₀’ and/or R₁₀” and R₁₀’” taken together with the carbon atom to which they are attached form a carbonyl group; or when m and r are 1 , Rwi and one of R10, R-io’, R10” or R10’” may form a double bond; and/or

R11 , R11’, R11” and R11’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably Rn , Rn’, Rn” and R11’” are all hydrogen; or

R11 and R11’ and/or Rn” and Rn’” taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; and/or

R₁₂ and R₁₂’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and/or

R₁₃ and R₁₃’ are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl and unsubstituted C_2-6 alkynyl; and/or

R14, RM’ and R14” are independently selected from the group consisting of hydrogen, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted aryl, unsubstituted cycloalkyl and unsubstituted heterocyclyl; and/or

R₂₁, R₂₁’ and R₂₁” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₂₁, R₂₁’ and R₂₁” are all hydrogen; and/or

R₄₁ and R₄₁’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and/or

R₇₁ and R₇₁’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; and/or

Rei, Rei’ and Rsi” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably Rsi is substituted or unsubstituted methyl; and/or

R₈₂, R₈₂’ and R₈₂” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably Rs₂ is substituted or unsubstituted methyl;

and/or

R₈₃, R₈₃’ and R_S3” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably Rs₃ is substituted or unsubstituted methyl;

and/or R₉₁, R₉₁’ and R₉₁” are independently selected from the group consisting of the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably R₉₁, R₉₁’ and R₉₁” are independently selected from the group consisting of the group consisting of hydrogen, substituted or unsubstituted methyl and substituted or unsubstituted isopropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

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

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₁ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C_1-6 alkyl is propyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₅, R₅’_, Rs” and R₅’” as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₆, Re’_, Re” and Re’” as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C_1-6 alkyl is methyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Re as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C_1-6 alkyl is methyl or ethyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or the cycloalkyl is C_3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C_3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C_3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Rg as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl, more preferably the C_1-6 alkyl is ethyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; and/or the cycloalkyl is C_3-8 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably is C_3-7 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; more preferably from C_3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and/or the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; more preferably the aryl is phenyl; and/or the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, indoline-2-one and quinazoline; preferably the heterocyclyl is pyridinyl or thiophenyl;

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

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

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Rn, Rn’, Rn” and Rn’” as defined in any of the embodiments of the present invention, 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; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₁₂ and R₁₂’ as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₁₃ and R₁₃’ as defined in any of the embodiments of the present invention,

R₁₃ and R₁₃’ are independently selected from the group consisting of hydrogen, unsubstituted C_1-6 alkyl, unsubstituted C_2-6 alkenyl and unsubstituted C_2-6 alkynyl; wherein the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R-u, R-u’ and R-u” as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; 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 C3-6 cycloalkyl like cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and/or the aryl is selected from phenyl, naphthyl, or anthracene; preferably is naphthyl and phenyl; and/or the heterocyclyl is a heterocyclic ring system of one or more saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring; preferably is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in the ring, more preferably is selected from oxazepan, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzothiazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, phthalazine, benzo-1 ,2,5-thiadiazole, indole, benzotriazole, benzoxazole oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, indoline-2-one and quinazoline;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R21, R21’ and R21” as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R41 and R41’ as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R71 and R71’ as defined in any of the embodiments of the present invention, the C1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; and/or the C2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Rs₂, R₈₂’ and R₈₂” as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; more preferably the C_1-6 alkyl is methyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in Rs₃, Rs₃’ and Rs₃” as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; more preferably the C_1-6 alkyl is methyl; and/or the C_2-6 -alkenyl is preferably selected from ethylene, propylene, butylene, pentylene, hexylene, isopropylene and isobutylene; and/or the C_2-6 -alkynyl is preferably selected from ethyne, propyne, butyne, pentyne, hexyne, isopropyne and isobutyne;

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein in R₉₁, R₉₁’ and R₉₁” as defined in any of the embodiments of the present invention, the C_1-6 alkyl is preferably selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, or 2-methylpropyl; more preferably the C_1-6 alkyl is methyl or isopropyl; 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;

[CH2] N(R_z)[CH2]q-; preferably X is selected from the group consisting of a bond, - [C(R_aRb)]p-, -[CH₂]_P-0-[CH₂]q, -[CH₂]_PC(0)[CH₂]q- and -[CH₂]_PN(R_z)[CH₂]_q-; more preferably selected from a bond, -CH2-, -C(O)-, -O- and -NH-; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

R_z is selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(0)-Ci-₆ alkyl; preferably R_z is hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

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

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

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

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

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

R₁ is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6alkynyl; preferably R₁ is substituted or unsubstituted C_1-6 alkyl; more preferably R₁ is substituted or unsubstituted propyl; even more preferably R₁ is unsubstituted propyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R2 is selected from the group consisting of -R21, -OR21, -NO2, halogen, -NR21R21’, - NR_2IC(0)R_2I’, -NR_2iS(0)₂R2i’, -S(0)₂NR_2iR2i’, - NR2iC(0)NR_2i’R_2i”, -SR21 , -S(0)R_2i, -S(0)2R2i, -CN, haloalkyl, haloalkoxy, -C(0)0R2i, -C(0)NR2iR2i’, -OCH2CH2OR21, - NR_2iS(0)₂NR2i’R2i” and -C(CH3)20R2i; preferably R2 is selected from the group consisting of -R21, halogen, -CN, -C(0)0R2i and -C(0)NR2iR2i’; more erably R2 is selected from the group consisting of hydrogen, fluorine, -CN, -C(0)0H and -C(0)NH₂; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₄ is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₄ is selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably R₄ is selected from hydrogen and a substituted or unsubstituted group selected from methyl, ethyl and propyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₅, R₅’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R5, R5’, Rs” and R5’” are independently selected from the group consisting of hydrogen and halogen; more preferably, R₅, Rs’_, Rs” and Rs’” are independently selected from the group consisting of hydrogen and fluorine; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R₅ and R₅’ and/or R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl 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.

R6, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl; preferably R6, Re’, Re” and Re’” are independently selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably R6, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen and substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₇ and R₇’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₇ and R₇’ are independently selected from the group consisting of hydrogen and substituted or unsubstituted C_1-6 alkyl; more preferably preferably R₇ and R₇’ are independently selected from the group consisting of hydrogen and a substituted or unsubstitutedgroup selected from methyl and ethyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

Re is selected from the group consisting of substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl; preferably Rs is substituted or unsubstituted C_1-6 alkyl; more Rs is a substituted or unsubstituted group selected from methyl and ethyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

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

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein Re and Re’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclyl; preferably Rs and Rs’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted azetidinyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

Rg is selected from the group consisting of substituted or unsubstituted Ci-₆ alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted alkylaryl and substituted or unsubstituted alkylheterocyclyl; preferably Rg is selected from the group consisting of substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted alkylaryl; more preferably Rg is selected from the group consisting of substituted or unsubstituted ethyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted thiophenyl and substituted or unsubstituted benzyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R10, R10’, R10” and R10’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₁₀, R₁₀’, R₁₀” and R₁₀’” are all hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R11 , R11’, R11” and R11’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably Rn , Rn’, Rn” and R11’” are all hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₂₁, R₂₁’ and R₂₁” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably R₂₁, R₂₁’ and R₂₁” are all hydrogen; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein R8i, R8i’ and Rsi” are independently selected from the group consisting of hydrogen, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; preferably Rsi is substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₈₂, R₈₂’ and R₈₂” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably Rs₂ is substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

R₈₃, R₈₃’ and R_S3” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably Rs₃ is substituted or unsubstituted methyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. In another preferred embodiment of the invention according to general Formula (I) the compound is a compound, wherein

R₉₁, R₉₁’ and R₉₁” are independently selected from the group consisting of the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, and substituted or unsubstituted C_2-6 alkynyl; preferably R₉₁, R₉₁’ and R₉₁” are independently selected from the group consisting of the group consisting of hydrogen, substituted or unsubstituted methyl and substituted or unsubstituted isopropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at 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 bond, -CH₂-, -C(O)-, -O- or -NH-; and/or

R_a is hydrogen; and/or

R_b is hydrogen; and/or

R_z is hydrogen; and/or p is 0 or 1 ; and/or q is 0; and/or

Wi is Nitrogen or CR_wi;

and/or

m is 0 or 1 ;

and/or

r is 0 or 1 ;

and/or

t is 0 or 1 ;

and/or

R_wi is hydrogen;

and/or

Ri is substituted or unsubstituted propyl;

and/or

R₂ is hydrogen, fluorine, -CN, -C(0)0H or -C(0)NH₂; and/or

and/or R₄ is hydrogen, methyl, ethyl or propyl; and/or

R₅, R₅’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen and fluorine; and/or

R₅ and R₅’ and/or R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl group; and/or

R₆, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen and substituted or unsubstituted methyl; and/or

R₇ and R₇’ are independently selected from the group consisting of hydrogen and a substituted or unsubstitutedgroup selected from methyl and ethyl; and/or Re is a substituted or unsubstituted group selected from methyl and ethyl; and/or

Re’ is selected from the group consisting of hydrogen and a substituted or unsubstituted group selected from methyl and ethyl; and/or Re and Re’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted azetidinyl; and/or Rg is selected from the group consisting of substituted or unsubstituted ethyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted thiophenyl and substituted or unsubstituted benzyl; and/or Rio, Rio’, Rio” and Rio’” are all hydrogen; and/or

Rwi and one of Rio, Rio’, Rio” or Rio’” form a double bond; and/or

R₁₁, R₁₁’, R₁₁” and Rn’” are all hydrogen; and/or

R21, R21’ and R21” are all hydrogen; and/or

Rei is substituted or unsubstituted methyl; and/or R₈₂ is substituted or unsubstituted methyl; and/or

R_S3 is substituted or unsubstituted methyl; and/or

R₉₁, R₉₁’ and R₉₁” are independently selected from the group consisting of the group consisting of hydrogen, substituted or unsubstituted methyl and substituted or unsubstituted isopropyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at 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

X is a bond, -CH2-, -C(O)-, -O- or -NH-.

In a preferred embodiment

In a preferred embodiment

R_a is hydrogen.

In a preferred embodiment

R_b is hydrogen.

In a preferred embodiment R_z is hydrogen.

In a preferred embodiment

p is 0 or 1.

In a preferred embodiment

q is 0.

In a preferred embodiment

Wi is Nitrogen or CR_wi.

In a preferred embodiment

m is 0 or 1.

In a preferred embodiment

r is 0 or 1.

In a preferred embodiment

t is 0 or 1.

In a preferred embodiment

R_wi is hydrogen.

In a preferred embodiment

Ri is substituted or unsubstituted propyl.

In a preferred embodiment

R₂ is hydrogen, fluorine, -CN, -C(0)OH or -C(0)NH₂.

In a preferred embodiment

In a preferred embodiment

R₄ is hydrogen, methyl, ethyl or propyl.

In a preferred embodiment R₅, R₅’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen and fluorine.

In a preferred embodiment

R5 and R5’ and/or R₅” and R5’” taken together with the carbon atom to which they are attached form a carbonyl group. In a preferred embodiment

R5 is hydrogen or fluorine.

In a preferred embodiment

R₅’ is hydrogen or fluorine.

In a preferred embodiment R₅” is hydrogen.

In a preferred embodiment

R₅’” is hydrogen.

In a preferred embodiment R₅ and R₅’ are both fluorine.

In a preferred embodiment R₅” and R₅’” are both hydrogen.

In a preferred embodiment

R₅ and R₅’ are both fluorine while R₅” and R₅’” are both hydrogen.

In a preferred embodiment R₅” and R₅’” are both fluorine.

In a preferred embodiment R₅ and R₅’ are both hydrogen.

In a preferred embodiment

R₅” and R₅’” are both fluorine while R₅ and R₅’ are both hydrogen.

In a preferred embodiment

R5, R5’, R5” and R5’” are all hydrogen.

In a preferred embodiment

R₅ and R₅’ taken together with the carbon atom to which they are attached form a carbonyl group.

In a preferred embodiment

R₅ and R₅’ taken together with the carbon atom to which they are attached form a carbonyl group, while R₅” and R₅’” are both hydrogen.

In a preferred embodiment

R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl group. In a preferred embodiment

R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl group, while R₅ and R₅’ are both hydrogen.

In a preferred embodiment R₆, Re’_, Re” and Re’” are independently selected from the group consisting of hydrogen and substituted or unsubstituted methyl.

In a preferred embodiment

R₆ is hydrogen or substituted or unsubstituted methyl.

In a preferred embodiment Re’ is hydrogen.

In a preferred embodiment

Re” is hydrogen or substituted or unsubstituted methyl.

In a preferred embodiment Re’” is hydrogen. In a preferred embodiment

R₆ and Re” are both substituted or unsubstituted methyl.

In a preferred embodiment Re’ and Re’” are both hydrogen.

In a preferred embodiment R₆ and Re” are both substituted or unsubstituted methyl, while Re’ and Re’” are both hydrogen.

In a preferred embodiment R₆ is substituted or unsubstituted methyl while Re’, Re” and Re’” are all hydrogen.

In a preferred embodiment

Re, Re’, Re” and Re’” are all hydrogen.

In a preferred embodiment R₇ and R₇’ are independently selected from the group consisting of hydrogen and a substituted or unsubstituted group selected from methyl and ethyl.

In a preferred embodiment

R₇ is hydrogen or a substituted or unsubstituted group selected from methyl and ethyl. In a preferred embodiment R₇’ is hydrogen.

In a preferred embodiment

R₇ is substituted or unsubstituted methyl, while R₇’ is hydrogen.

In a preferred embodiment

Re is a substituted or unsubstituted group selected from methyl and ethyl. In a preferred embodiment

Re’ is selected from the group consisting of hydrogen and a substituted or unsubstituted group selected from methyl and ethyl.

In a preferred embodiment

Re and Re’ taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted azetidinyl.

In a preferred embodiment Re is a substituted or unsubstituted group selected from methyl and ethyl, while Re’ is selected from the group consisting of hydrogen and a substituted or unsubstituted group selected from methyl and ethyl.

In a preferred embodiment Rs is substituted or unsubstituted methyl, while Rs’ is selected from the group consisting of hydrogen and a substituted or unsubstituted methyl.

In a preferred embodiment

Rs is substituted or unsubstituted ethyl, while Rs’ is selected from the group consisting of hydrogen and a substituted or unsubstituted group selected from methyl and ethyl. In a preferred embodiment

Re is a substituted or unsubstituted methyl, while Re’ is hydrogen.

In a preferred embodiment

Re is substituted or unsubstituted methyl, while Re’ is substituted or unsubstituted methyl. In a preferred embodiment

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

In a preferred embodiment

Re is substituted or unsubstituted ethyl, while Re’ substituted or unsubstituted methyl. In a preferred embodiment Re is substituted or unsubstituted ethyl, while Re’ substituted or unsubstituted ethyl.

In a preferred embodiment

Rg is selected from the group consisting of substituted or unsubstituted ethyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted thiophenyl and substituted or unsubstituted benzyl. In a preferred embodiment

R10, Rio’, R10” and R10’” are all hydrogen.

In a preferred embodiment

Rwi and one of R10, R10’, R10” or R10’” form a double bond.

In a preferred embodiment

Rwi and Re form a double bond.

In a preferred embodiment

R₁₁, R₁₁’, R₁₁” and Rn’” are all hydrogen.

In a preferred embodiment

R21, R21’ and R21” are all hydrogen;

In a preferred embodiment

R₂₁ is hydrogen;

In a preferred embodiment

R₂₁’ is hydrogen;

In a preferred embodiment

Rei is substituted or unsubstituted methyl.

In a preferred embodiment

R₈₂ is substituted or unsubstituted methyl.

In a preferred embodiment

R₈₃ is substituted or unsubstituted methyl.

In a preferred embodiment R₉₁, R₉₁’ and R₉₁” are independently selected from the group consisting of the group consisting of hydrogen, substituted or unsubstituted methyl and substituted or unsubstituted isopropyl.

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

(I), the haloalkoxy is -OCF₃; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at 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 compounds of the general Formula (I) are selected from

In a very preferred embodiment, the compounds are selected which act as dual ligands of the a2d subunit, particularly the a2d-1 subunit, of the voltage-gated calcium channel and the m-opioid receptor and especially compounds which have a binding expressed as Ki responding to the following scales:

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

Kί(a2d1 ) is preferably < 10000 nM, more preferably < 5000 nM, even more preferably < 500 nM.

In the following the phrase“compound of the invention” is used. This is to be understood as any compound according to the invention as described above according to general Formula (I), (I’), (I”), (I³’) and (IZ).

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

For the sake of clarity the expression“a compound according to Formula (I), wherein e.g. Ri, R₂, R3, R₄, RS, RS’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, X, W1, m, r and t are as defined below in the detailed description” would (just like the expression “a compound of Formula (I) as defined in any one of claims e.g. 1 to 8” found in the claims) refer to“a compound according to Formula (I)”, wherein the definitions of the respective substituents R₁ etc. (also from the cited claims) are applied. In addition, this would also mean, though (especially in regards to the claims) that also one or more disclaimers or provisos defined in the description (or used in any of the cited claims like e.g. claim 1 ) would be applicable to define the respective compound. Thus, a disclaimer or a proviso found in e.g. claim 1 would be also used to define the compound “of Formula (I) as defined in any one of the corresponding related claims e.g. 1 to 8”.

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

A preferred embodiment of the invention is a process for the production of a compound according to Formula (I), wherein, if not defined otherwise, R1, R₂, R₃, R₄, Rs, Rs’, R₉, R10, R10’, R10”, Rio’”, Rn , Rn’, Rn”, Rn’”, X, Wi, m, r and t have the meanings defined in the description. LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate).

In a particular embodiment there is a process for the production of a compound according to Formula (I), wherein Ri, R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, X, Wi, m, r and t have the meanings as defined in the description, and wherein R₃ is linked to the alkyl chain via a nitrogen atom, said process comprises reacting a compound of formula VIII’

with a suitable nucleophilic reagent of formula IX,

R₃H

IX in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K₂CO₃ or /V,/V-diisopropylethylamine, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating.

In another particular embodiment there is a process for the production of a compound according to Formula (I), wherein R1, R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11, R₁₁’, R₁₁”, R₁₁”’, X, Wi, m, r and t have the meanings as defined in the description, and wherein R₃ is linked to the alkyl chain via a carbon atom, said process comprises alkylation of a compound of formula XIV’

with a compound of formula XV (where LG means a leaving group),

R-,LG

XV using a suitable base, such as lithium bis(trimethylsilyl)amide, in a suitable solvent, such as tetrahydrofuran at a suitable temperature, such as room temperature.

In another particular embodiment there is a process for the production of a compound according to Formula (I), wherein Ri, R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, m, r and t have the meanings as defined in the description, said process comprises reacting a compound of Formula X,

x wherein T is halogen, with a compound of formula XIX, to give a compound of formula I where X is a bond and Wi is nitrogen, or with a compound of formula XX to give a compound of formula I where X is NR_Z and Wi is CRwi,

under Buchwald-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP or XPhos, using a suitable base such as sodium tert- butoxide or cesium carbonate, in a suitable solvent such as toluene or 1 ,4- dioxane, at a suitable temperature, preferably heating.

In another particular embodiment there is a process for the production of a compound according to Formula (I), wherein Ri, R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, m, r and t have the meanings as defined in the description, X is CH2 and Wi is nitrogen, said process comprises reacting a compound of Formula X

X wherein T is halogen, with a compound of formula XXI

XXI by coupling using a Pd catalyst such as palladium acetate, using a suitable base such as potassium carbonate, in a suitable solvent such as tert- butanol, at a suitable temperature, preferably heating and optionally under microwave irradiation.

In another particular embodiment there is a process for the production of a compound according to Formula (I), wherein Ri, R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, m, r and t have the meanings as defined in the description, X is -C(O)- and Wi is nitrogen, said process comprises reacting a compound of Formula X

wherein T is -C(0)0H by reaction with a compound of formula XIX

in the presence of a suitable coupling agent, such as 1-[bis(dimethylamino)methylene]- 1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, in the presence of a base, such as triethylamine, in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably at room temperature.

In another particular embodiment there is a process for the production of a compound according to Formula (I), wherein R1 , R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , Rii\ R₁₁”, Rii”’, m, r and t have the meanings as defined in the description, X is -O- and Wi is CRwi, said process comprises reacting a compound of Formula X,

X wherein T is -OH, with a compound of formula XXII

in the presence of a base, such as potassium carbonate, in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably heating.

In another particular embodiment there is a process for the production of a compound according to Formula (I), wherein Ri, R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11, R₁₁’, R₁₁”, R₁₁’”, m, r and t have the meanings as defined in the description, X is a bond and Wi is CRwi, said process comprises reacting a compound of Formula X,

X wherein T is a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, with a compound of formula XXIII

in the presence of a Pd catalyst such as Pd(PPh₃)₄, in a suitable solvent, such as dimethoxyethane/water, at a suitable temperature, such as heating to give a derivative which is finally reduced under hydrogen in the presence of Pd in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature.

In another particular embodiment there is a process for the production of a compound according to Formula (I), wherein Ri , R₂, R3, R₄, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, r and t have the meanings as defined in the description, m is 1 , X is a bond and Wi is CRwi , said process comprises reacting a compound of Formula X,

X wherein T is a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, with a compound of formula XXIII’

XXIII' in the presence of a Pd catalyst such as Pd(PPh₃)₄, in a suitable solvent, such as dimethoxyethane/water, at a suitable temperature, such as heating to give a derivative which is finally reduced under hydrogen in the presence of Pd in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature.

In a particular embodiment there is a process for the preparation of compounds of Formula (I) wherein : a) when R₃ is linked to the alkyl chain via a nitrogen atom, said process comprises reacting a compound of formula VIII’

with a suitable nucleophilic reagent of formula IX,

R₃H

IX in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K₂CO₃ or /V,/V-diisopropylethylamine, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating; or b) wherein R3 is linked to the alkyl chain via a carbon atom, said process comprises alkylation of a compound of formula XIV’

with a compound of formula XV,

R-,LG

XV using a suitable base, such as lithium bis(trimethylsilyl)amide, in a suitable solvent, such as tetrahydrofuran at a suitable temperature, such as room temperature; or c) wherein said process comprises reacting a compound of Formula X,

XIX XX under Buchwald-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP or XPhos, using a suitable base such as sodium tert- butoxide or cesium carbonate, in a suitable solvent such as toluene or 1 ,4- dioxane, at a suitable temperature, preferably heating;

or

d) when X is Chh and Wi is nitrogen, said process comprises reacting a compound of Formula X

X wherein T is halogen, with a compound of formula XXI

XXI by coupling using a Pd catalyst such as palladium acetate, using a suitable base such as potassium carbonate, in a suitable solvent such as tert- butanol, at a suitable temperature, preferably heating and optionally under microwave irradiation; or e) when X is -C(O)- and Wi is nitrogen, said process comprises reacting a compound of Formula X

wherein T is -C(0)0H by reaction with a compound of formula XIX

in the presence of a suitable coupling agent, such as 1 -[bis(dimethylamino)methylene]- 1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, in the presence of a base, such as triethylamine, in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably at room temperature; or f) when X is -O- and Wi is CRwi, said process comprises reacting a compound of Formula X,

X wherein T is -OH, with a compound of formula XXII

XXII in the presence of a base, such as potassium carbonate, in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably heating; or g) when X is a bond and Wi is CRwi, said process comprises reacting a compound of Formula X,

XXIII in the presence of a Pd catalyst such as Pd(PPh3)4, in a suitable solvent, such as dimethoxyethane/water, at a suitable temperature, such as heating to give a derivative which is finally reduced under hydrogen in the presence of Pd in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature;

h) when m is 1 , X is a bond and Wi is CRwi, said process comprises reacting a compound of Formula X,

XXIII' in the presence of a Pd catalyst such as Pd(PPh3)4, in a suitable solvent, such as dimethoxyethane/water, at a suitable temperature, such as heating to give a derivative which is finally reduced under hydrogen in the presence of Pd in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature; and wherein R_wi, R_å, Ri, R2, R3, R4, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, X, W1 , m, r, n, v and t, if not defined otherwise, have the meanings as defined in the description, LG represents a leaving group, such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, and Z represents OH or halogen.

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

In a particular embodiment there is a process for the production of a compound according to Formula (I), by deprotection reaction of a compound of formula I that contains an amine protecting group such as a carbamate, preferably tert-butoxy carbonyl, by any suitable method, such as treatment with an acid, preferably HCI or trifluoroacetic acid in an appropriate solvent such as 1 ,4-dioxane, DCM, ethyl acetate or a mixture of an organic solvent and water.

In a particular embodiment there is a process for the production of a compound according to Formula (I), by reductive amination reaction of a compound of formula I that contains an amino group with an aldehyde, preferably carried out with a reductive reagent, preferably sodium triacetoxyborohydride, in an organic solvent, preferably DCE, in the presence of an organic base, preferably DIPEA or TEA. Alternatively, the reaction can be carried out in the presence of an acid, preferably acetic acid.

In a particular embodiment there is a process for the production of a compound according to Formula (I), by reaction of a compound of formula I that contains an amino group with an alkylating reagent, in the presence of a base, preferably DIPEA or K2CO₃, in an organic solvent, preferably acetonitrile, at suitable temperature, such as in the range of 0-120 °C.

In a particular embodiment there is a process for the production of a compound according to Formula (I), by reaction of a compound of formula I that contains an amino group with a vinyl derivative, in an organic solvent, preferably 2-methoxyethanol, at suitable temperature, such as in the range of 20-140 °C.

A particular embodiment of the invention refers to the use of a compound of Formula

(II),

wherein T represents halogen, -OH, -C(0)OH or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, and R2 has the meaning as defined in the description, for the preparation of compounds of Formula (I).

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

H₂N - R₄

wherein R₄ has the meaning as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula

(IV),

wherein T represents halogen, OH, -C(0)0H or a boronic derivative like boronic acid or a boronic ester, usually pinacolborane , R₂ and R₄ have the meanings as defined in the description, for the preparation of compounds of Formula (I).

(V),

wherein Z represents OH or halogen, and Ri has the meaning as defined in the description, for the preparation of compounds of Formula (I).

(VI),

wherein T represents halogen, -OH, -C(0)0H or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, and Ri, R₂ and R₄ have the meaning as defined in the description, for the preparation of compounds of Formula (I).

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

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

wherein T represents halogen, -OH, -C(0)0H or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, and Ri, R₂ and R₄ have the meaning as defined in the description, for the preparation of compounds of Formula (I).

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

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, and Ri, R₂, R₄, Rs, Rs’, Rg, R10, R10’, R10”, R10’”, Rn, Rn’, Rn”, Rn’”, X, Wi, m, r and t have the meaning as defined in the description, for the preparation of compounds of Formula (I).

(IX),

R₃H

IX

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

(X),

wherein T represents halogen, -OH, -C(0)0H or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, and R1, R₂, R3 and R₄ have the meaning as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (XII),

XII

wherein Z represents OH or halogen, and R3 has the meaning as defined in the description, for the preparation of compounds of Formula (I).

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

wherein T represents halogen, -OH, -C(0)0H or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, and R2, R3 and R₄ have the meaning as defined in the description, for the preparation of compounds of Formula (I).

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

wherein T represents halogen, -OH, -C(0)0H or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, and R2, R3 and R₄ have the meaning as defined in the description, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (XIV),

wherein R₂, R3, R4, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, X, W1, m, r, and t have the meaning as defined in the description, for the preparation of compounds of Formula (I).

(XV),

R._| LG

XV

wherein LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, and R1 has the meaning as defined in the description, for the preparation of compounds of Formula (I).

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

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

XVII

wherein T represents halogen, -OH, -C(0)0H or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, and Ri, R₂ and R₄ have the meanings as defined in the description, for the preparation of compounds of Formula (I).

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

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

wherein R₈, Rs’, Rg, R10, R10’, R10”, R10’”, Rn , Rn’, Rn”, Rn’”, m, r and t have the meanings as defined in the description, for the preparation of compounds of Formula

(I). A particular embodiment of the invention refers to the use of a compound of Formula (XX),

wherein R_z, Rs, Rs’, Rg, R10, R10’, R10”, R10’”, Rn , Rn’, Rn”, Rn’”, m, r and t have the meanings as defined in the description, for the preparation of compounds of Formula

(I).

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

XXI wherein R₈, R₈’, R₉, R10, R10’, R10”, R10’”, R11, R11’, R11”, R11’”, m, r and t have the meanings as defined in the description, for the preparation of compounds of Formula

(I).

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

wherein R₈, R₈’, Rg, R10, R10’, R10”, Rio’”, Rn , Rn’, Rn”, Rn’”, m, r and t have the meanings as defined in the description, and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I).

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

XXIII

wherein R₈, R₈’, Rg, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, m, r and t have the meanings as defined in the description, and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I). A particular embodiment of the invention refers to the use of a compound of Formula (XXIII’),

XXIII'

wherein Re, Re’, R9, R10, R10’, R10”, R10’”, R1 1 , R11’, R11”, R11’”, r and t have the meanings as defined in the description, and LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, for the preparation of compounds of Formula (I).

A particular embodiment of the invention refers to the use of a compound of Formula II, III, IV, V, VI, VII, VIII, VIII’, IX, X, XI, XII, XIII, XIV, XIV’, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII or XXIII’

XV xvi XVII

XXIII' wherein R_z, R1 , R2, R3, R4, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, X, Wi, m, r and t have the meanings as defined in the description, LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Z represents -OH or halogen and T represents halogen, -OH, -C(0)0H or a boronic derivative, like boronic acid or a boronic ester, usually pinacolborane, for the preparation of compounds of Formula (I).

In a preferred embodiment,

T represents halogen.

In a preferred embodiment,

T represents -OH.

In a preferred embodiment,

T represents -C(0)0H.

In a preferred embodiment,

T represents a boronic derivative.

In a preferred embodiment,

T represents boronic acid.

In a preferred embodiment,

T represents a boronic ester.

In a preferred embodiment,

T represents pinacolborane.

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

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

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

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

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

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

General Experimental Part

SYNTHESIS DESCRIPTION

The compounds of formula I may be prepared by a four to six step process as described in Scheme 1 ,

Scheme 1

wherein R1 , R₂, R3, R₄, Rs-s·, R9, R10-10", R11-11 ^■, X, Wi, m, r and t have the meanings as defined in claim 1 , LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate), Z represents OH or a halogen atom and T represents the group A or any functional group that can be converted into it.

The process can be carried out as described below:

Step 1 : A compound of formula IV can be prepared by treating an acid of formula II with a suitable amine of formula III in the presence of a suitable coupling agent, such as 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, in the presence of a base such as triethylamine, in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably at room temperature. Step 2: A compound of formula VI can be prepared by treating a compound of formula IV with a suitable acid derivative of formula V. When Z is a halogen atom the reaction may be carried out in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, at a suitable temperature, such as room temperature. When Z is OH the reaction can be carried out using similar conditions to those described in step 1.

Step 3: A compound of formula VII can be prepared by treating a compound of formula VI with a suitable halogen such as iodine, in the presence of a base, such as hexamethyldisilazane, in a suitable solvent, such as dichloromethane, at a suitable temperature, preferably room temperature.

Step 4: A compound of formula VIII, where LG represents a leaving group, such as a halogen atom, can be prepared by reacting a compound of formula VII with a suitable halogenating agent, such as bromine in the presence of a suitable solvent, such as acetic acid, at a suitable temperature, preferably heating.

Alternatively a compound of formula VIII can be prepared by converting the hydroxyl group of a compound of formula XVIII into a leaving group. This can be done by using methanesulphonyl chloride in the presence of a suitable base, such as pyridine, at a suitable temperature, preferably at room temperature. A compound of formula XVIII may be obtained from a compound of formula XVII using the conditions described in Step 3. In turn, XVII may be prepared by coupling a compound of formula IV with an acid derivative of formula XVI using the conditions described in Step 2.

Step 5: A compound of formula I, in which F¾ is linked to the alkyl chain via a nitrogen atom, can be prepared by reacting a compound of formula VIII with a suitable nucleophilic reagent of formula IX, in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K₂CO₃ or N,N- diisopropylethylamine, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating. Alternatively, the reactions can be carried out under microwave heating and optionally using an activating agent such as sodium iodide or potassium iodide can be used. Alternatively a compound of formula I, in which R₃ is linked to the alkyl chain via a carbon atom, may be prepared by reacting a compound of formula IV with a compound of formula XII under the conditions used in Step 2 (Step 2’), followed by cyclization under the conditions used in Step 3 (Step 3’) and final alkylation of a compound of formula XIV with a compound of formula XV, using a suitable base, such as lithium bis(trimethylsilyl)amide, in a suitable solvent, such as tetrahydrofuran at a suitable temperature, such as room temperature (Step 4’).

In addition, certain compounds of the present invention can also be obtained by functional group interconversion over compounds of formula I or any of the intermediates shown in Scheme 1. In particular, for introducing the group A (Step 6), the following transformations may be carried out:

-a compound in which T is halogen may be converted to a compound in which T is A by reaction with a compound of formula XIX (to give a compound of formula I where X is a bond and Wi is N) or XX (to give a compound of formula I where X is NRz and Wi is C)

-a compound in which T is halogen may be converted to a compound in which T is A (to give a compound of formula I where X is Chh and Wi is N) by reaction with a compound of formula XXI

XXI by coupling using a Pd catalyst such as palladium acetate, using a suitable base such as potassium carbonate, in a suitable solvent such as tert- butanol, at a suitable temperature, preferably heating and optionally under microwave irradiation. A compound of formula XXI may be obtained by reaction of a compound of formula XIX with potassium (bromomethyl)trifluoroborate, using a suitable base such as triethylamine, in a suitable solvent, such as mixtures of tetrahydrofuran/ferf-butanol, at a suitable temperature, preferably heating.

-a compound in which T is COOH may be converted to a compound in which T is A (to give a compound of formula I where X is CO and Wi is N) by reaction with a compound of formula XIX in the presence of a suitable coupling agent, such as 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, in the presence of a base, such as triethylamine, in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably at room temperature.

-a compound in which T is OH may be converted to a compound in which T is A (to give a compound of formula I where X is O and Wi is C) by reaction with a compound of formula XXII

-a compound in which T is halogen may be converted to a compound in which T is A (to give a compound of formula I where X is a bond and Wi is C) via a three step procedure. First, the halogen atom is converted to a boronic derivative by reaction with a boronic ester, such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), in the presence of a Pd catalyst, such as (1 ,1 - bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, in a suitable solvent, such as 1 ,4-dioxane, at a suitable temperature, such as heating. The boronic derivative is then treated with a compound of formula XXIII

XXIII in the presence of a Pd catalyst such as Pd(PPh3)₄, in a suitable solvent, such as dimethoxyethane/water, at a suitable temperature, such as heating to give a derivative which is finally reduced under hydrogen in the presence of Pd in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature. In addition, the following conversions are examples of other transformations that may be carried out: -a compound in which T or R₂ is halogen may be converted to a compound in which T or R₂ is OH by reaction with a boronic ester, such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), in the presence of a Pd catalyst such as (1 ,1 '-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, in a suitable solvent, such as 1 ,4-dioxane, at a suitable temperature, such as heating, followed by treatment with H₂0₂ in a suitable solvent such as acetic acid, at a suitable temperature, such as room temperature. Alternatively, a compound in which T or R₂ is halogen may be directly converted to a compound in which T or R₂ is OH by reaction with potassium hydroxide in the presence of a Pd catalyst, such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand, such as BINAP or XPhos, in a suitable solvent such as toluene or 1 ,4-dioxane, at a suitable temperature, preferably heating.

-a compound in which T or R₂ is a fluorine atom may be converted to a compound in which T or R₂ is CN by reaction with sodium cyanide in the presence of a phase transfer agent, such as tetrabutylammonium bromide, in a suitable solvent, such as dimethylformamide, at a suitable temperature, such as room temperature.

-a compound in which T or R₂ is a bromine atom may be converted to a compound in which T or R₂ is CN by reaction with Zn(CN)₂ in the presence of a Pd catalyst such as Pd(PPh3)₄, in a suitable solvent, such as dimethylformamide, at a suitable temperature, such as heating.

-a compound in which T or R₂ is a CN may be converted to a compound in which T or R₂ is COOH by reaction with sodium hydroxide in a suitable solvent, such as ethanol, at a suitable temperature, such as heating.

In addition, the functional groups present in groups A or R3 may be transformed at any stage of the synthesis. For example, a hydroxyl group can be converted to an acyloxy group by reaction with a suitable acylating agent, such as an acid anhydride, in the presence of a base such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, at a suitable temperature such as 0 °C; an amino group can be alkylated using a suitable alkylating agent, in the presence of a base, such as triethylamine or sodium hydride, in a suitable solvent, such as ethanol or dimethylformamide, at a suitable temperature, preferably heating.

The compounds of formula II, III, V, IX, XII, XV, XVI, XIX, XX, XXI, XXII and XXIII 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 some of the processes described above it may be necessary to protect the reactive or labile groups present with suitable protecting groups, such as for example Boc (tert- butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups, and common silyl protecting groups for the protection of the hydroxyl group. The procedures for the introduction and removal of these protecting groups are well known in the art and can be found thoroughly described in the literature.

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

Examples

The following abbreviations are used in the examples:

ACN: acetonitrile

Aq: aqueous

Anh: anhydrous

Boc: tert- butoxycarbonyl

Chx: Cyclohexane

Cone: concentrated

DavePhos: 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

DCM: dichloromethane

DEA: diethylamine DME: dimethoxyethane

DMF dimethylformamide

EDC.HCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

Eq: equivalent/s

Et₂0; diethyl ether

EtOAc; ethyl acetate

EtOH: ethanol

EX: example

h: hours

HATU: 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HMDS: hexamethyldisilazane

HPLC: high performance liquid chromatography

I PA: isopropanol

LiHMDS: lithium bis(trimethylsilyl)amide

MeOH: methanol

MS: mass spectrometry

Min.: minutes

NMP: N-Methyl-2-pyrrolidone

Quant: quantitative

Rt: retention time

r.t: room temperature

Sat: saturated

Sol: solution

tBuOH: tert-butanol

TBAB: Tetrabutylammonium bromide TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Wt: weight

XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

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

METHOD A

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% B in 0.1 min; isocratic 2 min 100% B.

METHOD B

Column Acquity UPLC BEH C18 2.1 x50 mm, 1 .7 pm; flow rate 0.61 mL/min; A: NH4HCO3 10 mM; B: ACN; gradient: 0.3 min in 98% A, 98% A to 5% A in 2.52 min, isocratic 1 .02 min 5% A.

METHOD C

Column Aquity UPLC BEH C18 2.1 x 50 mm, 1 .7 pm, flow rate 0.60 mL/min; A: NH4HCO3 10 mM, B: ACN; gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 2 min 5% A.

METHOD D

Column Acquity UPLC BEH C18 2.1 x50 mm, 1 .7 pm; flow rate 0.60 mL/min; A: NH4HCO3 10 mM; B: ACN; Gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 0.7 min 5% A.

METHOD E

Column Acquity UPLC BEH C18 2.1 x50 mm, 1 .7 pm; flow rate 0.60 mL/min; A: NH4HCO3 10 mM pH 10.6; B: ACN; Gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 0.7 min 5% A.

METHOD F Column Aquity UPLC BEH C18 2.1 x 50 mm, 1 .7 pm, flow rate 0.60 mL/min; A: NH4HCO3 10 mM pH 10.6, B: ACN; gradient: 0.3 min in 90% A, 90% A to 5% A in 2.7 min, isocratic 2 min 5% A.

METHOD G

Column Zorbax BONUS RP 2.1x50 mm, 1.8 pm; flow rate 0.5 mL/min; A: NH₄HCO₃ 10 mM; 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 isocratic 90% A.

METHOD H

Column Aquity UPLC BEH C18 2.1 x 50 mm, 1 .7 pm, flow rate 0.60 mL/min; A: Water + 0.1 % TFA; B: ACN + 0.1 % TFA; gradient: 95% to 5% A in 4 min, 5% to 0% A in 0.2 min, isocratic 0.7 min 0% A.

Example 1. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-(1 -(( 3S,5R )- 3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Step a. 2-Amino-5-bromo-N-ethylbenzamide. To a solution of 2-amino-5-bromobenzoic acid (10.0 g, 46 mmol) in anh DMF (200 ml.) under argon atmosphere, TEA (13 ml_, 92.6 mmol) and HATU (21 .1 g, 55 mmol) were added and the reaction mixture was stirred at 0 °C for 10 min. Then, ethylamine (2 M in THF, 35 ml_, 69 mmol) was added drop wise and the reaction mixture was allowed to reach r.t. and stirred overnight. The reaction crude was diluted with EtOAc:Et₂0 (1 :1 , 300 ml.) and washed with aq aq NaHCCh sat sol. The organic layer was dried over Na₂S0₄, filtered and concentrated to dryness to give the title compound (10.8 g, Yield: 85%).

Step b. 5-Bromo-N-ethyl-2-pentanamidobenzamide.

To a solution of the compound obtained in step a (10.7 g, 44.1 mmol) in anh DCM (200 ml.) under argon atmosphere, TEA (9.23 ml_, 66 mmol) was added drop wise and the mixture was stirred for 10 min. The solution was cooled at 0 °C and pentanoyl chloride (6 ml_, 48.5 mmol) was added drop wise. The reaction mixture was allowed to reach r.t. and stirred overnight. The resulting mixture was diluted with DCM (200 ml_), washed with aq NaHCCh sat sol and the organic layer was dried over Na₂S0₄, filtered and the solvent was removed under vacuum to give the title compound (13.3 g, Yield: 82%).

Step c. 6-Bromo-2-butyl-3-ethylquinazolin-4(3/-/)-one.

To a solution of the compound obtained in step b (13.3 g, 40.7 mmol) in anh DCM (150 ml_), iodine (20.7 g, 81.4 mmol) was added portion wise and the reaction mixture was stirred until full solution was observed. The solution was cooled at 0 °C, HMDS (34 ml_, 26.3 mmol) was added drop wise and the mixture was allowed to reach r.t. and stirred overnight. The reaction mixture was diluted with DCM (200 ml_), washed with a 5% Na2S2C>3 sol, and the organic layer was dried over Na2S0₄, filtered and solvent was removed under vacuum to give the title compound (12.5 g, Yield: 89%).

Step d. 6-Bromo-2-(1 -bromobutyl)-3-ethylquinazolin-4(3/-/)-one.

To a solution of the compound obtained in step c (12.5 g, 40.5 mmol) in acetic acid (125 ml_), NaOAc (4 g, 48.6 mmol) was added portion wise and the reaction was stirred for 15 min at r.t. Bromine (3.1 ml_, 60.7 mmol) was added drop wise, and the reaction was heated at 50 °C for 3 h. The mixture was concentrated under vacuum; the residue was dissolved in EtOAc (250 ml.) and washed twice with 10% NaHSCh aq sol and brine. The organic layer was dried over Na₂S0₄, filtered and solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient Chx to Chx:EtOAc (9:1 ) to give the title compound (12.2 g, Yield: 78%).

Step e. 6-Bromo-2-(1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin- 4(3H)-one.

To a solution of the compound obtained in step d (3.0 g, 7.7 mmol) in ACN (180 ml_), TEA (4.3 ml_, 30.9 mmol) and Kl (128 mg, 0.77 mmol) were added and the reaction mixture was stirred at r.t. for 20 min. (2R,6S)-2,6-Dimethylpiperazine (2.2 g, 19.3 mmol) was added portion wise and the mixture was heated at 90 °C and stirred overnight. The mixture was concentrated under vacuum and the crude product was dissolved in EtOAc and washed with aq NaHCC>3 sat sol. The organic layer was dried over Na₂S0₄, filtered and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient Chx to Chx:EtOAc (4:1 ) to give the title compound (2.1 g, Yield: 64%).

Step f. Title compound.

A schlenk flask charged with the compound obtained in step e (4.4 g, 10.4 mmol), 3- (4-(dimethylamino)piperidin-4-yl)phenol dihydrochloride. (3.7 g, 12.5 mmol), DavePhos (614 mg, 1 .56 mmol), Pd2dba3 (952 mg, 1.04 mmol) and NaOtBu (4 g, 41.61 mmol) and it was evacuated and backfilled with argon. Dioxane (80 ml_), degassed by means of bubbling argon to the solution for 5 min, was added and the reaction mixture was heated at 100 °C overnight. The suspension was filtered through celite, washed with EtOAc and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (85:15) to give the title compound (2.74 g, Yield: 47%).

HPLC-MS (Method C): Rt, 1 .82 min; ESI+-MS m/z: 561.4 (M+1 )

This method was used for the preparation of examples 2-46 using suitable starting materials:

Examples 47 and 48. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((R)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 1 , a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 12 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 1 1 ', tr₂: 23'] was carried out to give the title compounds.

Examples 49 and 50. 6-(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)-2-((R)-1 -((3S,5R)-

3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4-

(dimethylamino)-4-phenylpiperidin-1 -yl)-2-((S)-1 -((3S,5R,)-3,5-dimethylpiperazin-1 - yl)butyl)-3-ethylquinazolin-4(3/-/]-one.

Starting from the compound obtained in example 2, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 10.9', tr₂: 15.7'] was carried out to give the title compounds.

Examples 51 and 52. 6-(4-(Dimethylamino)-4-(3-methoxyphenyl)piperidin-1 -yl)-2-((R)- 1 -((SS SR^-S^-dimethylpiperazin-l -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(3-methoxyphenyl)piperidin-1 -yl)-2-((S)-1 -{{3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 6, a chiral preparative HPLC [column: Chiralpak AD-H, temperature: ambient; flow: 1 1 mL/min, eluent n-Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 12.3', tr₂: 19.7'] was carried out to give the title compounds. Examples 53 and 54. 6-(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)-2-((S)-1 -((3S,5R)- 3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-phenylpiperidin-1 -yl)-2-((R)-1 -((3S,5R,)-3,5-dimethylpiperazin-1 - yl)butyl)-3-methylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 8, a chiral preparative HPLC separation [column: Chiralpak IA, temperature: ambient; flow: 12 mL/min, eluent n- Heptane/(IPA + 0.33% DEA) 85/15 v/v; tn: 27.3', tr₂:30.4] was carried out to give the title compounds.

Examples 55 and 56. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((R)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one and 6-(4- (Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 10, a chiral preparative HPLC separation [column: Lux C1 temperature: ambient; flow: 21 mL/min, eluent n- Heptane/EtOH/IPA (0.1 % NH₃) 70/15/15 v/v/v] was carried out to give the title compounds.

Examples 57 and 58. 7-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((R)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one and 7-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 1 1 , a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 10.9', tr₂: 23.1 '] was carried out to give the title compounds.

Examples 59 and 60. 6-(4-(Dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)-2-((S)-1 - ((SS SR -S^-dimethylpiperazin-l -yl)butyl)-3-methylquinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(thiophen-2-yl)piperidin-1 -yl)-2-((/?)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 15, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 13', tr₂: 19'] was carried out to give the title compounds.

Examples 61 and 62. 6-(4-(Dimethylamino)-4-(4-methoxyphenyl)piperidin-1 -yl)-2-((R)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(4-methoxyphenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 19, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 1 1 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 13.9', tr₂: 24.2'] was carried out to give the title compounds.

Examples 63 and 64. 6-(4-(Dimethylamino)-4-(2-methoxyphenyl)piperidin-1 -yl)-2-((/?)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(2-methoxyphenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 20, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 9', tr₂: 15'] was carried out to give the title compounds.

Examples 65 and 66. 7-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((R)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 7-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 21 , a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 8.5', tr₂: 18.9'] was carried out to give the title compounds.

Examples 67 and 68. (/?)-7-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3- ethyl-2-(1 -(4-methyl-1 ,4-diazepan-1 -yl)butyl)quinazolin-4(3/-/)-one and (S)-7-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3-ethyl-2-(1 -(4-methyl-1 ,4- diazepan-1 -yl)butyl)quinazolin-4(3/-/)-one. Starting from the compound obtained in example 26, a chiral preparative HPLC separation [column: Chiralpak 1C, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 18.4', tr₂: 22.1 '] was carried out to give the title compounds.

Examples 69 and 70. 2-((/?)-1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-6-(4- (3-hydroxyphenyl)-4-(methylamino)piperidin-1 -yl)quinazolin-4(3/-/)-one and 2-((S)-1 - ((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl-6-(4-(3-hydroxyphenyl)-4- (methylamino)piperidin-1 -yl)quinazolin-4(3/-/)-one.

Starting from the compound obtained in example 27, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 12.9', tr₂: 30.5’] was carried out to give the title compounds.

Examples 71 and 72. 6-(4-(Dimethylamino)-4-(4-fluorophenyl)piperidin-1 -yl)-2-((/?)-1 - ((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4-

(dimethylamino)-4-(4-fluorophenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 28, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 10.7', tr₂: 15.7'] was carried out to give the title compounds.

Examples 73 and 74. 6-(4-(Dimethylamino)-4-(3-fluorophenyl)piperidin-1 -yl)-2-((/?)-1 - ((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4-

(dimethylamino)-4-(3-fluorophenyl)piperidin-1 -yl)-2-((S)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 29, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 1 1.0', tr₂: 16.1’] was carried out to give the title compounds.

Example 75 and 76. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-((/?)-1 - ((SS SR^-S^-dimethylpiperazin-l -yl)butyl)quinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-((S)-1-((3S,5R)-3,5- dimethylpiperazin-1-yl)butyl)quinazolin-4(3/-/)-one.

Starting from the compound obtained in example 32, a chiral preparative HPLC [column: Chiralpak IA, temperature: ambient; flow: 10 mL/min, eluent n-Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 21.3’, tr₂: 29.2'] was carried out to give the title compounds.

Examples 77 and 78. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-((/?)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl-7-fluoroquinazolin-4(3/-/)-one and 6-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-((S)-1-((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethyl-7-fluoroquinazolin-4(3/-/)-one.

Starting from the compound obtained in example 33, a chiral preparative HPLC [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 85/15 v/v; tn: 8.0', tr₂: 10.5'] was carried out to give the title compounds.

Examples 79 and 80. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-((/?)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-propylquinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-((S)-1-((3S,5R)-3,5- dimethylpiperazin-1-yl)butyl)-3-propylquinazolin-4(3/-/)-one

Starting from the compound obtained in example 34, a chiral preparative HPLC [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 11.1', tr₂: 14.6'] was carried out to give the title compounds.

Examples 81 and 82. 7-(((1 S,4/?)-4-(Dimethylamino)-4-phenylcyclohexyl)amino)-2- ((S)-1-((3S,5R)-3,5-dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 7- (((1 S,4S)-4-(dimethylamino)-4-phenylcyclohexyl)amino)-2-((R)-1-((3S,5R)-3,5- dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one

Step a. 7-(((1 s,4S)-4-(Dimethylamino)-4-phenylcyclohexyl)amino)-2-(1 -(( 3S,5R)-3,5 - dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from 7-bromo-2-(1-((3S,5R,)-3,5-dimethylpiperazin-1-yl)butyl)-3- ethylquinazolin-4(3/-/)-one (0.25 g, 0.59 mmol) and following the procedure described in step f of example 1 , the title compound was obtained (0.25 g, Yield: 75%).

Step b. Title compounds.

Starting from the compound obtained in step a, a chiral preparative HPLC separation (column: Chiralpak IB, temperature: ambient; flow: 10 mL/min, eluent n-Heptane / (EtOH + 0.33% DEA) 80/20 v/v; tn: 1 1.9', tr₂: 14.9') was carried out to give the title compounds.

HPLC-MS (Method D) Rt, 3.21 min; ESI+-MS m/z: 559.3 (M+1 ).

Examples 83 and 84. 6-(4-(Diethylamino)-4-phenylpiperidin-1-yl)-2-((R)-1-((3S,5R)-

3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-(4-(diethylamino)- 4-phenylpiperidin-1 -yl)-2-((S)-1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3- ethylquinazolin-4(3/-/)-one

Step a. 6-(4-(Diethylamino)-4-phenylpiperidin-1 -yl)-2-(1 -(( 3S,5R)-3,5 - dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in step e of example 1 (0.2 g, 0.48 mmol) and following the procedure described in step f of example 1 , the title compound was obtained (139 mg, Yield: 51%). Step b. Title compounds.

Starting from the compound obtained in step a, a chiral preparative HPLC [column: Chiralpak IG (20mm x 250mm, 5 urn), temperature: 40 °C; flow: 50 mL/min, eluent: isocratic conditions: 50:50 EtOH:CC>2 (0.2% v/v NH₃)] was carried out to give the title compounds.

HPLC-MS (Method A) Rt, 3.04 min; ESI+-MS m/z: 573.4 (M+1 ).

Examples 85 and 86. 3-(4-(Dimethylamino)-1-(2-((R)-1-((3S,5R)-3,5- dimethylpiperazin-1-yl)butyl)-3-ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)piperidin-4- yl)phenyl isobutyrate. and 3-(4-(dimethylamino)-1-(2-((S)-1-((3S,5R)-3,5- dimethylpiperazin-1-yl)butyl)-3-ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)piperidin-4- yl)phenyl isobutyrate.

Step a. 3-(4-(dimethylamino)-1 -(2-(1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3- ethyl-4-oxo-3,4-dihydroquinazolin-6-yl)piperidin-4-yl)phenyl isobutyrate.

To a solution of the compound obtained in example 1 (0.1 g, 0.18 mmol) and DIPEA (56 mI_, 0.32 mmol) at 0 °C in anh DCM (3 ml_); isobutyric anhydride (21 mI_, 0.13 mmol) was added and the mixture was stirred 1 ,5 h at r.t. More isobutyric anhydride (6 mI_, 0.04 mmol) was added and after 3 h a further addition (3 mI_, 0.02) mmol)was effected, and the mixture was stirred at r.t. overnight. The solution was washed with water and KHCO₃ sat sol and the organic layer was dried over anh Na₂S0₄, filtered and the solvent was removed under vacuum to give the title compound (91 mg, Yiel: 81%).

Step b. Title compounds.

Starting from the compound obtained in step a, a chiral preparative HPLC separation (column: Chiralpak AD-H, temperature: room temperature; flow: 13 mL/min, eluent n- Heptane / (EtOH + 0.33% DEA) 70/30 v/v; tn: 14.4', tr₂: 23.6') was carried out to give the title compounds.

HPLC-MS (Method A) Rt, 2.51 min; ESI+-MS m/z: 631.1 (M+1 ).

Example 87. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-(1-((3S,5R)- 3,5-dimethylpiperazin-1-yl)butyl)-3-ethyl-4-oxo-3,4-dihydroquinazoline-7-carbonitrile.

To a solution of the compound obtained in example 33 (47 mg, 0.08 mmol) in DMF (2.3 ml_), NaCN (40 mg, 0.81 mmol) and TBAB (262 mg, 0.81 mmol) were added under Ar atmosphere. The mixture was heated at 100 °C for 48 h. NaCN (40 mg, 0.81 mmol) and TBAB (262 mg, 0.81 mmol) were added, and the mixture was heated at 100 °C for 72 h more. The mixture was diluted with DCM, washed with NaCI sat sol and water. The combined organic layers were dried over Na₂S0₄, filtered, concentrated to dryness and the crude product was purified by flash chromatography, silica gel, gradient DCM (100%) to MeOH (100%) to give the title compound (32 mg, Yield: 47%).

HPLC-MS (Method A) Rt, 2.05 min; ESI+-MS m/z: 586.6 (M+1 ).

Example 88. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-2-(1 -(( 3S,5R )-

3,5-dimethylpiperazin-1-yl)butyl)-3-ethyl-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid. To a solution of the compound obtained in example 87 (22 mg, 0.04 mmol) in EtOH (1 ml_), NaOH (2,5 M, 300 mI_, 0.75 mmol) and H2O2 (30%, 58 mI_, 0.56 mmol) were added and the mixture was heated at 90 °C for 16 h. The solvent was removed under vacuum and the crude product was dissolved in H2O and NH4CI sat sol to pH=7. The solvent was removed under vacuum, the crude product was dissolved in MeOH, passed through a SCX and eluted with NH3 (2 M in MeOH) to give the title compound (1.3 mg, Yield: 6%).

HPLC-MS (Method A): Rt, 1.83 min; ESI+-MS m/z: 561.4 (M+1 ).

Example 89. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-2-(1-((3S,5R)- 3,5-dimethylpiperazin-1-yl)butyl)-3-ethyl-4-oxo-3,4-dihydroquinazoline-7- carboxamide.

The title compound was obtained from the compound obtained in example 87 together with the compound of example 88 (4.1 mg, Yield: 18 %).

HPLC-MS (Method A): Rt, 1.61 min; ESI+-MS m/z: 604.4 (M+1 ).

Example 90. 6-(4-(Dimethylamino)-4-phenylpiperidin-1 -yl)-3-ethyl-2-(1 -(piperazin-1 - yl)butyl)quinazolin-4(3/-/)-one. Step a. tert-Butyl 4-(1 -(6-bromo-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)butyl)piperazine-1 -carboxylate.

Starting from the compound obtained in step d of example 1 (0.4 g, 1.03 mmol) and following the procedure described in step e of example 1 , the title compound was obtained (174 mg, Yield: 34%).

Step b. tert-Butyl 4-(1 -(6-(4-(dimethylamino)-4-phenylpiperidin-1 -yl)-3-ethyl-4-oxo-3,4- dihydroquinazolin-2-yl)butyl)piperazine-1 -carboxylate.

Starting from the compound obtained in step a (152 mg, 0.31 mmol) and following the procedure described in step f of example 1 , the title compound was obtained (190 mg, Yield: 71 %).

Step c. Title compound.

To a solution of the compound obtained in step b (135 mg, 0.22 mmol) in anh DCM (7.5 ml_), TFA (0.75 ml.) was added, and the mixture was stirred at r.t. overnight. The reaction mixture was basified with aq NaHCCh sat sol and the mixture extracted with DCM. The combined organic layers were dried over Na₂S0₄, filtered and concentrated to dryness to give the title compound (1 13 mg, Yield: 99%).

HPLC-MS (Method B): Rt, 1.98 min; ESI+-MS m/z: 517.4 (M+1 ).

This method was used for the preparation of examples 91 -101 using suitable starting materials:

Examples 102 and 103. (R)-6-(4-(Dimethylamino)-4-phenylpiperidin-1-yl)-3-ethyl-2-(1- (piperazin-1 -yl)butyl)quinazolin-4(3/-/)-one and (S)-6-(4-(dimethylamino)-4- phenylpiperidin-1 -yl)-3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)-one

Starting from the compound obtained in Example 90, a chiral preparative HPLC separation (column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane / (EtOH + 0.33% DEA) 40/60 v/v; tn: 17', tr₂: 32') was carried out to give the title compounds. Examples 104 and 105. (R)-6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-

3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)-one and (S)-6-(4-(Dimethylamino)-

4-(3-hydroxyphenyl)piperidin-1 -yl)-3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)- one

Starting from the compound obtained in Example 94, a chiral preparative HPLC separation (column: Chiralpak IA, temperature: ambient; flow: 10 mL/min, eluent n- Heptane / (EtOH + 0.33% DEA) 50/50 v/v; tn: 17', tr₂: 26') was carried out to give the title compounds.

Examples 106 and 107. (R)-7-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-

3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)-one and (S)-7-(4-(Dimethylamino)-

Starting from the compound obtained in Example 98, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 14 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 75/25 v/v; tn: 15.7', tr₂: 19.1’] was carried out to give the title compounds.

Examples 108 and 109. (S)-2-(1-(1 ,4-Diazepan-1-yl)butyl)-6-(4-(dimethylamino)-4-(3- hydroxyphenyl)piperidin-1-yl)-3-ethylquinazolin-4(3/-/)-one and (R)-2-(1-(1 ,4-diazepan- 1-yl)butyl)-6-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3-ethylquinazolin- 4(3H)-one.

Starting from the compound obtained in Example 99, a chiral preparative HPLC separation [column: Chiralpak IC, temperature: ambient; flow: 14 mL/min, eluent n- heptane/(EtOH + 0.33 DEA) 70/30 (v/v); tn:15.8’, tr₂: 19.6’)], was carried out to give the title compounds.

Examples 1 10 and 1 11. (R)-6-(4-(Dimethylamino)-4-(4-methoxyphenyl)piperidin-1-yl)-

4-(4-methoxyphenyl)piperidin-1 -yl)-3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)- one

Starting from the compound obtained in Example 100, a chiral preparative HPLC separation [column: Chiralpak IG (4.6 x 250) mm 5 mhh, temperature: ambient; flow: 1 mL/min, eluent 0.1 DEA in ACN/MeOH 35/65 (v/v); run time 50 min], was carried out to give the title compounds.

Examples 112 and 1 13. (S)-6-(4-(Dimethylamino)-4-(3-methoxyphenyl)piperidin-1-yl)- 3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)-one and (R)-6-(4-(dimethylamino)- 4-(3-methoxyphenyl)piperidin-1 -yl)-3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)- one.

Starting from the compound obtained in Example 101 , a chiral preparative HPLC separation [(column: Chiralpak IG (21 x 250) mm 5 mhh, temperature: ambient; flow: 25 mL/min, eluent 0.1 DEA in ACN/MeOH 35/65 (v/v); run time 50 min], was carried out to give the title compounds.

Examples 114, 115, 116 and 117. 7-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin- 1 -yl)-3-ethyl-2-((R)-1 -((S,)-3-methylpiperazin-1 -yl)butyl)quinazolin-4(3/-/)-one, 7-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3-ethyl-2-((S)-1-((R)-3- methylpiperazin-1 -yl)butyl)quinazolin-4(3/-/)-one, 7-(4-(dimethylamino)-4-(3- hydroxyphenyl)piperidin-1 -yl)-3-ethyl-2-((S)-1 -((S,)-3-methylpiperazin-1 - yl)butyl)quinazolin-4(3/-/)-one and 7-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin- 1 -yl)-3-ethyl-2-((R)-1 -((/?,)-3-methylpiperazin-1 -yl)butyl)quinazolin-4(3/-/)-one

Step a. tert-Butyl 4-(1-(7-bromo-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)-2- methylpiperazine-1 -carboxylate.

To a solution of 7-bromo-2-(1-bromobutyl)-3-ethylquinazolin-4(3/-/)-one, obtained with a similar procedure to that described in the preparation of step d of example 1 (0.75 g, 1.93 mmol), in NMP, tert-butyl 2-methylpiperazine-1-carboxylate (0.968 g, 4.8 mmol) was added and the mixture was heated under MW irradiation (150 W) at 120 °C for 1 h. The mixture was diluted with EtOAc and washed with water. The combined organic layers were dried over Na2S0₄, filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient Chx to Chx:EtOAc (1 :1 ) to give the title compound (329 mg, Yield: 33%). Step b. tert-Butyl 4-(1-(7-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3- ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)-2-methylpiperazine-1-carboxylate.

Starting from the compound obtained in step a (402 mg, 0.79 mmol) and following the procedure described in step f of example 1 , the title compound was obtained (306 mg, Yield: 60%).

Step c. 7-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3-ethyl-2-(1 -(3- methylpiperazin-1-yl)butyl)quinazolin-4(3/-/)-one.

Starting from the compound obtained in step b (306 mg, 0.473 mmol) and following the procedure described in step c of example 90, the title compound was obtained (245 mg, Yield: 95%).

Step d. Title compounds.

Starting from the compound obtained in step c, chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10ml_/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn: 1 1.5', tr₂: 17.9', tr₃: 28.7’] followed by Chiralpak IC temperature: ambient; flow: 10ml_/min, eluent n-Heptane / (IPA + 0.33% DEA) tn: 33.7', tr₂:47.8') was carried out to give the title compounds.

HPLC-MS (A): Rt, 1.76 min; ESI+-MS m/z: 530.4(M-1 ).

Examples 118 and 1 19. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3- ethyl-2-((S)-1-((S)-3-methylpiperazin-1-yl)butyl)quinazolin-4(3/-/)-one and 6-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3-ethyl-2-((R)-1-((S)-3- methylpiperazin-1-yl)butyl)quinazolin-4(3/-/)-one

Starting from 6-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3-ethyl-2-(1 - ((S)-3-methylpiperazin-1-yl)butyl)quinazolin-4(3/-/)-one a chiral SCF separation [column: Chiralart SA (20 x 250) mm 5 mpi, temperature: 40 °C; flow: 50 mL/min, eluent CC>2/EtOH 60/40 0.2 %(v/v) NH₃] was carried out to give the title compounds.

HPLC-MS (Method H): Rt, 2.25; ESI+-MS m/z: 547.5 (M+1 ).

Example 120. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3-ethyl-2-(1 - (piperidin-4-yl)butyl)quinazolin-4(3/-/)-one.

Step a. tert-Butyl 4-(2-((4-bromo-2-(ethylcarbamoyl)phenyl)amino)-2- oxoethyl)piperidine-1 -carboxylate.

To a solution of 2-(1 -(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (3.0 g, 12.3 mmol) in anh DMF (25 ml.) under Ar atmosphere, TEA (2.3 ml_, 16.5 mmol), HATU (3.7 g, 10 mmol) and 2-amino-5-bromo-N-ethylbenzamide (2.0 g, 8.2 mol) were added and the mixture was stirred at r.t. overnight. The reaction mixture was diluted with DCM, washed with NaHCC>3, and brine. The combined organic layers were dried over Na₂S0_4, filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient Chx (100%) to AcOEt (100%) to give the title compound (3.4 g, Yield: 88 %).

Step b. 6-Bromo-3-ethyl-2-(piperidin-4-ylmethyl)quinazolin-4(3/-/)-one.

To a solution of the compound obtained in step a (3.4 g, 7.3 mmol) and iodine (3.7 g, 14.6 mmol) in DCM (50 ml_), HMDS (6.1 ml_, 29.2 mmol) was added drop wise and the reaction mixture was stirred at r.t. overnight. The reaction mixture was diluted with DCM, washed with 5% Na2S2C>3 aq sol, water and brine. The organic layer was dried over Na₂S0₄ and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM (100%) to MeOH (100%) to give the title compound (2.2 g, Yield: 87 %). Step c. tert-Butyl 4-((6-bromo-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)piperidine-1-carboxylate.

To a solution of the compound obtained in step b (2.0 g, 5.7 mmol) under Ar atmosphere, TEA (1.6 ml_, 1 1.4 mmol) and di-tert-butyl dicarbonate (1.9 g, 8.5 mmol) were added and the reaction mixture was stirred at r.t. overnight. The reaction mixture was diluted with Na2CC>3, washed with water and brine and the organic layer was dried over Na2S0₄, filtered and the solvent was removed under vacuum to give the title compound (2.7 g, Yield: quant).

Step d. tert-Butyl 4-(1-(6-bromo-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)butyl)piperidine-1 -carboxylate.

To a solution of the compound obtained in step c (2.7 g, 6 mmol) in THF (50 ml.) under Ar atmosphere, LiHMDS (15.1 ml_, 15.1 mmol) was added and the mixture was stirred for 45 min at -78 °C. 1-lodopropane was added and the reaction mixture was stirred at the same temperature for 1 h and then was allowed to reach r.t. and stirred overnight. The reaction mixture was diluted with EtOAc and NH₄CI, and the organic layer was washed with water, Na2SC>3 and brine. The organic layer was dried over Na₂S0₄, filtered, and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient Chx (100%) to EtOAc (100%) to give the title compound (2.7 g, Yield: 90 %).

Step e. tert-Butyl 4-(1-(6-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3- ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)piperidine-1 -carboxylate.

To a solution of the compound obtained in step d (0.25 g, 0.51 mmol) and following the procedure described in step f of example 1 , the title compound was obtained (208 mg, Yield: 65 %). Step e. Title compound.

To a solution of the compound obtained in step d (208 mg, 0.33 mmol) and following the procedure described in step c of example 90, the title compound was obtained (137 mg, Yield: 78%).

HPLC-MS (Method A): Rt, 1.76 min; ESI+-MS m/z: 530.4 (M-1 ). Examples 121 and 122. (R)-6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)- 3-ethyl-2-(1 -(piperidin-4-yl)butyl)quinazolin-4(3/-/)-one and (S)-6-(4-(dimethylamino)-4- (3-hydroxyphenyl)piperidin-1-yl)-3-ethyl-2-(1-(piperidin-4-yl)butyl)quinazolin-4(3/-/)- one

Starting from the compound obtained in Example 120, a chiral preparative HPLC separation [column: Chiralpak IA, temperature: ambient; flow: 11 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 50/50 v/v; tn:17.3’ tr₂:21.0’] was carried out to give the title compounds.

Examples 123, 124, 125 and 126. 2-((SJ-1-((SJ-3,3-Difluoropiperidin-4-yl)butyl)-6-(4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3-ethylquinazolin-4(3/-/)-one, 2- ((/?)-1-((/?)-3,3-difluoropiperidin-4-yl)butyl)-6-(4-(dimethylamino)-4-(3- hydroxyphenyl)piperidin-1 -yl)-3-ethylquinazolin-4(3/-/)-one, 2-((S)-1 ~{{R)~ 3,3- difluoropiperidin-4-yl)butyl)-6-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3- ethylquinazolin-4(3/-/)-one, 2-((R)-1-((S)-3,3-difluoropiperidin-4-yl)butyl)-6-(4-

(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3-ethylquinazolin-4(3/-/)-one

Starting from 2-(1 -(3,3-difluoropiperidin-4-yl)butyl)-6-(4-(dimethylamino)-4-(3- hydroxyphenyl)piperidin-1-yl)-3-ethylquinazolin-4(3/-/)-one obtained following a similar procedure to that described in example 120, a chiral preparative HPLC separation [column: YMC Amy-C (20mm x 250 mm, 5 urn), temperature: 40 °C, flow: 50 mL/min. eluent: isocratic conditions, 45:55 EtOH:C02 (1% v/v DEA)].

HPLC-MS (Method A): Rt, 2.02 min; ESI+-MS m/z: 568.4 (M+1 ).

HPLC-MS (Method A): Rt, 1.96 min; ESI+-MS m/z: 568.4 (M+1 ).

Example 127. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3-ethyl-2-(1-(2- oxopiperazin-1-yl)butyl)quinazolin-4(3/-/)-one.

Step a. tert-Butyl 4-(1-(6-bromo-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)-3- oxopiperazine-1-carboxylate.

To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (1 16 mg, 0.58 mmol) in DMF (6 ml.) cooled at 0 °C, NaH (58 mg, 1.4 mmol, 60% dispersion in mineral oil) was added drop wise and the mixture was stirred at r.t. for 30 min. The product obtained in step d of example 1 (0.45 g, 1.12 mmol) was added and the reaction mixture was heated at 65 °C overnight. The solvent was removed under vacuum and the crude was dissolved in EtOAc and washed with NaHCOs sat sol. The organic layer was dried over Na₂S0_4, filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient Chx (100%) to AcOEt (100%) to give the title compound (144 mg, Yield:49%).

Step b. tert-Butyl 4-(1-(6-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3- ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)-3-oxopiperazine-1-carboxylate.

Starting from the product obtained in step a, and following the procedure described in step f of example 1 , the title product was obtained (109 mg, Yield: 30%).

c. Title compound.

Starting from the product obtained in step b, and following the procedure described in step c of example 90, the title product was obtained (30 mg, Yield: 33%).

HPLC-MS (A): Rt, 1.69 min; ESI+-MS m/z: 547.3 (M+1 ).

Example 128. 2-(1 -(4-(2,2-Difluoroethyl)-1 ,4-diazepan-1 -yl)butyl)-6-(4-

(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-yl)-3-ethylquinazolin-4(3/-/)-one.

To a solution of the compound obtained in example 99 (120 mg, 0.22 mmol) in EtOH (3 ml.) under argon atmosphere, TEA (92 mI_, 0.658 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (35 mI_, 0.263 mmol) were added and the reaction mixture was heated at 70 °C overnight. The solvent was removed under vacuum and the mixture was dissolved in EtOAc and washed with aq NaHCChsat sol. The organic layer was dried over Na₂S0_4, filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (9:1 ) to give the title compound (70 mg, Yield:52%).

HPLC-MS (Method A): Rt, 2.59 min; ESI+-MS m/z: 61 1.4 (M+1 ).

This method was used for the preparation of Examples 129-130 using suitable starting materials:

Examples 131 and 132. 6-(4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3- ethyl-2-((S)-1 -(4-(2-fluoroethyl)-1 ,4-diazepan-1 -yl)butyl)-4a,8a-dihydroquinazolin- 4(3H)-one and (R)-6-(4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)-3-ethyl-2- (1 -(4-(2-fluoroethyl)-1 ,4-diazepan-1 -yl)butyl)quinazolin-4(3/-/)-one. Starting from the compound obtained in Example 130, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 8 mL/min, eluent n- Heptane/(IPA + 0.33% DEA) 50/50 v/v; tn : 19.8’, tr₂: 28.6'] was carried out to give the title compounds.

Example 133. 2-(1 -((3S,5R)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-6-(4-((2- methoxyethyl)(methyl)amino)-4-phenylpiperidin-1 -yl)quinazolin-4(3/-/)-one.

Step a. (2S,6R)-tert-Butyl 4-(1 -(3-ethyl-6-(4-((2-methoxyethyl)(methyl)amino)-4- phenylpiperidin-1 -yl)-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)-2,6-dimethylpiperazine-

1 -carboxylate. A solution of the compound obtained in example 12 (252 mg, 0.4 mmol) in anh DMF (10 ml_), was cooled at 0 °C. NaH (80 mg, 2 mmol, 60% dispersion in mineral oil) was added portion wise and the mixture was stirred at r.t. for 30 min. 1 -Bromo-2- methoxyethane (1 .7 g, 12 mmol) and Kl (6.6 mg, 0.04 mmol) were added and the mixture was heated at 90 °C and stirred at this temperature overnight. The solvent was removed under vacuum, the residue was dissolved in EtOAc and the mixture was washed with aq NaHCChsat sol. The organic layer was dried over Na₂S0_4, filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM (100%) to MeOH (100%) to give the title compound (57 mg, Yield: 21%).

Step b. Title compound.

Starting from the compound obtained in step a (49 mg, 0.07 mmol) and following the procedure described in step c of example 90, the title compound was obtained (38 mg, Yield: 91 %).

HPLC-MS (Method A): Rt, 2.52 min; ESI+-MS m/z: 589.4 (M+1 ).

Example 134. 6-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)-2-(1 - ((3S,5R)-3,5-dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Step a. ((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1-ium-1- yl)methyl)trifluoroborate.

A schlenk flask charged with 3-(4-(dimethylamino)piperidin-4-yl)phenol (1.9 g, 8.7 mmol) and potassium (bromomethyl)trifluoroborate (2.08 g, 10.38 mmol), was evacuated and backfilled with argon. THF:tBuOH (2:1 , 45 ml_), degassed by means of bubbling argon to the solution for 5 min, was added and the reaction mixture was heated at 80 °C overnight. The mixture was dried under vacuum and the crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (9:1 ) to give the title compound (2.44 g, Yield: 93%).

Step b. Title compound. A sealed tube charged with the compound obtained in the step e of example 1 (0.7 g, 1 .66 mmol), the compound obtained in step a (0.9 g, 3 mmol), Pd(OAc)2 (67 mg, 0.3 mmol), XPhos (285 mg, 0.6 mmol) and CS₂CO₃ (1 .62 g, 5 mmol), was evacuated and backfilled with argon. DioxaneihhO (9:1 , 50 ml_), degassed by means of bubbling argon to the solution for 5 min, was added and the reaction mixture was stirred at 1 10 °C overnight. The solvent was removed under vacuum, the residue was dissolved in EtOAc and washed with aq NaHCCh sat sol_. The combined organic layers were dried over Na2S0₄, filtered and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (4:1 ) to give the title compound (588 mg, Yield: 61 %).

HPLC-MS (Method C): Rt, 1 .72 min; ESI+-MS m/z: 575.5 (M+1 ).

This method was used for the preparation of Examples 135-152 using suitable starting materials:

Examples 153 and 154. 6-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 - yl)methyl)-2-((/?,)-1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)- one and 6-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)-2-((S)-1 - ((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one

Starting from the compound obtained in example 134, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(IPA + 0.33% DEA) 70/30 v/v; tn :7.0’, tr₂: 1 1 .0'] was carried out to give the title compounds.

Examples 155 and 156. 7-((4-(Dimethylamino)-4-phenylpiperidin-1 -yl)methyl)-2-((S)-1 - ((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one and 7-((4- (dimethylamino)-4-phenylpiperidin-1 -yl)methyl)-2-((R)-1 -((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one Starting from the compound obtained in example 135, a chiral preparative HPLC separation [column: Chiralpak OD-H, temperature: ambient; flow: 9 mL/min, eluent n- Heptane/(IPA + 0.33% DEA) 70/30 v/v; tn : 13.1 tr₂: 18.5'] was carried out to give the title compounds.

Examples 157 and 158. 7-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 - yl)methyl)-2-((/?)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin- 4(3H)-one and 7-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)-2-((S)- 1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one

Starting from the compound obtained in example 142, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 1 1 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 70/30 v/v; tn : 1 1 .0’, tr₂: 13.1 '] was carried out to give the title compounds.

Examples 159 and 160. 6-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 - yl)methyl)-2-((/?)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin- 4(3H)-one and 6-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)-2-((S)- 1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-methylquinazolin-4(3/-/)-one

Starting from the compound obtained in example 145, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 1 1 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 85/15 v/v; tn : 11 .3’, tr₂: 19.6'] was carried out to give the title compounds.

Examples 161 and 162. 7-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 - yl)methyl)-2-((/?)-1 -((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)- one and 7-((4-(dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)-2-((S)-1 - ((3S,5R)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one

Starting from the compound obtained in Example 147, a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 1 1 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 90/10 v/v; tn:12.6’, tr₂: 15.7'] was carried out to give the title compounds.

Examples 163 and 164. (/?)-6-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 - yl)methyl)-3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)-one and (S)- 6-((4- (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)-3-ethyl-2-(1 -(piperazin-1 - yl)butyl)quinazolin-4(3/-/)-one

Starting from the compound obtained in example 149, a chiral preparative HPLC separation [column: Chiralpak IA, temperature: ambient; flow: 10 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 90/10 v/v; tn: 15.2’, tr₂: 19.7'] was carried out to give the title compounds.

Examples 165 and 166. (/?)-7-((4-(Dimethylamino)-4-(3-hydroxyphenyl)piperidin-1- yl)methyl)-3-ethyl-2-(1 -(piperazin-1 -yl)butyl)quinazolin-4(3/-/)-one and ( S)-7-{{4 - (dimethylamino)-4-(3-hydroxyphenyl)piperidin-1 -yl)methyl)-3-ethyl-2-(1 -(piperazin-1 - yl)butyl)quinazolin-4(3/-/)-one.

Starting from the compound obtained in example 151 , a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 1 1 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 80/20 v/v; tn : 15.1’, tr₂: 23.1] was carried out to give the title compounds.

Example 167. 6-(4-(Dimethylamino)-4-phenylpiperidine-1 -carbonyl)-2-(1 -(( 3S,5R)-3,5 - dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Step a. (2S,6R)-tert-Butyl 4-(1-(6-bromo-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)butyl)-2,6-dimethylpiperazine-1-carboxylate.

To a solution of the compound obtained in step e of example 1 (1.5 g, 3.6 mmol) in anh DCM (80 mL), TEA (1 mL, 7.1 mmol) and di-tert-butyl dicarbonate (1 g, 4.4 mmol) were added and the reaction mixture was stirred at r.t. overnight. NaHCC>3 sat. sol. was added and the product was extracted with DCM. The combined organic layers were joined, dried over Na₂S0₄, filtered and the solvent was removed under vacuum to give the title compound (1.8 g, Yield: 97%). Step b. (2S,6R)-tert-Butyl 4-(1 -(6-cyano-3-ethyl-4-oxo-3,4-dihydroquinazolin-2- yl)butyl)-2,6-dimethylpiperazine-1 -carboxylate.

A mixture of the compound obtained in step a (0.1 g, 0.19 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol) and Zn(CN)₂ (24 mg, 0.2 mmol) was charged under Ar atmosphere in a MW tube. DMF (4 ml_), degassed by means of bubbling argon, was added and the reaction mixture was heated under MW irradiation (150 W) at 100 °C for 45 min. The solvent was removed under vacuum and the crude product was purified by flash chromatography, silica gel, gradient Chx (100%) to EtOAc (100%) to give the title compound (0.1 g, Yield: 55%).

Step c. 2-(1 -((3S,5F?,)-4-(tert-Butoxycarbonyl)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethyl- 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid.

To a solution of the compound obtained in step b (72 mg, 0.15 mmol) in EtOH (4 ml_), 5 M NaOH (0.15 ml_, 0.77 mmol) was added at 0 °C and the mixture was stirred at 90 °C overnight. The solvent was removed under vacuum, the residue was diluted with EtOAc and washed with water. The organic layer was dried over Na₂S0₄, filtered and the solvent was removed under vacuum to give the title compound (74.2 mg, Yield: 99%).

Step d. (2S,6R)-tert-Butyl 4-(1 -(6-(4-(dimethylamino)-4-phenylpiperidine-1 -carbonyl)- 3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)-2,6-dimethylpiperazine-1 -carboxylate.

To a solution of the compound obtained in step c (73 mg, 0.15 mmol), under Ar atmosphere, in DMF (4 ml_), HATU (71 mg, 0.19 mmol), TEA (42 mI_, 0.3 mmol) and N,N-dimethyl-4-phenylpiperidin-4-amine (46 mg, 0.23 mmol) were added and the reaction mixture was stirred at r.t. overnight. The reaction crude was diluted with EtOAc:Et₂0 (1 :1 ) and washed with NaHCCh and NaCI. The combined organic layers were joined, dried over Na₂S0₄, filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM (100%) to MeOH (100%), to give the title compound (25 mg, Yield: 25%).

Step e. Title compound.

Starting from the compound obtained in step d (25 mg, 0.04 mmol) and following the procedure described in step c of example 90, the title compound was obtained (18 mg, Yield: 85 %). HPLC-MS (Method B): Rt, 1.93 min; ESI+-MS m/z: 573.7 (M+1 ).

This method was used for the preparation of Example 168 using suitable starting materials:

Example 169. 6-(((1 s,4s)-4-(Dimethylamino)-4-phenylcyclohexyl)oxy)-2-(1 -(( 3S,5R )- 3,5-dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

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

To a solution of 4-(dimethylamino)-4-phenylcyclohexanone (7.5 g, 34.5 mmol) in MeOH (80 ml_), NaBhU (3.9 g, 9,1 mol) was added portion wise and stirred at r.t. for2 h. NhUCI sat sol was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2S0₄, filtered and the solvent was removed under vacuum to give the title compound (6.5 g, Yield: 86%).

Step b. (1 s,4s)-4-(Dimethylamino)-4-phenylcyclohexyl 4-methylbenzenesulfonate. To a solution of the product obtained in step a (6.5 g, 29.7 mmol) in anh DCM (6 ml_), TEA (8.4 ml_; 60.3 mmol) was added drop wise at r.t. The reaction mixture was cooled at 0 °C and DMAP (0.2 g, 1.64 mmol) and p-toluenesulfonyl chloride (6.8 g, 35.7 mmol) were added. The reaction mixture was allowed to reach r.t. and stirred for 48 h. Aq NaHCC>3 sat. sol. was added and the mixture was extracted with DCM and washed with H2O and NaCI sat. sol. The combined organic layers were dried over Na₂S0₄, filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography, silica gel, petroleum ether: EtOAC (7:3) followed by 6% MeOH in CHCI3 to give the title compound (3.4 g, Yield: 30%).

Step c. (2S,6R)-tert-Butyl 4-(1 -(3-ethyl-6-hydroxy-4-oxo-3,4-dihydroquinazolin-2- yl)butyl)-2,6-dimethylpiperazine-1 -carboxylate.

To a Radley tube charged with the compound obtained in step a of example 167 (0.4 g, 0.77 mmol), XPhos (29.2 mg, 0.06 mmol), Pd₂(dba)₃ (14 mg, 0.015 mmol) and KOH (86 mg, 1 .5 mmol); anh dioxane (5 ml_), degassed by means of bubbling argon, was added and the reaction mixture was stirred under Ar atmosphere at 1 10 °C overnight. The solvent was removed under vacuum and the residue was dissolved with EtOAc, washed with aq NaHCC>3 sat sol and NaCI. The combined organic layers were dried over Na₂S0₄, filtered and evaporated under vacuum to give the title product (225 mg, Yield: 54%).

Step d. (2S,6R)-tert-Butyl 4-(1 -(6-(((1 s,4S)-4-(dimethylamino)-4- phenylcyclohexyl)oxy)-3-ethyl-4-oxo-3,4-dihydroquinazolin-2-yl)butyl)-2,6- dimethylpiperazine-1 -carboxylate.

To a solution of the compound obtained in step c (0.1 g, 0.22 mmol) in anh DMF (3 ml_), K₂CO₃ (150.7 mg, 1.1 mmol) and the compound obtained in step b (163 mg, 0.44 mmol) were added and the reaction mixture was stirred at 80 °C overnight. The mixture was diluted with EtOAc and H2O and the aq phase was extracted with EtOAc, washed with aq NaHCOs sat sol and NaCI. The combined organic layers were dried over Na₂S0₄, filtered and evaporated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to DCM:MeOH (90:10) to give the title compound (69 mg, Yield: 48%).

Step e. Title compound.

Starting from the compound obtained in step d (35 mg, 0.05 mmol) and following the procedure described in step c of example 90, the title compound was obtained (29.6 mg, Yield: 99 %). HPLC-MS (Method C): Rt, 2.41 min; ESI+-MS m/z: 560.4 (M+1 ).

This method was used for the preparation of Example 170 using suitable starting materials:

Example 171. 6-((1 r„4/?)-4-(Dimethylamino)-4-phenylcyclohexyl)-2-(1-((3S,5R)-3,5- dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Step a. 1 -(Dimethylamino)-1 ,2,3,6-tetrahydro-[1 , 1 '-biphenyl]-4-yl trifluoromethanesulfonate. To a solution of 4-(dimethylamino)-4-phenylcyclohexanone (400 mg, 1.8 mmol) in anh THF (30 ml_), LiHDMS 1 M (2.2 ml_, 2.2 mmol) was added drop wise at -78 °C and the mixture was stirred at this temperature for 1 h. Then, a solution of 1 ,1 ,1 -trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (921 mg, 2.6 mmol) in anh THF (30 ml.) was added drop wise, and the reaction mixture was allowed to warm at r.t. and stirred for 12 h. Aq NH₄CI sat sol was added and the mixture was extracted with Et2<D. The combined organic layers were washed with Na2CC>3 sat sol, dried over Na₂S0₄, filtered and evaporated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM (100%) to MeOH (100%) to give the title compound (411.9 mg, Yield: 64%).

Step b. 2-(1 -((3S,5R,)-3,5-Dimethylpiperazin-1 -yl)butyl)-3-ethyl-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)quinazolin-4(3/-/)-one.

To a solution of the compound obtained in step e of example 1 (0.25 g, 0.6 mmol), bispinacol (0.23 mg, 0.9 mmol), potassium acetate (0.175 mg, 1.8 mmol) and anh dioxane (25 ml_), Pd(dppf)Fe.Cl2 was added under Ar atmosphere, and the mixture was heated at 1 15 °C overnight. The solvent was removed under vacuum and the crude product was used in the next step under further purification. The title compound was obtained (277 mg, Yield: Quant).

Step c. 6-(1 -(Dimethylamino)-1 ,2,3,6-tetrahydro-[1 , 1 '-biphenyl]-4-yl)-2-(1 -(( 3S,5R)-3,5 - dimethylpiperazin-1-yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

To a solution of the compound obtained in step b (50 mg, 0.12 mmol) in DME:H₂0 (1 :1 ) under Ar atmosphere, the compound obtained in step a (27 mg, 0.08 mmol), K₂CO₃ (21 mg, 0.15 mmol) and Pd(PPh₃)₄ (9 mg, 0.008 mmol) were added and the mixture was heated at 130 °C under MW irradiation (150 W) for 20 min. The solvent was removed under vacuum and the crude product was purified by flash chromatography, silica gel, gradient DCM (100%) to MeOH (100%) to give the title compound (21 mg, Yield: 51%). Step d. Title compound.

A solution of the compound obtained in step c (89 mg, 0.17 mmol) in MeOH (3.3 ml.) was passed through an H-Cube^® continuous flow reactor (5% Pd/C, 30 mm, 30 ba R, 25 ⁰ C). The solvent was removed under vacuum to give the title compound (69 mg, Yield: 77%). HPLC-MS (A): Rt, 2.29 min; ESI+-MS m/z: 544.5 (M+1 ).

Examples 172 and 173. 6-((1 r,4R)-4-(Dimethylamino)-4-phenylcyclohexyl)-2-((R)-1- ((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one and 6-((1 r,4S)- 4-(dimethylamino)-4-phenylcyclohexyl)-2-((S)-1-((3S,5R)-3,5-dimethylpiperazin-1- yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in Example 171 , a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent n- Heptane/(EtOH + 0.33% DEA) 95/5 v/v; tn: 8.9’, tr₂: 12.1 '] was carried out to give the title compounds.

Examples 174, 175, 176 and 177. 6-((S)-1-(Dimethylamino)-1 ,2,3,6-tetrahydro-[1 ,1'- biphenyl]-4-yl)-2-((R)-1 -((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-

4(3/-/)-one, 6-((R)-1-(dimethylamino)-1 ,2,3,6-tetrahydro-[1 ,1 '-biphenyl]-4-yl)-2-((S)-1- ((3S,5R,)-3,5-dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one, 6-((R)-1 - (dimethylamino)-1 ,2,3,6-tetrahydro-[1 ,1 '-biphenyl]-4-yl)-2-((/?)-1-((3S,5R)-3,5- dimethylpiperazin-1 -yl)butyl)-3-ethylquinazolin-4(3/-/)-one, 6-((S)-1 -(dimethylamino)- 1 ,2,3,6-tetrahydro-[1 , 1 '-biphenyl]-4-yl)-2-((S)-1 -((3S,5R,)-3,5-dimethylpiperazin-1 - yl)butyl)-3-ethylquinazolin-4(3/-/)-one.

Starting from the compound obtained in step c of the example 171 , a chiral preparative HPLC separation [column: Chiralpak AD-H, temperature: ambient; flow: 13 mL/min, eluent n-Heptane/(IPA + 0.33% DEA) 95/5 v/v; tn: 16', tr₂₊3: 26', tr₄: 4.31’followed by Chiralpak AD-H temperature: ambient; flow: 13 mL/min, eluent n-Heptan /( IPA + 0.33% DEA) tr₂: 8.2', tr3: 10.2') was carried out to give the title compounds.

Table of Examples with binding to the u-opioid Receptor and the a₂d-1 Subunit of the voltage-gated calcium channel:

BIOLOGICAL ACTIVITY Pharmacological study

Human a₂d-1 subunit of Ca_v2.2 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 either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki). 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 hour and 30 mI of scintillation cocktail 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 1 nM of [³H]- DAMGO 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 either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki). Plates were incubated at 27°C for 60 minutes. After the incubation period, the reaction mix was then transferred to Multiscreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice-cold 10 mM Tris-HCL (pH 7.4). Filters were dried and counted at approximately 40% efficiency in a MicroBeta scintillation counter (Perkin-Elmer) using EcoScint liquid scintillation cocktail.

Results:

As this invention is aimed at providing a compound or a chemically related series of compounds which act as dual ligands of the 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(a,₂d-1 ) is preferably < 10000 nM, more preferably < 5000 nM, or even more preferably < 500 nM.

The following scale has been adopted for representing the binding to m-opioid receptor expressed as K,:

+ K, (m) >= 500 nM

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

+++ K_ΐ(m) < 100 nM

+ K, (m) > 500 nM or inhibition ranges between 1 % and 50 %.

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_i(a,2d-1) <500 nM

Preferably, when K,(a₂d-1 ) > 5000 nM, the following scale has been adopted for representing the binding to the a₂d-1 subunit of voltage-gated calcium channels:

+ K_ϊ(a₂d-1) > 5000 nM or inhibition ranges between 1 % and 50 % 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

CLAIMS:

1. Compound of general formula (I),

wherein

[CH₂]_PN(R_z)[CH₂]q-; R_a is selected from the group consisting of hydrogen, substituted or unsubstituted

C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R_zis selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl and -C(0)-Ci-₆ alkyl; p is 0, 1 , 2, 3, 4 or 5; q is 0, 1 , 2, 3, 4 or 5; Wi is Nitrogen or CR_wi; m is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 or 2;

R1 is selected from the group consisting of substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;

R2 is selected from the group consisting of -R21, -OR21, -NO2, halogen, -NR21R21’, - NR₂IC(0)R₂I’, -NR_2iS(0)₂R2i’, -S(0)₂NR_2iR2i’, - NR2iC(0)NR_2i’R_2i”, -SR21 , -S(0)R_2i, -S(0)2R2i, -CN, haloalkyl, haloalkoxy, -C(0)OR2i, -C(0)NR2iR2i’, -OCH2CH2OR21, - NR_2iS(0)₂NR2i’R2i” and -C(CH3)20R2i; wherein R21, R21’ and R21” are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;

R3 is selected from the group consisting of

wherein,

W₃ is nitrogen or -CH-; n is 1 or 2; v is 1 or 2;

R₅, R₅’_, R₅” and R₅’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, R₅ and R₅’ and/or R₅” and R₅’” taken together with the carbon atom to which they are attached form a carbonyl group;

R₇ and R₇’ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl;

R₄ is selected from the group consisting of hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; Re is selected from the group consisting of substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted alkylcycloalkyl;

R₁₁, R₁₁’, R₁₁” and R₁₁’” are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl and substituted or unsubstituted C_2-6 alkynyl; alternatively, Rn and Rn’ and/or Rn” and Rn’” taken together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl; optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

2. Compound according to claim 1 , wherein R₃ is selected from the group consisting of

3. Compound according to claim 1 , wherein R₃ is selected from the group consisting of

4. Compound according to claim 1 , wherein R₃ is selected from the group consisting of

preferably R3 is

5. Compound according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (G)

O').

6. Compound according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (I”)

(I").

7. Compound according to any one of claims 1 to 6, wherein Rg is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted alkylaryl; preferably substituted or unsubstituted phenyl, substituted or unsubstituted thiophenyl or substituted or unsubstituted benzyl.

8. Compound according to any one of claims 1 to 7, wherein X is selected from the group consisting of a bond, -[C(R_aRb)]_P-, -[CH2]_PC(0)[CH2]_q-, -

[CH₂]_P0[CH₂]q-, and -[CH₂]_PN(Rz)[CH₂]_q-; preferably a bond, -CH2-, -C(O)-, -O- and -NH-.

9. Compound according to any one of claims 1 to 8 wherein the compound is selected from

10. Process for the preparation of compounds of Formula (I) as defined in any one of claims 1 to 9 wherein :

a) when R₃ is linked to the alkyl chain via a nitrogen atom, said process comprises reacting a compound of formula VIII’

with a suitable nucleophilic reagent of formula IX,

R₃H

IX in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K₂CO₃ or /V,/V-diisopropylethylamine, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating;

b) wherein R3 is linked to the alkyl chain via a carbon atom, said process comprises alkylation of a compound of formula XIV’

with a compound of formula XV,

R-,LG

s 11 Ri i"Rio

XIX XX under Buchwald-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP or XPhos, using a suitable base such as sodium tert- butoxide or cesium carbonate, in a suitable solvent such as toluene or 1 ,4-dioxane, at a suitable temperature, preferably heating; or

X wherein T is halogen, with a compound of formula XXI

by coupling using a Pd catalyst such as palladium acetate, using a suitable base such as potassium carbonate, in a suitable solvent such as tert- butanol, at a suitable temperature, preferably heating and optionally under microwave irradiation; or e) when X is -C(O)- and Wi is nitrogen, said process comprises reacting a compound of Formula X

wherein T is -C(0)0H by reaction with a compound of formula XIX

in the presence of a suitable coupling agent, such as 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, in the presence of a base, such as triethylamine, in a suitable solvent, such as dimethylformamide, at a suitable temperature, preferably at room temperature; or f) when X is -O- and Wi is CRwi, said process comprises reacting a compound of Formula X,

X wherein T is -OH, with a compound of formula XXII R ' R

^Rs' ^R1 l " R-_| -_| '"R-I_Q ¹^¹⁰ "

XXIII in the presence of a Pd catalyst such as Pd(PPh₃)₄, in a suitable solvent, such as dimethoxyethane/water, at a suitable temperature, such as heating to give a derivative which is finally reduced under hydrogen in the presence of Pd in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature; or h) when m is 1 , X is a bond and Wi is CRwi, said process comprises reacting a compound of Formula X,

CCIIG in the presence of a Pd catalyst such as Pd(PPh3)₄, in a suitable solvent, such as dimethoxyethane/water, at a suitable temperature, such as heating to give a derivative which is finally reduced under hydrogen in the presence of Pd in a suitable solvent, such as methanol, at a suitable temperature, such as room temperature; and wherein R_wi, R_å, Ri, R2, R3, R₄, Re, Re’, Re, R10, R10’, R10”, R10’”, Rn, Rn’, R11”, Rii”’, X, Wi, m, r, n, v and t, if not defined otherwise, have the meanings as defined in the preceding claims, LG represents a leaving group, such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, and Z represents OH or halogen.

1 1. Use of the compounds of Formula II, III, IV, V, VI, VII, VIII, VIII’, IX, X, XI, XII, XIII, XIV, XIV’, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII or XXIII’

XXIII'

wherein R_z, R1 , R2, R3, R4, Rs, Rs’, R9, R10, R10’, R10”, R10’”, R11 , R11’, R11”, R11’”, X, Wi, m, r and t have the meanings as defined in the preceding claims, LG represents a leaving group such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate, Z represents -OH or halogen and T represents halogen, - OH, -C(0)OH ora boronic derivative, like boronic acid ora boronic ester, usually pinacolborane, for the preparation of compounds of Formula (I) as defined in any one of claims 1 to 9.

12. A pharmaceutical composition which comprises a compound of Formula (I) as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

13. A compound of Formula (I) as defined in any one of claims 1 to 9 for use as a medicament.

14. A compound of Formula (I) as defined in any one of claims 1 to 9 for use as a medicament; preferably for use as a medicament for the treatment of pain, especially medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia.