Application of ALC1 inhibitor and synergistic effect of ALC1 inhibitor and PARPi

Abstract

The present invention relates to the use of small molecule compounds that allosteric inhibit ALC1 (CHD1L) and induce the capture of PARP1, PARP2 and / or PARP3 on chromatin or at a DNA damage site for the treatment of proliferative diseases. In several proliferative diseases, especially BRCA-deficient cancers, disruption of the chromatin remodeling force of ALC1 by these agents achieves highly selective therapies for the DNA damage function of the targeted PARP enzyme. Via inhibition of enzymatic activity, the compounds participate in synthetic lethal between mutations in the HRD pathway, including between BRCA1 / 2 and ALC1. By capturing PARP enzyme, the inhibitor of ALC1 enhances the cancer cell killing characteristic of the PARP inhibitor, a treatment method under the condition that ALC1 is used for oncogene amplification is realized, and overcoming of the drug resistance mechanism of the PARP inhibitor becomes possible in treatment; and enables an alternative approach to the treatment of germline or acquired BRCA1 / BRCA2 defects, including tumors defined by "BRCANs" or other changes in the DNA repair network.

Description

[0001] The present invention relates to small molecule compounds that allosterically inhibit ALC1 (CHD1L) and synergistically inhibit the PARP family of enzymes. These inhibitors have antiproliferative activity in cancers that have acquired BRCA1 or BRCA2 defects. In several proliferative diseases, especially BRCA-deficient cancers, highly selective therapies for targeting the DNA damage function of PARP enzymes are achieved by disrupting the chromatin remodeling power of ALC1 by these agents. Through the inhibition of enzyme activity, the compounds participate in the synthetic lethality between BRCA1 / 2 and ALC1. Through synergistic effects with PARP enzyme inhibitors, ALC1 inhibitors enhance the cancer cell killing properties of these PARP inhibitors, achieving a therapeutic method in the case of ALC1 as an oncogene amplification. In addition, these ALC1 inhibitors make it possible to overcome PARP inhibitor resistance mechanisms and achieve alternative methods for treating germline or acquired BRCA1 / BRCA2 deficiencies (including tumors defined by "BRCAness" or other changes in the DNA repair network). Background Art

[0002] Nuclear poly (ADP-ribose) polymerases (PARPs) are key early players in the DNA damage response (DDR) in order to recognize single-strand breaks and double-strand breaks (SSBs / DSBs). + , PARP-1 and PARP-2 add poly ADP-ribose (PAR) chains to chromatin components and factors belonging to the DDR, and PARP-3 targets chromatin components via mono ADP ribosylation. PARPs are recruited to DNA lesions by recognizing DNA damage-induced structures that undergo specific alterations, which activates their PARylation activity, which in turn regulates their activity and that of other DDR and chromatin proteins, thereby promoting the DDR (Ray Chaudhuri and Nussenzweig, 2017).

[0003] This catalytic activity can be catalyzed by NAD +Analogs inhibit, and have become particularly interesting and clinically useful in genetically determined cancers. Notably, so-called PARP inhibitors (PARPi) are used to treat homologous recombination (HR)-deficient cancers and other cancers by targeting synthetic lethality in the case of BRCA1 or BRCA2 defects. This is thought to occur by reducing PARP activity and / or by biochemically "trapping" PARP-1 / 2 / 3 on chromatin (Murai et al., 2012, 2014). Although "trapping" remains poorly defined molecularly, the term defines an enhanced recruitment, association and / or retention of PARP-1 / 2 / 3 enzymes on damaged chromatin, typically induced by treatment of PARP-1 enzymes with PARP inhibitors (PARPi) or a reduction in the release of PARP-1 / 2 / 3 enzymes after their initial recruitment (which results in prolonged retention). This manifests itself biochemically as an enhanced steady-state association / retention / binding ("trapping") of PARP enzymes to damaged genomic regions / locuses.

[0004] Since the clinical emergence of PARPi, PARP-1 has become a powerful target for an increasing number of cancers, including in combination with immuno-oncology therapies (such as the Lynparza / Keytruda trial), to name one of many examples. In addition, first-line PARPi therapy and in settings beyond germline BRCA-1 / 2 mutations are becoming possible.

[0005] Importantly, clinical PARPi compounds all work by blocking the substrate NAD + The binding of nicotinamide (NAD + part of a nucleotide) has a similar structure.

[0006] However, PARPi have shown very different clinical efficacy in terms of tumor killing and patient outcomes in the clinic. A fundamental difference in the actions of these PARPi is that they promote highly different levels of PARP-1 / -2 capture on chromatin. It is currently generally believed that the most powerful and clinically effective PARPi captures PARP-1 more strongly at sites of DNA breaks than clinically less useful PARPi. After PARP capture, DNA damage becomes more cytotoxic, especially in mutant tumor cells with genetic or epigenetic defects in DNA strand break repair (such as functional HR-deficient BRCA-1 / 2 mutant tumor cells). In addition, it is not clear what the relative or dominant contribution of the PARP-1 enzyme compared to the PARP-2 enzyme compared to the PARP-3 enzyme is, because all enzymes are involved in sensing DNA strand breaks and recruiting to sites of DNA damage, and both PARP-1 and PARP-2 promote PARylation of chromatin factors, and all existing clinical PARPi molecules are almost unable to distinguish between these two related PAR polymerases, PARP-1 and PARP-2. In turn, PARP capture is thought to lead to DNA replication stress, genomic instability, and cell death in cancer cells (Lord and Ashworth, 2012). For example, enhanced capture of PARP1 is thought to lead to an increased ability to kill cancer cells, especially cancers with defective DNA repair pathways (Zandarashvili et al., 2020). Figure 1 The cytotoxic mechanism of PARP trapping via PARPi is shown.

[0007] Thus, "PARP trapping" is described as the (enhanced) association of PARP-1 and / or PARP-2 and / or PARP-3 with chromatin in living cells. Using PARPi, the allosteric mechanisms that contribute to PARP-1 binding to DNA can be disrupted (Zandarashvili et al., 2020), where some PARPi contribute to retention mechanisms and others promote release mechanisms based on in vitro PARP-1, PARPi and DNA interactions (Zandarashvili et al., 2020). U2OS cells treated with talazoparib showed enhanced retention of GFP-tagged PARP1 and PARP2 at induced DNA lesions, while cells treated with veliparib showed overall less recruitment of PARP1 / PARP2 to DNA lesions.

[0008] PARP-1 or PARP-2 is necessary for sufficient recruitment of SSB repair proteins to the damage site. Through PARylation, chromatin remodeling enzymes or histone modifying enzymes are activated at DNA damage sites, which leads to changes in chromatin compaction (Luijsterburg et al., 2016; Mehrotra et al., 2011; Sellou et al., 2016; Smeenk et al., 2013; Timinszky et al., 2009).

[0009] Activation of the PARP-1 and / or PARP-2 enzymes results in the recruitment of many proteins, especially specific chromatin remodeling enzymes, including in particular the macrodomain-containing nucleosome remodeler ALC1 (CHD1L) (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017). Macrodomains typically bind ADP-ribose, oligo-ADP-ribose, and poly-ADP-ribose (Karras et al., 2005), so macrodomain-containing proteins respond and recruit to PARP activation sites on the genome, including during DNA damage and in association with cancer. Importantly, binding of PAR or oligo ADP-ribose to the macrodomain of ALC1 robustly turns on chromatin remodeling activity (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017), revealing ALC1 as an allosterically regulated chromatin remodeling enzyme, the first of its kind and one of very few enzymes whose catalytic activity is directly regulated by PAR. In addition, ALC1 is a validated oncogene and is often genetically amplified along with PARP1 in BRCA1 / 2-deficient ovarian and breast cancer samples (see Figure 2). ALC1 inhibitors (such as small molecules that inhibit the ATPase function and or nucleosome remodeling function of ALC1) can enhance the effects of PARPi, resulting in enhanced cancer cell killing and / or reduced off-target effects, thereby reducing cytotoxicity to non-cancerous cells. The fact that altering the expression level of ALC1 (via CRISPR-based knockout) affects the sensitivity of cancer cells to PARP inhibitors also provides an opportunity that altering the activity level of ALC1 can overcome PARP inhibitor resistance, because removing ALC1 robustly enhances the PARPi olaparib to levels that may be sufficient to circumvent PARPi resistance, such as (but not limited to) reversal of the BRCA-deficient state (e.g., by internal deletion or by loss of epigenetic BRCA1 / 2 gene silencing). Since the sensitivity of cancer cells to PARP inhibitors is generally believed to (also) stem from the ability of PARPi to trap PARP1 on chromatin (and possibly also the PARP2 enzyme - this has not been formally established in the art), we hypothesized that small molecule ALC1 inhibitors may mediate PARPi sensitization. In particular, we hypothesized that inhibition of ALC1 with small molecules would promote DNA damage accumulation and cancer cell killing.

[0010] Since ALC1 is upregulated in several tumors and is a validated oncogene in hepatocellular carcinoma (Cheng et al., 2013; Li et al., 2019; Su et al., 2014), inhibition of ALC1 via small molecule inhibitors could drive robust changes in the DNA damage response.

[0011] The inventors hypothesized that manipulation of ALC1 activity via small molecules could induce a strong antiproliferative effect and furthermore be sufficient to bypass low-level or high-level PARPi resistance. Therefore, in addition to potential use as monotherapy, combined inhibition of ALC1 and PARP-1 / 2 could be used to improve PARP-targeted therapies in oncology.

[0012] This hypothesis led to part of the present invention, namely that manipulation of ALC1 via small molecule inhibitors would affect the response to DNA damage. These compounds, designed to inhibit the enzymatic activity of the ATP-dependent chromatin remodeler ALC1 (CHD1L), would enhance the accumulation of DNA damage and thus mediate synthetic lethality following BRCA deficiency or more generally in HRD-high tumors, as PARP inhibition has been well demonstrated to be associated with synthetic lethality with loss of function of the BRCA-1 / 2 tumor suppressors. Based on preclinical and clinical evidence, ALC1 inhibition could therefore serve as an additional therapeutic approach for cancers with an intact HR pathway and / or allow targeting of ALC1-amplified tumors by disrupting the oncogenic function of ALC1. Furthermore, since the ALC1 gene is a key mediator of PARP-chromatin rearrangements at sites of induced DNA damage (Sellou et al., 2016), small molecules targeting ALC1 activity may affect the nuclear DNA damage-related functions of PARP-1 / 2 / 3 on chromatin rearrangements without affecting other roles of PARP-1 / 2 / 3 in or outside the nucleus or without affecting non-DNA damage-induced PARP enzymes, which may result in “second-generation PARPi” with reduced off-target effects and / or reduced side effects.

[0013] In view of the above-mentioned relevance of ALC1 to various proliferative diseases, especially those with BRCA1 / 2 deficiency, the present invention provides a new class of compounds for treating or ameliorating tumor diseases, and especially tumor diseases characterized by increased ALC1 activity (eg, due to increased expression).

[0014] Furthermore, the inventors have determined that the effect of PARPi can be unexpectedly enhanced by using a combination of PARPi and an ALC1 inhibitor, preferably an allosteric ALC1 inhibitor of the present invention. Thus, the present invention provides, inter alia, (i) effective treatment of HRD-deficient and therefore PARPi-sensitive tumors, (ii) mediating PARPi sensitization, (iii) bypassing PARPi resistance, (iv) and / or allowing a reduction in the amount of PARPi administered. Summary of the invention

[0015] In a first aspect, the present invention is directed to an inhibitor of ALC1 (ALC1i) according to formula (I)

[0016]

[0017] in

[0018] A5 and A8 are each independently selected from N or CH;

[0019] A6 is selected from N or CH, or when A6 participates in a cyclic carbocyclic or heterocyclic ring Z, A6 is C;

[0020] A7 is selected from N or CH, or when A7 participates in a cyclic carbocyclic or heterocyclic ring Z, A7 is C;

[0021] L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4;

[0022] L3 is selected from CH2-R5, -CF2-R5, -CH2-CH2-R5, -CH2-CF2-R5, -CH2-CH2-CH2-R5, -O-R5, -NH-R5, -N=R5;

[0023] or

[0024] L2 and L3 together with A8 to which they are attached form a 5-membered or 6-membered heterocyclic ring substituted by R4 and / or R5;

[0025] L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N and NH, or is absent;

[0026] Z is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0027] and can be linked to the central core in a ring shape or by covalent bonds

[0028] R4 is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe, or R4 is hydrogen, methyl or COOH;

[0029] R5 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0030] R6 is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe;

[0031] or R6 is H;

[0032] or

[0033] When A7 participates in a cyclic carbocyclic or heterocyclic ring Z, then A5 and A6 are independently selected from -N or -CH, and A8 is selected from -N, -CH, -CH2-N, -CH2-CH or -NH-CH;

[0034] or a pharmaceutically acceptable salt thereof,

[0035] Used to treat or improve proliferative diseases in patients.

[0036] In a second aspect, the present invention relates to a bifunctional compound, comprising the ALC1i for the use according to the first aspect of the present invention and a compound that recruits E3 ubiquitin ligase to ALC1 (E3 recruiter), wherein the ALC1i and the E3 recruiter are optionally covalently linked via a linker.

[0037] In a third aspect, the present invention relates to a pharmaceutical composition comprising the ALC1i for use according to the first aspect of the present invention or the bifunctional compound according to the second aspect of the present invention and one or more pharmaceutically acceptable excipients.

[0038] In a fourth aspect, the present invention relates to the ALC1i of the first aspect of the present invention or the bifunctional compound of the second aspect of the present invention for use in treating or improving a proliferative disease, wherein the treating and improving the proliferative disease comprises administering the ALC1i or the bifunctional compound and administering a poly (ADP-ribose) -polymerase inhibitor (PARPi).

[0039] In the fifth aspect, the present invention relates to a PARPi for use in treating or improving a proliferative disease in a patient, wherein the treating and improving the proliferative disease comprises administering the PARPi and administering the ALC1i for the use according to the first aspect of the present invention or the bifunctional compound according to the second aspect of the present invention.

[0040] In a sixth aspect, the present invention relates to a kit of parts, comprising separately packaged PARPi and ALC1i of the first aspect of the present invention for said use or the bifunctional compound of the second aspect of the present invention or a composition containing PARPi and ALC1i, preferably with instructions for use in treating or ameliorating a proliferative disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In the following, the contents of the drawings included in this specification are described. In this context, please also refer to the above and / or below detailed description.

[0042] Figure 1: Cytotoxic mechanism of PARPi on DNA repair pathways leading to PARP capture. The upper pathway shows interference with single-strand break (SSB) repair of DNA via DNA replication fork damage, leading to repair via homologous recombination (HR) mechanism. The lower pathway shows that PARP1 / 2 proteins are trapped on damaged DNA, leading to replication fork damage, thereby utilizing alternative repair pathways (including Fanconi pathway (FA), template switching (TS), ATM, FEN1 (replication flap endonuclease) and DNA polymerase β) (Murai et al., 2012, S.5591).

[0043] Figure 2 : The chromatin remodeling factor ALC1 (CHD1L) is often co-amplified with the PARP1 gene in human ovarian and breast cancer samples. Genomic alterations of ALC1 (CHD1L), PARP1, PARP2, BRCA1, BRCA2, and the most closely related chromatin remodeling factor CHD1 in the genomes of 10,792 patients with breast cancer, fallopian tube cancer, and ovarian cancer (OncoPrint analysis performed on cBioPortal on December 8, 2020 - www.cbioportal.org). The percentage numbers indicate the percentage of changes in a specific gene across all genomes when a specific gene has been analyzed. Gene amplification (black) and deep gene deletion (dark gray) are highlighted. Compared with CHD1, ALC1 is often amplified with PARP1 (ALC1-PARP1: odds ratio (OR) = 1.581, q value = <0.001; CHD1-PARP1: OR = -0.125, q value = 0.250). While tumors exhibited deep deletions or mutations in the BRCA1 or BRCA2 tumor suppressor genes, neither ALC1 nor PARP1 exhibited deep deletions or frequent mutations (ALC1-BRCA1 / 2: OR = <-3 / -2.178, q value = <0.001; PARP1-BRCA1 / 2: OR = <-3, q value = <0.001).

[0044] Figure 3: 96-hour SRB assay of BRCA-positive and BRCA-negative cells treated with ALCi. MDA-MB-231 cells (BRCA1 / 2 wild type) and SUM-149-PT cells (BRCA1 negative) were seeded into 96-well plates and treated with different ALCi titrations starting from 50 μM. Cells were cultured for 4 days at 37°C, CO2 5%, fixed with 10% TCA, and stained with sulforhodamine staining to analyze cell survival. Data were normalized to DMSO control (indicating 100% survival). GraphPad Prism was used to fit inhibitor-response curves (four parameters) with variable slopes. Standard deviation bars for two technical replicates are shown.

[0045] Figure 4 : PARPi co-treatment cell proliferation assay of pancreatic cancer cells. PSN-1 cells were seeded into 96-well plates and treated with 2-D titrations of PARPi and ALC1i. Cells were cultured for 4 days at 37°C, CO2 5%, fixed with 10% TCA, and stained with sulforhodamine staining to analyze cell survival. Single-agent titration curves are shown on the left, the dose-response matrix is ​​shown in the middle, and the synergy score calculation is shown on the right. The highest synergy area scores shown by treatment with ALC1i-1002 and talazoparib, olaparib, or niraparib were 14.28, 13.27, and 15.41, respectively. ZIP synergy scores exceeding 0.0 are indicative of strong synergy.

[0046] Figure 5 : Structures and related compound codes of ALC1 inhibitors.

[0047] Figure 6 : Nucleosome remodeling inhibition. IC of ALC1 inhibitors in a FRET-based nucleosome remodeling assay 50 (μM). IC 50 Values ​​are presented using the following symbols: +++: IC 50 <25μM; ++: IC 50 =25-100μM; +:IC 50 =>100-250 μM; and "-": compound inactive, ie inhibition >50% was never observed.

[0048] Figure 7 : Cell proliferation inhibition. EC50 (μM) of ALC1 inhibitors in a 4-day cell proliferation assay with SRB-based readout. EC 50 Values ​​are presented using the following symbols: +++: EC 50 <10μM; ++: EC 50 =10-25μM; +:EC 50=>25-50 μM; and "-": compound inactive, ie inhibition >50% was never observed.

[0049] Figure 8 : Table containing the supplier of each inhibitor used.

[0050] Fig. 9 : General synthetic scheme for inhibitors according to formula I.

[0051] Fig.10 : General synthetic scheme for inhibitors according to formula I.

[0052] Fig.11 : Table containing the percent inhibition of ALC1 by each inhibitor in a FRET-based nucleosome sliding assay at a compound concentration of 250 μM. For some compounds, the concentration of 250 μM had to be lowered due to solubility issues, as indicated in the legend at the bottom of the table.

[0053] Fig.12 : EC50 values ​​of 96-hour SRB assays and 11-day colony formation assays of HR normal (HRP) and HR defective (HRD) cells treated with ALCi. Different cancer cell lines (downloaded from https: / / depmap.org / portal / ) with different deleterious mutations in the homologous recombination repair pathway (HR) were seeded into 96-well plates and treated with different ALCi titrations starting from 50 μM. Cells were cultured at 37 ° C, CO25% for 4 days (96h) or 11 days (colony formation), fixed with 10% TCA, and stained with sulforhodamine staining to analyze cell survival. The data were normalized to DMSO controls (indicating 100% survival). GraphPad Prism was used to fit inhibitor-response curves (four parameters) with variable slopes. The standard deviation bars of two technical replicates are shown.

[0054] Fig.13 : List of genes involved in the DNA damage response (DDR) (Human DNA Repair Genes, n.d.) cited in Wood RD, Mitchell M and Lindahl T Mutation Research, 2005, Science, 2001, the reference book DNA Repair and Mutagenesis, 2nd edition, 2006, and Nature Reviews Cancer, 2011 (revised by R. Wood and M. Lowery on Wednesday, June 10, 2020). Fig.14: List of genes involved in the homologous recombination repair pathway (HR). Genes from Toh and Ngeow, 2021, Kim et al., 2021, Yamamoto and Hirasawa, 2021 and summary of HRD signature genes from Pent et al., 2021. DETAILED DESCRIPTION

[0055] Before describing the present invention in detail below, it should be understood that the present invention is not limited to the specific methods, protocols and reagents described herein, as these may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which will only be limited by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art.

[0056] Several documents are cited throughout the text of this specification. Each document cited herein, whether above or below (including all patents, patent applications, scientific publications, manufacturer specifications, instructions, etc.) is hereby incorporated by reference in its entirety. Nothing herein should be construed as admitting that the present invention is not entitled to such disclosures due to prior invention. Some of the documents cited herein are characterized as "incorporated by reference". In the event of a conflict between the definition or teaching of such incorporated references and the definition or teaching described in this specification, the text of this specification takes precedence.

[0057] Hereinafter, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they can be combined in any manner and in any number to produce other embodiments. The embodiments and preferred embodiments described in difference should not be interpreted as limiting the present invention to only the embodiments clearly described. This specification should be understood to support and encompass the embodiments of the embodiments of the combination clearly described with any number of disclosed and / or preferred elements. In addition, unless the context indicates otherwise, it should be considered that the specification of the present application discloses any arrangement and combination of the elements described in the present application.

[0058] definition

[0059] To practice the present invention, conventional methods of chemistry, biochemistry and recombinant DNA techniques explained in the literature in the field are employed unless otherwise indicated (see, e.g., Molecular Cloning: A Laboratory Manual, 2nd edition, J. Sambrook et al., eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0060] In the following, some definitions of terms frequently used in this specification are provided. These terms will have the respectively defined meanings and preferred meanings in the rest of this specification in each case where they are used.

[0061] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0062] The term "Chromodomain-helicase-DNA-binding protein 1-like protein" (abbreviated CHD1L) refers to a protein also known as ALC1. The amino acid sequence of human ALC1 is shown in SEQ ID NO: 1. The 897 amino acid residue long protein consists of an N-terminal Snf2-like DNA-dependent ATPase domain spanning amino acid residues 40 to 513, which contains a conserved helicase motif that is critical for catalysis (Flaus et al., 2006). This domain consists of two RecA-like lobes (ranging from amino acid residues 48 to 261 and 351 to 513, respectively). The structure of the truncated N-terminal lobe of the ATPase domain has been determined by homology modeling in order to identify the putative allosteric binding site, and a minimal coordinate file of this model is provided in Figure 20 to allow the skilled artisan to identify model compounds within the allosteric binding pocket first defined by the inventors. The allosteric binding pocket is spatially separated from the part of ALC1 involved in binding ATP. The ATPase domain is followed by a linker region ranging from amino acid residues 514 to 703, which contains a putative coiled-coil region (amino acid residues 638 to 675) and a C-terminal macrodomain (amino acid residues 704 to 897). The macrodomain has been shown to interact directly with the ATPase domain, thereby inhibiting its catalytic function (Lehmann et al., 2017; Singh et al., 2017). This interaction is released upon binding of poly(ADP-ribose) to the macrodomain, leading to the activation of chromatin remodeling enzymes.

[0063] The term "alkyl" as used in the context of the present invention refers to a saturated straight or branched carbon chain. Preferably, the chain contains 1 to 10 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms, such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, octyl, nonyl, decyl. Alkyl is optionally substituted.

[0064] The term "heteroalkyl" as used in the context of the present invention refers to a saturated straight or branched carbon chain. Preferably, the chain contains 1 to 9 (i.e., 1, 2, 3, 4, 5, 6, 7, 8 or 9) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, which is interrupted one or more times, such as 1, 2, 3, 4, 5 times, by the same or different heteroatoms. Preferably, the heteroatoms are selected from O, S and N, such as -(CH2) n -X-(CH2) m CH3, wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, m=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, and X=S, O or NR', wherein R'=H or hydrocarbon (e.g., C1 to C6 alkyl). In particular, "heteroalkyl" refers to -O-CH3, -OC2H5, -CH2-O-CH3, -CH2-O-C2H5, -CH2-O-C3H7, -CH2-O-C4H9, -CH2-O-C5H 11 , -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-O-C3H7, -C2H4-O-C4H9, etc. Heteroalkyl is optionally substituted.

[0065] The term "haloalkyl" refers to a saturated straight or branched carbon chain in which one or more hydrogen atoms are replaced by a halogen atom, such as fluorine, chlorine, bromine or iodine. Preferably, the chain contains 1 to 10 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms. In particular, "haloalkyl" refers to -CH2F, -CHF2, -CF3, -C2H4F, -C2H3F2, -C2H2F3, -C2HF4, -C2F5, -C3H6F, -C3H5F2, -C3H4F3, -C3H3F4, -C3H2F5, -C3HF6, -C3F7, -CH2Cl, -CHCl2, -CCl3, -C2H4Cl, -C2H3Cl2, -C2H2Cl3, -C2HCl4, -C2Cl5, -C3H6Cl, -C3H5Cl2, -C3H4Cl3, -C3H3Cl4, -C3H2Cl5, -C3HCl6, and -C3Cl7. Haloalkyl is optionally substituted.

[0066] The term "carbocycle" is used in the context of the present invention to refer to monocyclic, bicyclic or tricyclic "cycloalkyl", "cycloalkenyl", "spiroalkyl", "spiroalkenyl" or "aryl", wherein the ring is formed by carbon atoms. Carbocyclic groups are optionally substituted.

[0067] The term "5-membered, 6-membered or 7-membered carbocycle" is used in the context of the present invention to refer to "cycloalkyl", "cycloalkenyl", "spiroalkyl" or "aryl", preferably "cycloalkyl" or "cycloalkenyl", wherein 5, 6 or 7 carbon atoms form a ring or a phenyl group.

[0068] The term "cycloalkyl" includes cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl is optionally substituted.

[0069] The term "cycloalkenyl" includes cyclopentenyl, cyclohexenyl and cycloheptenyl. Cycloalkenyl is optionally substituted.

[0070] The term "aryl" refers to phenyl. Aryl is optionally substituted, for example naphthyl.

[0071] The term "heterocycle" is used in the context of the present invention to refer to a monocyclic or bicyclic "heterocycloalkyl" or a monocyclic or bicyclic "heteroaryl"; wherein for a monocyclic heterocycle, at least one carbon atom is replaced by 1, 2 or 3 identical or different heteroatoms, or for a bicyclic heterocycle, at least one carbon atom is replaced by 1, 2, 3 or 4 identical or different heteroatoms, said heteroatoms being preferably selected from O, N and S.

[0072] The term "5-, 6- or 7-membered heterocycle" is used in the context of the present invention to refer to such monocyclic "5-, 6- or 7-membered heterocycloalkyl" or monocyclic "5-, 6- or 7-membered heteroaryl" wherein 5, 6 or 7 atoms form the ring.

[0073] The term "5-, 6- or 7-membered heterocycloalkyl" refers to a saturated monocyclic ring in which at least one carbon atom is replaced by 1 or 2 (for a five-membered ring) or 1, 2 or 3 (for a six-membered ring) or 1, 2, 3 or 4 (for a seven-membered ring) identical or different heteroatoms (preferably selected from O, N and S). Preferred examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl or 2-piperazinyl. Heterocycloalkyl is optionally substituted.

[0074] The term "heteroaryl" as used in the context of the present invention refers to a 5-, 6- or 7-membered aromatic monocyclic ring in which at least one carbon atom is replaced by 1, 2 or 3 (for a five-membered ring) or 1, 2, 3 or 4 (for a six-membered ring) identical or different heteroatoms, preferably selected from O, N and S. Examples of preferred heteroaryl groups are furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl. Heteroaryl groups are optionally substituted.

[0075] If two or more radicals can be selected independently of one another, the term "independently" means that the radicals can be identical or different.

[0076] The term "optionally substituted" refers, in each case if not further specified, to halogen (especially F, Cl, Br or I), -NO2, -CN, -OR"', -NR'R", -COOR"', -CONR'R", -NR'COR", -NR"COR"', -NR'CONR'R", -NR'SO2E, -COR"', -SO2NR'R", -OOCR"', -CR"'R""OH, -R"'OH and -E;

[0077] R' and R" are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and heteroaryl, or together form heteroaryl or heterocycloalkyl;

[0078] R'" and R"" are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R";

[0079] E is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, aliphatic ring systems, aryl, and heteroaryl; optionally substituted.

[0080] "Pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the U.S. Pharmacopeia (U.S. Pharmacopeia-33 / National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville, Maryland, Publication Date: April 2010) or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0081] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts, which can be formed, for example, by mixing a solution of a compound described herein or a derivative thereof with a solution of a pharmaceutically acceptable acid (such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid). In addition, in the case where the compound of the present invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counter anions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates).Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edisylate, etopoate, ethanesulfonate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2- hydroxyethanesulfonate, hydroxynaphthoate, iodide, isothiosulfate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methanesulfonate, methylsulfate, mucate, naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embolate) Bonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, undecanoate, valerate, etc. (see, e.g., Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into either base addition salts or acid addition salts.

[0082] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0083] In addition to salt forms, the present invention also provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide compounds of formula (I) to (IV), especially Fig.14 Those compounds of the compound shown. Prodrugs are active or inactive compounds, which are chemically modified to compounds of the present invention by physiological effects (such as hydrolysis, metabolism, etc.) in vivo after being applied to patients. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme, prodrugs can be slowly converted into compounds of the present invention. The suitability and technology involved in preparing and using prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson LA and Tunek A. (1988) Drug Metabolism Reviews 19 (2): 165-194 and Bundgaard H. " Design of Prodrugs ", Elsevier Science Ltd. (1985). Examples of masked carboxylate anions include various esters, such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g., pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl-substituted derivatives, which are cleaved by esterases in vivo, releasing free drug and formaldehyde (Bundgaard H. et al. (1989) J. Med. Chem. 32 (12): 2503-2507). In addition, drugs containing acidic NH groups (such as imidazoles, imides, indoles, etc.) have been masked with N-acyloxymethyl (Bundgaard H. "Design of Prodrugs", Elsevier Science Ltd. (1985)). Hydroxyl groups have been masked as esters and ethers. EP 0 039 051 A2 discloses Mannich base hydroxamic acid prodrugs, their preparation and use.

[0084] The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling the Compounds. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0085] As used herein, "para" when referring to a substituent on an aryl group means that the substituent occupies a position opposite to the position where the aryl group is attached to the backbone of the compound.

[0086] As used herein, "patient" means any mammal or bird that can benefit from treatment with the compounds described herein. Preferably, the "patient" is selected from experimental animals, livestock or primates (including chimpanzees and humans). It is particularly preferred that the "patient" is a human.

[0087] As used herein, "treat," "treating," or "treatment" of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing the development of symptoms characteristic of the disorder or disorders being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder or disorders being treated; (d) limiting or preventing the recurrence of the disorder or disorders in a patient who previously had the disorder or disorders; and (e) limiting or preventing the recurrence of symptoms in a patient who previously had symptoms of the disorder or disorders.

[0088] As used herein, "prevent", "preventing", "prevention" or "prophylaxis" of a disease or disorder means preventing the disorder from occurring in a subject over a certain amount of time. For example, if a compound described herein is administered to a subject for the purpose of preventing a disease or disorder, the disease or disorder is prevented from occurring at least on the day of administration and preferably also on one or more days (e.g., 1 to 30 days; or 2 to 28 days; or 3 to 21 days; or 4 to 14 days; or 5 to 10 days) after the day of administration.

[0089] The "pharmaceutical composition" according to the present invention may be in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other; or may be in the form of a combined preparation in which the active ingredients are present in part or in a completely different form. An example of such a combination or combined preparation is a multi-component kit.

[0090] An "effective amount" is an amount of a therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal receiving the therapeutic agent, and the purpose of the administration. The effective amount in each individual case can be determined empirically by the skilled artisan according to methods established in the art.

[0091] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient or vehicle used together with a therapeutic agent. Such pharmaceutical carriers can be sterile liquids, such as saline solutions and oils in water, and the oils include oils from petroleum, animal, plant or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, saline solutions are preferred carriers. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talcum powder, sodium chloride, skim milk, glycerol, propylene glycol, water, ethanol, etc. If desired, the composition can also contain a small amount of wetting agent or emulsifier or pH buffer. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. The composition can be formulated as a suppository with conventional binders and carriers such as triglycerides. The compounds of the present invention can be formulated in neutral form or salt form. Pharmaceutically acceptable salts include salts formed with free amino groups, such as salts derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc.; and salts formed with free carboxyl groups, such as salts derived from sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EWMartin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with an appropriate amount of carrier, so as to provide a form for appropriate administration to the patient. The formulation should conform to the mode of administration.

[0092] Embodiments of the present invention

[0093] The inventors have identified and characterized ALC1 inhibitors that show allosteric regulation of ALC1 nucleosome sliding activity. These compounds specifically bind to the allosteric pocket and are able to inhibit the activity of ALC1. Compounds that bind to the ATPase site of ALC1 and block ATPase activity must compete with ATP for binding to the ATPase site. Since cellular ATP concentrations range from 1 to 10 mM (depending on the cell compartment), very high binding affinities in the low nanomolar range are required to successfully prevent ATP from binding to the ATPase site of ALC1. Allosteric inhibitors of ALC1 do not have this limitation because they do not necessarily prevent ATP binding, but rather inhibit the ATPase activity of ALC1 through a different mechanism. The inventors have identified compounds that are able to specifically bind to the allosteric pocket of ALC1. The compounds were also tested for their ability to kill two different tumor cell lines, one of which is BRCA-deficient.

[0094] Therefore, in a first aspect, the present invention relates to the use of ALC1i of formula (I):

[0095]

[0096] in

[0097] A5 and A8 are each independently selected from N or CH;

[0098] A6 is selected from N or CH, or when A6 participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring, then A6 is C;

[0099] A7 is selected from N or CH, or when A7 participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring, then A7 is C;

[0100] L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4;

[0101] L3 is selected from CH2-R5, -CF2-R5, -CH2-CH2-R5, -CH2-CF2-R5, -CH2-CH2-CH2-R5, -O-R5, -NH-R5, -N=R5;

[0102] or

[0103] L2 and L3 together with A8 to which they are attached form a 5-membered or 6-membered heterocyclic ring substituted by R4 and / or R5;

[0104] L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N and NH, or is absent;

[0105] Z is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0106] and can be linked to the central core in a ring shape or by covalent bonds

[0107] R4 is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe, or R4 is hydrogen, methyl or COOH;

[0108] R5 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0109] R6 is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe;

[0110] or R6 is H;

[0111] or

[0112] When A7 participates in a cyclic carbocyclic or heterocyclic ring Z, then A5 and A6 are independently selected from -N or -CH, and A8 is selected from -N, -CH, -CH2-N, -CH2-CH or -NH-CH;

[0113] or a pharmaceutically acceptable salt thereof

[0114] Used to treat or improve proliferative diseases in patients.

[0115] ALC1i according to formula (I) exhibits inhibition of >50% at concentrations at or below 250 μM, preferably IC 50 <250 μM, and more preferably <25 μM. The IC is preferably measured in a FRET-based nucleosome remodeling assay as described in the Examples. 50 .

[0116] EC of ALC1i according to formula (I) 50 Preferably <250 μM, preferably <50 μM; and more preferably <10 μM. EC is preferably measured in a cell proliferation assay using an SRB-based readout as described in the Examples. 50 .

[0117] In an embodiment of the first aspect, it is preferred that:

[0118] A5 and A6 are N; and

[0119] A7 is a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2.

[0120] In an embodiment of the first aspect, it is preferred that:

[0121] A5 and A6 are N;

[0122] A7 is involved in a cyclic carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0123] A8 is -CH2-N, -CH2-CH or -NH-CH, preferably -NH-CH.

[0124] In an embodiment of the first aspect, it is preferred that:

[0125] A5 is N, and A8 is -N or -CH.

[0126] In an embodiment of the first aspect, it is preferred that:

[0127] A5 is N, and A8 is -N or -CH; and

[0128] A6 is a cyclic carbocyclic or heterocyclic ring, preferably a carbocyclic ring Z.

[0129] In a particularly preferred embodiment, A5, A7 and A8 are N.

[0130] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2.

[0131] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 participates in a cyclic carbocycle Z, in particular a 5-membered, 6-membered or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2.

[0132] In an embodiment of the first aspect, it is preferred that:

[0133] L2 is selected from -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4.

[0134] In an embodiment of the first aspect, it is preferred that:

[0135] L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -NH-R4; and

[0136] R4 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, preferably 5- or 6-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe, or R4 is hydrogen, methyl or COOH.

[0137] In an embodiment of the first aspect, it is preferred that:

[0138] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5.

[0139] In one embodiment, it is preferred that:

[0140] L3 is selected from -CH2-R5, -CH2-CH2-R5, -CH2-CF2-R5; and

[0141] R5 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0142] In an embodiment of the first aspect, it is preferred that:

[0143] L2 and L3 together with A8 to which they are attached form a 5- or 6-membered heterocyclic ring substituted by R4 and R5.

[0144] In an embodiment of the first aspect, it is preferred that:

[0145] L2 and L3 together with A8 to which they are attached form a 5- or 6-membered heterocyclic ring substituted by R4 and R5;

[0146] R4 is hydrogen, methyl or COOH; and

[0147] R5 is any 4-membered, 5-membered, 6-membered, 7-membered carbocyclic or heterocyclic ring, preferably phenyl or 5-membered or 6-membered heteroaryl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0148] In an embodiment of the first aspect, it is preferred that

[0149] L4 does not exist.

[0150] In a particularly preferred embodiment, A5, A7 and A8 are N; and

[0151] L4 does not exist.

[0152] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0153] L4 does not exist.

[0154] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0155] L4 does not exist.

[0156] In a particularly preferred embodiment, A5, A7 and A8 are N; and

[0157] L4 does not exist

[0158] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0159] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0160] L4 does not exist

[0161] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0162] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0163] L4 does not exist

[0164] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0165] In a particularly preferred embodiment, A5, A7 and A8 are N; and

[0166] L4 does not exist

[0167] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0168] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0169] L4 does not exist; and

[0170] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0171] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0172] L4 does not exist; and

[0173] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0174] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0175] L4 does not exist; and

[0176] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0177] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0178] L4 does not exist; and

[0179] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0180] In an embodiment of the first aspect, it is preferred that:

[0181] R4 is hydrogen, methyl, COOH or tetrazolyl.

[0182] In an embodiment of the first aspect, it is preferred that:

[0183] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; and

[0184] R4 is hydrogen, methyl, COOH or tetrazolyl.

[0185] In an embodiment of the first aspect, it is preferred that:

[0186] R5 is any 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe.

[0187] In an embodiment of the first aspect, it is preferred that:

[0188] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0189] In an embodiment of the first aspect, it is preferred that:

[0190] L3 is selected from -CH2-R5, -CH2-CH2-R5, -CH2-CF2-R5; and

[0191] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0192] In an embodiment of the first aspect, it is preferred that:

[0193] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe;

[0194] Alternatively, R6 is H.

[0195] In an embodiment of the first aspect, it is preferred that:

[0196] L4 does not exist; and

[0197] R6 is a 5-membered or 6-membered carbocyclic or heterocyclic ring, preferably a 6-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0198] In the above embodiment, it is preferred that:

[0199] Z is a 6-membered aryl, or a 5-membered, 6-membered heteroaryl, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2.

[0200] In an embodiment of the first aspect, it is preferred that:

[0201] A5 is N;

[0202] One of A6 and A7 is CH, and the other is N; or one of A6 and A7 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, and the other is N;

[0203] A8 is N or CH;

[0204] L2, L3, L4 are independently selected from CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N and NH, or are absent, or L2 and L3 together with A8 to which they are attached form a 5-membered or 6-membered heterocyclic ring substituted by R4 and R5;

[0205] Z is any 5-, 6- or 7-membered carbocyclic or heterocyclic ring and may be cyclically attached to the central core or attached by covalent bonds and optionally substituted by one, two or three (preferably one) substituents,

[0206] The substituent is selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0207] R4 is any 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe,

[0208] or R4 is hydrogen, methyl or COOH;

[0209] R5 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe;

[0210] R6 is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe,

[0211] Or R6 is H

[0212] or

[0213] When A7 participates in a cyclic carbon or heterocyclic ring Z, then A5 and A6 are N, and A8 is selected from -N, -CH, -CH2-N, -CH2-CH or -NH-CH, preferably -CH2-N, -CH2-CH or -NH-CH;

[0214] Among them are R4, R5 and R6.

[0215] In an embodiment of the first aspect, it is preferred that:

[0216] A5 is N;

[0217] One of A6 and A7 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, and the other is N;

[0218] A8 is N;

[0219] L2 is CH2-CH2, and L3 is CH2-CH2 or CH2-CF2, or L2 and L3 together with A8 to which they are attached form a 5-membered or 6-membered heterocyclic ring (preferably piperidine or pyrrolidine) substituted by R4 and R5;

[0220] L4 does not exist;

[0221] Z is a 6-membered carbocyclic or heterocyclic ring annularly attached to a central core, wherein Z is optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and NO2;

[0222] R4 is COOH or CH2N4;

[0223] R5 is a 4-, 5-, 6-, 7- or 10-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0224] R6 is a 5-membered or 6-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe,

[0225] Alternatively, R6 is H.

[0226] In an embodiment of the first aspect, it is preferred that:

[0227] Each of A5, A7, and A8 is N;

[0228] A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, preferably a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe;

[0229] L2 is CH2-CH2-R4;

[0230] L3 is CH2-CH2-R4 or -CH2-CF2-R5;

[0231] or L2 and L3 together with A8 to which they are attached form a piperidine ring or a pyrrolidine ring substituted by R4 and R5;

[0232] L4 does not exist;

[0233] Z is a phenyl or cyclohexyl group annularly attached to a central core, wherein Z is optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -OH, Me, -CF3, -OMe and -NO2,

[0234] R4 is COOH or tetrazolyl;

[0235] R5 is phenyl, cyclobutyl, cyclopentyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -CF3, Me, -CH2-CF3 and -OMe;

[0236] R6 is a 6-membered carbocyclic or heterocyclic ring optionally substituted by one, two or three, preferably one, substituent, preferably phenyl or cyclohexyl, more preferably phenyl, wherein the substituent is selected from Br, -Cl, -F, Me, -CF3, -OMe and -NO2.

[0237] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0238] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0239] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; and

[0240] L4 does not exist.

[0241] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0242] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0243] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; and

[0244] L4 does not exist.

[0245] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0246] L4 does not exist.

[0247] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0248] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0249] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0250] L4 does not exist; and

[0251] R6 is phenyl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0252] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0253] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0254] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0255] L4 does not exist; and

[0256] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0257] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0258] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0259] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0260] L4 does not exist; and

[0261] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0262] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0263] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0264] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0265] L4 does not exist; and

[0266] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0267] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0268] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0269] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0270] L4 does not exist; and

[0271] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0272] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0273] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0274] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0275] L4 does not exist; and

[0276] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0277] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0278] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0279] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0280] L4 does not exist; and

[0281] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0282] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0283] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0284] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0285] L4 does not exist; and

[0286] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0287] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0288] L4 does not exist; and

[0289] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0290] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0291] L4 does not exist; and

[0292] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0293] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0294] L4 does not exist; and

[0295] R5 is C5 to C7-cycloalkyl (i.e. C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0296] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0297] L4 does not exist;

[0298] R5 is C5 to C7-cycloalkyl (i.e. C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0299] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0300] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0301] L4 does not exist;

[0302] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0303] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0304] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0305] L4 does not exist;

[0306] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0307] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0308] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0309] L4 does not exist;

[0310] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0311] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0312] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0313] L4 does not exist;

[0314] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0315] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0316] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0317] L4 does not exist;

[0318] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0319] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0320] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0321] L4 does not exist;

[0322] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0323] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0324] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0325] L4 does not exist;

[0326] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0327] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0328] In a particularly preferred embodiment, A5, A7 and A8 are N; and

[0329] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0330] L4 does not exist; and

[0331] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0332] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0333] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0334] L4 does not exist; and

[0335] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0336] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0337] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0338] L4 does not exist; and

[0339] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0340] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0341] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0342] L4 does not exist;

[0343] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0344] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0345] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0346] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0347] L4 does not exist; and

[0348] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0349] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0350] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0351] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0352] L4 does not exist; and

[0353] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, - CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; R6 is a 6-membered aryl or a 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0354] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0355] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0356] L4 does not exist;

[0357] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10-bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0358] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0359] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0360] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0361] L4 does not exist;

[0362] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0363] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0364] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0365] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0366] L4 does not exist;

[0367] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0368] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0369] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0370] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0371] L4 does not exist; and

[0372] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0373] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0374] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0375] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0376] L4 does not exist;

[0377] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0378] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0379] In a particularly preferred embodiment, A5, A7 and A8 are N; and

[0380] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0381] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0382] L4 does not exist; and

[0383] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0384] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0385] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0386] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0387] L4 does not exist; and

[0388] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0389] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0390] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0391] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0392] L4 does not exist; and

[0393] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0394] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0395] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0396] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0397] L4 does not exist;

[0398] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0399] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0400] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0401] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0402] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0403] L4 does not exist; and

[0404] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0405] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0406] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0407] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0408] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0409] L4 does not exist; and

[0410] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, - CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; R6 is a 6-membered aryl or a 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0411] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0412] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0413] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0414] L4 does not exist;

[0415] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0416] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0417] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0418] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0419] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0420] L4 does not exist;

[0421] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0422] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0423] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0424] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0425] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0426] L4 does not exist;

[0427] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10-spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0428] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0429] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0430] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0431] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0432] L4 does not exist; and

[0433] R5 is C5 to C7-cycloalkyl, C4 to C7-cycloalkyl (i.e., C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0434] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0435] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0436] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0437] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0438] L4 does not exist;

[0439] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0440] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0441] In a particularly preferred embodiment, A5, A7 and A8 are N; and

[0442] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0443] L4 does not exist; and

[0444] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0445] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0446] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0447] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0448] L4 does not exist; and

[0449] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0450] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0451] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0452] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0453] L4 does not exist; and

[0454] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0455] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0456] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0457] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0458] L4 does not exist;

[0459] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0460] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0461] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0462] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0463] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0464] L4 does not exist; and

[0465] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0466] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0467] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0468] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0469] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0470] L4 does not exist; and

[0471] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0472] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, - CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; R6 is a 6-membered aryl or a 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0473] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0474] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0475] L4 does not exist;

[0476] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0477] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0478] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0479] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, particularly a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0480] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0481] L4 does not exist;

[0482] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0483] R5 C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0484] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0485] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0486] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0487] L4 does not exist;

[0488] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0489] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0490] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0491] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0492] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0493] L4 does not exist; and

[0494] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0495] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0496] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0497] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0498] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0499] L4 does not exist;

[0500] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0501] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0502] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0503] In a particularly preferred embodiment, A5, A7 and A8 are N; and

[0504] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0505] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0506] L4 does not exist; and

[0507] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0508] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0509] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0510] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0511] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0512] L4 does not exist; and

[0513] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0514] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0515] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0516] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0517] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0518] L4 does not exist; and

[0519] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0520] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0521] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0522] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0523] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0524] L4 does not exist;

[0525] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0526] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0527] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0528] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0529] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0530] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0531] L4 does not exist; and

[0532] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0533] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0534] R6 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0535] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0536] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0537] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0538] L4 does not exist; and

[0539] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0540] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one, substituents selected from -Br, -Cl, -F, -I, Me, - CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; R6 is a 6-membered aryl or a 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0541] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0542] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0543] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0544] L4 does not exist;

[0545] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0546] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0547] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0548] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0549] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0550] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0551] L4 does not exist;

[0552] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0553] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0554] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0555] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0556] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0557] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0558] L4 does not exist;

[0559] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0560] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0561] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0562] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0563] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0564] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0565] L4 does not exist; and

[0566] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0567] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0568] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0569] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and

[0570] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0571] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0572] L4 does not exist;

[0573] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0574] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0575] R6 is phenyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0576] In particularly preferred embodiments of the above embodiments:

[0577] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0578] In particularly preferred embodiments of the above embodiments:

[0579] L4 does not exist; and

[0580] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0581] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0582] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0583] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0584] L4 does not exist;

[0585] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0586] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0587] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0588] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0589] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0590] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0591] L4 does not exist;

[0592] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0593] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0594] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0595] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0596] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0597] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0598] L4 does not exist;

[0599] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0600] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0601] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0602] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0603] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0604] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0605] L4 does not exist;

[0606] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0607] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10-spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0608] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0609] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0610] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0611] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0612] L4 does not exist;

[0613] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0614] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0615] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0616] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0617] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0618] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0619] L4 does not exist;

[0620] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0621] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0622] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0623] In a particularly preferred embodiment, A5, A7 and A8 are N;

[0624] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0625] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0626] L4 does not exist;

[0627] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0628] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0629] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0630] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-membered, 6-membered or 7-membered carbocyclic ring Z, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0631] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0632] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0633] L4 does not exist;

[0634] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0635] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0636] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0637] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0638] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0639] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0640] L4 does not exist;

[0641] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0642] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0643] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0644] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0645] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0646] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0647] L4 does not exist;

[0648] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0649] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0650] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0651] In a particularly preferred embodiment, A5, A7 and A8 are N, and A6 is C and participates in a cyclic carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2;

[0652] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0653] L3 is selected from -CH2-R5, -CH2-CH2-R5 and -CH2-CF2-R5;

[0654] L4 does not exist;

[0655] R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;

[0656] R5 is C4 to C7-cycloalkyl (i.e. C4-, C5-, C6- or C7-cycloalkyl), C6 to C 10 -bicycloalkyl (i.e. C6-, C7-, C8-, C9- or C 10 -bicycloalkyl), C6 to C 10 -spiroalkyl (i.e. C6-, C7-, C8-, C9- or C 10-spiroalkyl), phenyl, 5-membered or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0657] R6 is phenyl substituted by a substituent in the ortho position, wherein the substituent is selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0658] In particularly preferred embodiments, the compounds of the first and further aspects of the invention have Figure 5 The specific structure depicted.

[0659] The use of bifunctional compounds to recruit proteins involved in targeting proteins for degradation by the proteasome has become a potential therapeutic strategy for degrading proteins involved in disease processes. This approach is of particular interest in cancer therapy (Khan S. et al., 2020 and Bushweller JH, 2019). Such bifunctional compounds are generally referred to as proteolysis targeting chimeras (PROTACs). The inhibitors of ALC1 of the first aspect of the present invention specifically bind to ALC1 and are therefore suitable for recruiting proteins that are part of the ALC1 ubiquitination pathway.

[0660] Thus, in a second aspect, the present invention relates to a bifunctional compound comprising an allosteric inhibitor of ALC1 of the first or further aspects of the present invention and a compound that recruits proteins that are part of the ubiquitination pathway to ALC1, preferably recruits an E3 ubiquitin ligase to ALC1 (E3 recruiter), wherein the allosteric inhibitor of ALC1 and the E3 recruiter are optionally covalently linked via a linker. In the context of the bifunctional compounds of the present invention, the ability of the allosteric inhibitor of ALC1 of the first and further aspects of the present invention to bind specifically to ALC1 is particularly important. Thus, preferably, the allosteric inhibitor of ALC1 binds to full-length human ALC1 having an amino acid sequence according to SEQ ID NO: 1 with a KD of 50 μM, more preferably 10 μM or less, more preferably 5 μM or less, even more preferably 1 μM, more preferably 500 nM, more preferably 200 nM, even more preferably 100 nM or less.

[0661] The proteins of the ubiquitination pathway can be bound by small molecules or protein ligands (e.g., antibodies or antibody-like proteins) that specifically bind to the proteins of the ubiquitination pathway. Such protein ligands have been described, for example, in US 7,223,556B1. Small molecule compounds that bind to proteins that are part of the ubiquitination pathway are well known in the art and can be used in the bifunctional compounds of the present invention. Examples of such molecules are described in EP 3 131 588, WO 2017 / 024317, US 6,306,663, US 7,041 ,298, US 2016 / 0176916, US 2016 / 0235730, US 2016 / 0235731 , US 2016 / 0243247, WO 2016 / 105518, WO 2016 / 077380, WO 2016 / 105518, WO 2016 / 077375, WO 2017 / 007612 and WO 2017 / 024317.

[0662] In one embodiment, ALC1i is covalently linked to a compound that recruits proteins that are part of the ubiquitination pathway of ALC1. Preferably, the two components are covalently linked to each other via a linker. Suitable linkers have different lengths and functions. Preferably, the linker is a carbon chain. In a preferred embodiment, the carbon chain optionally contains one, two, three or more heteroatoms selected from N, O and S. In a preferred embodiment, the carbon chain contains only saturated chain carbon atoms. In a preferred embodiment, the carbon chain optionally contains two or more unsaturated chain carbon atoms (e.g., C=C or C≡EC). In certain embodiments, one or more chain carbon atoms in the carbon chain are optionally substituted by one or more substituents, preferably oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, OH, halogen, NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, CN, C3-C7 cycloalkyl, heterocyclyl, phenyl and heteroaryl.

[0663] In certain embodiments, the linker comprises at least 5 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises less than 20 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 5, 7, 9, 11, 13, 15, 17, or 19 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 5, 7, 9, or 11 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 6, 8, 10, 12, 14, 16, or 18 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 6, 8, 10, or 12 chain atoms (e.g., C, O, N, and S).

[0664] In certain embodiments, the linker is a carbon chain optionally substituted with non-bulky substituents, preferably oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, OH, halogen, NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, CN, C3-C7 cycloalkyl and CN.

[0665] In certain embodiments, the linker has the formula L(VI):

[0666]

[0667] or an enantiomer, diastereomer or stereoisomer thereof, wherein

[0668] p1 is an integer selected from 0 to 12;

[0669] p2 is an integer selected from 0 to 12;

[0670] p3 is an integer selected from 1 to 6;

[0671] Each W is independently absent, CH2, O, S, NH or NR5;

[0672] Z is absent, CH2, O, NH or NR5;

[0673] Each R5 is independently H or C1-C3 alkyl, preferably C1-C3 alkyl; and

[0674] Q does not exist or is -CH2C(O)NH-,

[0675] Wherein the linker is covalently bonded to a compound (with a bond immediately to Q) and an allosteric inhibitor of ALC1 (with a bond immediately to Z), the compound recruits proteins that are part of a ubiquitination pathway, and wherein the total number of chain atoms in the linker is less than 20.

[0676] In the third aspect, the present invention relates to a pharmaceutical composition, comprising ALC1i as described in the first aspect or the bifunctional compound as described in the second aspect of the present invention and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is preferably used for treating and improving proliferative diseases.

[0677] In a fourth aspect, the present invention relates to the ALC1i for use of the first aspect of the present invention or the bifunctional compound of the second aspect of the present invention for use in treating or ameliorating a proliferative disease, wherein the treating and ameliorating a proliferative disease comprises administering the ALC1i or the bifunctional compound and administering a poly(ADP-ribose)-polymerase inhibitor (PARPi). The inventors have found that the PARP trapping activity of a known PARPi can be enhanced by ALC1i. Due to this unexpected synergistic effect, it is particularly advantageous to combine PARPi and the ALC1i for use of the first aspect of the present invention for the treatment of various proliferative diseases.

[0678] ALC1i may be provided to a physician who administers the antiproliferative therapy separately from the PARPi or in a multi-component kit. Thus, in embodiments where the two are combined to obtain the benefit of a synergistic effect, the ALC1i may be provided with instructions for combining it with the PARPi, or alternatively in the fifth aspect, the PARPi may be provided with instructions for combining it with the ALC1i. Thus, in the fifth aspect, the present invention relates to a PARPi for use in treating or ameliorating a proliferative disease in a patient, wherein the treatment and amelioration of the proliferative disease comprises administering the PARPi and administering the ALC1i for use of the first aspect of the invention or the bifunctional compound of the second aspect of the invention.

[0679] In a preferred embodiment of the ALC1i for use of the fourth aspect of the invention or the PARPi for use of the fifth aspect of the invention, the PARPi reduces PARP activity and / or inhibits PARP1, PARP2 and / or PARP3 on chromatin, preferably PARP2. The latter phenomenon is also referred to as PARP capture. Therefore, in a preferred embodiment, PARP1, PARP2 and / or PARP3, preferably PARP2, is captured.

[0680] In a preferred embodiment of the ALC1i for use of the fourth aspect of the invention or the PARPi for use of the fifth aspect of the invention:

[0681] (i) PARPi that reduces PARP activity is selected from small interfering RNA, and

[0682] (ii) PARPi that inhibits PARP1 is selected from the following compounds:

[0683] (a) Formula (II)

[0684]

[0685] and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein:

[0686] A and B together represent an optionally substituted fused aromatic ring;

[0687] X is NR X or CR X R Y ;

[0688] If X = NR X , then n is 1 or 2, and if X=CR X R Y , then n is l;

[0689] R X is selected from H, optionally substituted Cl-20 Alkyl, C 5-20 Aryl, C 3-20 heterocyclic groups, amide groups, thioamide groups, ester groups, acyl groups, and sulfonyl groups;

[0690] R Y Selected from H, hydroxyl, amino;

[0691] or R X and R Y Can form spiro-C 3-7 Cycloalkyl or heterocyclic group;

[0692] R C1 and R C2 are independently selected from hydrogen and C l-4 Alkyl, or when X is CR X R Y When R C1 , R C2 , R X and R Y together with the carbon atoms to which they are attached are capable of forming an optionally substituted fused aromatic ring; and

[0693] R 1 is selected from H and halo;

[0694] as well as

[0695] (b) Formula (III)

[0696]

[0697] and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein:

[0698] Y and Z are each independently selected from:

[0699] 1. Aryl optionally substituted by 1, 2 or 3 R6;

[0700] 2. heteroaryl optionally substituted by 1, 2 or 3 R6;

[0701] 3. Substituents independently selected from the following: hydrogen, alkenyl (e.g., C 2-6 -alkenyl), alkoxy (e.g. C 1-6 -alkoxy), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6 -alkyl), alkoxycarbonyl (e.g. C 1-6 -alkoxy-carbonyl), alkoxycarbonylalkyl (e.g. C 1-6 -alkoxy-carbonyl-C 1-6 -alkyl), alkyl (e.g. C 1-6 -alkyl), alkynyl (e.g. C2-6 -alkynyl), arylalkyl (e.g. aryl-C 1-6 -alkyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), cycloalkylalkyl (e.g. C 3-8 -cycloalkyl-C 1-6 -alkyl), haloalkyl (e.g. C 1-6 -haloalkyl), hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene), oxo, heterocycloalkyl (e.g. C 2-8 -heterocycloalkyl), heterocycloalkylalkyl (e.g. C 2-8 -heterocycloalkyl-C 1-6 -alkyl), alkylcarbonyl (e.g. C 1-6 -alkyl-carbonyl), arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl (e.g., C 1-6 -alkyl-sulfonyl), arylsulfonyl, heteroarylsulfonyl, (R A R B ) alkylene (e.g. (R A R B )-C 1-6 -alkylene), (NR A R B )carbonyl, (NR A R B )carbonylalkylene (e.g. (NR A R B )Carbonyl-C 1-6 -alkylene), (NR A R B )sulfonyl and (R A R B )sulfonylalkylene (e.g. (R A R B )sulfonyl-C 1-6 -alkylene);

[0702] Wherein each R6 is selected from OH, NO2, CN, Br, Cl, F, I, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 2-8 -heterocycloalkyl, C 2-6 -alkenyl, alkoxy (e.g. C 1-6 -alkoxy), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6 -alkyl), alkoxycarbonyl (e.g. C 1-6 -alkoxy-carbonyl), alkoxycarbonylalkyl (e.g. C 1-6 -alkoxy-carbonyl-C 1-6 -alkyl), C 2-6- Alkynyl, aryl, arylalkyl (e.g. aryl-C1-6 -alkyl), C 3-8 -cycloalkylalkyl (e.g. C 3-8 -cycloalkyl-C 1-6 -alkyl, haloalkoxy (e.g. C 1-6 -haloalkoxy), haloalkyl (e.g. C 1-6 -haloalkyl), hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene), oxo, heteroaryl, heteroarylalkoxy (e.g., heteroaryl-C 1-6 -alkoxy), heteroaryloxy, heteroarylthio, heteroarylalkylthio (e.g., heteroaryl-C 1-6 -alkylthio), heterocycloalkoxy (e.g. C 2-8 -heterocycloalkoxy), C 2-8 -heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (R A R B )C 1-6 -alkylene, (NR A R B )carbonyl, (R A R B )carbonylalkylene (for example (R A R B )Carbonyl-C 1-6 -alkylene), (NR A R B )sulfonyl and (NR A R B )sulfonylalkylene (e.g. (NR A R B )sulfonyl-C 1-6 -alkylene);

[0703] R1, R2 and R3 are each independently selected from hydrogen, halogen, alkenyl (e.g., C 2-6 -alkenyl), alkoxy (e.g. C 1-6 -alkoxy), alkoxycarbonyl (e.g. C 1-6 -alkoxy-carbonyl), alkyl (e.g. C 1-6 -alkyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), alkynyl (e.g. C 2-6 -alkynyl), cyano, haloalkoxy (e.g. C 1-6 -haloalkoxy), haloalkyl (e.g. C 1-6 -haloalkyl), hydroxy, hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene), nitro, NR A R B NR A R BAlkylene (such as NR A R B C 1-6 -alkylene) and (R A R B )carbonyl;

[0704] A and B are each independently selected from hydrogen, Br, Cl, F, I, OH, C 1-6 -alkyl, C 3-8 - cycloalkyl, alkoxy (e.g. C 1-6 -alkoxy), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6 -alkyl), wherein C 1-6- Alkyl, C 3-8 -cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted by at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C 1-6- Alkyl and C 3-8 - cycloalkyl, wherein B is not OH;

[0705] R A and R B independently selected from hydrogen, alkyl (e.g. C 1-6 -alkyl), cycloalkyl (e.g. C 3-8 -cycloalkyl) and alkylcarbonyl (e.g. C 1-6 -alkyl-carbonyl); or RA and RB together with the atoms to which they are attached form a 3-10 membered heterocyclic ring optionally having one to three heteroatoms or heterofunctional groups selected from: -O-, -NH, -N(C 1-6 -alkyl)-, -NCO(C 1-6 -alkyl)-, -N(aryl)-, -N(aryl-C 1-6 -alkyl-), -N(substituted-aryl-C 1-6 -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C 1-6 alkyl-)- and -S- or S(O)q-, wherein q is 1 or 2, and the 3-10 membered heterocyclic ring is optionally substituted with one or more substituents;

[0706] R4 and R5 are each independently selected from hydrogen, alkyl (e.g., C 1-6 -alkyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6 -alkyl), haloalkyl (e.g. C 1-6 -haloalkyl), hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene) and (NRA R B ) alkylene (e.g. NR A R B C 1-6 -alkylene);

[0707] (iii) PARPi that inhibits PARP1 and PARP2 is selected from the following compounds:

[0708] (a) Formula (IV)

[0709]

[0710] and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein:

[0711] R1 is hydrogen or fluorine; and

[0712] R2 is hydrogen or fluorine;

[0713] as well as

[0714] (b) Formula (V)

[0715]

[0716] and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein:

[0717] R1, R2 and R3 are independently selected from hydrogen, alkenyl (e.g., C 1-6 -alkenyl), alkoxy (e.g. C 1-6 -alkoxy), alkoxycarbonyl (e.g. C 1-6 -alkoxycarbonyl), alkyl (e.g. C 1-6 -alkyl), alkynyl (e.g. C 1-6 -alkynyl), cyano, haloalkoxy (e.g. C 1-6 -haloalkoxy), haloalkyl (e.g. C 1-6 -haloalkyl), halogen, hydroxy, hydroxyalkyl (e.g. C 1-6 -hydroxyalkyl), nitro, NR A R B and (NR A R B )carbonyl;

[0718] A is a non-aromatic 4, 5, 6, 7 or 8 membered ring containing 1 or 2 nitrogen atoms and optionally one sulfur or oxygen atom, wherein the non-aromatic ring is optionally substituted with 1, 2 or 3 substituents selected from: alkenyl (e.g., C 1-6 -alkenyl), alkoxy (e.g. C 1-6 -alkoxy), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6-alkyl), alkoxycarbonyl (e.g. C 1-6 -alkoxycarbonyl), alkoxycarbonylalkyl (e.g. C 1-6 -Alkoxycarbonyl-C 1-6 -alkyl), alkyl (e.g. C 1-6 -alkyl), alkynyl (e.g. C 1-6 -alkynyl), aryl, arylalkyl (e.g. aryl-C 1-6 -alkyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), cycloalkylalkyl (e.g. C 3-8 -cycloalkyl-C 1-6 -alkyl), cyano, haloalkoxy (e.g. C 1-6 -haloalkoxy), haloalkyl (e.g. C 1-6 -haloalkyl), halogen, heterocycle, heterocycloalkyl (e.g. heterocycle-C 1-6 -alkyl), heteroaryl, heteroarylalkyl (e.g., heteroaryl-C 1-6 -alkyl), hydroxy, hydroxyalkyl (e.g. C 1-6 -hydroxyalkyl), nitro, NR C R D ,(NR C R D )alkyl (e.g. (NR C R D )-C 1-6 -alkyl), (NR C R D )carbonyl, (NR C R D )carbonylalkyl (e.g. (NR C R D )Carbonyl-C 1-6 -alkyl) and (NR C R D )sulfonyl; and

[0719] R A , R B , R C and R D independently selected from hydrogen, alkyl (e.g. C 1-6 -alkyl) and alkylcarbonyl (e.g. C 1-6 -alkylcarbonyl).

[0720] (iv) PARPi that inhibits PARP1, PARP2 and PARP3 is a compound of formula (VI)

[0721]

[0722] and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein:

[0723] R1 is: H; halogen; cyano; optionally substituted alkyl (e.g. C 1-6 -alkyl), alkenyl (e.g. C 2-6 -alkenyl), alkynyl (e.g. C 2-6 -alkynyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), heterocycloalkyl (e.g. C 2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro and amino, alkoxy (e.g., C-heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, carboxyl, and optionally substituted amino and ether (e.g., O-aryl) 1-6 -alkoxy), alkyl (e.g. C 1-6 -alkyl) and aryl); or -C(O)-R 10 , where R 10 is: H; optionally substituted alkyl (eg, C 1-6 -alkyl), alkenyl (e.g. C 1-6 -alkenyl), alkynyl (e.g. C 1-6 -alkynyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), heterocycloalkyl (e.g. C 2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl (e.g., C 1-6 -alkyl) and aryl); or OR 100 or NR 100 R 110 , where R 100 and R 110 are each independently H or an optionally substituted alkyl group (e.g., C 1-6 -alkyl), alkenyl (e.g. C 2-6 -alkenyl), alkynyl (e.g. C 2-6 -alkynyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), heterocycloalkyl (e.g. C 2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from alkyl (e.g., C 1-6 -alkyl), alkenyl (e.g. C 2-6 -alkenyl), alkynyl (e.g. C 2-6 -alkynyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), heterocycloalkyl (e.g. C 2-8-heterocycloalkyl), aryl and heteroaryl, wherein the one or more substituents are selected from halogen, hydroxy, nitro, amino, and alkyl (e.g., C 1-6 -alkyl) and aryl);

[0724] R2 is H or alkyl (e.g. C 1-6 -alkyl);

[0725] R3 is H or alkyl (e.g. C 1-6 -alkyl);

[0726] R4 is H, halogen or alkyl (e.g. C 1-6 -alkyl);

[0727] X is O or S;

[0728] Y is (CR5R6)(CR7R8) n or NC(R5), where:

[0729] n is 0 or 1;

[0730] R5 and R6 are each independently H or an optionally substituted alkyl group (eg, C 1-6 -alkyl), alkenyl (e.g. C 2-6 -alkenyl), alkynyl (e.g. C 2-6 -alkynyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), heterocycloalkyl (e.g. C 2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl (e.g., C 1-4 -alkyl), lower alkoxy (e.g. C 1-4 -alkoxy) or aryl); and

[0731] R7 and R8 are each independently H or an optionally substituted alkyl group (e.g., C 1-6 -alkyl), alkenyl (e.g. C 2-6 -alkenyl), alkynyl (e.g. C 2-6 -alkynyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), heterocycloalkyl (e.g. C 2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl (e.g., C 1-4-alkyl), lower alkoxy (e.g. C 1-4 -alkoxy) and aryl);

[0732] wherein when R1, R4, R5, R6 and R7 are each H, R8 is not unsubstituted phenyl.

[0733] In a preferred embodiment of the ALC1i or the bifunctional compound for use according to the fourth aspect of the invention or the PARPi for use according to the fifth aspect of the invention, the PARPi is selected from olaparib, talazoparib, niraparib, rucaparib and veliparib, in particular veliparib, olaparib and talazoparib.

[0734] In a preferred embodiment of the ALC1i or the bifunctional compound for use of the fourth aspect of the invention or the PARPi for use of the fifth aspect of the invention, ALC1i is an inhibitor of ALC1 of any one of the first or further aspects of the invention or the bifunctional compound of the second aspect.

[0735] In a preferred embodiment of the ALC1i or the bifunctional compound for use according to the fourth aspect of the invention or the PARPi for use according to the fifth aspect of the invention, the tumor disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer and colorectal cancer.

[0736] In preferred embodiments of the ALC1i or bifunctional compound for use according to the fourth aspect of the invention or the PARPi for use according to the fifth aspect of the invention, (i) ALC1i enhances the cancer cell killing efficacy of PARPi, (ii) a reduced amount of PARPi is administered, and / or (iii) PARPi resistance is bypassed.

[0737] In a preferred embodiment of the ALC1i for use of the fourth aspect of the invention or the PARPi for use of the fifth aspect of the invention, PARPi and ALC1i are administered concomitantly or separately.

[0738] In a sixth aspect, the present invention relates to a kit of parts comprising separately packaged PARPi and ALCli or a composition containing PARPi and ALCli, preferably with instructions for use in treating or ameliorating a proliferative disease.

[0739] BRCA1 and BRCA2 proteins are involved in both promoting homologous recombination (HR)-mediated DNA repair and controlling the stability of stalled replication forks. Many tumor types (including, for example, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, and uveal melanoma) often have potential defects in BRCA1 or BRCA2 activity. These defects are usually due to germline or somatic mutations in the BRCA1 or BRCA2 genes. These tumors with potential HR repair defects are often sensitive to PARP inhibitors. However, over time, they develop PARP inhibitor resistance. In order to treat such tumors, if used alone or in combination with PARPi, the use of ALC1i for the use of the first aspect of the present invention, the bifunctional compound of the second aspect of the present invention, the drug of the third aspect of the present invention, the ALC1i or bifunctional compound for the use of the fourth aspect of the present invention is particularly suitable. In a preferred embodiment of the ALC1i for use according to the first aspect of the invention, the bifunctional compound of the second aspect of the invention, the medicament of the third aspect of the invention, the ALC1i or bifunctional compound for use according to the fourth aspect of the invention or the PARPi for use according to the fifth aspect of the invention, the proliferative disease is selected from cancer.

[0740] As used herein, the term "cancer" refers to cells with autonomous growth capacity. Examples of such cells include cells with abnormal states or conditions characterized by rapid proliferation of cell growth. This term is meant to include cancerous growth, such as tumors; carcinogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, regardless of the histopathological type or invasion stage. Malignant tumors of various organ systems are also included, such as the respiratory system, cardiovascular system, renal system, reproductive system, blood system, nervous system, liver system, gastrointestinal system, and endocrine system; and adenocarcinomas, which include malignant tumors, such as most colon cancers, renal cell carcinomas, prostate cancers, and / or testicular tumors, non-small cell lung cancers, and small intestinal cancers. "Naturally occurring" cancers include any cancer that is not experimentally induced by implanting cancer cells into a subject, and include, for example, spontaneously occurring cancers, cancers caused by exposure of a patient to one or more carcinogens, cancers caused by insertion of transgenic oncogenes or knockout of tumor suppressor genes, and cancers caused by infection (e.g., viral infection). The term "cancer" is recognized in the art and refers to a malignant tumor of epithelial or endocrine tissue. The term also includes carcinosarcoma, which includes a malignant tumor composed of cancerous tissue and sarcoma tissue."Adenocarcinoma" refers to a cancer derived from glandular tissue or in which tumor cells form an identifiable glandular structure. The term "sarcoma" is recognized in the art and refers to a malignant tumor of mesenchymal origin. The term "hematopoietic neoplastic disorder" includes diseases involving hyperplasia / neoplastic cells of hematopoietic origin. Hematopoietic neoplastic disorders can be caused by myeloid, lymphoid or erythroid or their precursor cells. In some embodiments, cancer is breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), gastric cancer, gastroesophageal cancer, non-small cell lung cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia or uveal melanoma. In some embodiments, cancer is basal-like cancer, basal-like breast cancer, triple-negative breast cancer, high-grade cancer or high-grade serous ovarian cancer cells.

[0741] Thus, a BRCA1-deficient or BRCA2-deficient cancer is a cancer that has one or more cells with abnormal BRCA1 levels or activity or abnormal BRCA2 levels or activity. These abnormal levels or activities interfere with the normal function of BRCA1 or BRCA2 and may lead to defects in HR-mediated DNA repair or reduced replication fork stability. Preferably, the proliferative disease is selected from BRCA-1 and / or BRCA-2-deficient tumors, and / or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer or pancreatic cancer.

[0742] Therefore, in the seventh aspect, according to the ALC1i for use according to the first aspect of the present invention, the bifunctional compound according to the second aspect of the present invention, the medicament according to the third aspect of the present invention, the ALC1i or bifunctional compound for use according to the fourth aspect of the present invention, or the PARPi for use according to the fifth aspect of the present invention (the proliferative disease is selected from cancer) or the kit according to the sixth aspect of the present invention, wherein the proliferative disease, preferably cancer, and more preferably cancer is selected from BRCA1 and / or 2 deficient tumors and tumors with increased expression of PARP1, PARP2, PARP3 and / or ALC1 compared to non-tumor cells.

[0743] Preferred examples of cancers treatable according to various aspects of the present invention are ovarian and fallopian tube cancer, breast cancer, pancreatic cancer and gastric cancer, colorectal cancer and lung cancer.

[0744] Preferably, the cancer to be treated according to the various aspects of the invention has relapsed or progressed, preferably after a first line of chemotherapy.Thus, preferably, the inhibitor of ALC1 (ALC1i) according to the invention is used as a second or third line therapy.

[0745] Preferably, the cancer to be treated is at stage III (locally advanced) or stage IV (metastatic).

[0746] Preferably, the cancer to be treated according to various aspects of the present invention has a potential defect in DNA damage repair, such as HR repair, i.e., the cancer is a HR-deficient cancer. In one embodiment, the cancer cell has a mutation / deletion / insertion in one or more DNA repair genes listed in Tables 13 and 14.

[0747] In one embodiment, the cancer to be treated or the cancer patient to be treated is selected based on the presence of tumor markers. In a clinical setting, cancer / patient selection will include, but is not limited to, eligible tumor biomarkers, i.e., deleterious mutations, including BRCA1, BRCA2, BARD1, BRIP1, ANCA, FANCE, NBN, PALB2, RAD51C, RAD51D, RAD51 and / or RAD51B and / or other gene variants in the HR pathway, as shown in Tables 13 and 14.

[0748] Preferably, the patient to be treated according to various aspects of the present invention is a cancer patient, preferably suffering from breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), fallopian tube cancer, peritoneal cancer, acute myeloid leukemia or uveal melanoma, and optionally has a mutation / deletion / insertion in one or more HR genes as listed in Tables 13 and 14.

[0749] Experimental Section

[0750] Cell lines used

[0751] As a BRCA wild-type cell line, MDA-MB-231 cells were used. These cells were established from aneuploid human females. These cells were extracted from the mammary gland (breast) as pleural effusion from the metastatic site. (MDA-MB-231( HTB-26 TM Homo sapiens epithelial mammary gland)). It can be obtained from a variety of sources (including HTB-26 TM )get.

[0752] As a BRCA-negative cell line, SUM-149-PT cells were used. This cell line is a triple-negative breast cancer (TNBC) cell line derived from a primary human invasive ductal carcinoma metastatic nodule from a 40-year-old female. It contains a hemizygous BRCA1 mutation (p.Pro724Leufs*12) and is available from a variety of sources, including bioIVT.

[0753] As an example of pancreatic cancer, PSN1 cells are used. The human cell line is derived from pancreatic adenocarcinoma tissue. It contains amplification of c-myc and activated c-Ki-ras and a deletion of one of the two p53 alleles. The cell line can be obtained from many sources, including MERCK (94060601).

[0754] BxPC-3 cells were used. The cells were extracted from pancreatic tissue of a 61-year-old woman with adenocarcinoma. The established cell line does not express CFTR (cystic fibrosis transmembrane conductance regulator), but it expresses mucin, pancreatic cancer-specific antigen, and CEA (carcinoembryonic antigen). Cell lines can be obtained from many sources, including MERCK (93120816).

[0755] CaCo2 cells were used. The cells were established from colon tissue of a 72-year-old woman with colorectal adenocarcinoma and are available at ATCC (Caco-2 [Caco2] HTB-37 TM )get.

[0756] Capan-1 cells were used. The cells were isolated from the pancreas of a 40-year-old male with pancreatic adenocarcinoma. Cells are available at ATCC (Capan-1

[0757] HTB-79 TM )get.

[0758] 22Rv1 cells were used. The cell line was derived from a xenograft that was continuously propagated in mice after castration-induced regression and relapse of the androgen-dependent parental CWR22 xenograft. The cells were derived from prostate cancer and are epithelial cells. They express PSA (prostate-specific antigen) and have damaging mutations in BRCA2. The cell line can be obtained from a variety of sources (Accegen (ABC-TC0004)).

[0759] DU145 cells were used. The cells were isolated from the brain of a 69-year-old male patient with prostate cancer and the established cell line has an epithelial morphology. It is hypotriploid and has mutations in BRCA1, BRCA2, RAD50, WRN, and TP53. The cell line is available at ATCC HTB-81 TM get.

[0760] DLD1-wt cells were used. Cells were extracted from the large intestine of adult male colorectal cancer patients with colorectal cancer, and cell lines were established. They are pseudodiploid (2n=46), express p53 antigen, and have damaging mutations in BRCA2, FANCA, and TP53. Cell lines can be obtained from many sources, including MERCK (90102540).

[0761] DLD1-BRCA2- / - cells were used. This cell line is derived from DLD1-wt and is a BRCA2 knockout cell line. It can be obtained from multiple sources including Creative Biogene (CSC-RT0028).

[0762] HCT116 cells were used. This cell line was derived from colon tissue of an adult male with colorectal cancer. It has damaging mutations in BRCA2, FANCA, and POLD1. This cell line is available from many sources, including DSMZ (ACC 581).

[0763] PC-3 cells were used. The cell line was derived from a 62-year-old man with grade IV prostate cancer, specifically from bone metastases. These cells are epithelial, nearly triploid, and have damaging mutations in TP53. They can be obtained from many sources, including MERCK (90112714).

[0764] SW620 cells were used. Cells were isolated from the lymph nodes of a 51-year-old male with Dukes' C colorectal adenocarcinoma and the cell line was established. Cell lines can be obtained from many sources (including ATCC CCL-227 TM )get.

[0765] T47D cells were used. The cell line was established from a 54-year-old female with invasive ductal carcinoma of the breast. The cells were extracted from the mammary gland (breast) as a pleural effusion. They are available from many sources including ATCC HTB-133 TM )get.

[0766] Use HUH7 cells. They can be obtained, for example, from the cell lines service (CLS.shop). These cells were isolated from a liver tumor of a 57-year-old male.

[0767] HCC1428 cells were used. They are available from ATCC (HCC1428 CRL-2327 TM ) and originated from the breast of a Caucasian female patient with adenocarcinoma.

[0768] HCC1937 cells were used. They were isolated from a 23-year-old woman with primary ductal carcinoma, specifically from the breast. The cell line has a homozygous BRCA1 mutation and is negative for p53 and Her2-neu expression and has an epithelial morphology. Cells can be obtained from a number of sources, including Amsbio (Catalog No. AMS.EP-CL-0093).

[0769] MDA-MB-436 cells are used. The cell line is derived from a 43-year-old woman with breast adenocarcinoma, which is extracted from the breast as pleural effusion in the metastatic site. The cells are pleomorphic, with multinuclear component cells. They can be obtained from many sources (including Accegen (Catalog No. ABC-TC0655)).

[0770] HEPG2 cells were used. The cell line was established from a 15-year-old male patient with hepatocellular carcinoma. The cells express several major plasma proteins such as albumin, fibrinogen, and α2-macroglobulin and have an epithelial-like morphology. The cell line is available under ATCC HB-8065 TM get.

[0771] LnCap cells were used. The cells were isolated from the left supraclavicular lymph node of a male with metastatic prostate cancer and are available at ATCC (LNCaP clone FGC CRL-1740 TM )get.

[0772] Use U2OS cells. They are available from ATCC (U-2OS HTB-96 TM ) and was isolated from the tibia of a 15-year-old female with osteosarcoma.

[0773] Synergistic effect with PARPi

[0774] To determine the ZIP synergy score, 2-D titrations of both compounds were added to cells in a 96h-SRB survival assay format. The score was calculated by adding readouts of survival data from at least 3 replicate plates of the SRB assay into an open source program called SynergyFinder.

[0775] “SynergyFinder” (https: / / synergyfinder.fimm.fi) is a standalone web application for interactive analysis and visualization of drug combination screening data. Since its initial release in 2017, SynergyFinder has become a widely used web tool both for discovering new synergistic drug combinations in preclinical model systems (e.g., cell lines or primary patient-derived cells) and for better understanding the mechanisms of combination therapy efficacy or resistance” (Ianevski et al. 2020).

[0776] In the Zero Interaction Potency (ZIP) model, drug interaction relationships are determined by comparing the potency changes in the dose-dependency curves between individual drugs and their combination (https: / / synergyfinder.fimm.fi / synergy / synfin_docs / ). The model is further described at https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC4759128 / . The results of the combination therapy of ALC1 inhibitors and PARP inhibitors are shown in Figure 4 middle.

[0777] Inhibitor-response (cell survival) assay

[0778] To validate small molecule inhibitors, MDA-MB-231 cells were used as BRCA wild-type cell lines and SUM-149-PT was used as BRCA1-deficient cell lines to address the synthetic lethality of BRCA and ALC1. Cells were seeded in 96-well plates (5000 cells / well) and treated with ALC1 inhibitor titrations starting from 50 μM. DMSO was added to cells as a "no treatment" control. Cells were cultured for 5 days at 37 ° C, CO2 5%, until they were fixed with 10% TCA for 1 h and stained with sulforhodamine dye for 30 minutes. After the cells were washed with 1% acetic acid, 10 mM Tris (pH 10.5) solution was used to dissolve the stained cells. Absorbance was measured at 492 nm using SUNRISE TECAN, and the data were normalized relative to the number of cells at time point 0 and relative to 100% survival (=DMSO control), and analyzed using GraphPad Prism. Survival curves were fitted using the "Inhibitor-response curve with variable slope (four parameters)". IC of ALC1 inhibitor treatment 50 The value is shown in Figure 7 middle.

[0779] To further validate the compounds, colony formation assays were applied. Here, fewer cells were seeded for the assay (100 cells / well). Cells were treated with ALC1 inhibitors or with a combination of PARPi and ALC1 inhibitors for 11 days. Cells were fixed and data analyzed as described above. Results of treatment with ALC1 inhibitors are shown in Figure 3 and Figure 7 middle.

[0780] FRET-based nucleosome sliding assay

[0781] This assay utilizes a mononucleosome positioned in the middle, thereby allowing the use of FRET readings to monitor the sliding activity of the ALC1 remodeling enzyme. Each nucleosome is labeled with two FRET dyes: the octamer is labeled with Cy5 (Cy5-maleimide is coupled to H2B), and one of the DNA ends is labeled with Cy3. The DNA template includes a 147bp 601 DNA positioning sequence, with DNA overhangs flanking each side. Other nucleosome positioning sequences (both artificial constructs and naturally occurring sequences) can also be used, even if the efficiency is lower than the 601 sequence in terms of positioning nucleosomes. Nucleosomes are assembled by salt gradient dialysis using purified Cy5-labeled histone octamers and purified Cy3-labeled DNA templates to produce FRET-labeled intermediately positioned nucleosomes. These nucleosomes will start with low FRET and will have low Cy5 fluorescence signals when excited with Cy3 excitation maximum wavelength, because the two fluorophores are too far apart for effective FRET. As the ALC1 remodeling reaction proceeds and the remodeling enzyme slides the octamer toward the DNA end, the distance between the two FRET dyes decreases and the signal from Cy5 / FRET increases. Therefore, the increase in FRET can be used directly as a readout of sliding.

[0782] Construction of DNA template for mononucleosome remodeling

[0783] In order to reconstruct a mononucleosome, the non-natural Widom 601 nucleosome positioning sequence is used as a high affinity binding site for the histone octamer (see Lowary, PT and Widom, J. New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. J. Mol. Biol. 276, 19-42 (1998)). Cy3-labeled DNA containing these 601 sequences can be constructed using methods including PCR amplification, restriction digestion of DNA plasmids, followed by Klenow end labeling reactions or other standard molecular biology techniques.

[0784] Preparation of ALC1 and histone octamers

[0785] As previously published (Singh, HR et al., 2017), full-length human ALC1 (1-897) or its truncated forms were expressed and purified from Escherichia coli (E. coli) as N-terminal 6×His-tagged fusion proteins.

[0786] Human histones are recombinantly expressed in E. coli (using classical IPTG induction or using autoinduction medium) and purified from E. coli inclusion bodies. The purification scheme involves extraction / solubilization of histones from inclusion bodies using guanidine hydrochloride followed by reverse phase chromatography. The purified histones are lyophilized to produce the TFA salt of the purified histones.

[0787] Preparation of nucleosomes

[0788] In order to assemble nucleosomes, template DNA (250 μ g / ml final concentration) is mixed with purified histone octamer in high salt buffer with different molar ratios of histone octamer and DNA. Then the ionic strength of this mixture is reduced by <600mM NaCl at 4 ° C for low salt buffer by continuous dialysis. Finally, the material is dialyzed for TEA-20 (10mM triethanolamine-Cl pH7.5, 20mM NaCl, 0.1mM EDTA). Select the best molar ratio, that is, make DNA fully assembled into the ratio of nucleosomes, and use it for further assembly.

[0789] Alternatively, nucleosomes can be assembled by other methods such as deposition of histone octamers onto DNA using polyglutamate or a histone chaperone, or by salt step dilution.

[0790] Methods for measuring ALC1-mediated sliding; ALC1 nucleosome sliding assay

[0791] 10 mM Tris-HCl (pH 8.1), 75 mM KCl, 1 mM MgCl2, 1.0 mM EGTA, 10% glycerol, 0.5 mM dithiothreitol (DTT), 0.01% TritonX100, 0.02% NP40 and cells containing intermediately positioned nucleosomes, tri-ADP-ribose or (ADP-ribose) were cultured in 384-well plates at room temperature. n The sliding reaction was carried out in a reaction mixture containing 1% paraformaldehyde and ALC1 chromatin remodeling enzyme. The sliding was started by adding ATP, and the plates were then shaken at 1450 rpm for 5 seconds, and they were sealed with foil compatible with fluorescence reading. The FRET signal was recorded immediately using a fluorimeter (BMG reader PheraStar FSX, channel A: excitation 520 nm, emission 680 nm; channel B: excitation 520 nm, emission 590 nm), and remodeling was performed for 30 min unless otherwise stated.

[0792] The FRET signal was calculated as the signal at 680 nm (emission of Cy5) divided by the signal at 590 nm (emission of Cy3) and multiplied by 10,000. To obtain the apparent rate of ALC1-mediated nucleosome sliding, the increase in FRET over time was plotted and the resulting kinetic trace was fitted by a linear curve fit to obtain the initial velocity of ALC1-mediated nucleosome sliding.

[0793] High-throughput screening (HTS) and IC of molecules that modulate ALC1-mediated sliding 50 Determination

[0794] To perform high throughput screening (HTS) and IC of compounds that modulate the sliding activity of ALC1 50 To assay, nucleosomes were incubated with ALC1 and either tris(ADP-ribose) or (ADP-ribose) as described above before initiating sliding by adding ATP. n Incubate for 30 min in the presence of putative ALCi. Then, the gliding rate (initial velocity) is determined as described above and compared to the gliding rate in the absence of putative modulator / compound (% inhibition). To determine the IC 50 The observed % inhibition (y-axis) was plotted against compound concentration (x-axis) using GraphPad Prism and fitted using a nonlinear regression model (four parameters). IC of inhibition of nucleosome sliding 50 The results are shown in Figure 6 IC 50 Values ​​are presented using the following symbols: +++: IC 50 <25μM; ++: IC 50 =25-100μM; +:IC 50 = 100-250 μM; and "-": compound inactive, ie inhibition > 50% was never observed.

[0795] SAR analysis of ALC1 inhibitors

[0796] Overall, the ALCi clusters presented here have straightforward SARs clearly demonstrated by the presence of a large number of molecular matching pairs. For example, in R6 substitutions, there is a clear preference for halogen substitutions over oxygen or methyl substitutions, as demonstrated by the superior potency of ALCi-1002 over ALCi-1009 and ALCi-1055. Furthermore, in the R4 region, tetrazoles are preferred over carboxylic acids (IC50 > 25 μM for compounds without tetrazoles). In the R5 region of the molecule, there is a tendency to prefer non-aromatic, hydrophobic moieties, which increase cellular potency and selectivity, particularly when combined with tetrazoles in the R4 region (ALCi-1013 vs. ALCi-1002). By extrapolating from the currently available SARs, the skilled artisan should be able to readily develop additional ALC1 inhibitors of the same type as those presented below.

[0797] Synthesis of ALC1 inhibitors

[0798] The synthesis of the compound of general formula (I) can be carried out according to Fig. 9 and Fig.10 The general synthetic scheme is shown. Fig. 9 and Fig.10 The compounds prepared in reflect a basic compound scaffold in which the phenyl group can be substituted at any position, not just where the R group is described.

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Claims

1. An inhibitor of ALC1 (ALC1i) according to formula (I) in A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or when A6 participates in a cyclic carbocyclic or heterocyclic ring Z, A6 is C; A7 is selected from N or CH, or when A7 participates in a cyclic carbocyclic or heterocyclic ring Z, A7 is C; L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4; L3 is selected from CH2-R5, -CF2-R5, -CH2-CH2-R5, -CH2-CF2-R5, -CH2-CH2-CH2-R5, -O-R5, -NH-R5, -N=R5; or L2 and L3 together with A8 to which they are attached form a 5-membered or 6-membered heterocyclic ring substituted by R4 and / or R5; L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N and NH, or is absent; Z is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and can be linked to the central core in a ring shape or by covalent bonds R4 is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe, or R4 is hydrogen, methyl or COOH; R5 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; R6 is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe; or R6 is H; or When A7 participates in a cyclic carbocyclic or heterocyclic ring Z, then A5 and A6 are independently selected from -N or -CH, and A8 is selected from -N, -CH, -CH2-N, -CH2-CH or -NH-CH; or a pharmaceutically acceptable salt thereof, Used to treat or improve proliferative diseases in patients.

2. The ALC1i for use according to claim 1, wherein A5 is N; One of A6 and A7 is CH, and the other is N; or one of A6 and A7 is C and participates in a cyclic carbocyclic or heterocyclic ring Z, and the other is N; A8 is N or CH, or A5 is N; One of A6 and A7 is C and participates in a 5-, 6- or 7-membered cyclic carbocyclic or heterocyclic ring, preferably a 5- or 6-membered aryl or heteroaryl Z, and the other is N; A8 is N; L2 is CH2-CH2-R4, and L3 is CH2-CH2-R5 or CH2-CF2-R5, or L2 and L3 together with A8 to which they are attached form a 5-membered or 6-membered heterocyclic ring substituted with R4 and R5, preferably piperidinyl or pyrrolidinyl; L4 does not exist; Z is any 6-membered carbocyclic or heterocyclic ring, preferably a 6-membered aryl or heteroaryl, annularly attached to a central core, wherein Z is optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and NO2; R4 is COOH or tetrazolyl; R5 is any 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; R6 is any 5-membered or 6-membered carbocyclic or heterocyclic ring, optionally substituted by one, two or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, or R6 is H.

3. The ALC1i for use according to claim 1 or 2, wherein Each of A5, A7, and A8 is N; A6 is C and participates in a cyclic carbocyclic or heterocyclic ring Z; L3 is CH2-CF2-R5, or each of L2 and L3 is CH2-CH2; or L2 and L3 together with A8 to which they are attached form a piperidine ring or a pyrrolidine ring substituted with R4 and R5; L4 does not exist; Z is a phenyl or cyclohexyl group annularly attached to a central core, wherein Z is optionally substituted by one, two or three, preferably one, substituent selected from -Br, -Cl, -F, -OH, Me, -CF3, -OMe and -NO2, R4 is COOH or tetrazolyl; R5 is phenyl, cyclobutyl, cyclopentyl or adamantyl, optionally substituted with one, two or three, preferably one, substituent selected from -Br, -Cl, -CF3, Me, -CH2-CF3 and -OMe; R6 is any 6-membered carbocyclic or heterocyclic ring (preferably phenyl or cyclohexyl; more preferably phenyl), optionally substituted with one, two or three, preferably one, substituent selected from Br, -Cl, -F, Me, -CF3, -OMe and -NO2.

4. The ALC1i for use according to any one of claims 1 to 3, wherein the ALC1 is selected from:

5. A bifunctional compound comprising the ALC1i for use according to claims 1 to 4 and a compound that recruits E3 ubiquitin ligase to ALC1 (E3 recruiting agent), wherein the ALC1i and the E3 recruiting agent are optionally covalently linked via a linker.

6. A pharmaceutical composition comprising the ALC1i for use according to claims 1 to 4 or the bifunctional compound according to claim 5 and a pharmaceutically acceptable excipient.

7. The ALC1i for use according to claims 1 to 4, the bifunctional compound according to claim 5 or the pharmaceutical composition according to claim 6, wherein the ALC1i, the bifunctional compound or the pharmaceutical composition is used for treating or improving a proliferative disease, wherein the treating and improving the proliferative disease comprises administering the ALC1i or the bifunctional compound and administering a poly (ADP-ribose) -polymerase inhibitor (PARPi).

8. A PARPi for use in treating or improving a proliferative disease in a patient, wherein the treating and improving the proliferative disease comprises administering the PARPi and administering the ALC1i for use according to claims 1 to 4, the bifunctional compound according to claim 5, or the pharmaceutical composition according to claim 6.

9. The ALC1i for use according to claim 7 or the PARPi for use according to claim 8, wherein the PARPi reduces PARP activity and / or inhibits PARP1, PARP2 and / or PARP3 on chromatin, preferably PARP2, wherein preferably (i) PARPi that reduces PARP activity is selected from small interfering RNA, and (ii) PARPi that inhibits PARP1 is selected from the following compounds: (a) Formula (II) and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein: A and B together represent an optionally substituted fused aromatic ring; X is NR X or CR X R Y ; If X = NR X , then n is 1 or 2, and if X=CR X R Y , then n is l; R X is selected from H, optionally substituted C l-20 Alkyl, C 5-20 Aryl, C 3-20 heterocyclic groups, amide groups, thioamide groups, ester groups, acyl groups, and sulfonyl groups; R Y Selected from H, hydroxyl, amino; or R X and R Y Can form spiro-C 3-7 Cycloalkyl or heterocyclic group; R C1 and R C2 are independently selected from hydrogen and C l-4 Alkyl, or when X is CR X R Y When R C1 , R C2 , R X and R Y together with the carbon atoms to which they are attached are capable of forming an optionally substituted fused aromatic ring; and R 1 is selected from H and halo; as well as (b) Formula (III) and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein: Y and Z are each independently selected from:

1. Aryl optionally substituted by 1, 2 or 3 R6; 2. heteroaryl optionally substituted by 1, 2 or 3 R6; 3. Substituents independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonylalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (R A R B )alkylene, (NR A R B )carbonyl, (NR A R B )carbonyl alkylene, (NR A R B )sulfonyl and (R A R B )sulfonylalkylene; Wherein each R6 is selected from OH, NO2, CN, Br, Cl, F, I, C 1-6 -alkyl, C 3-8 -Cycloalkyl, C 2-8 -heterocycloalkyl, C 2-6 -alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 2-6- Alkynyl, aryl, arylalkyl, C 3-8 -cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C 2-8 -heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (R A R B )C 1-6 -alkylene, (NR A R B )carbonyl, (R A R B )carbonyl alkylene, (NR A R B )sulfonyl and (NR A R B )sulfonylalkylene; R1, R2 and R3 are each independently selected from hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkylene, nitro, NR A R B NR A R B Alkylene and (R A R B )carbonyl; A and B are each independently selected from hydrogen, Br, Cl, F, I, OH, C 1-6 -alkyl, C 3-8 -cycloalkyl, alkoxy, alkoxyalkyl, where C 1-6 -alkyl, C 3-8 -cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted by at least one substituent selected from the group consisting of OH, NO2, CN, Br, Cl, F, I, C 1-6 -alkyl and C 3-8 - cycloalkyl, wherein B is not OH; R A and R B RA and RB, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring optionally having one to three heteroatoms or heterofunctional groups selected from the group consisting of: -O-, -NH, -N(C 1-6 -alkyl)-, -NCO(C 1-6 -alkyl)-, -N(aryl)-, -N(aryl-C 1-6 -alkyl-), -N(substituted-aryl-C 1-6 -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C 1-6 alkyl-)- and -S- or S(O)q-, wherein q is 1 or 2, and the 3-10 membered heterocyclic ring is optionally substituted with one or more substituents; R4 and R5 are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene and (NR A R B ) alkylene; and isomers, salts, solvates, chemically protected forms and prodrugs thereof; (iii) PARPi that inhibits PARP1 and PARP2 is selected from the following compounds: (a) Formula (IV) and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein: R1 is hydrogen or fluorine; and R2 is hydrogen or fluorine; as well as (b) Formula (V) and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein: R1, R2 and R3 are independently selected from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B and (NR A R B )carbonyl; A is a non-aromatic 4-, 5-, 6-, 7-, or 8-membered ring containing 1 or 2 nitrogen atoms and optionally one sulfur or oxygen atom, wherein the non-aromatic ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocycloalkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NR C R D ,(NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl and (NR C R D )sulfonyl; and R A , R B , R C and R D independently selected from hydrogen, alkyl and alkylcarbonyl (iii) PARPi that inhibits PARP1, PARP2 and PARP3 is a compound of formula (VI) and isomers, salts, solvates, chemically protected forms and prodrugs thereof, wherein: R is: H; halogen; cyano; optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro and amino, alkoxy, alkyl and aryl unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, carboxyl, and optionally substituted amino and ether (e.g., O-aryl)); or -C(O)-R 10 , where R 10 is: H; optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halo, hydroxy, nitro, amino, and alkyl and aryl unsubstituted or substituted with one or more substituents selected from halo, hydroxy, nitro and amino); or OR 100 or NR 100 R 110 , where R 100 and R 110 each independently is H or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl that are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl and aryl that are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro and optionally substituted amino); R2 is H or alkyl; R3 is H or alkyl; R4 is H, halogen or alkyl; X is O or S; Y is (CR5R6)(CR7R8) n or NC(R5), where: n is 0 or 1; R5 and R6 are each independently H or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl, lower alkoxy or aryl which are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro and amino); and R7 and R8 are each independently H or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl, lower alkoxy and aryl which are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro and amino); wherein when R1, R4, R5, R6 and R7 are each H, R8 is not unsubstituted phenyl.

10. The ALC1i for use according to claim 7 or 9 or the PARPi for use according to claim 8 or 9, wherein the PARPi is selected from olaparib, talazoparib, niraparib, rucaparib and veliparib, in particular selected from veliparib, olaparib and talazoparib.

11. ALC1i for use according to claim 7 or 9 to 10 or PARPi for use according to claims 8 to 10, wherein the proliferative disease is selected from BRCA-1 and / or BRCA-2 deficient tumors and tumors with increased expression of PARP-1, PARP-2, PARP-3 and / or ALC1 compared to non-tumor cells, and / or wherein the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, colorectal cancer.

12. ALC1i for use according to claims 7 or 9 to 11 or PARPi for use according to claims 8 to 11, wherein the PARPi and the ALC1i or the bifunctional compound are administered concomitantly or separately.

13. A multi-component kit comprising separately packaged PARPi and ALC1i according to claims 1 to 4, or a bifunctional compound according to claim 5, or a composition comprising PARPi and ALC1i according to claims 1 to 4, or a bifunctional compound according to claim 5, preferably with instructions for use in treating or ameliorating a proliferative disease.

14. The ALCi for use according to claims 1 to 4, the pharmaceutical composition according to claim 6, the ALC1i for use according to claims 7 or 9 to 13, or the PARPi for use according to claims 8 to 12, or the kit according to claim 13, wherein the proliferative disease is selected from BRCA1 and / or 2-deficient tumors and tumors with increased expression of PARP1, PARP2, PARP3 and / or ALC1 compared to non-tumor cells.

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