Use of ALC1 inhibitors and synergy with PARPI

Abstract

The present invention relates to the use of small molecule compounds that allosterically inhibit ALC1 (CHD1L) and induce PARP1, PARP2 and / or PARP3 to be captured on chromatin or at sites of DNA damage to treat proliferative diseases. Disrupting the chromatin remodeling power of ALC1 through these agents allows highly selective therapy targeting the DNA damage function of PARP enzymes in several proliferative diseases, especially BRCA-deficient tumors. Through inhibition of enzyme activity, the compounds are involved in synthetic lethality between mutations in the HRD pathway, including BRCA1 / 2 and ALC1. By complementing the PARP enzyme, inhibitors of ALC1 enhance the cancer cell killing properties of PARP inhibitors, allowing therapeutic solutions when ALC1 is amplified as an oncogene, which allows therapeutically overcoming PARP inhibitor resistance mechanisms, allowing alternative solutions to the treatment of germline or acquired BRCA1 / BRCA2 deficiencies, including tumors defined by "BRCAness" or other changes in the DNA repair network.

Description

[Technical field]

[0001] The present invention relates to small molecule compounds that allosterically inhibit ALC1 (CHD1L) and exert synergistic inhibitory effects with enzymes of the PARP family. These inhibitors have antiproliferative activity in cancers with acquired BRCA1 or BRCA2 deficiency. Disruption of the chromatin remodeling forces of ALC1 through these agents allows highly selective therapy targeting the DNA-damaging function of PARP enzymes in several proliferative diseases, especially BRCA-deficient cancers. The compounds mediate synthetic lethality between BRCA1 / 2 and ALC1 through inhibition of enzymatic activity. By exerting synergy with PARP enzyme inhibitors, ALC1 inhibitors enhance the cancer cell killing properties of these PARP inhibitors, making them effective therapeutic solutions when ALC1 is amplified as an oncogene. In addition, these ALC1 inhibitors overcome PARP inhibitor resistance mechanisms and are effective as alternative solutions for the treatment of germline or acquired BRCA1 / BRCA2 deficiencies, including tumors defined by "BRCAness" or other alterations in the DNA repair network. [Background technology]

[0002] To recognize single- and double-strand breaks (SSB / DSB), nuclear poly-ADP-ribose polymerase (PARP) enzymes are early and key factors in the DNA damage response (DDR). Using the metabolite NAD+, PARP-1 and -2 add poly-ADP-ribose (PAR) chains to chromatin components and to factors belonging to the DDR, while PARP-3 targets chromatin components via mono-ADP-ribosylation. PARP gains recruitment to DNA lesions by recognizing specifically modified DNA damage-induced structures, which activates its PARylation activity, which in turn controls its activity and that of other DDR and chromatin proteins, promoting the DDR (Ray Chaudhuri and Nussenzweig, 2017).

[0003] This catalytic activity is + It can be inhibited by analogs, and has been of particular interest and clinical utility in genetically defined cancers. In particular, in the context of BRCA1 or BRCA2 deficiency, so-called PARP inhibitors (PARPi) are used to treat homologous recombination (HR)-deficient and other cancers by targeting synthetic lethality. 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). Molecularly, "trapping" remains poorly defined, and the term defines the enhanced recruitment, binding and / or retention of PARP-1 / 2 / 3 enzymes to damaged chromatin, typically induced by treating PARP-1 enzymes with PARP inhibitors (PARPi) or by reducing the release of PARP-1 / 2 / 3 enzymes after their initial recruitment, resulting in long-term retention. Biochemically, this is manifested in enhanced steady-state association / retention / binding ("trapping") of the PARP enzyme at the damaged genomic region / locus.

[0004] With the clinical advent of PARPi, PARP-1 has emerged as a powerful target for a growing array of cancers, including in combination with immuno-oncology therapies such as the Lynparza / Keytruda trial, conferring all but one of many examples, and even enabling application in settings other than frontline PARPi therapy and germline BRCA-1 / 2 mutations. Importantly, all clinical PARPi compounds inhibit the substrate NAD + The main purpose of this study is to block the binding of NAD, which inevitably binds to the same site in the catalytic center of the active site, thus preventing poly(ADP-ribose) synthesis. + This is because its structure is similar to that of nicotinamide, which is part of a nucleotide.

[0005] However, PARPis in the clinic show widely different clinical effects in tumor killing and patient outcomes. One fundamental difference in the action of these PARPis is that they promote the trapping of PARP-1 / -2 on chromatin at widely different levels. Currently, it is generally believed that the most potent and clinically effective PARPis trap PARP-1 at the site of DNA breaks much more potently than less clinically useful PARPis. Trapping PARP makes DNA lesions more cytotoxic, especially in mutant tumor cells that have genetic or epigenetic defects in repairing DNA strand breaks, such as functionally HR-deficient BRCA-1 / 2 mutant tumor cells. Furthermore, while all enzymes are involved in sensing DNA strand breaks and recruiting to DNA damage sites, it is currently unclear how PARP-1, PARP-2, and PARP-3 contribute relatively or predominantly because both PARP-1 and PARP-2 promote PARylation of chromatin factors and all existing clinical PARPi molecules barely distinguish between the two related PAR polymerase enzymes PARP-1 and PARP-2. As a result, PARP trapping is thought to lead to DNA replication stress, genomic instability, and cell death in cancer cells (Lord and Ashworth, 2012). For example, enhanced trapping of PARP1 is thought to lead to enhanced ability to kill cancer cells, especially cancers with defective DNA repair pathways (Zandarashvili et al., 2020). Figure 1 shows the cytotoxic mechanism of PARPi-mediated PARP trapping.

[0006] "PARP trapping" is thus described as (enhanced) binding of PARP-1 and / or PARP-2 and / or PARP-3 to chromatin in viable cells. PARPis can be used to disrupt allosteric mechanisms that contribute to PARP-1 binding to DNA (Zandarashvili et al., 2020), with certain PARPis contributing to retention and others promoting pro-release mechanisms based on the interaction of PARP-1, PARPi and DNA in vitro (Zandarashvili et al., 2020). Talazoparib-treated U2OS cells show enhanced retention of GFP-tagged PARP1 and PARP2 at induced DNA lesions, whereas veliparib-treated cells show overall less recruitment of PARP1 / PARP2 to DNA lesions.

[0007] Either PARP-1 or PARP-2 is required for the full recruitment of SSB repair proteins to the damage site. Through PARylation, chromatin remodeling or histone modifying enzymes are activated at the sites of DNA damage, 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).

[0008] Activation of PARP-1 and / or PARP-2 enzymes leads to the recruitment of numerous proteins, particularly also specific chromatin remodeling enzymes, including the macrodomain-containing nucleosome remodeler ALC1 (CHD1L) (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017). Macrodomains generally bind ADP-ribose, oligo-ADP-ribose and poly-ADP-ribose (Karras et al., 2005), and thus macrodomain-containing proteins are recruited in response to PARP activation sites on the genome during DNA damage, including relevance to cancer. Importantly, binding of PARs or oligo-ADP-ribose to the macrodomain of ALC1 tightly switches on chromatin remodeling activity (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017), marking ALC1 as an allosterically regulated chromatin remodeling enzyme, the first of its kind and one of the very few whose catalytic activity is directly regulated by PARs. In addition, ALC1 has been identified as an oncogene and is frequently 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 and / or nucleosome remodeling functions of ALC1, may potentiate the action of PARPi, enhance cancer cell killing, and / or reduce off-target effects, thus reducing cytotoxicity in non-cancer cells. The fact that altering the expression levels of ALC1 (by CRISPR-based knockout) affects the sensitivity of cancer cells to PARP inhibitors also provides an opportunity for altering the activity levels of ALC1 to overcome PARP inhibitor resistance, as ablation of ALC1 robustly enhances the PARPi olaparib to levels that may be sufficient to circumvent PARPi resistance, including (but not limited to) reversion of the BRCA-deficient state (e.g., by internal deletion or via loss of epigenetic BRCA1 / 2 gene silencing).Because the sensitivity of cancer cells to PARP inhibitors is generally accepted to result from the ability of PARPi to trap PARP1 (and possibly PARP2 enzymes, but this has not been formally established in the art) on chromatin, the inventors hypothesized that small molecule ALC1 inhibitors could mediate PARPi sensitization. Specifically, the inventors hypothesized that small molecule inhibition of ALC1 would promote accumulation of DNA damage and killing of cancer cells.

[0009] Since ALC1 is upregulated in several tumors and has been validated as an oncogene in hepatocellular carcinoma (Cheng et al., 2013; Li et al., 2019; Su et al., 2014), inhibition of ALC1 via small molecule inhibitors may result in robust changes in the DNA damage response. We hypothesized that small molecule-mediated manipulation of ALC1 activity could induce potent antiproliferative effects and be sufficient to bypass low or high levels of PARPi resistance. Thus, in addition to its potential use as a monotherapy, the combination of ALC1 and PARP-1 / 2 inhibition could be utilized to refine PARP-targeted therapy in oncology.

[0010] This hypothesis led to the present invention that ALC1 manipulation 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 in BRCA-deficient and more generally in HRD-high tumors, since it is well documented that PARP inhibition is synthetic lethal with loss of BRCA-1 / 2 tumor suppressor function. Based on preclinical and clinical evidence, ALC1 inhibition could therefore serve as an additional therapeutic solution for cancers with intact HR pathways and / or allow targeting ALC1-amplified tumors by disrupting the oncogene function of ALC1. Also, because the ALC1 gene is a key mediator of PARP-chromatin relocation upon DNA damage induction ( Sellou et al., 2016 ), small molecules targeting ALC1 activity may affect the nuclear DNA damage-related function of PARP-1 / 2 / 3 in chromatin relocation without affecting other roles of PARP-1 / 2 / 3 inside or outside the cell 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.

[0011] Given the above-mentioned relevance of ALC1 for various proliferative diseases, particularly diseases that are BRCA1 / 2 deficient, the present invention provides a series of novel compounds for treating or ameliorating oncological diseases, particularly certain oncological diseases characterized by increased activity of ALC1, e.g., due to increased expression. Moreover, the inventors have determined that the action 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) an effective treatment of tumors that are HRD-deficient and therefore sensitive to PARPi, (ii) a treatment that mediates PARPi sensitization, (iii) a treatment that circumvents PARPi resistance, and / or (iv) a treatment that allows a reduction in the amount of PARPi administered. Summary of the Invention

[0012] In a first aspect, the present invention provides a compound of formula (I): [ka] [In formula: A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or if A6 is involved in the ring formation of Z which is a carbocycle or heterocycle, then A6 is C; A7 is selected from N or CH, or if A7 is involved in the ring formation of Z which is a carbocycle or heterocycle, then A7 is C; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4; L3 is selected from the group consisting of -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- or 6-membered heterocycle substituted with R4 and / or R5; L4 is -CH2-, -CF2-, -CH2-CH2-, -CH2-CH2-CH2-, O, N, NH, or absent; Z is a 5-, 6-, or 7-membered carbocycle or heterocycle, optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; may be ringed to a central core or connected via covalent bonds; R4 is a 5-, 6-, or 7-membered carbocycle or heterocycle, optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -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 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe; or R6 is H; or When A7 is involved in the ring formation of Z which is a carbocycle or heterocycle, 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 pharma- ceutically acceptable salt thereof, which is an inhibitor of ALC1 (ALC1i) for treating or ameliorating a proliferative disease in a patient.

[0013] In a second aspect, the present invention relates to a bifunctional compound comprising ALC1i for use as identified in the first aspect of the present invention and a compound that recruits E3 ubiquitin ligase to ALC1 (E3 recruiter), wherein ALC1i and the E3 recruiter are covalently linked, optionally via a linker.

[0014] In a third aspect, the present invention relates to a pharmaceutical composition comprising an ALC1i for use in the first aspect of the invention, or a bifunctional compound of the second aspect of the invention, and one or more pharma- ceutically acceptable excipients.

[0015] In a fourth aspect, the present invention relates to ALC1i in use according to the first aspect of the invention, or a bifunctional compound according to the second aspect of the invention, for use in treating or ameliorating a proliferative disease, wherein treating or ameliorating the proliferative disease comprises administering the ALC1i or the bifunctional compound, and administering a poly(ADP-ribose) polymerase inhibitor (PARPi).

[0016] In a fifth aspect, the present invention relates to a PARPi for use in treating or ameliorating a proliferative disease in a patient, wherein treating or ameliorating the proliferative disease comprises administering said PARPi, and administering an ALC1i for use according to the first aspect of the invention, or administering a bifunctional compound according to the second aspect of the invention.

[0017] In a sixth aspect, the present invention relates to a kit of parts comprising a PARPi and an ALC1i for use in the first aspect of the invention, or a bifunctional compound of the second aspect of the invention, packaged separately, or comprising a composition comprising a PARPi and an ALC1i, preferably together with instructions for use in treating or ameliorating a proliferative disease. [Brief description of the drawings]

[0018] The contents of the drawings contained in this specification are described below, in which context reference is also made to the detailed description of the invention given above and / or below. [Figure 1] The cytotoxic mechanism of PARPi in DNA repair pathways leading to PARP trapping. The upper pathway shows that PARPi interferes with DNA repair of single-strand breaks (SSBs) through 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 utilizing additional repair pathways including Fanconi pathway (FA), template switching (TS), ATM, FEN1 (replicative flap endonuclease) and DNA polymerase β (Murai et al., 2012, S. 5591). [Diagram 2] Figure 1 shows that the chromatin remodeler ALC1 (CHD1L) is frequently 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 associated chromatin remodeler CHD1 are shown in the genomes of 10792 breast, fallopian tube, and ovarian cancer patients (OncoPrint analysis performed on 08 / 12 / 2020 in cBioPortal (www.cbioportal.org)). Percentage numbers indicate the percentage of alterations of a given gene in the whole genome where that particular gene was profiled. Gene amplifications (black), deep gene deletions (dark grey) are highlighted. Compared with CHD1, ALC1 was more frequently co-amplified with PARP1 (ALC1-PARP1: odds ratio (OR)=1.581, q-value=<0.001; CHD1-PARP1: OR=-0.125, q-value=0.250). When tumors showed deep deletions or mutations in the BRCA1 or BRCA2 tumor suppressor genes, neither ALC1 nor PARP1 showed 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). [Diagram 3]Shown is a 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) cells were seeded in 96-well plates and treated with different titrations of ALCi starting at 50 μM. Cells were cultured at 37°C, 5% CO2 for 4 days, fixed with 10% TCA, and stained with sulforhodamine staining to analyze cell viability. Data was normalized to DMSO control representing 100% viability. Inhibitors were fitted to response curves with variable slope (4 parameters) using GraphPad Prism. Standard deviation bars are shown for two technical replicates. [Figure 4] PARPi co-treatment cell proliferation assay of pancreatic cancer cells. PSN-1 cells were seeded in 96-well plates and treated with PARPi against ALC1i in a 2-D titration. Cells were cultured at 37°C, 5% CO2 for 4 days, fixed with 10% TCA, and stained using sulforhodamine staining to analyze cell viability. Single agent titration curves are shown on the left, dose-response matrix is ​​shown in the middle, and calculation of synergy scores is shown on the right. Treatment with ALC1i-1002 and Talazoparib, Olaparib, or Niraparib shows the most synergistic area scores of 14.28, 13.27, and 15.41, respectively. ZIP synergy scores above 0.0 indicate significant synergy. [Diagram 5] The structural formulas and related compound codes of ALC1 inhibitors are shown. [Figure 6] Nucleosome remodeling inhibition is shown. The IC50 (μM) of ALC1 inhibitors in the FRET-based nucleosome remodeling assay is shown. IC50 values ​​are represented by the following symbols: +++: IC50<25μM; ++: IC50=25-100μM; +: IC50=>100-250μM; and "-": compound is inactive, i.e. no inhibition of >50% is observed. [Figure 7]Figure 1 shows the cell proliferation inhibition EC50 (μM) of ALC1 inhibitors in a 4-day cell proliferation assay with an SRB-based readout. EC50 values ​​are represented by the following symbols: +++: EC50 < 10 μM; ++: EC50 = 10-25 μM; +: EC50 = > 25-50 μM; and "-": compound is inactive, i.e. no inhibition of > 50% is observed. [Figure 8] A table is provided including the supplier used for each inhibitor. [Figure 9] 1 shows a general synthesis scheme for inhibitors of formula I. [Figure 10] 1 shows a general synthesis scheme for inhibitors of formula I. [Figure 11] A table is shown containing the % inhibition of ALC1 in a FRET-based nucleosome sliding assay for each inhibitor at a compound concentration of 250 μM. For some compounds, the 250 μM concentration had to be lowered due to solubility issues, as indicated in the legend at the bottom of the table. [Figure 12] EC50 values ​​of ALCi-treated HR-proficient (HRP) and HR-deficient (HRD) cells subjected to SRB assay for 96 h and colony formation assay for 11 days are shown. Different cancer cell lines (downloaded from https: / / depmap.org / portal / ) with various deleterious mutations in the homologous recombination repair pathway (HR) were seeded in 96-well plates and treated with different titrations of ALCi starting at 50 μM. Cells were cultured at 37 °C and 5% CO2 for 4 days (96 h) or 11 days (colony formation), fixed with 10% TCA, and stained with sulforhodamine staining method to analyze cell viability. Data were normalized to DMSO control representing 100% viability. Inhibitors were fitted to response curves with variable slope (4 parameters) using GraphPad Prism. Standard deviation bars are shown for two technical replicates. [Figure 13]A list of genes involved in the DNA damage response (DDR) cited in Wood RD, Mitchell M & Lindahl T, Mutation Research, 2005, Science, 2001, the reference books DNA Repair and Mutagenesis, 2nd edition, 2006, and Nature Reviews Cancer, 2011 (Human DNA Repair Genes, nd) (modified by R. Wood and M. Lowery on Wednesday, June 10, 2020). [Figure 14] A list of genes related to the homology-directed repair pathway (HR) is shown. A summary of genes derived from HRD-signature genes from Toh & Ngeow, 2021; Kim et al., 2021; Yamamoto & Hirasawa, 2021, and Pent et al., 2021 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Before the present invention is described in detail below, it is to be understood that the present invention is not limited to the specific methodology, protocols, and reagents described herein, which may vary. It is also to be understood that the terms used herein are for the purpose of describing specific embodiments only, and are not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0020] Several documents are cited throughout the text of this specification. Each document cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by prior invention. Some of the documents cited herein are characterized as "incorporated by reference." In the event of a conflict between a definition or teaching of such an incorporated document and a definition or teaching cited herein, the body of this specification shall control.

[0021] The components of the present invention will be described below. Although these components are listed with specific embodiments, it should be understood that they can be combined in any manner and in any number to produce further embodiments. The various described examples and preferred embodiments should not be construed as limiting the present invention to only the embodiments explicitly described. This description should be understood to support and encompass embodiments that combine the explicitly described embodiments with any number of the disclosed components and / or preferred components. Furthermore, any permutation and combination of all components disclosed in this application should be considered to be disclosed by the description of this application, unless the context indicates otherwise.

[0022] definition To practice the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA techniques described in the literature of the art will be utilized (see, e.g., Molecular Cloning: A Laboratory Manual, 2nd Edition, edited by J. Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989). Provided below are definitions of several terms frequently used herein that have their respective defined and preferred meanings in each instance of their use in the remainder of the specification. 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.

[0023] The term "chromodomain-helicase-DNA-binding protein 1-like" refers to the protein abbreviated as CHD1L and also called ALC1. The amino acid sequence of human ALC1 is as specified 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 40-513, which contains a conserved helicase motif important for catalysis (Flaus et al., 2006). This domain is composed of two RecA-like lobes ranging from amino acid residues 48-261 and 351-513, respectively. The structure of the truncated N-terminal lobe of the ATPase domain has been determined by homology modeling to identify a putative allosteric binding site, and the minimal coordinate file of this model is provided in FIG. 20, allowing one of skill in the art to identify model compounds within the allosteric binding pocket defined for the first time by the present inventors. The allosteric binding pocket is spatially separated from the portion 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 activation of the chromatin remodeling enzyme.

[0024] 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 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, such as methyl, ethyl, propyl (n-propyl or iso-propyl), butyl (n-butyl, iso-butyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, octyl, nonyl, decyl. An alkyl group may be optionally substituted. 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 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, 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, where 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', where R'=H or a hydrocarbon (e.g., C1-C6 alkyl). In particular, "heteroalkyl" includes -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. A heteroalkyl group may be optionally substituted.

[0025] The term "haloalkyl" refers to a saturated straight or branched carbon chain in which one or more hydrogen atoms have been replaced with a halogen atom, such as fluorine, chlorine, bromine or iodine. Preferably, the chain contains 1 to 10 carbon atoms, 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 groups may be optionally substituted. The term "carbocycle" is used in the context of the present invention to refer to a monocyclic, bicyclic or tricyclic "cycloalkyl", "cycloalkenyl", "spiroalkyl", "spiroalkenyl" or "aryl", in which the ring is formed by carbon atoms. Carbocycles may be optionally substituted.

[0026] The term "5-, 6- or 7-membered carbocycle" is used in the context of the present invention to refer to "cycloalkyl", "cycloalkenyl", "spiroalkyl" or "aryl", preferably having 5, 6 or 7 ring-forming carbon atoms, "cycloalkyl" or "cycloalkenyl" or phenyl. The term "cycloalkyl" includes cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may be optionally substituted. The term "cycloalkenyl" includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups can be optionally substituted. The term "aryl" refers to phenyl, which may be optionally substituted, for example, naphthyl.

[0027] 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"; in which at least one of the carbon atoms is replaced by 1, 2 or 3 in a monocyclic heterocycle, or 1, 2, 3 or 4 in a bicyclic heterocycle, which are the same or different heteroatoms, preferably selected from O, N and S. The term "5-, 6- or 7-membered heterocycle" is used in the context of the present invention to refer to a monocyclic "5-, 6- or 7-membered heterocycloalkyl" or a monocyclic "5-, 6- or 7-membered heteroaryl" having 5, 6 or 7 ring-forming carbon atoms.

[0028] The term "5-, 6- or 7-membered heterocycloalkyl" refers to a saturated monocyclic ring in which at least one of the carbon atoms is replaced with 1 or 2 (for 5-membered ring), 1, 2 or 3 (for 6-membered ring), or 1, 2, 3 or 4 (for 7-membered ring) heteroatoms, preferably the same or different, selected from O, N and S. Preferred examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, or 2-piperazinyl. Heterocycloalkyl groups may be optionally substituted.

[0029] 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 of the carbon atoms is replaced with 1, 2 or 3 (for 5-membered rings) or 1, 2, 3 or 4 (for 6-membered rings) heteroatoms, preferably the same or different, selected from O, N and S. Examples of preferred heteroaryls include 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 may be optionally substituted.

[0030] When two or more groups may be selected independently of each other, then the term "independently" means that the groups may be the same or different. The term "optionally substituted" in each instance, unless further specified, refers 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; R' and R'' are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl, or together form heteroaryl, or heterocycloalkyl; R''' and R'''' are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R''; E is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, alicyclic, aryl, and heteroaryl; and is optionally substituted.

[0031] "Pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia (United States Pharmacopeia-33 / National Formulary-28 Reissue, Published by the United States Pharmacopeial Convention Corp., Rockville, Maryland, Publication Date: April 2010) or other pharmacopoeias generally approved for use in animals, and more specifically, in humans.

[0032] The term "pharmaceutical acceptable salt" refers to a salt of the compound of the present invention. Suitable pharmaceutical acceptable salts of the compound of the present invention include acid addition salts, which may be formed, for example, by mixing a solution of the compound described herein or its derivative with a solution of a pharmaceutical 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. Furthermore, when the compound of the present invention has an acidic moiety, suitable pharmaceutical acceptable salts 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 with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkylsulfonates, and arylsulfonates).Specific examples of pharma- ceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, dibenzoate, diisopropyl ether ... Gluconate, dihydrochloride, dodecyl sulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolyl arsenate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodine , 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, paclitaxel Examples of suitable salts include moate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, undecanoate, valerate, and the like (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 group properties, allowing the compounds to be converted into either base or acid addition salts.

[0033] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent compounds of the compounds for purposes of this invention.

[0034] In addition to salt forms, the present invention provides compounds in the form of prodrugs. Prodrugs as described herein are those compounds that undergo easy chemical changes under physiological conditions to provide the compounds of formula (I)-(IV), particularly those shown in FIG. 14. Prodrugs are active or inactive compounds that are chemically modified to the compounds of the present invention through in vivo physiological action, such as hydrolysis, metabolism, and the like, after the prodrug is administered to a patient. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir containing the appropriate enzyme. The suitability and techniques for making and using prodrugs are well known to those skilled in the art. For a general description of prodrugs, including esters, see Svensson LA and Tunek A. (11988) 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 are masked as arylcarbonyloxymethyl-substituted derivatives that are cleaved by esterases in vivo to release free drug and formaldehyde (Bundgaard H. et al., (1989) J. Med. Chem. 32(12):2503-2507). Drugs containing acidic NH groups, such as imidazole, imide, indole, etc., are also masked with N-acyloxymethyl groups (Bundgaard H. "Design of Prodrugs", Elsevier Science Ltd. (1985)). Hydroxy groups are masked as esters and ethers.EP 0039051A2 discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

[0035] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), element-125( 125 I) or carbon-14( 14 C). 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. As used herein, when referring to an aryl substituent, "para" means that the substituent occupies the position opposite to the position at which the aryl is attached to the backbone of the compound.

[0036] As used herein, a "patient" refers to any mammal or bird that may benefit from treatment with the compounds described herein. Preferably, the "patient" is selected from the group consisting of laboratory animals, livestock, or primates, including chimpanzees and humans. It is particularly preferred that the "patient" is a human. As used herein, "treat," "treating," or "treatment" of a disease or disorder means achieving one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing the onset of symptoms characteristic of the disorder being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder being treated; (d) limiting or preventing the recurrence of the disorder in a patient previously suffering from the disorder; and (e) limiting or preventing the recurrence of symptoms in a patient previously suffering from symptoms of the disorder.

[0037] As used herein, "prevent", "preventing", "prevention" or "prevention" of a disease or disorder means preventing the disorder from occurring in a subject for a certain period of time. For example, when 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, preferably up to one or more days after the day of administration (e.g., 1 to 30 days; or 2 to 28 days; or 3 to 31 days; or 4 to 14 days; or 5 to 10 days).

[0038] 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 in the form of a combined preparation, in which the active ingredients are partially or totally present in different forms. An example of such a combination or combined preparation is a kit-of-parts. 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 to which the therapeutic agent is administered, and the purpose of the administration. The effective amount in each individual case can be empirically determined by one of ordinary skill in the art using methods established in the art.

[0039] The term "carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle in which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water, oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Saline solutions are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition can also contain minor amounts of wetting or emulsifying agents, or pH adjusters, if desired. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. The compositions may be formulated as suppositories using traditional binders and carriers, such as triglycerides. The compounds of the present invention may be formulated as neutral or salt forms. 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, and the like, and salts formed with free carboxyl groups, such as salts derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, and the like. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier to provide the form for proper administration to the patient. The formulation must suit the mode of administration.

[0040] EMBODIMENTS OF THE PRESENTINVENTION The present inventors have identified and characterized ALC1 inhibitors that appear to be involved in the allosteric regulation of ALC1 nucleosome sliding activity. These compounds have the ability to specifically bind to the allosteric pocket and inhibit the activity of ALC1. Compounds that bind to the ATPase site of ALC1 and block the ATPase activity need to compete with ATP to bind to the ATPase site. Since intracellular ATP concentrations range from 1 to 10 mM depending on the cellular 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 need to prevent ATP from binding and inhibit the ATPase activity of ALC1 through a different mechanism. The present inventors have identified compounds that have the ability to specifically bind to the allosteric pocket of ALC1. These compounds were also tested for their ability to kill two different tumor cell lines, one of which is BRCA-deficient.

[0041] Thus, in a first aspect, the present invention provides a compound of formula (I): [ka] [In formula: A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or if A6 is involved in the ring formation of a carbocycle or heterocycle Z, particularly a 5-, 6-, or 7-membered carbocycle or heterocycle, then A6 is C; A7 is selected from N or CH, or if A7 is involved in the ring formation of a carbocycle or heterocycle Z, particularly a 5-, 6-, or 7-membered carbocycle or heterocycle, then A7 is C; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4; L3 is selected from the group consisting of 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- or 6-membered heterocycle substituted with R4 and / or R5; L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N, NH, or absent; Z is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; it can be ring-formed with the central nucleus or connected via a covalent bond; R4 is a 5-, 6- or 7-membered carbocycle or heterocycle, optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -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 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5-, 6-, or 7-membered carbocycle or heterocycle, optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe; Or R6 is H; or When A7 participates in the ring formation of a carbocycle or heterocycle 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 pharma- ceutically acceptable salt thereof for treating or ameliorating a proliferative disease in a patient.

[0042] The ALC1i of formula (I) preferably exhibits >50% inhibition at a concentration of 250 μM or less, and preferably has an IC 50 is <250 μM, more preferably <25 μM. 50 is preferably measured using the FRET-based nucleosome remodeling assay described in the Examples. The ALC1i represented by formula (I) is preferably EC 50 is <250 μM, preferably <50 μM; more preferably <10 μM. 50 is preferably measured in a cell proliferation assay with an SRB-based readout as described in the Examples.

[0043] In an embodiment of the first aspect, A5 and A6 are N; A7 is involved in the ring formation of a carbocyclic or heterocyclic ring Z, particularly a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, particularly a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2. It is preferable.

[0044] In an embodiment of the first aspect, A5 and A6 are N; A7 is involved in the ring formation of a carbocycle or heterocycle, preferably a carbocycle Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and A8 is -CH2-N, -CH2-CH, or -NH-CH, preferably -NH-CH It is preferable. In an embodiment of the first aspect, A5 is N and A8 is -N or -CH It is preferable. In an embodiment of the first aspect, A5 is N and A8 is -N or -CH; A6 is involved in the ring formation of a carbocycle or heterocycle, preferably a carbocycle Z. It is preferable. In particularly preferred embodiments, A5, A7 and A8 are N.

[0045] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is involved in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2. In a particularly preferred embodiment, A5, A7 and A8 are N and A6 participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2.

[0046] In an embodiment of the first aspect, L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4 It is preferable. In an embodiment of the first aspect, L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -NH-R4; and R4 is a 6-membered aryl, or a 5-, 6- or 7-membered heteroaryl, preferably a 5- or 6-membered heteroaryl, which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH. It is preferable.

[0047] In an embodiment of the first aspect, L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; It is preferable. In an embodiment, L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, -CH2-CF2-R5; and R5 is a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered carbocyclic or heterocyclic ring, which is optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. It is preferable.

[0048] In an embodiment of the first aspect, L2 and L3 together with A8 to which they are attached form a 5- or 6-membered heterocycle substituted with R4 and R5. It is preferable. In an embodiment of the first aspect, L2 and L3 together with A8 to which they are attached form a 5- or 6-membered heterocycle substituted with R4 and R5; R4 is hydrogen, methyl, or COOH; R5 is a 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, preferably phenyl, or a 5- or 6-membered heteroaryl, which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. It is preferable.

[0049] In an embodiment of the first aspect, L4 is preferably absent. In a particularly preferred embodiment, A5, A7 and A8 are N and L4 is absent. In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L4 does not exist.

[0050] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L4 does not exist. In particularly preferred embodiments, A5, A7 and A8 are N; L4 absent; R6 is a 6-membered aryl or a 5-, 6- or 7-membered heteroaryl, optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0051] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L4 absent; R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0052] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 absent; R6 is a 6-membered aryl or a 5-, 6- or 7-membered heteroaryl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In particularly preferred embodiments, A5, A7 and A8 are N; L4 absent; R6 is phenyl and is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0053] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 is absent; and R6 is phenyl and is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0054] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 is absent; and R6 is phenyl, optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0055] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 is absent; and R6 is phenyl, optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0056] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 is absent; and R6 is phenyl and is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0057] In an embodiment of the first aspect, R4 is hydrogen, methyl, COOH or tetrazolyl It is preferable. In an embodiment of the first aspect, L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl It is preferable. In an embodiment of the first aspect, R5 is any 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered carbocyclic or heterocyclic ring, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe. It is preferable.

[0058] In an embodiment of the first aspect, R5 is C4-C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6-C 10 Bicycloalkyl, i.e., C6, C7, C8, C9 or C 10 Bicycloalkyl, C6-C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably unsubstituted phenyl, or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. It is preferable.

[0059] In an embodiment of the first aspect, L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, -CH2-CF2-R5; and R5 is C4-C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6-C 10 Bicycloalkyl, i.e., C6, C7, C8, C9 or C 10 Bicycloalkyl, C6-C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. It is preferable.

[0060] In an embodiment of the first aspect, R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which is optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe; Or R6 is H It is preferable. In an embodiment of the first aspect, L4 is absent; and R6 is a 5- or 6-membered carbocyclic or heterocyclic ring, preferably a 6-membered carbocyclic or heterocyclic ring, which is optionally substituted with 1, 2 or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. It is preferable. In the above embodiment, Z is a 6-membered aryl or a 5- or 6-membered heteroaryl, preferably phenyl, which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2. It is preferable.

[0061] In an embodiment of the first aspect, 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 the ring formation of a carbocyclic or heterocyclic ring Z and the other is N; A8 is N or CH; L2, L3 and L4 are each independently selected from the group consisting of 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- or 6-membered heterocycle substituted with R4 and R5; Z is any 5-, 6- or 7-membered carbocyclic or heterocyclic ring that can be annulated with a central core or linked via a covalent bond, which can be optionally substituted with 1, 2 or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; R4 is any 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which may be optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -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 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe; R6 is a 5-, 6-, or 7-membered carbocycle or heterocycle, which is optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe; Or R6 is H; or If A7 participates in the ring formation of a carbocycle or heterocycle 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; where R4, R5, and R6 are as defined above. It is preferable.

[0062] In an embodiment of the first aspect, A5 is N; one of A6 and A7 is C and participates in the ring formation of the carbocyclic or heterocyclic ring Z, and the other is N; A8 is N; 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- or 6-membered heterocycle (preferably piperidine or pyrrolidine), which is substituted with R4 and R5; L4 absent; Z is a 6-membered carbocyclic or heterocyclic ring in annulation with a central nucleus, where Z is optionally substituted with 1, 2 or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and NO2; R4 is COOH or CH2N4; R5 is a 4-, 5-, 6-, 7-, or 10-membered carbocyclic or heterocyclic ring, which is optionally substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe; Or R6 is H; It is preferable.

[0063] In an embodiment of the first aspect, Each of A5, A7 and A8 is N; A6 is C and participates in the ring formation of a carbocycle or heterocycle Z, preferably a 5-, 6- or 7-membered carbocycle or heterocycle, which may be optionally substituted with 1, 2 or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe; L2 is CH2-CH2-R4; L3 is -CH2-CH2-R4 or -CH2-CF2-R5; or L2 and L3 together with A8 to which they are attached form a piperidine or pyrrolidine ring substituted with R4 and R5; L4 absent; Z is phenyl or cyclohexyl in a ring with the central nucleus, where Z may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -OH, Me, -CF3, -OMe, and -NO2; R4 is COOH or tetrazolyl; R5 is phenyl, cyclobutyl, cyclopentyl or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -CF3, Me, -CH2-CF3, and -OMe; R6 is a 6-membered carbocyclic or heterocyclic ring, preferably phenyl or cyclohexyl; more preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of Br, -Cl, -F, Me, -CF3, -OMe, and -NO2; It is preferable.

[0064] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 does not exist.

[0065] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 does not exist.

[0066] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C, which participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, and which is optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L4 does not exist.

[0067] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is phenyl or a 5-, 6- or 7-membered heteroaryl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0068] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0069] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In particularly preferred embodiments, A5, A7 and A8 are N; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0070] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0071] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0072] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0073] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0074] In particularly preferred embodiments, A5, A7 and A8 are N; L4 is absent; and 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0075] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 is absent; and 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0076] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 is absent; and 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0077] In particularly preferred embodiments, A5, A7 and A8 are N; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0078] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0079] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0080] In particularly preferred embodiments, A5, A7 and A8 are N; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0081] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0082] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0083] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0084] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0085] In particularly preferred embodiments, A5, A7 and A8 are N; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0086] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0087] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R5 is C4 to C7 cycloalkyl, i.e., C4, 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0088] In particularly preferred embodiments, A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6- or 7-membered heteroaryl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0089] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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 10Bicycloalkyl, C6 to C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl, or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0090] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C 10Bicycloalkyl, 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0091] In particularly preferred embodiments, A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0092] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may optionally be substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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 C10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0093] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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 10Bicycloalkyl, C6 to C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0094] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C 10Bicycloalkyl, 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0095] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C10 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0096] In particularly preferred embodiments, A5, A7 and A8 are N; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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 10Bicycloalkyl, C6 to C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0097] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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 10Bicycloalkyl, C6 to C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0098] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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 10Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0099] In particularly preferred embodiments, A5, A7 and A8 are N; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0100] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0101] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0102] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0103] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may optionally be substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0104] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0105] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R5 is C5 to C7 cycloalkyl, C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C 10Bicycloalkyl, 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0106] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0107] In particularly preferred embodiments, A5, A7 and A8 are N; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5. L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C10 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0108] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C 10Bicycloalkyl, 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0109] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 C10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0110] In particularly preferred embodiments, A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0111] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C10 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0112] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0113] In particularly preferred embodiments, A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0114] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may optionally be substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0115] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0116] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0117] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R5 is C4 to C7 cycloalkyl, i.e., C4, i.e., C5, C6 or C7 cycloalkyl, C6 to C 10 Bicycloalkyl, i.e., C6, C7, C8, C9 or C 10Bicycloalkyl, C6 to C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0118] In particularly preferred embodiments, A5, A7 and A8 are N; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10Bicycloalkyl, C6 to C 10 Spiroalkyl, i.e., C6, C7, C8, C9 or C 10 spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0119] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C 10Bicycloalkyl, 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0120] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R5 is C4 to C7 cycloalkyl, i.e., C4, C5, C6 or C7 cycloalkyl, C6 to C10 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0121] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0122] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0123] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be optionally substituted with 1, 2, or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0124] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0125] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0126] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0127] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0128] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; and L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0129] In a particularly preferred embodiment of the above embodiment, R6 is phenyl ortho-substituted with a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably Br.

[0130] In a particularly preferred embodiment of the above embodiment, L4 is absent; and R6 is phenyl ortho-substituted with a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably Br.

[0131] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0132] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0133] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0134] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0135] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0136] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0137] In particularly preferred embodiments, A5, A7 and A8 are N; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0138] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocyclic or heterocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic or heterocyclic ring Z, preferably a carbocyclic ring Z, in particular a 5-, 6- or 7-membered carbocyclic ring Z, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0139] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0140] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0141] In a particularly preferred embodiment, A5, A7 and A8 are N and A6 is C and participates in the ring formation of a carbocycle Z, in particular a 5-, 6- or 7-membered carbocycle Z, preferably phenyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2; L2 is selected from the group consisting of -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4; L3 is selected from the group consisting of -CH2-R5, -CH2-CH2-R5, and -CH2-CF2-R5; L4 absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; 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 10spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which may be optionally substituted with 1, 2 or 3, preferably 1, substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; more preferably, unsubstituted phenyl or adamantyl substituted with 1 or 2 substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a substituent selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably phenyl ortho-substituted with Br.

[0142] In particularly preferred embodiments, the compounds of the first and further aspects of the invention have the specific structure as shown in FIG. The use of bifunctional compounds that recruit proteins involved in targeting proteins for degradation by the proteasome has emerged as a potential therapeutic solution to degrade proteins involved in disease processes. This solution meets a particular focus in cancer treatment (Khan S. et al., 2020 and Bushweller JH, 2019). Such bifunctional compounds are generally referred to as PROteolysis TArgeting Chimeras (PROTACs). The inhibitor of ALC1 of the first aspect of the present invention is suitable for specifically binding to ALC1 and therefore recruiting proteins that are part of the ubiquitination pathway to ALC1.

[0143] Thus, in a second aspect, the present invention relates to a bifunctional compound comprising an allosteric inhibitor of ALC1 according to the first or further aspect of the present invention and a compound that recruits a protein that is part of the ubiquitination pathway to ALC1, preferably an E3 ubiquitin ligase to ALC1 (E3 recruiter), where the allosteric inhibitor of ALC1 and the E3 recruiter are covalently linked, optionally via a linker. In the context of the bifunctional compound of the present invention, the ability of the allosteric inhibitor of ALC1 according to the first and further aspects of the present invention to specifically bind to ALC1 is particularly important. Thus, it is preferred that the allosteric inhibitor of ALC1 binds to full-length human ALC1 having the amino acid sequence shown in 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.

[0144] Proteins in the ubiquitination pathway can be bound by either small molecules or protein ligands, such as antibodies or antibody-like proteins, that specifically bind to proteins in the ubiquitination pathway. Such protein ligands are described, for example, in US 7,223,556 B1. 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 EP3131588, WO2017 / 024317, US6,306,663, US7,041,298, US2016 / 0176916, US2016 / 0235730, US2016 / 0235731, US2016 / 0243247, WO2016 / 105518, WO2016 / 077380, WO2016 / 105518, WO2016 / 077375, WO2017 / 007612, and WO2017 / 024317.

[0145] In one embodiment, ALC1i is covalently linked to a compound that recruits proteins that are part of the ubiquitination pathway to ALC1. The two components are preferably covalently linked to each other via a linker. Suitable linkers have various lengths and functionalities. The linker preferably has a carbon chain. In a preferred embodiment, the carbon chain may optionally contain 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 may optionally contain 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 may be optionally substituted with 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), CN, C3-C7 cycloalkyl, heterocyclyl, phenyl, and heteroaryl.

[0146] 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 (eg, C, O, N and S).

[0147] 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), CN, C3-C7 cycloalkyl, and CN.

[0148] In certain embodiments, the linker has formula L(VI): [ka] [In formula: p 1 is an integer selected from 0 to 12; p 2 is an integer selected from 0 to 12; p 3 is an integer selected from 0 to 6; each W is independently absent, CH2, O, S, NH, or NR5; Z is absent, CH2, O, NH or NR5; Each R5 is independently H or C1-C3 alkyl, preferably C1-C3 alkyl; and Q is absent or -CH2C(O)NH-. or an enantiomer, diastereomer or stereoisomer thereof, wherein the linker covalently attaches the compound to a compound that recruits a protein that is part of a ubiquitination pathway at the bond adjacent to Q, and to an allosteric inhibitor of ALC1 at the bond adjacent to Z, and the total number of chain atoms in the linker is less than 20.

[0149] In a third aspect, the present invention relates to a pharmaceutical composition comprising an ALC1i as defined in the first aspect of the present invention or a bifunctional compound of the second aspect and at least one pharma- ceutically acceptable excipient, preferably for use in treating or ameliorating a proliferative disease.

[0150] In a fourth aspect, the present invention relates to ALC1i for use according to 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 treating or improving 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 known PARPi can be enhanced by ALC1i.Due to this unexpected synergistic effect, the combination of PARPi and ALC1i for use in the first aspect of the present invention in treating various proliferative diseases is particularly advantageous.

[0151] A physician may provide that ALC1i is administered as an antiproliferative therapy separately from PARPi or in a kit of parts.Thus, in the embodiment where both are combined to obtain synergistic benefits, ALC1i may be provided with instructions to combine it with PARPi, or alternatively, in the fifth aspect, PARPi may be provided with instructions to combine it with ALC1i.Thus, in the fifth aspect, the present invention relates to PARPi for use in treating or ameliorating a proliferative disease in a patient, where treating or ameliorating a proliferative disease comprises administering PARPi and administering ALC1i for use in the first aspect of the present invention or administering a bifunctional compound of the second aspect of the present invention.

[0152] In a preferred embodiment of ALC1i for use in the fourth aspect of the invention or PARPi for use in the fifth aspect of the invention, PARPi reduces PARP activity and / or inhibits PARP1, PARP2 and / or PARP3, preferably PARP2, in chromatin. The latter phenomenon is also called PARP trapping. Thus, in a preferred embodiment, PARP1, PARP2 and / or PARP3, preferably PARP2, are trapped.

[0153] In a preferred embodiment of an ALC1i for use in the fourth aspect of the invention or a PARPi for use in the fifth aspect of the invention, (i) a PARPi that reduces PARP activity is selected from small interfering RNAs; and (ii) PARPi, which inhibits PARP1, is one of the following: (a) Formula (II): [ka] [In formula: A and B together represent an optionally substituted fused aromatic ring; X is NR X or CR X R Y and; X=NR X If, then n is 1 or 2 and X=CR X R Y If, then n is 1; R X is H, optionally substituted C l-20 Alkyl, C 5-20 Aryl, C 3-20 selected from the group consisting of heterocyclyl, amide, thioamide, ester, acyl, and sulfonyl groups; R Y is selected from H, hydroxy, amino; or R X and R Y Together, Spiro-C 3-7 may form a cycloalkyl or heterocyclyl group; R C1 and R C2 is hydrogen and C 1-4 alkyl, or X is CR X R Y If R C1 , R C2 , R X and R Ymay, together with the carbon atom to which they are attached, form an optionally substituted fused aromatic ring; and R 1 is selected from H and halo. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof; and (b) Formula (III): [ka] [In formula: Y and Z are each 1. an aryl group optionally substituted with 1, 2 or 3 R6; 2. a heteroaryl group optionally substituted with 1, 2 or 3 R6; 3. 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., C 2-6 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 1-6alkyl), 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 ) carbonyl alkylene (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); independently selected from the group consisting of: where each R6 is -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-C 1-6 Alkyl), C 3-8 Cycloalkylalkyl (e.g., C 3-8 Cycloalkyl-C1-6 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 ) carbonyl alkylene (e.g., 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); R1, R2, and R3 each independently represent 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 1-6haloalkoxy), haloalkyl (e.g., C 1-6 haloalkyl), hydroxyl, hydroxyalkylene (e.g., hydroxy-C 1-6 alkylene), nitro, NR A R B , N.R. A R B Alkylene (e.g., NR A R B C 1-6 alkylene), and (R A R B ) Carbonyl selected from the group consisting of; A and B are each independently hydrogen, Br, Cl, F, I, OH, or 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), where C 1-6 Alkyl, C 3-8 Cycloalkyl, alkoxy, and alkoxyalkyl are OH, NO2, CN, Br, Cl, F, I, and C. 1-6 Alkyl, and C 3-8 cycloalkyl, where B is a group other than OH; R A and R B is hydrogen, alkyl (e.g., C 1-6 alkyl), cycloalkyl (e.g., C 3-8 cycloalkyl), and alkylcarbonyl (e.g., C 1-6 or R A and R B together with their attached atoms, -O-, -NH, -N(C 1-6 alkyl), -NCO(C 1-6 Alkyl), -N(aryl), -N(aryl-C 1-6 Alkyl), -N(substituted aryl-C 1-6alkyl), -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 may optionally have 1 to 3 heteroatoms or heterofunctional groups, selected from the group consisting of: R4 and R5 each independently represent 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 (NR A R B ) alkylene (e.g., NR A R B C 1-6 alkylene). and isomers, salts, solvates, chemically protected forms, and prodrugs thereof. More selected; (iii) PARPi, which inhibits PARP1 and PARP2, (a) Formula (IV): [ka] [In formula: R1 is hydrogen or fluorine; and R2 is hydrogen or fluorine. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof; and (b) Formula (V): [ka] [In formula: R1, R2 and R3 are independently 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; A is a non-aromatic 4-, 5-, 6-, 7- or 8-membered ring containing one or two nitrogen atoms and optionally one sulfur or oxygen atom, where the non-aromatic ring is 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, heterocycle alkyl (e.g., heterocycle-C1-6 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 R A , R B , R C , and R D is hydrogen, alkyl (e.g., C 1-6 alkyl), and alkylcarbonyl (e.g., C 1-6 alkylcarbonyl). and isomers, salts, solvates, chemically protected forms, and prodrugs thereof; selected from the group consisting of; (iv) A PARPi that inhibits PARP1, PARP2, and PARP3 has the formula (VI): [ka] [In formula: R 1 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., C3-8 cycloalkyl), heterocycloalkyl (e.g., C 2-8 heterocycloalkyl), aryl, or heteroaryl groups (e.g., unsubstituted or substituted with halogen, hydroxy, nitro, and amino, alkoxy (e.g., C 1-6 alkoxy), alkyl (e.g., C 1-6 alkyl), and aryl groups (unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, carboxy, and optionally substituted amino and ether groups (such as O-aryl); or -C(O)-R 10 (where R 10 is H; optionally substituted alkyl (e.g., 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 groups (e.g., unsubstituted or substituted with halogen, hydroxy, nitro, amino, and alkyl (e.g., C 1-6 alkyl) and aryl groups (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 are each independently H or an 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 groups (e.g., unsubstituted or alkyl (e.g., C1-6 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 groups (unsubstituted or substituted with halogen, hydroxy, nitro, amino, and alkyl (e.g., C 1-6 alkyl) and aryl groups (unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and optionally substituted amino groups); R 2 is H or alkyl (e.g., C 1-6 alkyl); R 3 is H or alkyl (e.g., C 1-6 alkyl); R 4 is H, halogen or alkyl (e.g., C 1-6 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 an 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 groups (e.g., unsubstituted or substituted with halogen, hydroxy, nitro, amino, and lower alkyl (e.g., C 1-4 alkyl), lower alkoxy (e.g., C 1-4alkoxy), or aryl groups (unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino); and R7 and R8 are each independently H or an 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 groups (e.g., unsubstituted or substituted with halogen, hydroxy, nitro, amino, and lower alkyl (e.g., C 1-4 -alkyl), lower alkoxy (e.g., C 1-4 -alkoxy), and aryl groups (unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro and amino); Here, R 1 , R 4 , R5, R6, and R7 are each H, then R8 is a group other than unsubstituted phenyl. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof.

[0154] In a preferred embodiment of an ALC1i or bifunctional compound for use in the fourth aspect of the invention or a PARPi for use in the fifth aspect of the invention, the PARPi is selected from the group consisting of olaparib, talazoparib, niraparib, rucaparib, and veliparib, in particular veliparib, olaparib, and talazoparib. In a preferred embodiment of an ALC1i or bifunctional compound for use in the fourth aspect of the invention, or a PARPi for use in the fifth aspect of the invention, the ALC1i is an inhibitor of ALC1 according to the first or any further aspect of the invention, or a bifunctional compound according to the second aspect.

[0155] In a preferred embodiment of the ALC1i or bifunctional compound for use in the fourth aspect of the present invention, or the PARPi for use in the fifth aspect of the present invention, the tumor disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, and colorectal cancer. In preferred embodiments of ALC1i or a bifunctional compound for use in the fourth aspect of the invention, or PARPi for use in the fifth aspect of the invention, (i) ALC1i enhances the cancer cell killing efficacy of PARPi, (ii) lower amounts of PARPi are administered, and / or (iii) PARPi resistance is circumvented. In a preferred embodiment of an ALC1i for use in the fourth aspect of the invention, or a PARPi for use in the fifth aspect of the invention, the PARPi and the ALC1i are administered simultaneously or separately.

[0156] In a sixth embodiment, the present invention relates to a kit of parts comprising separately packaged PARPi and ALC1i, or a composition comprising PARPi and ALC1i, preferably together with instructions for use in treating or ameliorating a proliferative disease.

[0157] BRCA1 and BRCA2 proteins are involved in both facilitating homologous recombination (HR)-mediated DNA repair and controlling the stability of stalled replication forks. For example, many types of tumors, including breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, and uveal melanoma, often have underlying defects in BRCA1 or BRCA2 activity. These defects are often due to germline or somatic mutations in the BRCA1 or BRCA2 genes. These tumors with underlying defects in HR repair are typically sensitive to PARP inhibitors. However, they may develop resistance to PARP inhibitors over time. To treat such tumors, the use of ALC1i for use according to the first aspect of the invention, the bifunctional compound for use according to the second aspect of the invention, the medicament for use according to the third aspect of the invention, or ALC1i or bifunctional compound for use according to the fourth aspect of the invention, when used alone or in combination with PARPi, 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.

[0158] As used herein, the term "cancer" refers to cells that have the ability to grow autonomously. Examples of such cells include cells in an abnormal state or condition characterized by rapidly proliferating cell growth. The term is intended to include cancerous growths, such as tumors; malignantly transformed cells, tissues, or organs, regardless of the type or stage of carcinogenic processes, metastatic tissues, and histopathological invasiveness. It also includes malignant tumors of various organ systems, such as respiratory, cardiovascular, renal, reproductive, hematological, neurological, hepatic, gastrointestinal, and endocrine systems; and adenocarcinomas, including most colon, renal cell, prostate, and / or testicular tumors, non-small cell lung cancer, and small intestine cancer. "Naturally occurring" cancer includes any cancer that is not experimentally induced by transplanting cancer cells into a subject, including, for example, spontaneous cancers, cancers caused by exposing a patient to a carcinogen, cancers caused by the insertion of a transgenic oncogene or the knockout of a tumor suppressor gene, and cancers caused by infection, such as viral infection. The term "carcinoma" is art-recognized and refers to malignant tumors of epithelial cells or endocrine tissue. The term also encompasses carcinosarcomas, including malignant tumors composed of carcinomatous or sarcomatous tissue. "Adenoma" refers to cancers derived from glandular tissue or in which the tumor cells form recognizable glandular structures. The term "sarcoma" is art-recognized and refers to malignant tumors of mesenchymal origin. The term "hematopoietic tumor disorder" encompasses diseases involving hyperplasia / tumor cells of hematopoietic origin. Hematopoietic tumor disorders may arise from myeloid, lymphoid or erythroid lineages, or their precursor cells. In some embodiments, the 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, the cancer is a basal-like carcinoma, a basal-like breast cancer, a triple-negative breast cancer, a high-grade carcinoma, or a high-grade serous ovarian cancer cell.

[0159] Thus, BRCA1-deficient or BRCA2-deficient cancer refers to a cancer in which one or more cells have abnormal BRCA1 levels or activity or abnormal BRCA2 levels or activity. These abnormal levels or activities can interfere with the normal function of BRCA1 or BRCA2, causing defects in HR-mediated DNA repair and reducing the stability of replication forks.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.

[0160] Thus in a seventh aspect relating to ALC1i for use according to the first aspect of the invention, the bifunctional compound according to the second aspect of the invention, the medicament according to the third aspect of the invention, ALC1i or the bifunctional compound for use according to the fourth aspect of the invention, or PARPi for use according to the fifth aspect of the invention, or the kit according to the sixth aspect of the invention, the proliferative disease is selected from cancer, wherein the proliferative disease is preferably cancer, more preferably the cancer is selected from BRCA1 and / or 2 deficient tumors and tumors in which expression of PARP1, PARP2, PARP3 and / or ALC1 is increased compared to non-tumor cells.

[0161] Preferred examples of cancers treatable according to various aspects of the present invention are ovarian and fallopian tube cancer, breast cancer, pancreatic and gastric cancer, colorectal cancer, and lung cancer. Preferably, the cancers that can be treated according to the various aspects of the present invention have recurred or progressed, preferably after first-line chemotherapy.Thus, preferably, the inhibitors of ALC1 (ALC1i) according to the present invention are for use as second- or third-line therapy.

[0162] Preferably, the cancers that may be treated are those that are at stage III (locally advanced) or stage IV (metastatic). Preferably, the cancers that can be treated according to various aspects of the present invention have an underlying defect in DNA damage repair, such as HR repair, i.e., HR deficient cancers. In one embodiment, the cancer cells have mutations / deletions / insertions in one or more DNA repair genes as listed in Tables 13 and 14.

[0163] In one embodiment, the cancers or cancer patients that can be treated are selected based on the presence of tumor markers. The selection of cancers / patients in a clinical setting includes, but is not limited to, qualified biomarkers of tumors, including BRCA1, BRCA2, BARD1, BRIP1, ANCA, FANCE, NBN, PALB2, RAD51C, RAD51D, RAD51 and / or RAD51B and / or other genetic variants in the HR pathway as listed in Table 13 and Table 14.

[0164] Preferably, patients who may be treated according to various aspects of the present invention are cancer patients, preferably 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 patients, optionally having mutations / deletions / insertions in one or more HR genes as listed in Tables 13 and 14.

[0165] Experimental Section Cell lines used MDA-MB-231 cells were used as a BRCA wild-type cell line. The cells were established from a human female with chromosomal aneuploidy. The cells were extracted from the mammary gland (breast) at the metastatic site as pleural effusion (MDA-MB-231 (ATCC® HTB-26™ Homo sapiens epithelial mammary gland). It is available from a number of sources, including ATCC® HTB-26™. As a BRCA negative cell line, SUM-149-PT cells were used. The cell line is a triple negative breast cancer (TNBC) cell line, derived from a primary human invasive ductal carcinoma metastatic nodule of a 40-year-old woman. It harbors a hemizygous BRCA1 mutation (p.Pro724Leufs*12) and is available from multiple sources, including bioIVT. As an example of pancreatic cancer, PSN1 cells were used. The human cell line was derived from pancreatic adenocarcinoma tissue. It harbors amplification of c-myc and activated c-Ki-ras, and loss of one of the two p53 alleles. The cell line is available from multiple sources, including MERCK (94060601).

[0166] 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 does express mucin, pancreatic cancer specific antigen, and CEA (carcinoembryonic antigen). The cells are available from a number of sources, including MERCK (93120816). CaCo2 cells were used, which were established from colon tissue of a 72-year-old woman with colorectal cancer and are available at ATCC (Caco-2 [Caco2] HTB-37™).

[0167] Capan-1 cells were used. These cells were isolated from the pancreas of a 40-year-old man with pancreatic adenocarcinoma. The cells are available at ATCC (Capan-1 HTB-79™). 22Rv1 cells were used. The cell line is derived from a xenograft that was serially propagated in mice after castration-induced regression and recurrence of the parental CWR22 xenograft, which is androgen-dependent. The cells originate from prostate cancer and are epithelial. The cells express PSA (prostate-specific antigen) and carry damaging mutations in BRCA. The cell line is available from a number of sources, including Accegen (ABC-TC0004).

[0168] DU145 cells were used. The cells were isolated from the brain of a 69-year-old man 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 under ATCC HTB-81™. DLD1-wt cells were used. The cells were extracted from the colon of an adult male patient 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 are available from a number of sources, including MERCK (90102540). We used DLD1-BRCA2- / - cells, which originate from DLD1-wt and are a BRCA2 knockout cell line. They are available from a number of sources, including Creative Biogene (CSC-RT0028).

[0169] HCT116 cells were used. This cell line originates from colon tissue derived from an adult male with colorectal cancer. It harbors damaging mutations in BRCA2, FANCA, and POLD1. This cell line is available from multiple sources, including DSMZ (ACC 581). PC-3 cells were used. The cell line originated from a 62-year-old male patient with grade IV prostate cancer, specifically bone metastasis. The cells are epithelial, near triploid, and carry a damaging mutation in TP53. They are available from a number of sources, including MERCK (90112714). SW620 cells were used. Cells were isolated from lymph nodes of a 51-year-old man with Duke's colorectal cancer and cell lines were established. Cell lines are available from a number of sources, including ATCC CCL-227™.

[0170] T47D cells were used. The cell line was established from a 54-year-old human female with invasive ductal carcinoma of the breast. The cells were extracted from the mammary gland (breast) as pleural effusion. They are available from a number of sources, including ATCC HTB-133™. HUH7 cells were used, which are available, for example, from cell line services (CLS Shop), and were isolated from a liver tumor of a 57-year-old man. HCC1428 cells were used: they are available from ATCC (HCC1428 CRL-2327™) and were derived from the breast of a Caucasian female patient with adenocarcinoma.

[0171] HCC1937 cells were used. They were isolated specifically from the mammary gland of a 23-year-old woman with primary ductal carcinoma. The cell line has a homozygous BRCA1 mutation, is negative for p53 and Her2-neu expression, and is epithelial in morphology. Cells are available from a number of sources, including Amsbio (catalog number AMS.EP-CL-0093). MDA-MB-436 cells were used. The cell line was derived from a 43-year-old woman with breast adenocarcinoma, which was extracted from the metastatic mammary gland as pleural effusion. The cells are pleomorphic with multinucleated components. They are available from a number of sources, including Accegen (catalog number ABC-TC0655).

[0172] HEPG2 cells were used. The cell line was established from a 15-year-old male patient with hepatocellular carcinoma. The cells express major plasma proteins such as albumin, fibrinogen, and alpha2-macroglobulin. The cell line is available under ATCC HB-8065™. LnCap cells were used. The cells were isolated from the left subclavian lymph node of a man with metastatic prostate cancer and are available from ATCC (LNCaP clone FGC CRL-1740™). Available at. U2OS cells were used: they are available from the ATCC (U-2 OS HTB-96™) and were isolated from the tibia of a 15-year-old female with osteosarcoma.

[0173] Synergy with PARPi To determine the ZIP synergy score, a 2D titration of two compounds is added to cells in a 96h-SRB-viability assay format. The score is calculated by adding the viability data readouts derived from the SRB assay of at least three replicate plates to an open source program called Synergy Finder. "Synergy Finder (https: / / synergyfinder.fimm.fi)" is a standalone web application for subjecting drug combination screening data to interaction analysis and visualization. Since its first release in 2017, Synergy Finder has become a widely used web tool both to find novel synergistic effects of drug combinations in preclinical experimental systems (e.g., cell lines or primary patient-derived cells) and to better understand the mechanism of action of efficacy or resistance of combination treatments (Ianevski et al., 2020).

[0174] In the Zero Interaction Potency (ZIP) study, the drug interaction relationship is determined by comparing the change in efficacy of the dose-response curve between each drug and its combination (https: / / synergyfinder.fimm.fi / synergy / synfin_docs / ). The study is further described at https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC4759128 / . The results of treatment with ALC1 inhibitor and PARP inhibitor together are shown in Figure 4.

[0175] Inhibitor versus response (cell viability) assay To test small molecule inhibitors, MDA-MB-231 cells were used as a BRCA wild-type cell line and SUM-149-PT as a BRCA1-deficient cell line to address the synthetic lethality of BRCA and ALC1. Cells (5000 cells / well) were seeded in 96-well plates and treated with titrations of ALC1 inhibitors starting at 50 μM. DMSO was added to the cells as an "untreated" control. Cells were fixed with 10% TCA for 1 h and incubated at 37°C, 5% CO2 for 5 days before staining with sulforhodamine dye for 30 min. Cells were washed with 1% acetic acid and then stained cells were solubilized with 10 mM Tris (pH 10.5) solution. Absorbance was measured at 492 nm using a SUNRISE TECAN and data were normalized to cell number at time point 0 and 100% viability (=DMSO control) and analyzed using GraphPad Prism. Survival curves were fitted using “Inhibitor vs. response curves with variable slope (4 parameters)”. IC treated with ALC1 inhibitors 50 The values ​​are shown in FIG.

[0176] To further validate the compounds, a colony formation assay was applied. Here, a small number of cells (100 cells / well) were seeded to assay. Cells were treated with ALC1 inhibitor or a combination of PARPi and ALC1 inhibitor for 11 days. Cells were fixed and data were analyzed as described above. The results of ALC1 inhibitor treatment are shown in Figures 3 and 7.

[0177] FRET-based nucleosome sliding assay The assay utilizes an intermediately positioned mononucleosome that allows monitoring the sliding activity of the ALC1 remodeling enzyme with a FRET readout. Each nucleosome is labeled with two FRET dyes: the octamer is labeled with Cy5 (Cy5 maleimide coupled to H2B) and one of the DNA ends is labeled with Cy3. The DNA template contains a 147 bp 601 DNA positioning sequence flanked on both sides by DNA overhangs. Other nucleosome positioning sequences, both artificial constructs and naturally occurring sequences, can also be used, even if they are less efficient than the 601 sequence in positioning nucleosomes. Nucleosomes are assembled by salt gradient dialysis using purified Cy5-labeled histone octamer and purified Cy3-labeled DNA template to obtain nucleosomes with an intermediately positioned FRET label. These nucleosomes start out with low FRET and when excited at the wavelength maximum for Cy3, the two fluorophores are too far apart for efficient FRET, so the Cy5 fluorescent signal will be low. As the ALC1 remodeling reaction proceeds and the remodeling enzyme slides the octamer towards the DNA end, the distance between the two FRET dyes decreases and the signal from Cy5 / FRET increases. Thus, the increase in FRET can be used directly as a readout of the slide.

[0178] Construction of DNA templates for mononucleosome reconstitution To reconstitute mononucleosomes, the non-natural Widom601 nucleosome positioning sequence was used as a high affinity binding site to histone octamer (see Lowary, PT & 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 DNAs containing these 601 sequences can be constructed using methods including PCR amplification, restriction digestion of DNA plasmids followed by Kleno-end labeling reactions, or other standard molecular biology techniques.

[0179] Preparation of ALC1 and histone octamers Full-length human ALC1(1-897) or its truncated versions were expressed and purified as N-terminal 6xHis-tagged fusion proteins from E. coli as previously published ( Singh, HR et al., 2017 ). Human histone proteins were recombinantly expressed in E. coli (either using classical IPTG induction or using an autoinducing medium) and purified from E. coli inclusion bodies. The purification scheme involved extraction / solubilization of the histones from the inclusion bodies using guanidinium chloride, followed by reversed-phase chromatography. The purified histones were lyophilized to obtain the TFA salt of the purified histone proteins.

[0180] Nucleosome purification To assemble nucleosomes, template DNA (final concentration 250 μg / ml) was mixed with purified histone octamers in high salt buffer at different molar ratios of histone octamers to DNA. The ionic strength of this mixture was then reduced to <600 mM NaCl by successive dialysis at 4°C against low salt buffer. Finally, the material was dialyzed against TEA-20 (10 mM triethanolamine-Cl pH 7.5, 20 mM NaCl, 0.1 mM EDTA). The best molar ratio, i.e., the ratio that results in complete assembly of the DNA into nucleosomes, was chosen and used for further assembly. Alternatively, nucleosomes can be assembled by other methods such as depositing histone octamers onto DNA using polyglutamates or histone sheperons, or by salt serial dilution.

[0181] A method for measuring ALC1-mediated sliding; ALC1 nucleosome sliding assay Sliding reactions were performed in 384-well plates at room temperature in 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% Triton X100, 0.02% NP40, and intermediately placed nucleosomes, triADP-ribose or (ADP-ribose) n and ALC1 chromatin remodeling enzymes. Sliding was initiated by adding ATP, followed by shaking the plates at 1450 rpm for 5 seconds and sealing them with foil compatible for fluorescence measurement. FRET signals were recorded immediately using a fluorometer (BMG reader PheraStar FSX, channel A: excitation 520 nm, emission 680 nm; channel B: excitation 520 nm, emission 590 nm) and remodeling was carried out for 30 min unless otherwise stated.

[0182] The FRET signal was calculated by dividing the signal at 680 nm (Cy5 emission) by the signal at 590 nm (Cy3 emission) and multiplying by 10,000. To obtain the apparent rate of ALC1-mediated nucleosome sliding, the increase in FRET was plotted as a function of time, and the resulting kinetic trace was fitted by linear curve fitting to obtain the initial rate of ALC1-mediated nucleosome sliding.

[0183] High-throughput screening and IC of molecules that regulate ALC1-mediated sliding 50 measurement High-throughput screening (HTS) and IC for compounds that modulate the sliding activity of ALC1 50 For the measurements, nucleosomes were incubated with ALC1 and triADP-ribose or (ADP-ribose) in the presence of the putative ALCi before initiating sliding by adding ATP. n The cells were incubated with 100 mM EDTA for 30 min as described above. The sliding velocity (initial velocity) was then measured as described above and compared to the sliding velocity in the absence of the putative modulator / compound (% inhibition). IC 50 For measurements, the % inhibition observed (y-axis) was plotted against the compound concentration (x-axis) using GraphPad Prism and fitted with a nonlinear regression model (4 parameters). IC for inhibition of nucleosome sliding 50 The results are shown in Figure 6. 50 Values ​​are indicated by the following symbols: +++: IC 50 <25μM;++:IC 50 =25-100 μM; +:IC 50 = 100-250 μM; and "-": compound is not active, i.e. no >50% inhibition is observed.

[0184] SAR analysis of ALC1 inhibitors In general, the ALCi clusters presented here have a straightforward SAR manifested by the presence of numerous molecular match pairs. For example, at the R6 substitution, there is a clear preference for halogen over either oxygen or methyl substitution, as evidenced by the improved potency of ALCi-1002 compared to ALCi-1009 and ALCi-1055. Additionally, in the R4 region, tetrazole is preferred over carboxylic acid (IC for tetrazole-containing compounds). 50 (None >25 μM). The R5 region of the molecule tends to be favored for its non-aromatic and hydrophobic nature, especially when combined with the R4 region of the tetrazole, due to increased cellular potency and selectivity (ALCi-1013 vs ALCi-1002). By extrapolating from the currently available SARs, one skilled in the art should be able to easily develop additional ALC1 inhibitors of the same series as those shown below.

[0185] Synthesis of ALC1 inhibitors Synthesis of compounds of general formula (I) may be carried out according to the general synthetic schemes shown in Figures 9 and 10. The compounds prepared in Figures 9 and 10 reflect a basic compound scaffold in which the phenyl group may be substituted at any position, not just where the R groups are depicted.

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Claims

1. A pharmaceutical product for treating or improving proliferative disorders in patients, comprising formula (I): 【Chemistry 1】 [In the formula: A5, A7, and A8 are N; A6 is C and is involved in the formation of a carbon ring or heterocyclic Z; L2 is -CH ２ -R4, -CF ２ -R4, -CH ２ -CH ２ -R4, -CH ２ -CH ２ -CH ２ Selected from the group consisting of -R4, -O-R4, -NH-R4, and -N=R4; L3 is CH ２ -R5, -CF ２ -R5, -CH ２ -CH ２ -R5, -CH ２ -CF ２ -R5, -CH ２ -CH ２ -CH ２ selected from the group consisting of -R5, -O-R5, -NH-R5, -N=R5; or L2 and L3, together with A8 to which they are joined, form a 5 or 6-membered heteroring substituted with R4 and / or R5; L4 is CH ２ , -CF ２ - , CH ２ -CH ２ ,CH ２ -CH ２ -CH ２ , O, N, and NH, or not present; Z is a 5, 6, or 7-membered carbon ring or heteroring, and is -Br, -Cl, -F, -I, -OH, Me, -CF ３ , Et, -OMe, -SMe, and -NO ２ It may be substituted with one, two, or three substituents, preferably one, selected from the group consisting of the following, and forms a ring with the central nucleus; R4 is a 5, 6, or 7-membered carbon ring or heteroring, and is -Br, -Cl, -F, -I, -CF ３ , may be substituted with one, two, or three substituents, preferably one, selected from the group consisting of Me, Et, -OMe, and -SMe, or R4 may be hydrogen, methyl, or COOH; R5 is a 4, 5, 6, 7, 8, 9, or 10-membered carbon ring or heteroring, and is -Br, -Cl, -F, -I, Me, -CF ３ It may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of Et, -OMe, and -SMe; R6 is a 5, 6, or 7-membered carbon ring or heteroring, and is -Br, -Cl, -F, -I, -OH, -NO ２ , Me, -CF ３ It may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of Et, -OMe, and -SMe; Alternatively, R6 is H. A pharmaceutical product comprising an ALC1 inhibitor (ALC1i), as indicated by [the formula], or a pharmaceutically acceptable salt thereof.

2. In formula (I), L2 is CH ２ -CH ２ -R4 and L3 is CH ２ -CH ２ - R5 or CH ２ -CF ２ -R5, or L2 and L3 together with A8 to which they bind, form a 5 or 6-membered heterocycle, preferably a piperidinyl or pyrrolidinyl substituted with R4 and R5; L4 does not exist; Z is any six-membered carbon ring or heteroring, preferably a six-membered aryl or heteroaryl, that forms a ring with the central core, where Z is -Br, -Cl, -F, -I, -OH, Me, -CF ３ , Et, -OMe, -SMe, and NO ２ They may be substituted with one, two, or three substituents, preferably one, selected from the group consisting of; R4 is COOH or tetrazolyl; R5 is any 4, 5, 6, or 7-membered carbon ring or heteroring, and is -Br, -Cl, -F, -I, Me, -CF ３ , may optionally be substituted with one, two, or three substituents, preferably one, selected from the group consisting of Et, -OMe, and -SMe; R6 is any 5 or 6-membered carbon ring or heteroring, where -Br, -Cl, -F, -I, -OH, -NO ２ , Me, -CF ３ , may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of Et, -OMe, and -SMe, or R6 is H, The pharmaceutical product according to claim 1.

3. In formula (I), L3 is CH ２ -CF ２ - R5, or each of L2 and L3 is CH ２ -CH ２ or L2 and L3, together with A8 to which they are bonded, form a piperidine ring or pyrrolidine ring substituted with R4 and R5; L4 does not exist; Z is a phenyl or cyclohexyl molecule that forms a ring with the central core, where Z is -Br, -Cl, -F, -OH, Me, -CF ３ -OMe, and -NO ２ They may be substituted with one, two, or three substituents, preferably one, selected from the group consisting of; R4 is COOH or tetrazolyl; R5 is phenyl, cyclobutyl, cyclopentyl or adamantyl, and -Br, -Cl, -CF ３ , Me, -CH ２ -CF ３ , and -OMe may be substituted with one, two, or three substituents, preferably one, selected from the group consisting of -OMe; R6 is any six-membered carbocyclic or heterocyclic ring (preferably phenyl or cyclohexyl; more preferably phenyl), and is Br, -Cl, -F, Me, -CF ３ -OMe, and -NO ２ It may be substituted with one, two, or three substituents, preferably one, selected from the group consisting of the following: The pharmaceutical product according to claim 1.

4. ALC1i is Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 The pharmaceutical product according to claim 1, which is an ALC1i or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

5. Formula (I): 【Chemistry 2】 [In the formula: A5, A7, and A8 are N; A6 is C and is involved in the formation of a carbon ring or heterocyclic Z; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, and -N=R4; L3 is selected from the group consisting of 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 joined, form a 5 or 6-membered heteroring substituted with 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 carbon ring or heteroring which may be substituted with 1, 2, or 3, preferably 1 substituent, selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2, and which forms a ring with the central core; R4 is a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted with 1, 2, or 3 substituents, preferably 1, selected from the group consisting of -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 carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5, 6, or 7-membered carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO₂, Me, -CF₃, Et, -OMe, and -SMe; Alternatively, R6 is H. A bifunctional compound comprising an ALC1 inhibitor (ALC1i) or a pharmaceutically acceptable salt thereof, and a compound that recruits E3 ubiquitin ligase to ALC1 (E3 recruiter), wherein the ALC1i and the E3 recruiter are optionally covalently bonded via a linker.

6. Formula (I): 【Transformation 3】 [In the formula: A5, A7, and A8 are N; A6 is C and is involved in the formation of a carbon ring or heterocyclic Z; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, and -N=R4; L3 is selected from the group consisting of 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 joined, form a 5 or 6-membered heteroring substituted with 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 carbon ring or heteroring which may be substituted with 1, 2, or 3, preferably 1 substituent, selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2, and which forms a ring with the central core; R4 is a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted with 1, 2, or 3 substituents, preferably 1, selected from the group consisting of -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 carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5, 6, or 7-membered carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO₂, Me, -CF₃, Et, -OMe, and -SMe; Alternatively, R6 is H. ALC1 inhibitors (ALC1i), or pharmaceutically acceptable salts thereof, Or the two-functional compound according to claim 5, Medicinally acceptable excipients and A pharmaceutical composition containing the following:

7. A pharmaceutical product for use in the treatment or improvement of a proliferative disorder, comprising formula (I): 【Chemistry 4】 [In the formula: A5, A7, and A8 are N; A6 is C and is involved in the formation of a carbon ring or heterocyclic Z; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, and -N=R4; L3 is selected from the group consisting of 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 joined, form a 5 or 6-membered heteroring substituted with 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 carbon ring or heteroring which may be substituted with 1, 2, or 3, preferably 1 substituent, selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2, and which forms a ring with the central core; R4 is a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted with 1, 2, or 3 substituents, preferably 1, selected from the group consisting of -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 carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5, 6, or 7-membered carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO₂, Me, -CF₃, Et, -OMe, and -SMe; Alternatively, R6 is H. A pharmaceutical product comprising an ALC1 inhibitor (ALC1i) as shown in, or a pharmaceutically acceptable salt thereof, or the bifunctional compound described in claim 5, wherein the treatment or improvement of a proliferative disorder comprises administering ALC1i or the bifunctional compound and administering a poly(ADP-ribose) polymerase inhibitor (PARPi).

8. A pharmaceutical agent for treating or improving a proliferative disorder in a patient, comprising PARPI, wherein the proliferative disorder is treated and improved by administering PARPI, and formula (I): 【Transformation 5】 [In the formula: A5, A7, and A8 are N; A6 is C and is involved in the formation of a carbon ring or heterocyclic Z; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, and -N=R4; L3 is selected from the group consisting of 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 joined, form a 5 or 6-membered heteroring substituted with 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 carbon ring or heteroring which may be substituted with 1, 2, or 3, preferably 1 substituent, selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2, and which forms a ring with the central core; R4 is a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted with 1, 2, or 3 substituents, preferably 1, selected from the group consisting of -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 carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5, 6, or 7-membered carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO₂, Me, -CF₃, Et, -OMe, and -SMe; Alternatively, R6 is H. A pharmaceutical agent comprising administering an ALC1 inhibitor (ALC1i) as shown in, or a pharmaceutically acceptable salt thereof, or the bifunctional compound described in claim 5.

9. PARPi reduces PARP activity and / or inhibits PARP1, PARP2, and PARP3, preferably PARP2, on chromatin, where preferably, (i) PARPi that reduce PARP activity are selected from small interfering RNAs, and (ii) PARPi that inhibit PARP1 are as follows: (a) Equation (II): 【Transformation 6】 [In the formula: A and B together represent a substituted fused aromatic ring; X is NR Ｘ or CR Ｘ R Ｙ And; X = NR Ｘ If so, then n is either 1 or 2, and X = CR Ｘ R Ｙ If that is the case, then n is 1; R Ｘ H, and C which may be substituted as desired. ｌ－２０ Alkyl, C ５－２０ Ariel, C ３－２０ Selected from the group consisting of heterocyclyl, amide, thioamide, ester, acyl, and sulfonyl groups; R Ｙ is selected from H, hydroxy, and amino; or R Ｘ and R Ｙ Together, Spiro C ３－７ They may form cycloalkyl or heterocyclyl groups; R Ｃ１ and R Ｃ２ is hydrogen and C ｌ－４ Independently selected from the group consisting of alkyl groups, or X is CR Ｘ R Ｙ If R Ｃ１ , R Ｃ２ , R Ｘ and R Ｙ They may, together with the carbon atoms to which they are bonded, form a substituted fused aromatic ring; and R １ [Selected from H and Halo] Compounds represented by, as well as their isomers, salts, solvates, chemically protected forms, and prodrugs; and (b) Formula (III): 【Transformation 7】 [In the formula: Y and Z are, respectively, 1. One, two, or three R ６ Aryl groups that may be substituted with; 2. One, two, or three R ６ A heteroaryl group which may be substituted with; 3. Hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (R Ａ R Ｂ ) Alkilen, (NR Ａ R Ｂ ) Carbonyl, (NR Ａ R Ｂ ) Carbonyl alkylene, (NR Ａ R Ｂ ) sulfonyl, and (R Ａ R Ｂ ) substituents independently selected from the group consisting of sulfonylalkylenes; Selected independently from the group consisting of; Here, each R ６ is selected from -OH, NO ２ , 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 )carbonylalkylene, (NR Ａ R Ｂ )sulfonyl, and (NR Ａ R Ｂ )sulfonylalkylene; R １ , R ２ , and R ３ Each of these independently consists of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, and NR. Ａ R Ｂ , NR Ａ R Ｂ Alkylene and (R Ａ R Ｂ ) Selected from the group consisting of carbonyls; A and B are, independently, hydrogen, Br, Cl, F, I, OH, and C. １－６ Alkyl, C ３－８ Selected from cycloalkyl, alkoxy, and alkoxyalkyl, where C １－６ Alkyl, C ３－８ Cycloalkyl, alkoxy, and alkoxyalkyl groups are OH, NO ２ ,CN,Br,Cl,F,I,C １－６ Alkyl and C ３－８ It may be substituted with at least one substituent selected from cycloalkyl groups, where B is a group other than OH; R Ａ and R Ｂ is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R Ａ and R Ｂ Together with the atoms they bond to, they form -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-C) １ -C ６ -alkyl)-, -N(substituted heteroaryl-C) １－６ Alkyl)-, and -S- or S(O) ｑ - forms a 3-10 membered heterocyclic ring which may have one to three heteroatoms or heterofunctional groups selected from the group consisting of -, where q is 1 or 2, and the 3-10 membered heterocyclic ring may be substituted with one or more substituents; R ４ and R ５ Each of these independently comprises hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR Ａ R Ｂ ) Selected from the group consisting of alkylenes. Compounds represented by, as well as their isomers, salts, solvates, and chemically protected forms. More selected; (iii) PARPi, which inhibits PARP1 and PARP2, (a) Equation (IV): 【Transformation 8】 [In the formula: R １ is hydrogen or fluorine; and R ２ [is hydrogen or fluorine] Compounds represented by, as well as their isomers, salts, solvates, and chemically protected forms; and (b) Formula (V): 【Chemistry 9】 [In the formula: R １ , R ２ and R ３ These are independently hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR Ａ R Ｂ , and (NR Ａ R Ｂ ) Selected from the group consisting of carbonyls; A is a non-aromatic 4, 5, 6, 7, or 8-membered ring containing one or two nitrogen atoms and possibly one sulfur or oxygen atom, wherein the non-aromatic ring is an alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclicalkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NR Ｃ R Ｄ , (NR Ｃ R Ｄ ) alkyl, (NR Ｃ R Ｄ ) Carbonyl, (NR Ｃ R Ｄ ) Carbonyl alkyl, and (NR Ｃ R Ｄ ) may be substituted with one, two, or three substituents selected from the group consisting of sulfonyls; and R Ａ , R Ｂ , R Ｃ , and R Ｄ [These are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl.] Compounds represented by, as well as their isomers, salts, solvates, and chemically protected forms. More selected; (iii) PARPi that inhibits PARP1, PARP2, and PARP3 is given by formula (VI): 【Chemistry 10】 [In the formula: R １ (wherein H; halogen; cyano; substituted with one or more substituents selected from optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups); or -C(O)-R １０ (Here, R １０ H is an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group which may be substituted; or OR １００ or NR １００ R １１０ And here R １００ and R １１０ Each of these is independently an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, which may be substituted with H; R ２ is H or alkyl; R ３ is H or alkyl; R ４ is H, halogen, or alkyl; X is either O or S; Y is (CR ５ R ６ ) (CR ７ R ８ ) ｎ or N-C(R ５ ) and here: n is either 0 or 1; R ５ and R ６ Each of these is independently an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, which may be substituted with H; and R ７ and R ８ Each of these is independently an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, which may be substituted with H; Here R １ , R ４ , R ５ , R ６ , and R ７ However, if each of them is H, then R ８ [ is an unsubstituted group other than phenyl] The compounds represented by, as well as their isomers, salts, solvates, and chemically protected forms, The pharmaceutical product according to claim 7 or 8.

10. The pharmaceutical product according to claim 7 or 8, wherein PARPi is selected from the group consisting of olaparib, talazoparib, niraparib, lucaparib, and veliparib, and more particularly from the group consisting of veliparib, olaparib, and talazoparib.

11. The pharmaceutically acceptable agent according to claim 7 or 8, wherein the proliferative disorder is selected from BRCA-1 and / or BRCA-2-deficient tumors and tumors in which the expression of PARP-1, PARP-2, PARP-3 and / or ALC1 is increased compared to non-tumor cells, and / or the proliferative disorder is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, and colorectal cancer.

12. The pharmaceutical product according to claim 7 or 8, wherein PARPi and ALC1i or a bifunctional compound are administered simultaneously or separately.

13. PARPi, and formula (I): 【Chemistry 11】 [In the formula: A5, A7, and A8 are N; A6 is C and is involved in the formation of a carbon ring or heterocyclic Z; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, and -N=R4; L3 is selected from the group consisting of 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 joined, form a 5 or 6-membered heteroring substituted with 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 carbon ring or heteroring which may be substituted with 1, 2, or 3, preferably 1 substituent, selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2, and which forms a ring with the central core; R4 is a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted with 1, 2, or 3 substituents, preferably 1, selected from the group consisting of -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 carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5, 6, or 7-membered carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO₂, Me, -CF₃, Et, -OMe, and -SMe; Alternatively, R6 is H. The ALC1 inhibitor (ALC1i), or a pharmaceutically acceptable salt thereof, or the bifunctional compound described in claim 5, can be packaged separately. or PARPi and formula (I): 【Chemistry 12】 [In the formula: A5, A7, and A8 are N; A6 is C and is involved in the formation of a carbon ring or heterocyclic Z; L2 is selected from the group consisting of -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, and -N=R4; L3 is selected from the group consisting of 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 joined, form a 5 or 6-membered heteroring substituted with 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 carbon ring or heteroring which may be substituted with 1, 2, or 3, preferably 1 substituent, selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2, and which forms a ring with the central core; R4 is a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted with 1, 2, or 3 substituents, preferably 1, selected from the group consisting of -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 carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; R6 is a 5, 6, or 7-membered carbon ring or heteroring, which may be substituted with 1, 2, or 3 (preferably 1) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO₂, Me, -CF₃, Et, -OMe, and -SMe; Alternatively, R6 is H. A component kit comprising, preferably together with instructions for use to treat or improve a proliferative disorder, a composition comprising an ALC1 inhibitor (ALC1i) as shown in, or a pharmaceutically acceptable salt thereof, or the bifunctional compound described in claim 5.

14. The pharmacopoeia according to claim 1, 7, or 8, wherein the proliferative disorder is selected from BRCA1 and / or BRCA2-deficient tumors and tumors in which the expression of PARP1, PARP2, PARP3 and / or ALC1 is increased compared to non-tumor cells.

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