ALC1 INHIBITORS FOR USE IN CANCER TREATMENT BY ENHANCEMENT OF MULTIPLE CLASSES OF APPROVED ANTICANCER DRUGS

Abstract

The present invention relates to the use of small molecule compounds that allosterically inhibit ALC1 (CHD1L), in particular two classes allosteric inhibitors of ALC1 (CHD1L), of Formula (I) and Formula (II), that show a potentiating, preferably additive effect in the treatment of proliferative disease when combined with several classes of cancer drugs, namely inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or when combined with mitomycin C, paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. Furthermore, the present invention relates to said inhibitors of ALC1 of Formula (II) that show a synergistic effect in the treatment of pancreatic cancer or fallopian tube cancer when combined with a PARP inhibitor (Poly(ADP-ribose)-Polymerase inhibitor (PARPi)). By being synergistic with the function of said cancer drugs, said ALC1 inhibitors, in particular those of Formula (I) and Formula (II), potentiate the cancer cell killing properties of the aforementioned cancer drugs, in particular enabling therapeutic approaches where any of the aforementioned inhibitors is already used as part of the standard of care.

Description

[0001] ALC1 INHIBITORS FOR USE IN TREATING CANCER BY POTENTIATING THE EFFECTS OF SEVERAL CLASSES OF APPROVED CANCER DRUGS The present invention relates to the use of small molecule compounds that allosterically inhibit ALC1 (CHD1L), in particular the use of two classes of allosteric inhibitors of ALC1 (CHD1L), of Formula (I) and Formula (II), that show a potentiating, preferably synergistic effect in the treatment of proliferative disease when combined with several classes of cancer drugs, namely inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or when combined with mitomycin C, paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. Furthermore, the present invention relates to said inhibitors of ALC1 of Formula (II) that show a synergistic effect in the treatment of pancreatic cancer or fallopian tube cancer when combined with a PARP inhibitor (Poly(ADP-ribose)-Polymerase inhibitor (PARPi)). By being synergistic with said inhibitors classes, ALC1 inhibitors potentiate the cancer cell killing properties of these inhibitors, enabling therapeutic approaches where ALC1 is amplified as an oncogene and / or where the cancer is a homologous recombination deficient (HRD) cancer. Additionally, these ALC1 inhibitors make it possible to overcome said inhibitor resistance mechanisms and enable an alternative approach to the treatment of germline or acquired BRCA1 / BRCA2 deficiency, including tumors defined by “BRCAness” or other changes in DNA repair networks. Importantly, the toxicity mechanisms of said drugs with ALC1 inhibitors are non- overlapping, hence no synergistic toxicity is expected. Background of the Invention Generally, cancers are classified into two categories: blood cancer and solid cancer. Solid cancers occur in almost every part of the body, resulting in pancreatic cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer among others. Although some methods of treatment include targeted drugs such as Gleevec or Herceptin, the majority of cancers are still treated by chemotherapy or radiation therapy. Since chemotherapies are not targeted therapies, the biggest problems of conventional chemotherapeutic agents are the side effects caused by cytotoxicity on one hand and the development of drug resistance on the other. The latter is the main factor that eventually causes the treatment to fail despite an initial successful response to the chemotherapeutic agents. Therefore, in order to overcome the limitations of such chemotherapeutic agents, it is necessary to develop new targeted therapeutic agents that specifically interfere with cancer cell proliferation. While in oncology, combinations of known cancer drugs have been shown successful in several cases, it remains the exception that, and it cannot be foreseen whether synergistic effects are achieved by two different drugs in the treatment of proliferative diseases. Therefore, there is a high medical need to develop novel combination therapies in which chemotherapeutic agents with established effectiveness in the treatment of cancer are combined with novel anticancer drugs that potentiate the effect of the established treatment regiments. Without wishing to be bound by any theory the present inventors considered the rationale that ALC1 inhibitors as a known class of cancer drugs could be combined with several classes of known cancer drugs, e.g. inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, or MEK, or combined with specific established cancer drugs, namely mitomycin C or paclitaxel, or could be combined with ionizing radiation, or could be combined with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. However, combinations of some representatives of said classes of known cancer drugs with known ALC1 inhibitors did not show synergism. The present invention is based on the surprising finding that specific ALC1 inhibitors, namely those wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1, in particular those of Formula (I) and of Formula (II), possess synergistic, anti-proliferative activity when being combined with several classes of known cancer drugs, namely inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, MEK, or when being combined with specific established cancer drugs, namely mitomycin C or paclitaxel, or when being combined with ionizing radiation, or when being combined with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. Thus, these combinations are expected to be particularly suitable in the treatment of proliferative disease. The rationale that, at least for specific combinations, ALC1 inhibitors in combination with other cancer drugs may lead to more than the expected additive efficacy is as follows. Activation of the DNA damage pathway leads to the recruitment of many proteins to damaged chromatin, notably 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 (PAR) (Karras et al., 2005), thus proteins containing macrodomains respond and recruit to PARP activation sites on the genome, including during DNA damage and with relevance for cancer. Importantly, PAR or oligo-ADP-ribose binding to the macrodomains of ALC1 robustly turns on chromatin remodeling activity (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017), revealing ALC1 as an allosterically- regulated chromatin remodeling enzyme, the first of its kind, and one of the very few enzymes whose catalytic activity is directly regulated by PAR. Additionally, ALC1 is a validated oncogene and is often genetically amplified together with PARP1 in BRCA1 / 2-deficient ovarian and breast cancer samples. Few ALC1i are described in the art e.g. by Abbott et al. in 2020 (Abbott et al., 2020). This document discloses inhibitors of CHD1L and their in vitro antitumor activity. Two of the most active ALC1i described, namely “Compound 1” and “Compound 3”, have the following chemical structures: Compound 1 Compound 3 WO 2022 / 117782 A1 discloses specific ALC1 inhibitors. In a BRCA negative breast cancer cell line, an at least additive effect is shown when combined with a PARP inhibitor. The present inventors tested known ALC1 inhibitors, namely Compounds 1 and 3 as shown above, in combination with the known commercially available ATR inhibitor, namely elimusertib and with the known and commercially available PARP inhibitor olaparib. Contrary to the above rationale, only about additive effects were achieved in vitro against cancer cell lines. However, extensive further studies then revealed that specific ALC1 inhibitors, wherein the inhibitors specifically bind to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1, in particular inhibitors with structures according to Formula (I) and Formula (II), and which inhibit the ATPase function and / or nucleosome remodeling function of ALC1, show synergistic effects in combination with and potentiate the effects of a) a number of compounds from several classes of cancer drugs, namely • inhibitors of Topoisomerase I (e.g. topotecan) • inhibitors of Topoisomerase II (e.g. teniposide) • inhibitors of ATM (e.g. AZ-32, AZD-1056, or AZD-1390) • inhibitors of ATR (e.g. ceralasertib, elimusertib) • inhibitors of WEE1 (e.g. adavosertib) • inhibitors of BRD (e.g. BAY-299 or ABBV-744), • inhibitors of MEK (e.g. trametinib) b) specific established cancer drugs, namely mitomycin C or paclitaxel, c) ionizing radiation, and d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan). Furthermore, it has been found that specific ALC1 inhibitors, with structures according to Formula (II), that inhibit the ATPase function and / or nucleosome remodeling function of ALC1, potentiate the effects of PARP inhibitors (e.g. AZD-5305, niraparib, olaparib, pamiparib, rucaparib, talazoparib, and veliparib) against pancreatic cancer or fallopian tube cancer cell lines. Thus, this combination of specific ALC1 inhibitors and PARP inhibitors has been found to be particularly suitable for use in treating pancreatic cancer or fallopian tube cancer. Thus, the present inventors consider that ALC1 inhibition by the specific ALC1 inhibitors inhibits efficient DNA repair by rendering chromatin less accessible to DNA repair enzymes. This leads to enhanced cancer cell killing and / or reduce off-target effects of the chemotherapeutic agent or the cancer drugs even if used at lower doses and thus lessen cellular toxicity in non-cancer cells. ALC1 inhibitors used according to the invention, in particular of Formula (I) and Formula (II), may thus also mediate sensitization to compounds a), b), and d) as listed above. The present inventors further expect that manipulation of ALC1 activity via the present ALC1 inhibitors used according to the invention could induce strong anti-proliferative effects and in addition be sufficient to bypass an acquired resistance to compounds a),b), and d) listed above, as well as to PARP1 and PARP2 inhibition. Thus, combined use of the ALC1 inhibitors of the invention, in particular of Formula (I) and Formula (II), respectively, and compounds a), b), and d), PARP1 and / or PARP2 inhibitor treatment can be used for therapies in oncology, including in a relapse condition and when there is progression in advanced clinical progression stages. Given the above described relevance of the specific ALC1 inhibitors used according to the invention, in particular of Formula (I) and Formula (II), for cancers, in particular those that are amenable to treatment with adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib and / or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan, the present invention provides a novel combination regimen to treat or ameliorate proliferative disease and preferably tumor diseases, in particualar characterized by loss of sensitivity to the above-mentioned chemotherapy. Furthermore, the present inventors determined that by using a combination of ALC1 inhibitors used according to the invention, in particular characterized by Formula (I) and Formula (II), and adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, or talazoparib, as well as trastuzumab deruxtecan, the effect of adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan, can all surprisingly be enhanced. Thus, the use of ALC1 inhibitors used according to the invention, in particular characterized by Formula (I) and Formula (II), in combination with adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD- 5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan provides inter alia (i) an efficient therapy of cancers that are amenable to adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and / or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan containing chemotherapeutic regimens, (ii) mediate adavosertib, AZ- 32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and / or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan, sensitization, (iii) bypass adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topoteca n, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and / or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan, resistance, (iv) and / or allow the reduction of the amount of adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and / or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan, that is administered, collectively leading to improved anti-cancer effects and less unwanted side effects. Summary of the Invention In a first aspect, the present invention is directed at an allosteric inhibitor of Chromodomain- helicase-DNA-binding protein 1-like (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1, preferably an inhibitor of ALC1 (ALC1i) according to Formula (I) or pharmaceutically acceptable salts, isomers, solvates, chemically protected forms, and prodrugs thereof, wherein A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or when A6 takes part in the annulated carbo- or heterocycle Z, then A6 is C; A7 is selected from N or CH, or when A7 takes part in the annulated carbo- or heterocycle Z, 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 the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and / or R5; L4 is CH2, –CF2–, CH2-CH2, CH2-CH2-CH2, O, N, and NH, or is absent; Z is a 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three, (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, - CF3, Et, -OMe, -SMe, and -NO2; and can be annulated to the central core or connected via a covalent bond R4 is 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three, (preferably one) substituent(s) 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 carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, - CF3, Et, -OMe, and -SMe; R6 is a 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) 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 takes part in the annulated carbo- 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 an inhibitor of ALC1 according to Formula (II): or pharmaceutically acceptable salts, isomers, solvates, chemically protected forms, and prodrugs thereof, wherein: X is N or S; A is C or N; R1is –CO-OR6, -CO-R7, or -CO-NR6RA, preferably R1is –CO-OR6; R2is -R7, -NHR8, -O-R7, -C-O-R7, Br, -C3-8-cycloalkyl (preferably cyclopropyl), or –C4-8-cycloalkenyl (preferably cyclohexenyl); or R1and R2together form a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, =O, [-O-CH2-CH2]-NH-CH(OH)-O-tBu, ; R3is H, =O, -OH, -O-R7, -R7, or –(CH2)m-L, wherein m is 0, 1 or 2, and L is a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, -hydroxyC1-3-alkyl and =O; R4is H or -C1-3-alkyl, preferably H; R5is -(CH2)m-L, or -(CH2)m-(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5, 6 or 7 membered carbo- or heterocycle, adamantyl, C1-4-alkyl, or -N(CH3)2, optionally substituted, preferably with 1, 2, 3 or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O, and [-O-CH2-CH2]q-NH-biotin with q being 1, 2, 3, or 4, or two adjacent substituents form a 5, 6 or 7 membered carbo- or heterocycle; or R4and R5together form a 5, 6, or 7 membered carbocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, - O-R9, -R9, =CH-RA, and –CH2-RA, preferably R4and R5together form a C5-7-cycloalkyl; R6 is H, -C1-6-alkyl, -C2-6-alkenyl, -C2-6-alkynyl, optionally substituted, preferably R6 is H; R7is -C1-3-alkyl, -C2-3-alkenyl, -C2-3-alkynyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8is H or C1-6-alkyl, preferably H, R9is -C1-6-alkyl, -C2-6-alkenyl, -C2-6-alkynyl, -C1-6-alkyl-aryl, or C1-6-alkyl-heteroaryl (preferably isooxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4- oxadiazole, pyrazine, or pyrazole), optionally substituted with 1, 2 or 3 substituents selected from the group consisting of -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C1-3-alkyl (preferably –CONH- CH3), -NH-CO-C1-3-alkyl (preferably -NH-CO-CH3), -C1-6-alkyl (preferably -CH3, ethyl, propyl, t- butyl, or pentyl), -C1-3-haloalkyl (preferably-CF3, or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably –CO-(1-pyrrolidinyl)),-SO2-CH3, -SO2- N(CH3)2, -O-C1-4-alkyl (preferably -OCH3), -O-C1-3-alkyl-O-C1-3-alkyl (preferably –O-CH2-O-CH3), -SCH3, or when R9is -C1-6-alkyl-aryl, then two adjacent substituents on the aryl moiety can form a 5, 6 or 7 membered carbo- or heterocycle, which is optionally substituted; RAis H, carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2)o-R9, - SO2NH2, and =O, wherein o is 0 or 1 for use in treating or ameliorating a proliferative disease, preferably cancer, in a patient in combination with a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, b) mitomycin C, or paclitaxel, c) ionizing radiation, or d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan); and / or for use in enhancing efficacy of a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK b) mitomycin C, or paclitaxel, c) ionizing radiation, or d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan) in treating or ameliorating a proliferative disease, preferably cancer, in a patient, In a second aspect, the inhibitor of ALC1 (ALC1i) according to formula (II) is for use in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient in combination with an inhibitor of PARP, or for use in enhancing efficacy of an inhibitor of PARP in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient. In a third aspect, the present invention is directed at a pharmaceutical composition comprising an ALC1i as defined herein and a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, b) mitomycin C, paclitaxel, or c) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan). In a fourth aspect, the present invention is directed to a kit of parts, comprising an ALC1i as described herein with instructions to combine it with a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, b) mitomycin C, or paclitaxel, c) ionizing radiation; or d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan); or comprising a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, b) mitomycin C, or paclitaxel, or c) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan); with instructions tocombine it with an ALC1i as defined herein, or comprising separately packaged an ALC1i as defined herein and a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, b) mitomycin C, or paclitaxel, or c) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan), optionally with instructions for use in treating or ameliorating a proliferative disease, preferably cancer. Description of the Figures In the following, the content of the Figures comprised in this specification is described. In this context it is also referred to the detailed description of the invention above and / or below. Figure 1: Structures and molecule names of selected ALC1 inhibitors. These selected ALC1 inhibitors (or isomers, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs thereof) are preferably used in accordance with the present invention. Figure 2: Synergy Scores and MSA of cancer cells treated with a combination of ALC1i vs. other drugs. Results of the 2-D titrations of different combinations of an ALC1i (compound A) with another drug (compound B) in different cancer cell lines are summarized in this table. Drug combinations with an MSA (most synergistic area) score below 9 indicate interactions that are likely not synergistic and are labeled with a “-”. An MSA score between 9-10 is labeled with “+” and indicates that the interaction of compound A and B is likely to be synergistic. MSA scores above 10 are marked “++” are synergistic. MSA scores greater than 20 are labeled as “+++” and considered highly synergistic. Figure 3: Example for 96-hour SRB assay: pancreatic cancer cell line treated with ALC1i or ATMi. PSN1 cells were seeded into 96-well plates and treated with titrations of ALC1i-101 or an ATMi (ATM inhibitor AZD-1390). The cells were cultured at 37°C, CO25% for 4 days, fixed with 10%TCA and stained with sulforhodamine staining to analyze cell survival. The data was normalized to DMSO controls indicating 100 % survival. Inhibitor vs. response curves were fitted with the Synergy Finder using the curve fitting parameter “LL4”. The curves show an average fit of 3 technical replicates. Figure 4: Example for 2-D titration: co-treatment cell proliferation assay of pancreatic cancer cells. Cancer cells were seeded into 96-well plates and treated with a 2-D titration of an ALC1i vs. the indicated drug. The cells were cultured at 37°C, CO25% for 4 days, fixed with 10%TCA and stained with sulforhodamine staining to analyze cell survival. The synergy score is calculated using the Synergy Finder. Treatment with ALC1i-101 in combination with ATMi show highly synergistic area scores of above 10 respectively. MSA scores over 10 are an indication of strong synergy. Figure 5: cell cycle analysis of ALC1i treated cancer cells. SUM-149-PT cells were seeded into 6-well plates and treated with ALC1i or DMSO for 48h. Cells were fixed in 75% EtOH and stained with DAPI. FACS analysis shows cells in different cell cycle stages. Treatment with DMSO shows cells in G1, S and G2 phase. Cells treated with ALC1i show enrichment / block in G2 phase. Figure 6: γH2AX protein levels increase under ALC1i treatment. PSN1 cells were treated with a titration of ALC1i or DMSO for 24h. A Western Blot was run with antibodies against phosphorylated H2AX (γH2AX) and a-tubulin. Image of protein bands is shown above, graph below shows γH2AX protein levels normalized to a-tubulin loading control and normalized to DMSO treated sample. Figure 7: EC50 values (µM) of 96 hour SRB assay and 11 days colony formation assay of HR proficient (HRP) and HR deficient (HRD) cells treated with ALCi. Different cancer cell lines with a variation of mutations in the homologous recombination repair pathways (HR) were seeded into 96-well plates and treated with titrations of different ALCi. The cells were cultured at 37°C, CO25% for 4 days (96h) or 11 days (colony formation), fixed with 10%TCA and stained with sulforhodamine staining to analyze cell survival. The data was normalized to DMSO controls indicating 100 % survival. Inhibitor vs. response curves with variable slope (four parameters) were fitted using GraphPad Prism. Figure 8: List of HR genes. List of genes involved in DNA Damage Response (DDR) (Human DNA Repair Genes, n.d.) cited in Wood RD, Mitchell M, & Lindahl T Mutation Research, 2005, in Science, 2001, in the reference book DNA Repair and Mutagenesis, 2nd edition, 2006, and in Nature Reviews Cancer, 2011 (modified by R. Wood and M. Lowery on Wednesday 10th June 2020). Figure 9: List of genes related to the homologous recombination repair pathway (HR). Summary of genes from Toh & Ngeow, 2021; Kim et al., 2021; Yamamoto & Hirasawa, 2021 and the HRD-signature genes from Peng et al,.2014. Figure 10: Synergistic effect of ALC1i-101 and trametinib in a MiaPaCa2 CDX experiment. Detailed Description of the Invention Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Several documents are cited throughout the text of this specification. Each of the documents 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 is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Some of the documents cited herein are characterized as being “incorporated by reference”. In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence. In the following, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise. Definitions To practice the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA techniques are employed which are explained in the literature in the field (cf., e.g., Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989). In the following, some definitions of terms frequently used in this specification are provided. These terms will, in each instance of its use, in the remainder of the specification have the respectively defined meaning and preferred meanings. As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents, unless the content clearly dictates otherwise. The term “Chromodomain-helicase-DNA-binding protein 1-like” abbreviated CHD1L refers to a protein that is also termed ALC1. The amino acid sequence of human ALC1 is as specified in SEQ ID NO: 1 as known in the art, e.g. as specified in WO2022 / 117782 A1. The 897 amino acid residues long protein consists of an N-terminal Snf2-like DNA dependent ATPase domain spanning amino acid residues 40 to 513, which contains the conserved helicase motifs critical for catalysis (Flaus et al., 2006). This domain is composed of two RecA like lobes ranging from amino acid residues 48 to 261 and 351 to 513, respectively. The allosteric binding pocket is spatially separated from that part of ALC1 involved in binding ATP. The ATPase domain is followed by a linker region ranging from amino acid residues 514 to 703, which contains a putative coiled-coil region (amino acid residues 638 to 675), and a C-terminal macrodomain (amino acid residues 704 to 897). The macrodomain has been shown to directly interact with the ATPase domain, thereby inhibiting its catalytic function (Lehmann et al., 2017; Singh et al., 2017). This interaction is released upon poly(ADP-ribose) binding to the macrodomain, leading to an activation of the chromatin remodelling enzyme. Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Kölbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland). The term "alkyl" as used in the context of the present invention refers to a saturated straight or branched hydrocarbon chain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, e.g. methyl, ethyl propyl (n-propyl or iso-propyl), butyl (n-butyl, iso-butyl, sec-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, nonyl, or decyl. Alkyl groups are optionally substituted. The term "heteroalkyl" as used in the context of the present invention refers to a saturated straight or branched hydrocarbon chain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e.1, 2, 3, 4, 5, 6, 7, 8, or 9, e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, or 5, with the same or different heteroatoms. Preferably, the heteroatoms are selected from O, S, and N, e.g. -(CH2)n-X-(CH2)mCH3, with 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' with R' = H or hydrocarbon (e.g. C1to C6alkyl). In particular "heteroalkyl" refers to O-CH3, -OC2H5, -CH2-O-CH3, - CH2-O-C2H5, -CH2-O-C3H7, -CH2-O-C4H9, -CH2-O-C5H11, C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-O- C3H7, -C2H4-O-C4H9etc. Heteroalkyl groups are optionally substituted. The term "haloalkyl" refers to a saturated straight or branched hydrocarbon chain in which one or more hydrogen atoms are replaced by halogen atoms, e.g. by fluorine, chlorine, bromine or iodine. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. 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 are optionally substituted. The term “5, 6, or 7 membered carbocycle” is used in the context of the present invention to refer to “cycloalkyl", “cycloalkenyl” or "aryl" with 5, 6, or 7 carbon atoms forming a ring. The term “cycloalkyl” includes cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups are optionally substituted. The term “cycloalkenyl” includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups are optionally substituted. The term “aryl” refers to a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Preferably, the aryl group comprises 6 to 10 carbon atoms, i.e. a C6-10aryl group. In a preferred embodiment, an aryl group is a phenyl group, which is most preferred, or a naphthyl group. Aryl is optionally substituted. The term “5, 6, or 7 membered heterocycle” is used in the context of the present invention to refer to monocyclic "5, 6, or 7 membered heterocycloalkyl" or monocyclic “5, 6, or 7 membered heteroaryl” with 5, 6, or 7 atoms forming a ring. The term “5, 6, or 7 membered heterocycloalkyl” refers to a saturated monocycle, wherein at least one of the carbon atoms are replaced by 1, or 2 (for the five membered ring) or 1, 2, or 3 (for the six membered ring) or 1, 2, 3, or 4 (for the seven membered ring) of the same or different heteroatoms, preferably 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 are optionally substituted. The term “heteroaryl” as used in the context of the present invention refers to a 5, 6 or 7-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, or 3 (for the five membered ring) or 1, 2, 3, or 4 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S. Examples of preferred heteroaryls are furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl. Heteroaryl groups are optionally substituted. The term “aralkyl” corresponds to an arylalkyl residue, i.e. an alkyl that is substituted with an aryl group as defined above. If two or more radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different. The term "optionally substituted" in each instance if not further specified refers to halogen (in particular 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 a 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, an alicyclic system, aryl and heteroaryl; optionally substituted. "Pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia (United States Pharmacopeia-33 / National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of a compound described herein or a derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 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, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of Formula (I) or Formula (II), and especially a compound shown in Fig.1. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. Additionally, 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 with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson L.A. and Tunek A. (1988) Drug Metabolism Reviews 19(2): 165-194 and Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard H. et al. (1989) J. Med. Chem.32(12): 2503- 2507). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985)). Hydroxy groups have been masked as esters and ethers. EP 0039051 A2 discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. 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 be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). 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, “para position” when referring to the substituent of an aryl means that the substituent occupies the position opposite to the position at which the aryl is linked to the backbone of the compound. As used herein, a “patient” means any mammal or bird that may benefit from a treatment with the compounds described herein. Preferably, a “patient” is selected from the group consisting of laboratory animals, domestic animals, or primates including chimpanzees and human beings. It is particularly preferred that the “patient” is a human being. As used herein, "treat", "treating" or “treatment”, or ameliorating, respectively, of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s). As used herein, “prevent”, “preventing”, “prevention”, or “prophylaxis” of a disease or disorder means preventing that a disorder occurs in a subject for a certain amount of time. For example, if a compound described herein is administered to a subject with the aim of preventing a disease or disorder, said disease or disorder is prevented from occurring at least on the day of administration and preferably also on one or more days (e.g. on 1 to 30 days; or on 2 to 28 days; or on 3 to 21 days; or on 4 to 14 days; or on 5 to 10 days) following the day of administration. A “pharmaceutical composition” according to the invention may be present in the form of a composition, wherein the different active ingredients and diluents and / or carriers are admixed with each other, or may take the form of a combined preparation, where the active ingredients are present in partially or totally distinct form. An example for such a combination or combined preparation is a kit-of-parts. An “effective amount” is an amount of a therapeutic agent sufficient to achieve the 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 receive the therapeutic agent, and the purpose of the administration. The effective amount in each individual case may be determined empirically by a skilled artisan according to established methods in the art. The term “carrier”, as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A saline solution is a preferred carrier 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, gelatine, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. SEQ ID NO 1: MERAGATSRGGQAPGFLLRLHTEGRAEAARVQEQDLRQWGLTGIHLRSYQLEGVNWLAQR FHCQNGCILGDEMGLGKTCQTIALFIYLAGRLNDEGPFLILCPLSVLSNWKEEMQRFAPG LSCVTYAGDKEERACLQQDLKQESRFHVLLTTYEICLKDASFLKSFPWSVLVVDEAHRLK NQSSLLHKTLSEFSVVFSLLLTGTPIQNSLQELYSLLSFVEPDLFSKEEVGDFIQRYQDI EKESESASELHKLLQPFLLRRVKAEVATELPKKTEVVIYHGMSALQKKYYKAILMKDLDA FENETAKKVKLQNILSQLRKCVDHPYLFDGVEPEPFEVGDHLTEASGKLHLLDKLLAFLY SGGHRVLLFSQMTQMLDILQDYMDYRGYSYERVDGSVRGEERHLAIKNFGQQPIFVFLLS TRAGGVGMNLTAADTVIFVDSDFNPQNDLQAAARAHRIGQNKSVKVIRLIGRDTVEEIVY RKAASKLQLTNMIIEGGHFTLGAQKPAADADLQLSEILKFGLDKLLASEGSTMDEIDLES ILGETKDGQWVSDALPAAEGGSRDQEEGKNHMYLFEGKDYSKEPSKEDRKSFEQLVNLQK TLLEKASQEGRSLRNKGSVLIPGLVEGSTKRKRVLSPEELEDRQKKRQEAAAKRRRLIEE KKRQKEEAEHKKKMAWWESNNYQSFCLPSEESEPEDLENGEESSAELDYQDPDATSLKYV SGDVTHPQAGAEDALIVHCVDDSGHWGRGGLFTALEKRSAEPRKIYELAGKMKDLSLGGV LLFPVDDKESRNKGQDLLALIVAQHRDRSNVLSGIKMAALEEGLKKIFLAAKKKKASVHL PRIGHATKGFNWYGTERLIRKHLAARGIPTYIYYFPRSKSAVLHSQSSSSSSRQLVP Embodiments of the Invention The present inventors have identified and characterized ALC1 inhibitors that appear to be involved in allosteric regulation of the nucleosome sliding activity of ALC1. These compounds specifically bind to an allosteric pocket and are capable of inhibiting activity of ALC1. Compounds that bind to the ATPase site of ALC1 and block the ATPase activity have to compete with ATP for binding to the ATPase site. These compounds had been tested for their ability to kill different tumor cell lines one of which was BRCA deficient. The present inventors have identified that said allosteric inhibitors of ALC1 (CHD1L), in particular those of Formula (I) and Formula (II), show a potentiating, preferably synergistic effect in the treatment of proliferative disease when combined with several classes of cancer drugs, namely inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, with mitomycin C, paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. Furthermore, it has been found that said inhibitors of ALC1 of Formula (II) show a synergistic effect in the treatment of pancreatic cancer or fallopian tube cancer when combined with a PARP inhibitor. The present inventors considered the rationale that ALC1 inhibitors as a known class of cancer drugs could be combined with several other classes of known cancer drugs, e.g. inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, or MEK, with mitomycin C, or paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. However, tests with known ALC1i showed not over-additive efficacies against cancer cell lines. The present invention is based on the surprising finding that said specific allosteric ALC1 inhibitors, preferably those of Formula (I) and of Formula (II), possess synergistic anti-proliferative activity when combined with inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, with mitomycin C, or paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. Thus, these combinations are expected to be suitable in the treatment of proliferative diseases. The ALC1 inhibitors, preferably those characterized by Formula (I) and Formula (II), the latter being known from the art (WO 2022 / 117782 A1), which are used in accordance with the present invention, appear to be involved in allosteric regulation of the nucleosome sliding activity of ALC1. These compounds specifically bind to an allosteric pocket and are capable of inhibiting activity of ALC1. Compounds that bind to the ATPase site of ALC1 and block the ATPase activity have to compete with ATP for binding to the ATPase site. Since the cellular ATP concentration is in the range of 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. The allosteric inhibitors of ALC1 used according to the invention, in particular those that are characterized by Formula (I) and Formula (II), do not have this limitation since they do not have to prevent ATP from binding but inhibit ALC1’s activity through a different mechanism. The present inventors have identified ALC1 inhibitors that are capable of specifically binding to an allosteric pocket of ALC1. The question remained and has been not answered by the art yet, whether these specific ALC1 inhibitors would provide synergistic efficacy with other classes of cancer drugs. In a first aspect, the present invention is directed at an allosteric inhibitor of Chromodomain- helicase-DNA-binding protein 1-like (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1 for use in treating or ameliorating a proliferative disease in a patient in combination with and / or for use in enhancing the efficacy in treating a proliferative disease of a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, or b) mitomycin C, paclitaxel, c) ionizing radiation, or d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan). The term “specifically binds” as used in this context indicates a KDof the compound to full length human ALC1 with an amino acid sequence according to SEQ ID NO: 1 of 200 µM or lower, preferably of 100 µM, more preferably of 50 µM, more preferably of 10 µM or lower, more preferably of 5 µM or lower, even more preferably of 1 µM and even more preferably of 500 nM or lower. The skilled person is well aware of how to measure dissociation constants of small molecules with regard to proteins, which includes surface plasmon resonance. Preferably the KDof a compound of the invention is measured by immobilizing full length human ALC1 on the surface of a chip and the compound is subsequently applied to the immobilized protein. Preferably such measurement is carried out at 37°C. In a preferred embodiment of the present invention, the allosteric inhibitor of ALC1 used according to the invention exhibits an IC50value in a FRET based nucleosome remodeling assay of 500 µM or less, preferably 250 µM or less, more preferably 100 µM or less, more preferably 50 µM or less, more preferably 10 µM or less, more preferably 5 µM or less, or even more preferably 1 µM or less. The KDand the IC50as described herein are determined as disclosed in WO 2022 / 117782 A1. Not every amino acid within the amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1 is forming the surface of the allosteric pocket of ALC1 available for binding to the compounds used according to the invention. This is due to the fact that some amino acids are buried in the pocket and are poorly accessible and others are not even part of the pocket but are located within or on the outside surface of ALC1. Thus, in a preferred embodiment the allosteric binding pocket to which the inhibitors of ALC1 used according to the present invention specifically bind comprises or consists of amino acids L101, Y153, C156, L157, A160, L163, K164, V173, D174, E175, A176, H177, R178, L179, S183, L186, H187, T189, L190, F193, L200, L201, T202, N208, S209, E212, L213, L216, and F219 of SEQ ID NO: 1, more preferably the binding pocket comprises or consists of Y153, C156, L157, A160, L163, V173, E175. R178, L186, H187, L190 F 193, L200, and E212 of SEQ ID NO: 1. The skilled person can model the allosteric binding pocket of ALC1 based on the homology to other chromatin remodelling enzymes. Such models are also depicted in WO2022 / 117782 A1 with and without compounds used in the invention in the pocket. WO2022 / 117782 A1 depicts how the skilled person can visualize the suitability of a given compound to fit into the allosteric binding pocket, and thus provides further guidance on the selection of compounds that fulfill the steric, hydrophobicity, and hydrophilicity as well as charge requirements in the pocket. A minimal set of structural coordinates of the amino acids of ALC1 involved in binding to the compounds of the invention is provided in Fig. 20 of WO2022 / 117782 A1. That is, with the detailed teaching given in WO2022 / 117782 A1, it can be determined whether the inhibitor specifically binds to the allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1. Based on their orientation within the pocket the different amino acids that are accessible at the surface of the pocket can form different non-covalent bonds, in particular hydrogen bonds, ionic interactions, van der Waals interactions and hydrophobic interactions. Accordingly, in a preferred embodiment the inhibitor used according to the invention forms non-covalent bond(s) with one or more amino acids of the allosteric binding pocket, preferably with one or more of the backbone of amino acids L157, A160, K164, V173, D174, H177, R178, L179, L186, N208, and / or E212 of ALC1 and / or the sidechains of L101, Y153, C156, L157, A160, L163, E175, R178, L179, L186, H187, L190, F193, T202, N208, E212, or L213 of ALC1, more preferably with the backbone of D174, H177, and R178 of ALC1, and the sidechain of Y153, E175, R178, H187, T202, N208 and / or E212 of ALC1. In a preferred embodiment the inhibitor of ALC1 used according to the invention non-covalently binds to: (i) the aromatic ring of the sidechain of amino acid Y153 of ALC1 ring face-to-face or edge-to-face pi-pi interaction with aromatic carbo- or heterocyclic substituents or forming cation-pi, polar-pi, or halogen- pi interactions with polar, charged, or carbo-halogen substituents; (ii) the terminal oxygen of the sidechain of amino acid Y153 of ALC1 with a hydrogen bond donating group; (iii) the carbonyl oxygen of the backbone of H177 with carbo halogens or hydrogen bond donating groups; (iv) the carbonyl oxygen of the backbone of D174 with carbo halogens or hydrogen bond donating groups; (v) the sidechain of E175 with a hydrogen bond donating or accepting group; (vi) the sidechain of R178 with a hydrogen bond donating or accepting group; (vii) the backbone carbonyl oxygen of R178 with carbo halogens or hydrogen bond donating groups; (viii) the sidechain of H187 ring face-to-face or edge-to-face pi-pi interaction with aromatic carbo- or heterocyclic substituents or forming cation-pi, polar-pi, or halogen-pi interactions with polar, charged, or carbo-halogen substituents or with a hydrogen bond donating or accepting group (ix) the sidechain of T202 with a hydrogen bond donating or accepting group; (x) the sidechain of N208 with a hydrogen bond donating or accepting group; and (xi) the sidechain of E212 with a hydrogen bond donating or accepting group. In an preferred embodiment, the inhibitor of ALC1 (ALC1i) used according to the invention is an inhibitor of ALC1 (ALC1i) according to Formula (II) wherein (i) R5comprises an aromatic ring that pi-stacks with the aromatic ring of Y153; and / or (ii) N is a hydrogen bond accepting group for the terminal OH of Y153; and / or (iii) R1comprises a group that is a hydrogen bond donating group to the backbone carbonyl oxygen of H177; and / or (iv) R3comprises a carbohalogen or hydrogen bond donating group that binds to the carbonyl oxygen of the backbone of D174; and / or (v) R1and R2together form an aromatic or heteroaromatic monocyle comprising a hydrogen bond donating or accepting group especially at or adjacent to the R1position which can act as a hydrogen bond doating or accepting group to the side chain of E175 and / or R178; and / or (vi) R1and R2together form a substituted carbo- or heteromonocycle comprising a hydrogen bond donating or accepting group, preferably at or adjacent to the R1position which is a hydrogen bond donating or accepting group to the side chain of R178; and / or (vii) R3comprises an aromatic ring that pi-stacks with the aromatic ring H187 or is an electron poor substituent, especially at, forming polar-pi or cation-pi interactions with the aromatic ring of H187; and / or (viii) R1and R2together form an aromatic or heteroaromatic monocyle comprising a hydrogen bond donating or accepting group especially at or adjacent to the R2position which can act as a hydrogen bond donating or accepting group to the side chain of T202 and / or N208; and / or (ix) R4is H or -C1-3-alkyl, preferably H; and / or (x) R5is -(CH2)m-L, or -(CH2)m-(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5, 6 or 7 membered carbo- or heterocycle, or adamantyl, optionally substituted, preferably with 1, 2, 3 or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents form a 5, 6 or 7 membered carbo- or heterocycle; and / or (xi) R4and R5together form a 5, 6, or 7 membered carbocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-RA, preferably R4and R5together form a C5-7-cycloalkyl; and / or (xii) X is N or S; and / or (xiii) A is C or N; or pharmaceutically acceptable salts, isomers, solvates, chemically protected forms, and prodrugs thereof. In a preferred embodiment, the inhibitor of ALC1 (ALC1i) used according to the invention is an inhibitor of ALC1 (ALC1i) according to Formula (I) wherein A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or when A6 takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle, then A6 is C; A7 is selected from N or CH, or when A7 takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- 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-R9, –CF2– R9, -CH2-CH2- R9, -CH2-CF2-R9, -CH2-CH2-CH2-R9, -O-R9, -NH-R9, -N=R9; or L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and / or R9; L4 is CH2, –CF2–, CH2-CH2, CH2-CH2-CH2, O, N, and NH, or is absent; Z is a 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and can be annulated to the central core or connected via a covalent bond R4 is 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -CF3, Me, Et, - OMe, and -SMe, or R4 is hydrogen, methyl, or COOH; R9 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, - CF3, Et, -OMe, and -SMe; R6 is a 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) 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 takes part in the annulated carbo- 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 pharmaceutically acceptable salt, isomers, solvate, chemically protected form, or prodrugs thereof for use in treating or ameliorating a proliferative disease in a patient in combination with an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, with mitomycin C, paclitaxel, an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, such as trastuzumab deruxtecan, or with ionizing radiation. Preferred embodiments of the inhibitor of ALC1 (ALC1i) according to formula (I) The ALC1i according to Formula (I) preferably shows inhibition >50% at concentrations at or below 250 µM, preferably has an IC50of < 250 µM, and more preferably of < 25 µM. The IC50is preferably measured in a FRET based nucleosome remodeling assay as described in WO 2022 / 117782 A1. The ALC1i according to Formula (I) preferably has an EC50of < 250 µM, preferably of < 50 µM; and more preferably of < 10 µM. The EC50is preferably measured in cell proliferation assay with an SRB based readout as described in WO 2022 / 117782 A1. If not specifically indicated otherwise, the residues with normal, i.e. not subscript, integers, relate to compounds of formula (I), those residues with subscript integers relate to compounds of formula (II). In an embodiment, it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): A5 and A6 are N; and A7 takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2. In an embodiment it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): A5 and A6 are N; A7 takes part in the annulated carbo- or heterocycle, preferably carbocycle Z, optionally substituted with one, two, or three, preferably one substituent(s) 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. In an embodiment it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): A5 is N and A8 is -N or -CH. In an embodiment it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): A5 is N and A8 is -N or -CH; and A6 takes part in the annulated carbo- or heterocycle, preferably carbocycle Z. In a particularly preferred embodiment A5, A7 and A8 are N. In a particularly preferred embodiment A5, A7 and A8 are N and A6 takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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 takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2. In an embodiment it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): L2 is selected from the group consisting of -CH2-R4, -CH2-CH2- R4, -CH2-CH2-CH2-R4. In an embodiment it is preferred that:L2 is selected from the group consisting of -CH2-R4, –CF2– R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -NH-R4; and R4 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, preferably 5- or 6 -membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH. In an embodiment it is preferred that: L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9. In an embodiment it is preferred that: L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, -CH2-CF2-R9; and R9 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, - CF3, Et, -OMe, and -SMe. In an embodiment it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and R9. In an embodiment it is preferred that: L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and R9; R4 is hydrogen, methyl, or COOH; and R9 is a 4-, 5-, 6-, 7-membered carbo- or heterocycle, preferably phenyl or 5- or 6-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In an embodiment it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): L4 is 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 takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and L4 is absent. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and L4 is absent. In a particularly preferred embodiment A5, A7 and A8 are N; and L4 is absent R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and L4 is absent R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and L4 is absent R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; and L4 is absent R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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 one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) 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 one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In an embodiment it is preferred that: R4 is hydrogen, methyl, COOH or tetrazolyl. In an embodiment it is preferred that: L2 is -CH2-R4, -CH2-CH2- R4, -CH2-CH2-CH2-R4; and R4 is hydrogen, methyl, COOH or tetrazolyl. In an embodiment it is preferred that: R9 is any 4-, 5-, 6- 7-, 8-, 9-, or 10-membered carbo- or heterocycle, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, - CF3, Me, Et, -OMe, and -SMe. In an embodiment it is preferred that: R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In an embodiment it is preferred that: L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, -CH2-CF2-R9; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In an embodiment it is preferred that: R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe or R6 is H. In an embodiment it is preferred that: L4 is absent; and R6 is a 5-, or 6-membered carbo- or heterocycle, preferably 6-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In above embodiment it is preferred that: Z is a 6 membered aryl, or a 5-, 6-membered heteroaryl, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, - I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2. In an embodiment, it is preferred that: A5 is N; one of A6 and A7 is CH and the other one is N; or one of A6 and A7 is C and takes part in the annulated carbo- or heterocycle Z and the other one is N; A8 is N or CH; L2, L3, L4 are independently from each other 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 the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and R9; Z is any 5-, 6- or 7-membered carbo- or heterocycle and can be annulated to the central core or connected via a covalent bond and optionally substituted with one, two, or three (preferably one) substituent(s) 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 carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -CF3, Me, Et, - OMe, and -SMe, or R4 is hydrogen, methyl, or COOH; R9 is a 4-, 5-, 6- 7-, 8-, 9-, or 10-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) 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 carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) 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 takes part in the annulated carbo- 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; wherein R4, R9, and R6. In an embodiment it is preferred that: A5 is N; one of A6 and A7 is C and takes part in the annulated carbo- or heterocycle Z and the other one is N; A8 is N; L2 is CH2-CH2and L3 is CH2-CH2or CH2-CF2; or L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle (preferably piperidine or a pyrrolidine) substituted by R4 and R9; L4 is absent; Z is a 6-membered carbo- or heterocycle annulated to the central core, wherein Z is optionally substituted with one, two, or three (preferably one) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and NO2; R4 is COOH or CH2N4; R9 is a 4-, 5-, 6-, 7-, or 10-membered carbo- or heterocycle, optionally substituted with one, two, or three, preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 5- or 6-membered carbo- or heterocycle, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, - OMe, and -SMe, or R6 is H. In an embodiment it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): each one of A5, A7 and A8 is N; A6 is C and takes part in the annulated carbo- or heterocycle Z, preferably 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) 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-R9; or L2 and L3 together with the A8 to which they are connected form a piperidine ring or a pyrrolidine ring, substituted by R4 and R9; L4 is absent; Z is phenyl or cyclohexyl annulated to the central core, wherein Z is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -OH, Me, -CF3, -OMe, and -NO2, R4 is COOH or tetrazolyl; R9 is phenyl, cyclobutyl, cyclopentyl or adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -CF3, Me, -CH2-CF3, and –OMe; R6 is a 6-membered carbo- or heterocycle, preferably phenyl or cyclohexyl; more preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of Br, -Cl, -F, Me, -CF3, -OMe, and -NO2.In a particularly preferred embodiment 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; and L4 is absent. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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; and L4 is absent. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and L4 is absent. In a particularly preferred embodiment 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 a phenyl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, - CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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 phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) 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 phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; and R9 is C5to C7-cycloalkyl, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; L4 is absent; R9 is C5to C7-cycloalkyl, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; andR6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; and L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9 L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMeR6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, - CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe: and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6 to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMeR6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, - CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe: and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C5to C7-cycloalkyl C4to C7-cycloalkyl, i.e. C4-,, i.e. C5-, C6- or C7-cycloalkyl, C6to C10- bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, - OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; and L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9 L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMeR6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, - CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N; L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe: and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, i.e. C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6 to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;R9 is C4 to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6 to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMeR6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, - CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe: and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;R9 is C4 to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6 to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe. In a particularly preferred embodiment of the above embodiments: 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. In a particularly preferred embodiment of the above embodiments: 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. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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 In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;R9 is C4 to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6 to C10-bicycloalkyl, i.e. C6-, C7-, C8-, C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe: 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) 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-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C4to C7-cycloalkyl, i.e. C4-, C5-, C6- or C7-cycloalkyl, C6to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C9- or C10-bicycloalkyl, C6to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) 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, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one, or two substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; 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. In a particularly preferred embodiment the inhibitors of ALC1 (ALC1i) according to formula (I) of the first and further aspects of the invention have the specific structures as indicated in Fig.1. In the first aspect, in a preferred embodiment, the inhibitor of ALC1 (ALC1i) used according to the invention is an inhibitor of ALC1 (ALC1i) according to Formula (II): and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: X is N or S; A is C or N;R1 is –CO-OR6, -CO-R7, or -CO-NR6RA, preferably R1 is –CO-OR6; R2is -R7, -NHR8, -O-R7, -C-O-R7, Br, -C3-8-cycloalkyl (preferably cyclopropyl), or –C4-8-cycloalkenyl (preferably cyclohexenyl); or R1and R2together form a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, =O, [-O-CH2-CH2]-NH-CH(OH)-O-tBu, ; R3is H, =O, -OH, -O-R7, -R7, or –(CH2)m-L, wherein m is 0, 1 or 2, and L is a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, -hydroxyC1-3-alkyl and =O; R4is H or -C1-3-alkyl, preferably H; R5is -(CH2)m-L, or -(CH2)m-(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5, 6 or 7 membered carbo- or heterocycle, adamantyl, C1-4-alkyl, or -N(CH3)2, optionally substituted, preferably with 1, 2, 3 or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O, and [-O-CH2-CH2]q-NH-biotin with q being 1, 2, 3, or 4, or two adjacent substituents form a 5, 6 or 7 membered carbo- or heterocycle; or R4and R5together form a 5, 6, or 7 membered carbocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, - O-R9, -R9, =CH-RA, and –CH2-RA, preferably R4and R5together form a C5-7-cycloalkyl; R6is H, -C1-6-alkyl, -C2-6-alkenyl, -C2-6-alkynyl, optionally substituted, preferably R6is H; R7is -C1-3-alkyl, -C2-3-alkenyl, -C2-3-alkynyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8is H or C1-6-alkyl, preferably H, R9is -C1-6-alkyl, -C2-6-alkenyl, -C2-6-alkynyl, -C1-6-alkyl-aryl, or C1-6-alkyl-heteroaryl (preferably isooxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4- oxadiazole, pyrazine, or pyrazole), optionally substituted with 1, 2 or 3 substituents selected from the group consisting of -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C1-3-alkyl (preferably –CONH- CH3), -NH-CO-C1-3-alkyl (preferably -NH-CO-CH3), -C1-6-alkyl (preferably -CH3, ethyl, propyl, t- butyl, or pentyl), -C1-3-haloalkyl (preferably-CF3, or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably –CO-(1-pyrrolidinyl)),-SO2-CH3, -SO2-N(CH3)2, -O-C1-4-alkyl (preferably -OCH3), -O-C1-3-alkyl-O-C1-3-alkyl (preferably –O-CH2-O-CH3), -SCH3, or when R9is -C1-6-alkyl-aryl, then two adjacent substituents on the aryl moiety can form a 5, 6 or 7 membered carbo- or heterocycle, which is optionally substituted; RAis H, carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2)o-R9, - SO2NH2, and =O, wherein o is 0 or 1. Preferred embodiments of the inhibitor of ALC1 (ALC1i) according to formula (II) The ALC1i according to Formula (II) preferably shows inhibition >50% at concentrations at or below 250 µM, preferably has an IC50of < 250 µM, and more preferably of < 25 µM. The IC50is preferably measured in a FRET based nucleosome remodeling assay as described in WO 2022 / 117782 A1. The ALC1i according to Formula (II) preferably has an EC50of < 250 µM, preferably of < 50 µM; and more preferably of < 10 µM. The EC50is preferably measured in a cell proliferation assay with an SRB based readout as described in WO 2022 / 117782 A1. When in Formula (II), X is N, this includes the option of X being N-H, and / or when A is N, R4may be absent. In an embodiment, it is preferred that in the inhibitor of ALC1 (ALC1i) according to Formula (II): X is N or S; A is C or N; R1is –CO-OR6, -CO-R7, or -CO-NR6RA, preferably R1is –CO-OR6; R2is -R7, -NHR8, -O-R7, -C-O-R7, Br, -C3-8-cycloalkyl (preferably cyclopropyl), or –C4-8-cycloalkenyl (preferably cyclohexenyl); or R1and R2together form a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, =O, [-O-CH2-CH2]-NH-CH(OH)-O-tBu, ; R3is H, =O, -OH, -O-R7, -R7, or –(CH2)m-L, wherein m is 0, 1 or 2, and L is a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, -hydroxyC1-3-alkyl and =O; R4is H or -C1-3-alkyl, preferably H; R5is -(CH2)m-L, or -(CH2)m-(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5, 6 or 7 membered carbo- or heterocycle, adamantyl, C1-4-alkyl, or -N(CH3)2, optionally substituted, preferably with 1, 2, 3 or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O, and [-O-CH2-CH2]q-NH-biotin with q being 1, 2, 3, or 4, or two adjacent substituents form a 5, 6 or 7 membered carbo- or heterocycle; or R4and R5together form a 5, 6, or 7 membered carbocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, - O-R9, -R9, =CH-RA, and –CH2-RA, preferably R4and R5together form a C5-7-cycloalkyl; R6is H, -C1-6-alkyl, -C2-6-alkenyl, -C2-6-alkynyl, optionally substituted, preferably R6is H; R7is -C1-3-alkyl, -C2-3-alkenyl, -C2-3-alkynyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8is H or C1-6-alkyl, preferably H, R9is -C1-6-alkyl, -C2-6-alkenyl, -C2-6-alkynyl, -C1-6-alkyl-aryl, or C1-6-alkyl-heteroaryl (preferably isooxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4- oxadiazole, pyrazine, or pyrazole), optionally substituted with 1, 2 or 3 substituents selected from the group consisting of -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C1-3-alkyl (preferably –CONH- CH3), -NH-CO-C1-3-alkyl (preferably -NH-CO-CH3), -C1-6-alkyl (preferably -CH3, ethyl, propyl, t- butyl, or pentyl), -C1-3-haloalkyl (preferably-CF3, or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably –CO-(1-pyrrolidinyl)),-SO2-CH3, -SO2- N(CH3)2, -O-C1-4-alkyl (preferably -OCH3), -O-C1-3-alkyl-O-C1-3-alkyl (preferably –O-CH2-O-CH3), -SCH3, or when R9is -C1-6-alkyl-aryl, then two adjacent substituents on the aryl moiety can form a 5, 6 or 7 membered carbo- or heterocycle, which is optionally substituted; RAis H, carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2)o-R9, - SO2NH2, and =O, wherein o is 0 or 1. According to the invention, it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (II): X is N or S; A is C or N; R1is –CO-OR6, -CO-R7, or -CO-NR6RA, preferably R1is –CO-OR6; R2is -R7, -NHR8, -O-R7, -C-O-R7; or R1and R2together form a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O; R3is H, =O, -OH, -O-R7, -R7, or –(CH2)m-L, wherein m is 0, 1 or 2, and L is a 5, 6 or 7 membered carbo- or heterocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, - hydroxyC1-3-alkyl and =O; R4 is H or -C1-3-alkyl, preferably H; R5is -(CH2)m-L, or -(CH2)m-(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5, 6 or 7 membered carbo- or heterocycle, or adamantyl, optionally substituted, preferably with 1, 2, 3 or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents form a 5, 6 or 7 membered carbo- or heterocycle; or R4and R5together form a 5, 6, or 7 membered carbocycle, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-RA, preferably R4and R5together form a C5-7-cycloalkyl; R6is H, -C1-6-alkyl, i.e. C1-, C2-, C3-, C4-, C5- or C6-alkyl, -C2-6-alkenyl, i.e. C2-, C3-, C4-, C5- or C6- alkenyl, --C2-6-alkynyl, i.e. C2-, C3-, C4-, C5- or C6-alkynyl, optionally substituted, preferably R6is H; R7is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- alkynyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8is H or C1-6-alkyl, preferably H, R9is -C1-6-alkyl, i.e. C1-, C2-, C3-, C4-, C5- or C6-alkyl, -C2-6-alkenyl, i.e. C2-, C3-, C4-, C5- or C6- alkenyl, --C2-6-alkynyl, i.e. C2-, C3-, C4-, C5- or C6-alkynyl, or -C1-6-alkyl-aryl, i.e. C1-, C2-, C3-, C4-, C5- or C6-alkyl-aryl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3RAis H, carbo- or heterocycle, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, - O-(CH2)o-R9, -SO2NH2, and =O, wherein o is 0 or 1. In a preferred embodiment of the invention, X is N. In a preferred embodiment of the invention, A is C. In a preferred embodiment of the invention R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H; In a preferred embodiment of the invention, R1is –CO-OH. In a preferred embodiment of the invention, X is N and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H. In a preferred embodiment of the invention, A is C and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H. In a preferred embodiment of the invention, X is N, A is C and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6 is H. In a preferred embodiment of the invention, X is N, A is C and R1is –CO-OH or -CO-NH2.In a preferred embodiment of the invention, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, X is N and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, A is C and R2 is -NHR8, wherein R8 is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, - C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, R1is –CO-OH and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, X is N and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, A is C and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, X is N, A is C and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, X is N, A is C and R1is –CO-OH or -CO-NH2and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O. In a preferred embodiment of the invention, X is N, and R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O. In a preferred embodiment of the invention, A is C, and R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O. In a preferred embodiment of the invention, X is N, A is C and R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O. In a preferred embodiment of the invention, R1and R2together form an uracil or 3-deazauracil. In a preferred embodiment of the invention, X is N, R1and R2together form an uracil or 3- deazauracil. In a preferred embodiment of the invention, A is C, and R1 and R2 together form an uracil or 3- deazauracil. In a preferred embodiment of the invention, X is N, A is C and R1and R2together form an uracil or 3-deazauracil. In a preferred embodiment of the invention, R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OH and R3is H, =O, -OH, -R7, or –(CH2)m- L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OH or -CO-NH2and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, - C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OH and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6 is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OH or -CO-NH2and R2is - NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1 and R2 together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1and R2together form an uracil or 3-deazauracil and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1and R2together form an uracil or 3- deazauracil and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C R1and R2together form an uracil or 3-deazauracil and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1and R2together form an uracil or 3- deazauracil and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OH and R3is -C1-3-alkyl, i.e. C1-, C2-, C3- alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or – (CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OH or -CO-NH2R3is -C1-3- alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, - C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6 is H, R2 is -NHR8, wherein R8 is H or C1-6-alkyl, preferably H and R3 is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OH, R2is -NHR8, wherein R8is H or C1-6- alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OH or -CO-NH2and R2is - NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m- L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is - C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independentlyselected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl andR3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1, R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1and R2together form an uracil or 3-deazauracil and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independentlyselected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl.In a preferred embodiment of the invention, X is N, and R1and R2together form an uracil or 3- deazauracil and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is C, R1and R2together form an uracil or 3- deazauracil and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is C, R1and R2together form an uracil or 3- deazauracil and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, R1is –CO-OH and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is C, R1 is –CO-OH or -CO-NH2 and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is C, R2 is -NHR8, wherein R8 is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, - C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, R1is –CO-OH, R2is -NHR8, wherein R8is H or C1-6- alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is C, R1is –CO-OH or -CO-NH2and R2is - NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is C, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is C, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, R1and R2together form an uracil or 3-deazauracil and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, R1and R2together form an uracil or 3- deazauracil and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is C, R1and R2together form an uracil or 3- deazauracil and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is C and R1and R2together form an uracil or 3-deazauracil and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is N and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H. In a preferred embodiment of the invention, X is N, A is N and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H. In a preferred embodiment of the invention, X is N, A is N and R1is –CO-OH or -CO-NH2.In a preferred embodiment of the invention, A is N and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, A is N and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, X is N, A is N and R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, X is N, A is N and R1is –CO-OH or -CO-NH2and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H. In a preferred embodiment of the invention, A is N, and R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O. In a preferred embodiment of the invention, X is N, A is N and R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O. In a preferred embodiment of the invention, A is N, and R1and R2together form an uracil or 3- deazauracil. In a preferred embodiment of the invention, X is N, A is N and R1and R2together form an uracil or 3-deazauracil. In a preferred embodiment of the invention, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OH or -CO-NH2and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3 is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OH or -CO-NH2and R2is - NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N R1and R2together form an uracil or 3-deazauracil and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1and R2together form an uracil or 3- deazauracil and R3is H, =O, -OH, -R7, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or – (CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OH or -CO-NH2R3is -C1-3- alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, - C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, R1is –CO-OH, R2is -NHR8, wherein R8is H or C1-6- alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3 is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3 is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OH or -CO-NH2and R2is - NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m- L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R1and R2together form an uracil or 3- deazauracil and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl and R3 is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and -hydroxyC1-3-alkyl. In a preferred embodiment of the invention, X is N, A is N, R1and R2together form an uracil or 3- deazauracil and R3is -C1-3-alkyl, i.e. C1-, C2-, C3-alkyl, or –(CH2)m-L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and - hydroxyC1-3-alkyl. In a preferred embodiment of the invention, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OH or -CO-NH2and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is N, R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OR6, or -CO-NR6RApreferably R6is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-, -alkenyl, -C2-3-alkynyl, i.e. C2-, C3-optionally substituted, preferably R6is H and R2is -NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is N, R1is –CO-OH or -CO-NH2and R2is - NHR8, wherein R8is H or C1-6-alkyl, preferably H and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably -OH and =O and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is N, R1and R2together form a 6 membered aryl or heteroaryl moiety, optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C1-3-alkyl, and =O, preferably - OH and =O and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, A is N, R1and R2together form an uracil or 3- deazauracil and R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, X is N, A is N and R1and R2together form an uracil or 3-deazauracil and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3. In a preferred embodiment of the invention, R5is -(CH2)m-L, , wherein m is 0, or 1 or -(CH2)- (CH=CH)-L and L is phenyl or a 5, or 6 membered heteroaryl, or adamantyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents form a 5, 6 or 7 membered carbo- or heterocycle. In a preferred embodiment of the invention, R4and R5together form a 5 or 6 membered non- substituted or mono substituted heterocycloalkyl, preferably with =CH-RAsubstituted at the R4position. In a preferred embodiment of the invention, RAis a substituted carbocycle with 1 or 2 substituents independently selected from the group consisting of -Br, -Cl, -F, -O-(CH2)o-R9, or -SCH3, wherein o is 0 or 1. In a preferred embodiment of the invention, R4and R5together form a 5 or 6 membered non- substituted or mono substituted heterocycloalkyl, preferably with =CH-RAsubstituted at the R4position, wherein RAis a substituted carbocycle with 1 or 2 substituents independently selected from the group consisting of -Br, -Cl, -F, -O-(CH2)o-R9, or -SCH3, wherein o is 0 or 1. In a preferred embodiment of the invention, R9is -C1-4-alkyl, i.e. C1-, C2-, C3-, or C4-alkyl, -C2-4- alkenyl, i.e. C2-, C3-, or C4-alkenyl, or -C1-6-alkyl-aryl, i.e. C1-, C2-, C3-, C4-, C5- or C6-alkyl-aryl, optionally substituted with 1 or 2 substituents selected from the group consisting of -Cl, -CH3, -OCH3, or -SCH3. In a preferred embodiment of the invention, R5is -(CH2)m-L, , wherein m is 0, or 1 or -(CH2)- (CH=CH)-L and L is phenyl or a 5, or 6 membered heteroaryl, or adamantyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents form a 5, 6 or 7 membered carbo- or heterocycle, wherein R9is -C1-4-alkyl, i.e. C1-, C2-, C3-, or C4-alkyl, -C2-4- alkenyl, i.e. C2-, C3-, or C4-alkenyl, or -C1-6-alkyl-aryl, i.e. C1-, C2-, C3-, C4-, C5- or C6-alkyl-aryl, optionally substituted with 1 or 2 substituents selected from the group consisting of -Cl, -CH3, -OCH3, or -SCH3.In a particularly preferred embodiment of the invention, the ALC1i has the structure of Formula (IIa): and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: A is C or N; R1is –COOH R2is -CH3or -NH2or R1and R2together form a uracil or 3-deazauracil; R3is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethyl phenyl, CF2H, or CF3; R4is H R5is -L, or -CH2-(CH=CH)-L, wherein L is a 6 membered carbo- or heterocycle, or adamantyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OH, -NO2, -Br, -Cl, -F, CH3, -O-R9, and =O, or two adjacent substituents form a 5 or 6 membered heterocycle; or R4and R5together form a 5 or 6 membered non-substituted or mono substituted heterocycloalkyl, preferably with =CH-RAsubstituted at the R4position; R9is -C1-4-alkyl, i.e. C1-, C2-, C3-, or C4-alkyl, -C2-4-alkenyl, i.e. C2-, C3-, or C4-alkenyl, or -C1-6-alkyl- aryl, i.e. C1-, C2-, C3-, C4-, C5- or C6-alkyl-aryl, optionally substituted with 1 or 2 substituents selected from the group consisting of -Cl, -CH3, -OCH3, or -SCH3; RAis a substituted carbocycle with 1 or 2 substituents independently selected from the group consisting of -Br, -Cl, -F, -O-(CH2)o-R9, or -SCH3, wherein o is 0 or 1. In a particularly preferred embodiment, the ALC1i of the invention have the specific structures as indicated in Fig. 1. According to the present invention, the ALC1i are used in combination with an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, or with mitomycin C, paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor. The enzyme topoisomerase I (TOPI) is involved in relaxation of supercoiled DNA. It removes helical constrains that otherwise hinder DNA replication and transcription. Suitable inhibitors of Topoisomerase I are known in the art and are commercially available. Examples for use in accordance with the invention are irinotecan, SN-38, topotecan, camptothecin (NSC-100880) or derivatives thereof, such as hydroxy camptothecine, 7-ethylcamptothecin, or 9-aminocamptothecin, rubitecan, Genz-644282 (CAS No.529488- 28-6), belotecan (CKD-602) hydrochloride, or beta-lapachone. Irinotecan, SN-38, or topotecan are preferred, irinotecan is most preferred (preferably in the form of its active metabolite SN-38). Topoisomerase II (TOPII) manages DNA tangles and supercoils. It can pass one double helix through another, untangling DNA by cutting both strands of the DNA helix simultaneously. Suitable inhibitors of Topoisomerase II are known in the art and are commercially available. Examples of inhibitors of Topoisomerase II for use in accordance with the invention are teniposide, etoposide, anthracyclines like aclarubicin, epirubicin, idarubicin, doxorubicin, daunorubicin, pirarubicin (NSC-333054), zorubicin, aclarubicin or caminomycin, amonafide, mitoxantrone (NSC-301739), pixantrone maleate, dexrazoxane, ellipticine hydrochloride, phenoxodiol (haginin E), etoposide (VP-16), voreloxin (SNS-595) hydrochloride, and amsacrine. Teniposide and etoposide are preferred. Ataxia telangiectasia mutant (ATM) is a serine / threonine protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinase. Suitable inhibitors of ATM are known in the art and are commercially available. Examples of inhibitors of ATM for use in accordance with the invention are AZ-32 (CAS No. 2288709-96-4), AZD-0156 (CAS No.1821428-35-6), AZD-1390 (CAS No.2089288-03-7), RP-3500 (camonsertib; CAS No.2417489-10-0), KU-55933 (CAS No.587871- 26-9), KU-60019 (CAS No. 925701-49-1), CP-466722 (CAS No. 1080622-86-1), torin 2 (CAS No. 1223001-51-1), schisandrin B (Sch B) (CAS No.61281-37-6), AZ20 (CAS No.1233339-22-4), Berzosertib (VE-822) (CAS No. 1232416-25-9), CGK 733 (CAS No.905973-89-9), , ETP-46464 (CAS No.1345675- 02-6), AZ31 (CAS No. 2088113-98-6), VX-803 (M4344) (CAS No. 1613191-99-3), or M4076 (CAS No. 2495096-26-7). AZ-32, AZD-0156, and AZD-1390 are preferred. ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase) is a serine / threonine protein kinase. Suitable inhibitors of ATR are known in the art and are commercially available. Examples of inhibitors of ATR for use in accordance with the invention are ceralasertib (AZD6738) (CAS No. 1352226-88-0), elimusertib, VX-803 (M4344) (CAS No.1613191-99-3), AZ20 (CAS No.1233339-22-4), ETP-46464 (CAS No. 1345675-02-6), Berzosertib (VE-822) (CAS No. 1232416-25-9), Dactolisib (BEZ235) (CAS No. 915019-65-7), VE-821 (CAS No. 1232410-49-9), Schisandrin B (Sch B) (CAS No. 61281-37-6), HAMNO (NSC-111847) (CAS No. 138736-73-9), Torin 2 (CAS No. 1223001-51-1), CGK 733 (CAS No.905973-89-9), RP-3500 (CAS No.2417489-10-0), or SKLB-197 (CAS No.2713577-16-1). Ceralasertib and elimusertib are preferred. The WEE1 G2 Checkpoint kinase has a crucial role in cell cycle regulation and DNA damage recognition / repair. Suitable inhibitors of WEE1 are known in the art and are commercially available. Examples of inhibitors of WEE1for use in accordance with the invention are adavosertib (CAS No.955365- 80-7), Zn-C3 (CAS No. 2376146-48-2), PD0166285 (CAS No. 185039-89-8), or Debio 0123 (CAS No. 2243882-74-6). Adavosertib is preferred. Bromodomains are a family of evolutionarily conserved motifs that bind the acetylated lysines in histone tails and recruit transcriptional machinery promoting target gene transcription. Inhibitors of bromodomains (BET inhibitors) are known in the art and are commercially available. Examples of inhibitors of BRD for use in accordance with the invention are BAY-299 (CAS No.2080306-23-4), ABBV- 774 (CAS No. 2138861-99-9), (+)-JQ1 (CAS No. 1268524-70-4), I-BET762 (CAS No. 1260907-17-2), OTX015 (CAS No. 202590-98-5), I-BET151 (CAS No. 1300031-49-5), CPI-203 (CAS No. 1446144-04- 2), PFI-1 (CAS No. 1403764-72-6), MS436 (CAS. No.1395084-25-9), CPI-0610 (CAS No. 1380087-89- 7), see e.g. M. Pérez-Salvia et al. EPIGENETICS, 2017, 12(5), 323–339), or RVX2135 (CAS No.1253733- 17-3), FT-1101 (CAS No. 1776060-36-6), BAY1238097 (CAS. No. 1564268-08-1), INCB054329 (CAS. No. 1628607-64-6), BMS-986158 (CAS. No. 1800340-40-2), ABBV-075 (CAS. No.1445993-26-9), GS- 5829 (CAS. No. 1637771-14-2), and PLX51107 (CAS No. 1627929-55-8). BAY-299 and ABBV-774 are preferred. MEK is an integral part of the MAP kinase signal transduction pathway. MEK acts as a dual- specificity kinase, phosphorylating both serine / threonine and tyrosine residues. It specifically activates the extracellular signal-regulated kinase (ERK) through phosphorylation, which then goes on to regulate various targets in the cell, influencing processes such as growth, proliferation, differentiation, and survival. Examples of inhibitors of MEK for use in accordance with the invention are trametinib (CAS No.871700- 17-3), cobimetinib (CAS No. 934660-93-2), binimetinib (CAS No. 606143-89-9), selumetinib (CAS No. 606143-52-6) In the second aspect, the present invention is directed to the ALC1i according to Formula (II) as described above for use in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient in combination with an inhibitor of PARP, or for use in enhancing efficacy of an inhibitor of PARP in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient. The preferred embodiments described herein for the first aspect are also preferred for the second aspect, in particular the definitions of the ALC1i according to Formula (II) and of the PARP inhibitors. In a preferred embodiment, (i) the ALC1i according to formula (II) potentiates the cancer-cell killing efficacy of the PARPi, (ii) a reduced amount of PARPi is administered, and / or (iii) PARPi resistance is bypassed. That is, the present invention also relates to the ALC1i according to Formula (II) for use in treating or ameliorating pancreatic cancer, which is preferred, or fallopian tube cancer in a patient in combination with an inhibitor of PARP. Generally, inhibitors of PARP (PARPi) are known in the art and are commercially available. For recognition of single-strand and double-strand breaks (SSBs / DSBs), the nuclear Poly-ADP-ribose polymerase (PARP) enzymes are early 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. PARPs get recruited to DNA lesions by recognizing specifically altered, DNA-damage induced structures, which activates their PARylation activity, which in turn regulates their activity and the activity of other DDR and chromatin proteins, facilitating the DDR (Ray Chaudhuri and Nussenzweig, 2017). This catalytic activity can be inhibited by NAD+analogues and has become of particular interest and clinically useful in genetically-defined cancers. Notably, by targeting synthetic lethality in the context of BRCA1 or BRCA2 deficiency, so-called PARP inhibitors (PARPi) are used to treat homologous- recombination (HR)-deficient and other cancers. This is thought to occur by lowering PARP activity and / or by biochemically “trapping” of PARP-1 / 2 / 3 on chromatin (Murai et al., 2012, 2014). While “trapping” remains molecularly ill-defined, the term defines an enhanced recruitment, association and / or retention of PARP-1 / 2 / 3 enzymes on damaged chromatin, typically induced by treatment of PARP-1 enzyme with PARP inhibitors (PARPi), or a decrease in the release of PARP-1 / 2 / 3 enzymes following their initial recruitment, which leads to a prolonged retention. This biochemically manifests itself in an enhanced steady-state association / retention / binding (“trapping”) of the PARP enzymes with damaged genome regions / loci. Due to the clinical advent of PARPi, PARP-1 has emerged as a powerful target for an increasing list of cancers, including in combination with immuno-oncology therapies, such as the Lynparza / Keytruda trials, to give all but one of many examples. Moreover, first-line PARPi therapies and applications in contexts outside of germline BRCA-1 / 2 mutations are becoming possible. In a preferred embodiment, the PARPi: (i) that lowers PARP activity is selected from small interfering RNA, and (ii) that inhibits PARP1 is selected from the group consisting of a compound of (a) formula (III) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: IIIA andIIIB together represent an optionally substituted, fused aromatic ring; XIIIis NRXor CRXRY; if XIII=NRXthen n is 1 or 2 and if XIII=CRXRYthen n is l; RXis selected from the group consisting of H, optionally substituted Cl-20alkyl, C5-20aryl, C3-20heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; RYis selected from H, hydroxy, amino; or RXand RYmay together form a spiro-C3-7cycloalkyl or heterocyclyl group; RC1and RC2are independently selected from the group consisting of hydrogen and Cl-4alkyl or when XIIIis CRXRY, RC1, RC2, RXand RY, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and RIIIis selected from H and halo; and (b) formula (IV) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein:IVY andIVZ are each independently selected from the group consisting of: 1. an aryl group optionally substituted with 1, 2, or 3IVR6 ; 2. a heteroaryl group optionally substituted with 1, 2, or 3IVR6; 3. a substituent independently selected from the group consisting of hydrogen, alkenyl (e.g. C2-6- alkenyl), alkoxy (e.g. C1-6-alkoxy), alkoxyalkyl (e.g. C1-6-alkoxy-C1-6-alkyl), alkoxycarbonyl (e.g. C1-6-alkoxy-carbonyl), alkoxycarbonylalkyl (e.g. C1-6-alkoxy-carbonyl-C1-6-alkyl), alkyl (e.g. C1-6-alkyl), alkynyl (e.g. C2-6-alkynyl), arylalkyl (e.g. aryl-C1-6-alkyl), cycloalkyl (e.g. C3-8-cycloalkyl), cycloalkylalkyl (e.g. C3-8-cycloalkyl-C1-6-alkyl), haloalkyl (e.g. C1-6-haloalkyl), hydroxyalkylene (e.g. hydroxy-C1-6-alkylene), oxo, heterocycloalkyl (e.g. C2-8-hetero cycloalkyl), heterocycloalkylalkyl (e.g. C2-8-heterocycloalkyl-C1-6-alkyl), alkylcarbonyl (e.g. C1-6-alkyl-carbonyl), arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl (e.g. C1-6-alkyl-sulfonyl), arylsulfonyl, heteroarylsulfonyl, (RARB)alkylene (e.g. (RARB)-C1-6-alkylene), (NRARB)carbonyl, (NRARB)carbonylalkylene (e.g. NRARB)carbonyl-C1-6-alkylene), (NRARB)sulfonyl, and (RARB)sulfonylalkylene (e.g. (RARB)sulfonyl-C1-6-alkylene); wherein eachIVR6is selected from OH, NO2, CN, Br, Cl, F, I, C1-6-alkyl, C3-8-cycloalkyl, C2-8- heterocycloalkyl; C2-6-alkenyl, alkoxy (e.g. C1-6-alkoxy), alkoxyalkyl (e.g. C1-6-alkoxy-C1-6- alkyl), alkoxycarbonyl (e.g. C1-6-alkoxy-carbonyl), alkoxycarbonylalkyl (e.g. C1-6-alkoxy- carbonyl-C1-6-alkyl), C2-6-alkynyl, aryl, arylalkyl (e.g. aryl-C1-6-alkyl), C3-8-cycloalkylalkyl (e.g. C3-8-cycloalkyl-C1-6-alkyl, haloalkoxy (e.g. C1-6-haloalkoxy), haloalkyl (e.g. C1-6- haloalkyl), hydroxyalkylene (e.g. hydroxy-C1-6-alkylene), oxo, heteroaryl, heteroarylalkoxy (e.g. heteroaryl- C1-6-alkoxy), heteroaryloxy, heteroarylthio, heteroarylalkylthio (e.g. heteroaryl-C1-6-alkylthio), heterocycloalkoxy (e.g. C2-8-heterocycloalkoxy), C2-8- heterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (RARB)C1-6-alkylene, (NRARB)carbonyl, (RARB)carbonylalkylene (e.g. RARB)carbonyl-C1-6-alkylene), (NRARB)sulfonyl, and (NRARB)sulfonylalkylene (e.g. (NRARB)sulfonyl-C1-6-alkylene); IVR1,IVR2, andIVR3are each independently selected from the group consisting of hydrogen, halogen, alkenyl (e.g. C2-6-alkenyl), alkoxy (e.g. C1-6-alkoxy), alkoxycarbonyl (e.g. C1-6-alkoxy- carbonyl), alkyl (e.g. C1-6-alkyl), cycloalkyl (e.g. C3-8-cycloalkyl), alkynyl (e.g. C2-6-alkynyl), cyano, haloalkoxy (e.g. C1-6-haloalkoxy), haloalkyl (e.g. C1-6-haloalkyl), hydroxyl, hydroxyalkylene (e.g. hydroxy-C1-6-alkylene), nitro, NRARB, NRARBalkylene (e.g. NRARBC1-6-alkylene), and (RARB)carbonyl; IVA andIVB are each independently selected from hydrogen, Br, Cl, F, I, OH, C1-6-alkyl, C3-8-cycloalkyl, alkoxy (e.g. C1-6-alkoxy), alkoxyalkyl (e.g. C1-6-alkoxy-C1-6-alkyl), wherein C1-6-alkyl, C3-8-cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO2, CN, Br, Cl, F, I, C1-6-alkyl, and C3-8-cycloalkyl, wherein IVB is not OH; RA, and RB are independently selected from the group consisting of hydrogen, alkyl (e.g. C1-6-alkyl), cycloalkyl (e.g. C3-8-cycloalkyl), and alkylcarbonyl (e.g. C1-6-alkyl-carbonyl); or RAand RBtaken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of -O-, -NH, -N(C1-6-alkyl)-, -NCO(C1-6-alkyl)-, -N(aryl)-, -N(aryl-C1-6-alkyl-), -N(substituted-aryl-C1-6-alkyl-)-, - N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-6alkyl-)-, and -S- or S(O)q-, wherein q is 1 or 2 and the 3-10 membered heterocycle ring is optionally substituted with one or more substituents; IVR4andIVR5are each independently selected from the group consisting of hydrogen, alkyl (e.g. C1-6-alkyl), cycloalkyl (e.g. C3-8-cycloalkyl), alkoxyalkyl (e.g. C1-6-alkoxy-C1-6-alkyl), haloalkyl (e.g. C1-6-haloalkyl), hydroxyalkylene (e.g. hydroxy-C1-6-alkylene), and (NRARB)alkylene (e.g. NRARBC1-6-alkylene); (iii) that inhibits PARP1 and PARP2 is selected from the group consisting of a compound of (a) formula (V) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: VR1is hydrogen or fluorine; and VR2is hydrogen or fluorine; and (b) formula (VI) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: VIR1,VIR2, andVIR3are independently selected from the group consisting of hydrogen, alkenyl (e.g. C1-6-alkenyl), alkoxy (e.g. C1-6-alkoxy), alkoxycarbonyl (e.g. C1-6-alkoxycarbonyl), alkyl (e.g. C1-6-alkyl), alkynyl (e.g. C1-6-alkynyl), cyano, haloalkoxy (e.g. C1-6- haloalkoxy), haloalkyl (e.g. C1-6-haloalkyl), halogen, hydroxy, hydroxyalkyl (e.g. C1-6- hydroxyalkyl), nitro, NRARB, and (NRARB)carbonyl; VIA is a nonaromatic 4, 5, 6, 7, or 8-membered ring that contains 1 or 2 nitrogen atoms and, optionally, one sulfur or oxygen atom, wherein the nonaromatic ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl (e.g. C1-6-alkenyl), alkoxy (e.g. C1-6-alkoxy), alkoxyalkyl (e.g. C1-6-alkoxy-C1-6-alkyl), alkoxycarbonyl (e.g. C1-6-alkoxycarbonyl), alkoxycarbonylalkyl (e.g. C1-6- alkoxycarbonyl- C1-6-alkyl), alkyl (e.g. C1-6-alkyl), alkynyl (e.g. C1-6-alkynyl), aryl, arylalkyl (e.g. aryl- C1-6-alkyl), cycloalkyl (e.g. C3-8-cycloalkyl), cycloalkylalkyl (e.g. C3-8-cycloalkyl-C1-6-alkyl), cyano, haloalkoxy (e.g. C1-6-haloalkoxy), haloalkyl (e.g. C1-6- haloalkyl), halogen, heterocycle, heterocyclealkyl (e.g. heterocycle-C1-6-alkyl), heteroaryl, heteroarylalkyl (e.g. heteroaryl-C1-6-alkyl), hydroxy, hydroxyalkyl (e.g. C1-6- hydroxyalkyl), nitro, NRCRD, (NRCRD)alkyl (e.g. (NRCRD)-C1-6-alkyl), (NRCRD)carbonyl, (NRCRD)carbonylalkyl (e.g. (NRCRD)carbonyl-C1-6-alkyl), and (NRCRD)sulfonyl; and RA, RB, RC, and RDare independently selected from the group consisting of hydrogen, alkyl (e.g. C1-6-alkyl), and alkycarbonyl (e.g C1-6-alkylcarbonyl). (iv) that inhibits PARP1, PARP2 and PARP3 is a compound of formula (VII) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: VIIR1is: H; halogen; cyano; an optionally substituted alkyl (e.g. C1-6-alkyl), alkenyl (e.g. C2-6- alkenyl), alkynyl (e.g. C2-6-alkynyl), cycloalkyl (e.g. C3-8-cycloalkyl), heterocycloalkyl (e.g. C2-8-heterocycloalkyl), aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino, alkoxy (e.g. C1-6-alkoxy), alkyl (e.g. C1-6-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)-R10, where R10is: H; an optionally substituted alkyl (e.g. C1-6-alkyl), alkenyl (e.g. C1-6-alkenyl), alkynyl (e.g. C1-6-alkynyl), cycloalkyl (e.g. C3-8- cycloalkyl), heterocycloalkyl (e.g. C2-8-heterocycloalkyl), aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl (e.g. C1-6-alkyl) and aryl groups unsubstituted or substituted with one or more substituents selected from halo, hydroxy, nitro, and amino); or OR100or NR100R110, where R100and R110are each independently H or an optionally substituted alkyl (e.g. C1-6-alkyl), alkenyl (e.g. C2-6-alkenyl), alkynyl (e.g. C2-6-alkynyl), cycloalkyl (e.g. C3-8-cycloalkyl), heterocycloalkyl (e.g. C2-8-heterocycloalkyl), aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from alkyl (e.g. C1-6-alkyl), alkenyl (e.g. C2-6-alkenyl), alkynyl (e.g. C2-6-alkynyl), cycloalkyl (e.g. C3-8-cycloalkyl), heterocycloalkyl (e.g. C2-8-heterocycloalkyl), aryl, and heteroaryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl (e.g. C1-6-alkyl) and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and optionally substituted amino groups);VIIR2is H or alkyl (e.g. C1-6-alkyl); VIIR3is H or alkyl (e.g. C1-6-alkyl); VIIR4is H, halogen or alkyl (e.g. C1-6-alkyl); VIIX is O or S; Y is (CVIIR5VIIR6)(CVIIR7VIIR8)nor N-C(VIIR5), where: n is 0 or 1; VIIR5andVIIR6are each independently H or an optionally substituted alkyl (e.g. C1-6-alkyl), alkenyl (e.g. C2-6-alkenyl), alkynyl (e.g. C2-6-alkynyl), cycloalkyl (e.g. C3-8-cycloalkyl), heterocycloalkyl (e.g. C2-8-heterocycloalkyl), aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl (e.g. C1-4-alkyl), lower alkoxy (e.g. C1-4-alkoxy), or aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino); and VIIR7andVIIR8are each independently H or an optionally substituted alkyl (e.g. C1-6-alkyl), alkenyl (e.g. C2-6-alkenyl), alkynyl (e.g. C2-6-alkynyl), cycloalkyl (e.g. C3-8-cycloalkyl), heterocycloalkyl (e.g. C2-8-heterocycloalkyl), aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkyl (e.g. C1-4-alkyl), lower alkoxy (e.g. C1-4-alkoxy), and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino); where whenVIIR1,VIIR4,VIIR5,VIIR6, andVIIR7are each H,VIIR8is not unsubstituted phenyl. In a preferred embodiment of the invention, the PARPi is selected from the group consisting of AZD-5305, olaparib, talazoparib, niraparib, pamiparib, rucaparib, and veliparib, in particular the group consisting of olaparib, talazoparib, niraparib, pamiparib, rucaparib, and veliparib. In a preferred embodiment of the invention, the ALC1i and the inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, MEK, or of PARP, or mitomycin C, paclitaxel,ionizing radiation, or an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor are administered simultaneously or subsequently. In a third aspect the present invention relates to a pharmaceutical composition comprising the ALC1i as specified for the first aspect of the invention and an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, or mitomycin C, or paclitaxel, or an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor preferably for use in treating and / or amelioration of a proliferative disease, preferably cancer. In a fourth aspect, the present invention is directed to a kit of parts, comprising an ALC1i as described herein with instructions to combine it with an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, or mitomycin C, or paclitaxel, or ionizing radiation, or an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, or comprising an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, or mitomycin C, or paclitaxel or an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, with instructions to combine it with an ALC1i as defined herein, or comprising separately packaged an ALC1i as defined herein and an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK, or mitomycin C, paclitaxel or, or an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, optionally with instructions for use in treating or ameliorating a proliferative disease, preferably cancer. In one preferred embodiment of all aspects of the invention, the ALC1i used is a compound of formula (I) or a compound of formula (II), more preferably a compound having a structure as shown in Figure 1, or isomers, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs thereof. The preferred pharmaceutically acceptable salt is the sodium salt. In one preferred embodiment, the ALC1i as defined above, the pharmaceutical composition as defined above, and / or the kit of parts as defined above is for use in treating or ameliorating a proliferative disease, preferably cancer, more preferably the proliferative disease selected from a BRCA-1 and / or BRCA-2-deficient tumor, and / or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, or pancreatic cancer. BRCA1 and BRCA2 proteins are involved in both promoting homologous recombination (HR)- mediated DNA repair and controlling the stability of stalled replication forks. Many tumor types, including, e.g., breast cancer, ovarian cancer, prostate cancer, pancreatic carcinomas, 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 can develop PARP inhibitor resistance over the time. To treat such tumors the use of the ALC1i for use according to the invention is particularly suitable if used alone or in combination with PARPi. In a preferred embodiment of the ALC1i for use according to the invention, or the pharmaceutical composition or the kit according to the invention, the proliferative disease is selected from a cancer. As used herein, the term “cancer”, which preferably is a tumor (also called neoplasm), in particular a solid tumor, refers to cells having the capacity for autonomous growth. Examples of such cells include cells having an abnormal state or condition characterized by rapidly proliferating cell growth. The term is meant to include cancerous growths, e.g., tumors; oncogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Also included are malignancies of the various organ systems, such as respiratory, cardiovascular, renal, reproductive, hematological, neurological, hepatic, gastrointestinal, and endocrine systems; as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and / or testicular tumors, non-small cell carcinoma of the lung, and cancer of the small intestine. Cancer that is “naturally arising” includes any cancer that is not experimentally induced by implantation of cancer cells into a subject, and includes, for example, spontaneously arising cancer, cancer caused by exposure of a patient to a carcinogen(s), cancer resulting from insertion of a transgenic oncogene or knockout of a tumor suppressor gene, and cancer caused by infections, e.g., viral infections. The term “carcinoma” is art recognized and refers to malignancies of epithelial or endocrine tissues. The term also includes carcinosarcomas, which include malignant tumors composed of carcinomatous and sarcomatous tissues. An “adenocarcinoma” refers to a carcinoma 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 derivation. The term “hematopoietic neoplastic disorders” includes diseases involving hyperplastic / neoplastic cells of hematopoietic origin. A hematopoietic neoplastic disorder can arise from myeloid, lymphoid or erythroid lineages, or precursor cells thereof. In some embodiments of the aspects of the invention, the cancer is breast cancer, ovarian cancer, prostate cancer, pancreatic carcinomas, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), gastric cancer, gastroesophageal cancer, non-small cell lung cancer, bladder cancer, endometrial cancer, brain cancer, in particular astrocytoma cancer or glioma cancer, cervix cancer, kidney cancer (in particular RCC), thyroid cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanoma. In some embodiments, the cancer is basal-like cancer, basal-like breast cancer, triple negative breast cancer, high grade cancer, or high grade serous ovarian cancer cell. In a particularly preferred embodiment in accordance with the various aspects of the invention, the cancer is breast cancer, prostate cancer, pancreatic carcinomas, fallopian tube cancer, colorectal cancer, hepatocellular carcinoma, or bone cancer (preferably osteosarcoma). In a particularly preferred embodiment, the cancer is selected form the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, castration resistant prostate cancer, and pancreatic ductal adenocarcinoma, in particular metastatic ovarian cancer, metastatic fallopian tube cancer, metastatic primary peritoneal cancer, metastatic breast cancer, metastatic castration resistant prostate cancer, and metastatic pancreatic ductal adenocarcinoma. In some embodiments of the aspects of the invention, the cancer to be treated has at least one mutation in a homologous recombination (HR) gene, i.e. is a HR deficient cancer. A cancer that is HR deficient refers to a cancer that has one or more cells having abnormal levels or activities of at least one HR gene. These abnormal levels or activities interfere with the normal HR gene function and can cause a defect in HR- mediated DNA repair or decrease the stability of replication forks. In a preferred embodiment, the cancer to be treated is BRCA1 deficient and / or BRCA2 deficient. A cancer that is BRCA1 deficient or BRCA2 deficient refers to a cancer that has one or more cells having abnormal BRCA1 levels or activities, or abnormal BRCA2 levels or activities. These abnormal levels or activities interfere with the normal function of BRCA1 or BRCA2 and can cause a defect in HR-mediated DNA repair or decrease the stability of replication forks. Preferably, the proliferative disease is selected from a BRCA-1 and / or BRCA-2-deficient tumor, and / or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, or pancreatic cancer. Particularily preferred examples of cancers treatable according the various aspects of the invention are ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, colorectal cancer, and pulmonary cancer. Particularly preferred examples of cancers treatable according to the various aspects of the invention are ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, and pancreatic cancer. Preferably, the cancer is metastatic cancer, in particular a stage IV cancer. Preferably, the cancer to be treated in accordance with the various aspects of the invention has relapsed or progressed, preferably after a first line chemotherapy. Thus, preferably, the combinations according to the present invention are for use as second line or third line therapy, more preferably for second line or third line therapy for the treatment of a HR deficient cancer. Preferably, the cancer to be treated is at stage III (locally advanced) or IV (metastatic). Preferably, the cancer to be treated in accordance with the various aspects of the invention has underlying defects in DNA damage repair, like HR repair, i.e. is a HR deficient cancer (HRD cancer), in particular a HR deficient ovarian cancer, HR deficient fallopian tube cancer, HR deficient primary peritoneal cancer, HR deficient breast cancer, HR deficient (castration resistant) prostate cancer, or HR deficient pancreatic cancer, such as pancreatic ductal adenocarcinoma (mPDAC). In a particularly preferred embodiment, these cancers are advanced or metastatic, most preferred metastatic. In one embodiment, the cancer cells have mutations / deletions / insertions in one or more DNA repair genes as listed in Figures 8 and / or 9, in particular ARID1A, ATM, ATRX, BAP1, BLM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FANCA / C / D2 / E / F / G / L, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, RAD51, RAD51B and / or WRN. Most preferred are BRCA1 / 2. In one embodiment, the cancer to be treated or the cancer patients to be treated are selected based on the presence of tumor markers. In the clinical setting cancer / patient selection would include but is not limited to eligible tumor biomarkers, i.e., deleterious mutations including ARID1A, ATM, ATRX, BAP1, BLM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FANCA / C / D2 / E / F / G / L, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, RAD51, RAD51B and / or WRN, which are preferred, BRCA1 / 2 being most preferred, and / or other gene variants in the HR pathway as listed in Figures 8 and / or 9. In one preferred embodiment, the ACL1i is used in combination with several classes of cancer drugs, namely inhibitors of Topoisomerase I, preferably irinotecan, preferably in the form of its active metabolite SN-38, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or combined with mitomycin C paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, in treating or ameliorating a proliferative disease in a patient, in particular cancer. Preferably, the cancer is HR deficient cancer, in particular BRCA-1 and / or BRCA-2-deficient. The preferred ALC1i used are ALCi-2, ALCi-160, ALCi-101, or ALCi-123, or pharmaceutically acceptable salt, isomers, solvate, chemically protected form, or prodrugs thereof, particularily preferred ALCi-2 or ALCi-101, or pharmaceutically acceptable salt, isomers, solvate, chemically protected form, or prodrugs thereof, ALCi-101being most preferred. The most preferable pharmaceutically acceptable salt is the sodium salt. Most preferred, the sodium salt of ALCi-101 is used. Optionally, the cancer does not include pancreatic cancer, in particular when the ACL1i is used in combination with irinotecan or SN-38. In a specifically preferred embodiment, the ACL1i is used in combination with several classes of cancer drugs as listed above, preferably an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, such as trastuzumab deruxtecan, datopotamab deruxtecan (which is preferred), or sacituzumab govitecan, in treating or ameliorating a proliferative disease in a patient, in particular cancer, such as HR deficient cancer, in particular BRCA-1 and / or BRCA-2-deficient. The preferred cancer is hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer, or pancreatic cancer. Preferrably the cancer is advanced or metastatic, the latter being preferred. The preferred ALC1i used are ALCi-2, ALCi-160, ALCi- 101, or ALCi-123, particularly preferred ALCi-2 or ALCi-101, the latter being most preferred. Preferably, the patient to be treated in accordance with the various aspects of the invention is a cancer patient, preferably having the cancer as defined above, e.g. breast cancer, ovarian cancer, prostate cancer, pancreatic carcinomas, gastric, gastroesophageal, 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, more preferably ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, and pancreatic cancer, and optionally having mutations / deletions / insertions in one or more of the HR genes as listed in Figures 8 and / or 9, preferably BRCA1 / 2. In a particular preferred embodiment, the cancer patient has a HR deficient cancer, in particular BRCA-1 and / or BRCA-2-deficient. Optionally, patients having pancreatic cancer are not included, in particular when the ACL1i is used in combination with irinotecan or SN-38. Preferably, the patient to be treated in accordance with the various aspects of the invention is a cancer patient, preferably having the cancer as defined above, e.g. breast cancer, ovarian cancer, prostate cancer, pancreatic carcinomas, gastric, gastroesophageal, 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, more preferably ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, or pancreatic cancer, which preferably is a HR deficient cancer, and the patient is receiving or has received at least one previous cancer therapy, preferably the agents used in combination with the ACL1i as defined above, and the patient did not show or did only show partial or unsatisfactory response, typically after several cycles of treatment. In a preferred embodiment, the previous cancer therapy included administration of at least one antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, such as trastuzumab deruxtecan, datopotamab deruxtecan (which is preferred), or sacituzumab govitecan. In one preferred embodiment, the ALC1i as defined above, in the pharmaceutical composition as defined above, and / or in the kit of parts as defined above, the ACL1i is combined with any one of adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, talazoparib,trastuzumab deruxtecan, datopotamab deruxtecan, and / or sacituzumab govitecan. In one preferred embodiment, the ALC1i as defined above, in the pharmaceutical composition as defined above, and / or in the kit of parts as defined above, the ACL1i is administered orally, preferably as a tablet or capsule.

[0002] Experimental Section Combination therapy of an ALC1i with other drugs ALC1 inhibitors ALC1 is an allosterically regulated chromatin remodeler that relaxes chromatin and plays an important role in response to DNA damage. It is implicated in different repair pathways like nucleotide excision repair or base excision repair and is known to regulate replication fork progression at DNA damage sites (Ooka et al., 2018). Inhibition of ALC1 via specific small molecules (ALC1i) used according to the invention leads to inefficient DNA repair by rendering chromatin less accessible to DNA repair enzymes potentiating the accumulation of DNA damage. Disruption of the chromatin remodeling forces of ALC1 through ALC1i enables a highly selective therapy of several cancer-types. Treatment of cancer cells with ALC1i leads to increase of γH2AX protein levels, a marker for DNA damage (see Figure 6). Surprisingly, in our hands, treatment of cancer cells with ALC1i lead to cell cycle arrest in the G2 phase (see Figure 5), resembling the effect of an inhibitor for PARP1 / 2, olaparib, which also induces DNA damage and leads to an increased G2, M-phase (Zhao et al., 2018, Wu et al., 2018). Topoisomerase 1 inhibitors The enzyme topoisomerase 1 (TOP1) is involved in relaxation of supercoiled DNA. It removes helical constrains that otherwise hinder DNA replication and transcription (GILMOUR, 1986). A transient single strand break in the double helix leads to DNA passage events or controlled rotation about the DNA-break (Wang, 1996). Together with the 5′ phosphate group of the DNA during the topoisomerase reaction, TOP1 forms a covalent link intermediate (TOP1-DNA-cleavage complex, TOP1cc). During this process, toxic DNA lesions can occur by covalently trapped TOP1 on the DNA (Takahashi et al., 2010). Defects in TOP1 function lead to blockage of cellular proliferation. Under normal conditions, a balance between the utilization of TOP1 catalytic activity in order to maintain DNA topology and the accumulation of toxic DNA damage due to TOP1 trapping is critical (Li & Liu, 2016). Topoisomerase 1 inhibitors interrupt DNA replication and induce DNA breaks, leading to slowed proliferation and cytotoxicity. Irinotecan, IUPAC name (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H- pyrano[3′,4′:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4′bipiperidine]-1′-carboxylate is a TOP1 inhibitor (TOP1i) analog of the naturally-occurring alkaloid, camptothecin. Also known as CPT-11, irinotecan is currently marketed formulated as an aqueous solution as Camptosar® (irinotecan hydrochloride injection). Irinotecan arrests uncontrolled cell growth by inhibiting the unwinding of DNA and thereby preventing DNA replication. The active metabolite of Irinotecan is SN-38. Topotecan (IUPAC: (19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13- diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione) is a TOP1i that leads to stabilization of the TOP1-DNA covalent complex during S-Phase. Mediated single strand breaks cannot be re-ligated and develop to DNA double strand breaks (NCBI – Topotecan, n.d.-a). Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. According to the present invention, ADCs comprising a topoisomerase I inhibitor are also considered to be coverd by the topoisomerase I inhibitors used in combination with the ALC1i in accordance with the invention. Preferably a combination of an ALC1i used according to the present invention and datopotamab deruxtecan is used, in particular for treating (e.g. triple negative) breast cancer or non-small-cell lung cancer. Synergy of topoisomerase 1 inhibitors with ALC1i Inhibition of TOP1 results in DNA nicks and resealing associated with DNA relaxation during the process of replication. As a result of a collapsed replication fork, DNA strand breaks arise (Holm, 1989). Inhibition of ALC1 on top of TOP1 may not only promote replication fork disruption but also contribute to additional accumulation of DNA damage which cannot be repaired because of changes in chromatin accessibility or reorganization. It is hypothesized that via this mechanism, ALC1i co-dosed with topotecan or other TOP1i would lead to potentiation, through up to additive inhibition of cancer cell proliferation. As shown hererin for other cancer agents, up to additive combination effects could be obtained for known ALCli compounds. Contrary thereto, surprisingly synergistic inhibition of cancer cell proliferation was observed by the combinations of the invention. Thus, according to the present invention ALC1 inhibition via specific ALC1i synergistically impacts the cellular response to the DNA damage induced by TOP1i. Thus, the present inventors determined that by using a combination of a TOP1i and a specific ALC1i, the effects of both inhibitors can be synergistically enhanced. As TOP1i topotecan shows high MSA scores in combination with said specific ALC1i used according to the invention, thus, it can be expected that this will also be the case for other TOP1i. Thus, preferably a combination of an ALC1i used according to the present invention and a TOP1i is used, in particular for treating colorectal cancer. Topoisomerase 2 inhibitors Topoisomerase 2 (TOP2) manages DNA tangles and supercoils. It can pass one double helix through another, untangling DNA by cutting both strands of the DNA helix simultaneously (Holm, 1989). This leads to an increase / decrease of the linking number of DNA loops by two units, promoting chromosome disentanglement. As an intermediate of this process, transient DNA double strand breaks are generated, possibly leading to toxic genome fragmentation (McClendon & Osheroff, 2007). TOP2 enzymes are involved in numerous DNA processes including recombination, separation of daughter chromosomes and chromatin condensation / de-condensation. TOP2-DNA clea...

Claims

1. An allosteric inhibitor of chromodomain helicase DNA-binding protein 1-like (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by a stretch of amino acids spanning amino acid residues 101 to 219 of SEQ ID NO: 1, for use in treating or ameliorating a proliferative disease in a patient in combination with and / or for use in enhancing the efficacy of treating a proliferative disease using: a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, b) mitomycin C or paclitaxel, c) ionizing radiation, or d) an antibody-drug conjugate in which a tumor-specific antibody is conjugated to a TOR1 inhibitor.

2. An allosteric ALC1 inhibitor for use according to claim 1, wherein the allosteric binding pocket comprises or consists of L101, Y153, C156, L157, A160, L163, K164, V173, D174, E175, A176, H177, R178, L179, S183, L186, H187, T189, L190, F193, L200, L201, T202, N208, S209, E212, L213, L216 and F219 of the sequence SEQ ID NO: 1, preferably comprises or consists of Y153, C156, L157, A160, L163, V173, E175, R178, L186, H187, L190 F193, L200 and E212 sequences SEQ ID NO:

1.

3. An ALC1 inhibitor (ALC1i) for use according to claim 1 or 2, wherein the ALC1 inhibitor (ALC1i) corresponds to formula (I) as well as its isomers, salts, solvates, chemically protected forms and prodrugs, while: (i) A5 and A8 are in each case independently selected from N and CH; (ii) A6 is selected from N and CH, or, when A6 participates in the formation of an annelated carbocycle or heterocycle Z, then A6 is C; (iii) A7 is selected from N and CH, or, when A7 participates in the formation of an annelated carbocycle or heterocycle Z, then A7 is C; (iv) 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; (v) L3 is selected from the group consisting of -CH2-R9, -CF2-R9, -CH2-CH2-R9, -CH2-CH2-CH2-R9, -O-R9, -NH-R9, -N=R9; or (vi) L2 and L3 together with A8 to which they are attached form a 5- or 6-membered heterocycle substituted with R4 and / or R9; (vii) L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N and NH, or is absent; (viii) Z is a 5-, 6- or 7-membered carbocycle or heterocycle which is optionally substituted with one, two or three substituents, preferably with one or more substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2, and may be annelated to the central moiety or attached via a covalent bond; (ix) R4 is a 5-, 6- or 7-membered carbocycle or heterocycle optionally substituted with one, two or three substituents, preferably with one or more substituents selected from the group consisting of -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe and -SMe, or R4 is hydrogen, methyl or COOH; (x) R9 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocycle or heterocycle optionally substituted with one, two or three substituents (preferably one substituent) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; (xi) R6 is a 5-, 6- or 7-membered carbocycle or heterocycle optionally substituted with one, two or three substituents (preferably one substituent) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe; (xii) or R6 is H; or (xiii) when A7 participates in the formation of an annelated carbocycle or heterocycle Z, then A5 and A6 are independently selected from -N and -CH, and A8 is selected from -N, -CH, -CH2-N, -CH2-CH and -NH-CH; or corresponds to formula (II) as well as its isomers, salts, solvates, chemically protected forms and prodrugs, while: (i) X is N or S; (ii) A is C or N; (iii) R1 is -CO-OR6, -CO-R7, or -CO-NR6R A , preferably R1 is -CO-OR6; (iv) R2 is -R7, -NHR8, -O-R7, -CO-R7, Br, -C 3-8 -cycloalkyl (preferably cyclopropyl) or -C 4-8 -cycloalkenyl (preferably cyclohexenyl); or (v) R1 and R2 together form a 5-, 6- or 7-membered carbocycle or heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl, =O and [-O-CH2-CH2]-NH-CH(OH)-O-tBu; (vi) R3 is H, =O, -OH, -O-R7, -R7, or -(CH2) m-L, wherein m is 0, 1 or 2, and L is a 5-, 6- or 7-membered carbocycle or heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl, -hydroxy-C 1-3 -alkyl and =O; (vii) R4 is H or -C 1-3 -alkyl, preferably H; (viii) R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6- or 7-membered carbocycle or heterocycle, adamantyl, C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably with one, two, three or four substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O and [-O-CH2-CH2] q-NH-biotin, where q is 1, 2, 3 or 4, or two adjacent substituents form a 5-, 6- or 7-membered carbocycle or heterocycle; or (ix) R4 and R5 together form a 5, 6, or 7-membered carbocycle, optionally substituted, preferably with one, two, or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A and -CH2-R A , preferably R4 and R5 together form C 5-7 -cycloalkyl; (x) R6 is H, -C 1-6 -alkyl, -C 2-6 -alkenyl, -C 2-6 -alkynyl, optionally substituted, preferably R6 is H; (xi) R7 is -C 1-3 -alkyl, -C 2-3 -alkenyl, -C 2-3 -alkynyl, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3 and -SCH3; (xii) R8 is H or C 1-6 -alkyl, preferably H, (xiii) R9 represents -C 1-6 -alkyl, -C 2-6 -alkenyl, -C 2-6 -alkynyl, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine or pyrazole), optionally substituted with one, two or three substituents selected from the group consisting of -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl (preferably -NH-CO-CH 1-3 ), -C 1-6 -alkyl (preferably methyl, ethyl, propyl, tert-butyl or pentyl), -C 1-3-haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl (preferably -OCH3), -O-C 1-3 -alkyl-O-C 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or when R9 is -C 1-6 -alkyl-aryl, then two adjacent substituents on the aryl moiety can form a 5-, 6-, or 7-membered carbocycle or heterocycle, which is optionally substituted; (xiv) R A represents H, a carbocycle or a heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2) o -R9, -SO2NH2 and =O, where o is 0 or 1.

4. ALC1 inhibitor (ALC1i) according to formula (II) as well as its isomers, salts, solvates, chemically protected forms and prodrugs, while: (i) X is N or S; (ii) A is C or N; (iii) R1 is -CO-OR6, -CO-R7, or -CO-NR6R A , preferably R1 is -CO-OR6; (iv) R2 is -R7, -NHR8, -O-R7, -CO-R7, Br, -C 3-8 -cycloalkyl (preferably cyclopropyl) or -C 4-8 -cycloalkenyl (preferably cyclohexenyl); or (v) R1 and R2 together form a 5-, 6- or 7-membered carbocycle or heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl,=O and [-O-CH2-CH2]-NH-CH(OH)-O-tBu; (vi) R3 is H, =O, -OH, -O-R7, -R7, or -(CH2) m -L, wherein m is 0, 1 or 2, and L is a 5-, 6- or 7-membered carbocycle or heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, -hydroxy-C 1-3 -alkyl and =O; (vii) R4 is H or -C 1-3 -alkyl, preferably H; (viii) R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6- or 7-membered carbocycle or heterocycle, adamantyl, C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably with one, two, three or four substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O and [-O-CH2-CH2] q-NH-biotin, where q is 1, 2, 3 or 4, or two adjacent substituents form a 5-, 6- or 7-membered carbocycle or heterocycle; or (ix) R4 and R5 together form a 5, 6, or 7-membered carbocycle, optionally substituted, preferably with one, two, or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A and -CH2-R A , preferably R4 and R5 together form C 5-7 -cycloalkyl; (x) R6 is H, -C 1-6 -alkyl, -C 2-6 -alkenyl, -C 2-6 -alkynyl, optionally substituted, preferably R6 is H; (xi) R7 is -C 1-3 -alkyl, -C 2-3 -alkenyl, -C 2-3 -alkynyl, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3; (xii) R8 is H or C 1-6 -alkyl, preferably H, (xiii) R9 represents -C 1-6 -alkyl, -C 2-6 -alkenyl, -C 2-6 -alkynyl, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine or pyrazole), optionally substituted with one, two or three substituents selected from the group consisting of -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably methyl, ethyl, propyl, tert-butyl or pentyl), -C 1-3-haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl (preferably -OCH3), -O-C 1-3 -alkyl-O-C 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or, when R9 is -C 1-6 -alkyl-aryl, then two adjacent substituents on the aryl moiety can form a 5-, 6-, or 7-membered carbocycle or heterocycle, which is optionally substituted; (xiv) R A represents H, a carbocycle or a heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2) o -R9, -SO2NH2 and =O, where o is 0 or 1, for use in the treatment or amelioration of pancreatic cancer or fallopian tube cancer in a patient in combination with a PARP inhibitor, or to enhance the effectiveness of a PARP inhibitor in the treatment or amelioration of pancreatic cancer or fallopian tube cancer in a patient.

5. ALC1i for use according to any one of claims 1 to 5, wherein ALC1i has a structure of formula (I) in which: A5 represents N; of A6 and A7, one radical is CH and the other radical is N; of A6 and A7, one radical is C and takes part in the formation of an annelated carbocycle or heterocycle Z, and the other radical is N; A8 is N or CH, or A5 represents N; of A6 and A7, one radical is C and takes part in the formation of an annelated 5-, 6- or 7-membered carbocycle or heterocycle, preferably a 5- or 6-membered aryl or heteroaryl Z, and the other radical is N; A8 represents N; L2 is CH2-CH2-R4 and L3 is CH2-CH2-R9 or CH2-CF2-R9 or L2 and L3 together with A8 to which they are attached form a 5- or 6-membered heterocycle, preferably piperidinyl or pyrrolidinyl, substituted with R4 and R9; L4 is missing; Z is any 6-membered carbocycle or heterocycle, preferably a 6-membered aryl or heteroaryl, annelated to a central moiety, wherein Z is optionally substituted with one, two or three substituents, preferably with one or more substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and NO2; R4 is COOH or tetrazolyl; R9 is any 4-, 5-, 6-, or 7-membered carbocycle or heterocycle optionally substituted with one, two, or three substituents, preferably with one or more substituents selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is any 5- or 6-membered carbocycle or heterocycle optionally substituted with one, two or three substituents (preferably one substituent) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, or R6 is H, or ALC1i has a structure of formula (II), in which: X represents N or S; A represents C or N; R1 is -CO-OR6, -CO-R7, or -CO-NR6R A , preferably R1 is -CO-OR6; R2 is -R7, -NHR8, -O-R7, -CO-R7, Br, -C 3-8-cycloalkyl (preferably cyclopropyl) or -C 4-8 -cycloalkenyl (preferably cyclohexenyl); or R1 and R2 together form a 5-, 6- or 7-membered carbocycle or heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, =O and [-O-CH2-CH2]-NH-CH(OH)-O-tBu; R3 is H,=O, -OH, -O-R7, -R7 or -(CH2) m -L, wherein m is 0, 1 or 2, and L is a 5-, 6- or 7-membered carbocycle or heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, -hydroxy-C 1-3 -alkyl and =O; R4 is H or -C 1-3 -alkyl, preferably H; R5 is -(CH2) m -L or -(CH2)m -(CH=CH)-L, wherein m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6- or 7-membered carbocycle or heterocycle, adamantyl, C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably with one, two, three or four substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O and [-O-CH2-CH2] q -NH-biotin, where q is 1, 2, 3 or 4, or two adjacent substituents form a 5-, 6- or 7-membered carbocycle or heterocycle; or R4 and R5 together form a 5, 6, or 7-membered carbocycle, optionally substituted, preferably with one, two, or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A and -CH2-R A , preferably R4 and R5 together form C 5-7 -cycloalkyl; R6 is H, -C 1-6 -alkyl, -C2-6 -alkenyl, -C 2-6 -alkynyl, optionally substituted, preferably R6 is H; R7 represents -C 1-3 -alkyl, -C 2-3 -alkenyl, -C 2-3 -alkynyl, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3; R8 represents H or C 1-6 -alkyl, preferably H, R9 represents -C 1-6 -alkyl, -C 2-6 -alkenyl, -C 2-6 -alkynyl, -C 1-6 -alkyl-aryl, or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine or pyrazole), optionally substituted with one, two or three substituents selected from the group consisting of -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl (preferably -CONH-CH3), -NH-CO-C1-3 -alkyl (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably methyl, ethyl, propyl, tert-butyl or pentyl), -C 1-3 -haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl (preferably -OCH3), -O-C 1-3 -alkyl-O-C 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or, when R9 is -C 1-6 -alkyl-aryl, then two adjacent substituents on the aryl moiety can form a 5-, 6-, or 7-membered carbocycle or heterocycle, which is optionally substituted; R Arepresents H, a carbocycle or a heterocycle, optionally substituted, preferably with one, two or three substituents independently selected from the group consisting of -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2) o -R9, -SO2NH2 and =O, where o is 0 or 1.

6. ALC1i for use according to any one of claims 1 to 5, wherein ALC1i has a structure of formula (I) in which: each of the radicals A5, A7 and A8 represents N; A6 is C and takes part in the formation of the annelated carbocycle or heterocycle Z; L3 is CH2-CF2-R9 or each of L2 and L3 is CH2-CH2; or L2 and L3 together with A8 to which they are attached form a piperidine ring or a pyrrolidine ring substituted with R4 and R9; L4 is missing; Z is phenyl or cyclohexyl annelated to the central moiety, wherein Z is optionally substituted with one, two or three substituents, preferably with one or more substituents selected from the group consisting of -Br, -Cl, -F, -OH, Me, -CF3, -OMe and -NO2, R4 is COOH or tetrazolyl; R9 is phenyl, cyclobutyl, cyclopentyl or adamantyl, optionally substituted with one, two or three substituents, preferably with one or more substituents selected from the group consisting of -Br, -Cl, -CF3, Me, -CH2-CF3 and -OMe; R6 is any 6-membered carbocycle or heterocycle (preferably phenyl or cyclohexyl; more preferably phenyl), optionally substituted with one, two or three substituents, preferably with one or more substituents selected from the group consisting of Br, -Cl, -F, Me, -CF3, -OMe and -NO2.

7. ALC1i for use according to any one of claims 1-6, wherein ALC1i is selected from the group consisting of: as well as its isomers, pharmaceutically acceptable salts, solvates, chemically protected forms and prodrugs.

8. ALC1i for use according to any one of claims 1 to 7, wherein ALC1i and an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK, BRD or PARP, or mitomycin C, paclitaxel, or an antibody-drug conjugate in which a tumor-specific antibody is conjugated to a TOP1 inhibitor, such as trastuzumab deruxtecan, dapotamab deruxtecan or sacituzumab govitecan, are administered simultaneously or sequentially.

9. ALC1i for use according to any one of claims 1 to 8, wherein the proliferative disease is selected from HR-deficient cancer, preferably from a BRCA-1 and / or BRCA-2-deficient tumor, and / or wherein the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer, and pancreatic cancer.

10. A pharmaceutical composition comprising ALC1i as defined in any one of claims 1-7, and a) inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1 and / or BRD, MEK, b) mitomycin C or paclitaxel, or c) an antibody-drug conjugate in which a tumor-specific antibody is conjugated to a TOR1 inhibitor.

11. A pharmaceutical composition according to claim 10, which is intended for the treatment or amelioration of a proliferative disease, preferably selected from a cancer with HR deficiency, preferably from a tumor with BRCA-1 and / or BRCA-2 deficiency, and / or a proliferative disease selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer or pancreatic cancer.

12. A set of components containing: (i) ALC1i as defined in any one of paragraphs 1-7, with instructions for combining it with: a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK and / or BRD, b) mitomycin C or paclitaxel, or c) ionizing radiation; or d) an antibody-drug conjugate in which a tumor-specific antibody is conjugated to a TOR1 inhibitor, or (ii) containing a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK and / or BRD, or b) mitomycin C, paclitaxel, or an antibody-drug conjugate in which a tumor-specific antibody is conjugated to a TOR1 inhibitor, with instructions for its combination with ALC1i, which is defined by any of paragraphs 1-5, or (iii) comprising separately packaged ALC1i as defined in any one of paragraphs 1-5, and a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK and / or BRD, or b) mitomycin C or paclitaxel, or c) an antibody-drug conjugate in which a tumor-specific antibody is conjugated to a TOR1 inhibitor, optionally with instructions for use for the treatment or relief of a proliferative disease.

13. A kit of components according to claim 12, which is intended for use in the treatment or amelioration of a proliferative disease, preferably selected from a cancer with HR deficiency, preferably from a tumor with BRCA-1 and / or BRCA-2 deficiency, and / or selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer or pancreatic cancer.

14. ALC1i for use according to any one of claims 1-9, the pharmaceutical compositions according to claim 10 or 11, or the kit according to claim 12 or 13, wherein ACL1i is combined with any of the following drugs: adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, talazoparib, trastuzumab deruxtecan, dapotamab deruxtecan and / or sacituzumab govitecan.

15. A pharmaceutical composition comprising ALC1i-101 or a salt thereof and trastuzumab deruxtecan and intended for treating or ameliorating a proliferative disease, wherein the proliferative disease is preferably selected from HR-deficient cancer, preferably from BRCA-1 and / or BRCA-2-deficient cancer, and / or wherein the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer or pancreatic cancer.

16. A pharmaceutical composition comprising ALC1i-101 or a salt thereof and trastuzumab deruxtecan and intended for the treatment of advanced or metastatic cancer with mutations causing homologous recombination deficiency (HRD).

17. ALC1i for use according to any one of claims 1-9, the pharmaceutical compositions according to claims 10, 11, 15 or 16 or the kit according to claim 12 or 13, wherein the patient to be treated receives or has received trastuzumab deruxtecan and shows or does not show at least a partial response, preferably after several cycles of treatment.

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