Alcl inhibitors for the treatment of cancer by potentiating the effects of several classes of approved cancer drugs

Abstract

This invention relates to the use of small molecule compounds that allosterically inhibit ALC1 (CHD1L), particularly two classes of ALC1 (CHD1L) allosteric inhibitors of formulas (I) and (II). When combined with inhibitors of several classes of cancer drugs, namely topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or when combined with mitomycin C, paclitaxel, ionizing radiation, or antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors, the small molecule compounds and the allosteric inhibitors exhibit enhancing, preferably additive, effects in the treatment of proliferative diseases. Furthermore, this invention relates to the ALC1 inhibitor of formula (II), which, when combined with PARP inhibitors (poly(ADP-ribose)-polymerase inhibitors (PARPi)), exhibit synergistic effects in the treatment of pancreatic cancer or fallopian tube cancer. By synergizing with the functions of the aforementioned cancer drugs, the ALC1 inhibitors, particularly those of formulas (I) and (II) that enhance the cancer cell killing properties of the aforementioned cancer drugs, are particularly capable of achieving treatments in which any of the aforementioned inhibitors have already been used as part of standard care.

Description

[0001] This invention relates to the use of small molecule compounds that allosterically inhibit ALC1 (CHD1L), particularly the use of two classes of ALC1 (CHD1L) allosteric inhibitors of formula (I) and formula (II). When combined with inhibitors of several classes of cancer drugs, namely topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or when combined with mitomycin C, paclitaxel, ionizing radiation, or antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors, the small molecule compounds, or the allosteric inhibitors, exhibit enhanced, preferably synergistic, effects in the treatment of proliferative diseases. Furthermore, this invention relates to the ALC1 inhibitor of formula (II), which, when combined with PARP inhibitors (poly(ADP-ribose)-polymerase inhibitors (PARPi)), exhibit synergistic effects in the treatment of pancreatic cancer or fallopian tube cancer. By synergizing with the aforementioned inhibitor classes, ALC1 inhibitors enhance the cancer cell-killing properties of these inhibitors, enabling therapeutic approaches for cancers where ALC1 is an oncogene amplification and / or the cancer is homologous recombination defective (HRD). Furthermore, these ALC1 inhibitors make it possible to overcome resistance mechanisms to the aforementioned inhibitors and enable alternative approaches to treating germline or acquired BRCA1 / BRCA2 deficiencies, including tumors defined by “BRCAness” or other alterations in the DNA repair network. Importantly, the toxicity mechanisms of these drugs do not overlap with those of ALC1 inhibitors, therefore no synergistic toxicity is expected. Background Technology

[0002] Cancer is generally classified into two categories: hematologic malignancies and solid tumors. Solid tumors can occur in almost any part of the body, resulting in cancers such as pancreatic cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer. Although some treatments include targeted therapies, such as Gleevec or Herceptin, most cancers are still treated with chemotherapy or radiation therapy. Because chemotherapy is not a targeted therapy, the biggest problem with conventional chemotherapeutic agents is, on the one hand, the side effects caused by cytotoxicity, and on the other hand, the development of drug resistance. The latter is a major factor ultimately leading to treatment failure, despite an initial successful response to the chemotherapeutic agents. Therefore, to overcome the limitations of such chemotherapeutic agents, it is necessary to develop new targeted therapeutic agents that specifically interfere with the proliferation of cancer cells.

[0003] While combinations of cancer drugs have proven successful in several cases in oncology, there are exceptions, and it is impossible to predict whether two different drugs will achieve a synergistic effect in the treatment of proliferative diseases. Therefore, there is a great need in medicine to develop novel combination therapies that combine chemotherapeutic agents with proven efficacy in cancer treatment with novel anticancer drugs that enhance the effects of established treatment regimens.

[0004] Without being bound by any theory, the inventors considered the following basic principle: ALC1 inhibitors, as known classes of cancer drugs, can be combined with several classes of known cancer drugs (e.g., inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, or MEK), or with specific proven cancer drugs (i.e., mitomycin C or paclitaxel), or with ionizing radiation, or with antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors. However, some representatives of the aforementioned classes of known cancer drugs have not shown synergistic effects when combined with known ALC1 inhibitors.

[0005] This invention is based on the surprising discovery that specific ALC1 inhibitors (i.e., inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK) exhibit synergistic antiproliferative activity when combined with several classes of known cancer drugs (i.e., inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK), or with specific proven cancer drugs (i.e., mitomycin C or paclitaxel), or with ionizing radiation, or with antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors. Therefore, these combinations are expected to be particularly suitable for treating proliferative diseases.

[0006] The basic principle behind the ability of ALC1 inhibitors to produce additive efficacy beyond expectations, at least for certain combinations, is as follows: Activation of DNA damage pathways leads to the recruitment of numerous proteins (notably specific chromatin remodeling enzymes, including the nucleosome remodeling agent ALC1 (CHD1L) containing a metadomain) to damaged chromatin (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017). Metadomains typically bind ADP-ribose, oligo-ADP-ribose, and poly-ADP-ribose (PAR) (Karras et al., 2005), thus proteins containing metadomains respond and are recruited to PARP activation sites on the genome, including during DNA damage and in cancer-related contexts. Importantly, the binding of PAR or oligo-ADP-ribose to the macrodomains of ALC1 robustly initiates 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 in its class and one of the very few enzymes whose catalytic activity is directly regulated by PAR. Furthermore, ALC1 is a validated oncogene and is typically amplified along with PARP1 in BRCA1 / 2-deficient ovarian and breast cancer samples.

[0007] ALC1i are rarely described in this field, for example, Abbott et al. in 2020 (Abbott et al., 2020). This document discloses inhibitors of CHD1L and their in vitro antitumor activity. The two most active ALC1i described, namely "Compound 1" and "Compound 3", have the following chemical structures:

[0008]

[0009] Compound 1 Compound 3

[0010] WO 2022 / 117782 A1 discloses a specific ALC1 inhibitor. In BRCA-negative breast cancer cell lines, it showed at least an additive effect when combined with a PARP inhibitor.

[0011] The inventors tested known ALC1 inhibitors (i.e., compounds 1 and 3 as shown above) in combination with known commercially available ATR inhibitors (i.e., elimusertib) and with known commercially available PARP inhibitors (olaparib). In contrast to the above basic principle, this resulted in almost purely additive effects against cancer cell lines in vitro. However, subsequent extensive further studies revealed that specific ALC1 inhibitors (wherein these inhibitors specifically bind to an allosteric binding pocket formed by amino acid residues 101 to 219 across SEQ ID NO: 1, particularly inhibitors having structures according to formulas (I) and (II), and which inhibit the ATPase function and / or nucleosome remodeling function of ALC1) exhibit synergistic effects and enhance the effects of the following:

[0012] a) Many compounds derived from several classes of cancer drugs, namely

[0013] • Inhibitors of topoisomerase I (e.g., topotecan)

[0014] • Inhibitors of topoisomerase II (e.g., teniposide)

[0015] • Inhibitors of ATM (e.g., AZ-32, AZD-1056, or AZD-1390)

[0016] • Inhibitors of ATR (e.g., ceralasertib, elixetib)

[0017] • Inhibitors of WEE1 (e.g., adavosertib)

[0018] • Inhibitors of BRD (e.g., BAY-299 or ABBV-744)

[0019] • MEK inhibitors (e.g., trametinib)

[0020] b) Specific proven cancer drugs, namely mitomycin C or paclitaxel,

[0021] c) Ionizing radiation, and

[0022] d) Antibody drug conjugates that have tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan).

[0023] 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 enhance the effects of PARP inhibitors (e.g., AZD-5305, niraparib, olaparib, pamipanib, rucaparib, taprazolepanib, and veliparib) against pancreatic or fallopian tube cancer cell lines. Therefore, this combination of specific ALC1 inhibitors and PARP inhibitors has been found to be particularly suitable for the treatment of pancreatic or fallopian tube cancer.

[0024] Therefore, the inventors believe that specific ALC1 inhibitors inhibit ALC1 by making chromatin less accessible to DNA repair enzymes, thereby suppressing efficient DNA repair. This leads to enhanced cancer cell killing and / or reduced off-target effects of chemotherapeutic agents or cancer drugs, even at lower doses, and thus mitigates cytotoxicity in non-cancerous cells. Therefore, the ALC1 inhibitors used according to the present invention, particularly those of formulas (I) and (II), can also mediate sensitization to compounds a), b), and d) as listed above.

[0025] The inventors further anticipate that manipulating ALC1 activity via the ALC1 inhibitors of the present invention, as used according to the invention, can induce a strong antiproliferative effect, and is also sufficient to avoid acquired resistance to the compounds listed above (a), (b), and (d), as well as to PARP1 and PARP2 inhibition. Therefore, the combined use of the ALC1 inhibitors of the present invention (particularly the ALC1 inhibitors of formulas (I) and (II), respectively) with compounds (a), (b), and (d), PARP1 and / or PARP2 inhibitors can be used in oncology, including in recurrent cases and when progression is present in advanced clinical stages.

[0026] In view of the above-mentioned relevance of the specific ALC1 inhibitors used according to the present invention (especially the specific ALC1 inhibitors of formula (I) and (II)) to cancers (especially those suitable for treatment with adaceltetracycline, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetracycline, elixetine, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib and / or taprazole, as well as detrastuzumab, dedabrotuzumab or gosetuzumab), the present invention provides a novel combination regimen for treating or improving proliferative diseases and preferably neoplastic diseases (especially those characterized by loss of sensitivity to the above-mentioned chemotherapy).

[0027] Furthermore, the inventors have determined that by using an ALC1 inhibitor (particularly an ALC1 inhibitor characterized by formulas (I) and (II)) according to the present invention in combination with adaceltebrate, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetraceti, elixetide, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib, or taprazolepanib and detrastuzumab, ...azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetraceti, azetra 32. The effects of AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilaseti, elixetine, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib, and taprazolepanib, as well as detrastuzumab, dedabrotuzumab, or gosetuzumab, can all be unexpectedly enhanced.

[0028] Therefore, the use of ALC1 inhibitors (particularly those characterized by formulas (I) and (II)) according to the present invention in combination with adasetinib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetide, elixetide, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib, or taprazolepanib, as well as detrastuzumab, dedabrotuzumab, or gosetruzumab, particularly provides (i) Suitable for highly effective treatment of cancers treated with chemotherapy regimens containing adaceltetracycline, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetracycline, elixetine, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib, and / or taprazolepanib, as well as detrastuzumab, dedabrotuzumab, or gosetruzumab. (ii) Mediates sensitization of adaceltetracycline, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetracycline, elixetine, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib, and / or taprazolepanib, as well as detrastuzumab, dedabrotuzumab, or gosetruzumab, (iii) To avoid resistance to adaceltetracycline, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetracycline, elixetine, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib, and / or taprazolepanib, as well as detrastuzumab, dedabrotuzumab, or gosetruzumab, (iv) And / or allow for reductions in the amount of adaceltetracycline, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetracycline, elixetine, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamipanib, and / or taprazolepanib, as well as detrastuzumab, dedabrotuzumab, or gosetuzumab, collectively resulting in improved anticancer efficacy and fewer undesirable side effects. Summary of the Invention

[0029] In a first aspect, the present invention relates to an allosteric inhibitor of a cromo domain-helicase-DNA binding protein 1-like protein (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid segment spanning amino acid residues 101 to 219 of SEQ ID NO: 1, preferably an inhibitor of ALC1 (ALC1i) according to formula (I).

[0030]

[0031] Formula (I)

[0032] Or its pharmaceutically acceptable salts, isomers, solvates, chemically protected forms, and prodrugs, among which

[0033] A5 and A8 are each independently selected from N or CH;

[0034] A6 is selected from N or CH, or when A6 participates in a cyclic carbocyclic or heterocyclic Z, then A6 is C;

[0035] A7 is selected from N or CH, or when A7 participates in a cyclic carbocyclic or heterocyclic Z, then A7 is C;

[0036] L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4;

[0037] L3 is selected from CH2-R5, -CF2-R5, -CH2-CH2-R5, -CH2-CF2-R5, -CH2-CH2-CH2-R5, -O-R5, -NH-R5, -N=R5;

[0038] or

[0039] L2 and L3, together with A8 to which they are connected, form 5- or 6-membered heterocycles that are replaced by R4 and / or R5.

[0040] L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N, and NH, or it may not exist;

[0041] Z is a 5-, 6-, or 7-membered carbon ring or heterocycle, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0042] Furthermore, it can circulate to the central core or connect via covalent bonds.

[0043] R4 is a 5-, 6-, or 7-membered carbon ring or heterocycle, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH;

[0044] R5 is a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0045] R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe;

[0046] Or R6 is H;

[0047] or

[0048] When A7 participates in a cyclic carbocyclic ring or heterocyclic ring Z, A5 and A6 are independently selected from -N or -CH, and A8 is selected from -N, -CH, -CH2-N, -CH2-CH or -NH-CH;

[0049] Or, according to formula (II), the ALC1 inhibitor:

[0050]

[0051] Equation (II)

[0052] Or its pharmaceutically acceptable salts, isomers, solvates, chemically protected forms, and prodrugs, wherein:

[0053] X is N or S;

[0054] A is C or N;

[0055] R1 is -CO-OR6, -CO-R7, or -CO-NR6R A Preferably, R1 is -CO-OR6;

[0056] R2 can be -R7, -NHR8, -O-R7, -CO-R7, Br, or -C. 3-8 -cycloalkyl (preferably cyclopropyl) or -C 4-8 - Cycloalkenyl (preferably cyclohexenyl);

[0057] or

[0058] R1 and R2 together form a 5-, 6-, or 7-membered carbon ring or heterocycle, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl, =O, [-O-CH2-CH2]-NH-CH(OH)-O-tBu;

[0059] R3 can be H, =O, -OH, -O-R7, -R7, or -(CH2). m -L, where m is 0, 1, or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl, -hydroxy C 1-3 -alkyl and =O;

[0060] R4 is H or -C 1-3 -alkyl group, preferably H;

[0061] R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1, or 2, preferably 0 or 1, and L is a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic, adamantyl, or C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably substituted by 1, 2, 3 or 4 independently selected from the following substituents: -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-membered, 6-membered or 7-membered carbon ring or heterocycle;

[0062] or

[0063] R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which may optionally be substituted, preferably by one, two, or three independent substituents selected from the following: -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;

[0064] R6 is H, or optionally substituted -C. 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6-Alynyl group, preferably R6 is H;

[0065] R7 is -C 1-3 -alkyl, -C 2-3 -Alkenyl, -C 2-3 -Alynyl group, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3;

[0066] R8 is H or C 1-6 -alkyl, preferably H,

[0067] R9 is optionally substituted with 1, 2, or 3 substituents selected from -C 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6 -alkynyl group, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine, or pyrazole): -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl group (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl group (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably -CH3, ethyl, propyl, tert-butyl, or pentyl), -C 1-3 - Haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocyclic (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl group (preferably -OCH3), -OC 1-3 -alkyl-OC 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or when R9 is -C 1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form optionally substituted 5-, 6-, or 7-membered carbon rings or heterocycles;

[0068] R A It is an H, a carbocyclic or heterocyclic ring, which is optionally substituted, preferably substituted by one, two or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2).o -R9, -SO2NH2, and =O, where o is 0 or 1.

[0069] Used in combination with the following to treat or improve proliferative diseases, preferably cancer.

[0070] a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK.

[0071] b) Mitomycin C, or paclitaxel,

[0072] c) Ionizing radiation, or

[0073] d) Antibody drug conjugates that have tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab, dedabrotuzumab, or gosetuzumab).

[0074] and / or used for enhancement

[0075] a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK

[0076] b) Mitomycin C, or paclitaxel,

[0077] c) Ionizing radiation, or

[0078] d) Antibody-drug conjugates that have tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab, dedabrotuzumab, or gosetuzumab).

[0079] Its efficacy in treating or improving proliferative diseases and preferred cancers in patients.

[0080] In the second aspect, the combination of an ALC1 inhibitor (ALC1i) according to formula (II) with a PARP inhibitor is used to treat or improve pancreatic cancer or fallopian tube cancer in patients, or to enhance the efficacy of PARP inhibitors in treating or improving pancreatic cancer or fallopian tube cancer in patients.

[0081] In a third aspect, the present invention relates to a pharmaceutical composition comprising, as defined herein, ALC1i, and

[0082] a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK.

[0083] b) Mitomycin C, paclitaxel, or

[0084] c) Antibody drug conjugates that have tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab, dedabrotuzumab, or gosetuzumab).

[0085] In a fourth aspect, the present invention relates to a kit comprising ALC1i as described herein, and to combining it with...

[0086] a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK.

[0087] b) Mitomycin C, or paclitaxel,

[0088] c) Ionizing radiation; or

[0089] d) The product information for an antibody-drug conjugate (e.g., trastuzumab, dabenostatin, or gosetutuzumab) containing a tumor-specific antibody conjugated to a TOP1 inhibitor; or

[0090] Include

[0091] a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK.

[0092] b) Mitomycin C, or paclitaxel, or

[0093] c) Antibody drug conjugates that have tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab, dedabrotuzumab, or gosetuzumab).

[0094] And instructions for combining it with ALC1i as defined herein, or

[0095] Includes separately packaged ALC1i as defined herein, and

[0096] a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK.

[0097] b) Mitomycin C, or paclitaxel, or

[0098] c) Antibody drug conjugates that have tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab, dedabrotuzumab, or gosetuzumab).

[0099] And optional instructions for use in treating or improving proliferative diseases, preferably cancer. Attached Figure Description

[0100] The contents of the accompanying drawings included in this specification are described below. In this context, reference is also made to the detailed description of the invention above and / or below.

[0101] Figure 1The structure and molecular name of the selected ALC1 inhibitor. These selected ALC1 inhibitors (or their isomers, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs) are preferably used according to the present invention.

[0102] Figure 2 Synergistic effect score and MSA of cancer cells treated with ALC1i in combination with other drugs.

[0103] This table summarizes the two-dimensional titration results of different combinations of ALC1i (compound A) and another drug (compound B) in different cancer cell lines. Drug combinations with an MSA (maximum synergistic region) score below 9 indicate that the interaction may not be synergistic and are marked with "-". MSA scores between 9 and 10 are marked with "+" and indicate that the interaction between compounds A and B may be synergistic. MSA scores above 10 are marked with "++" and are synergistic. MSA scores above 20 are marked with "+++" and are considered highly synergistic.

[0104] Figure 3 Example of 96-hour SRB assay: pancreatic cancer cell lines treated with ALC1i or ATMi.

[0105] PSN1 cells were seeded into 96-well plates and treated with either ALC1i-101 or ATMi (an ATM inhibitor, AZD-1390). Cells were cultured at 37ºC and 5% CO2 for 4 days, fixed with 10% TCA, and stained with sulfonylrhodamine to analyze cell viability. Data were normalized relative to a DMSO control (indicating 100% viability). Inhibitor-response curves were fitted using Synergy Finder with curve fitting parameter “LL4”. The curves are shown as the average fit of three technical replicates.

[0106] Figure 4 Example of 2D titration: Co-processing of pancreatic cancer cells for cell proliferation assay.

[0107] Cancer cells were seeded into 96-well plates and treated with a two-dimensional titration solution of ALC1i and the designated drug. Cells were cultured at 37ºC and 5% CO2 for 4 days, fixed with 10% TCA, and stained with sulfonylrhodamine to analyze cell viability. Synergy scores were calculated using Synergy Finder. Treatment with the combination of ALC1i-101 and ATMi showed high synergy scores above 10. An MSA score above 10 indicated strong synergy.

[0108] Figure 5 Cell cycle analysis of ALC1i-treated cancer cells.

[0109] SUM-149-PT cells were seeded into 6-well plates and treated with ALC1i or DMSO for 48 h. Cells were fixed in 75% EtOH and stained with DAPI. FACS analysis showed cells at different cell cycle stages. DMSO treatment showed cells in G1, S, and G2 phases. Cells treated with ALC1i showed enrichment / arrest in G2 phase.

[0110] Figure 6 γH2AX protein levels increased under ALC1i treatment.

[0111] PSN1 cells were treated with ALC1i or DMSO for 24 h. Western blots were run with an antiphosphorylated H2AX (γH2AX) antibody and α-tubulin. Images of protein bands are shown in the top panel, and the bottom panel shows the γH2AX protein levels normalized relative to the α-tubulin-loaded control and normalized relative to the DMSO-treated sample.

[0112] Figure 7 EC50 values ​​(µM) of 96-hour SRB assay and 11-day colony formation assay for HR normal (HRP) and HR deficient (HRD) cells treated with ALCi.

[0113] Different cancer cell lines with multiple mutations in the homologous recombination repair pathway (HR) were seeded into 96-well plates and treated with titrants of different ALCi. Cells were cultured at 37ºC and 5% CO2 for 4 days (96 h) or 11 days (colony formation), fixed with 10% TCA, and stained with sulfonylrhodamine to analyze cell viability. Data were normalized relative to a DMSO control (indicating 100% viability). Inhibitor-response curves with variable slopes (four parameters) were fitted using GraphPad Prism.

[0114] Figure 8 List of HR genes.

[0115] List of genes involved in DNA damage response (DDR) (Human DNA Repair Genes, date unknown), cited in Wood RD, Mitchell M and Lindahl T Mutation Research, 2005, Science, 2001, the book DNA Repair and Mutagenesis, 2nd edition, 2006, and Nature Reviews Cancer, 2011 (revised by R. Wood and M. Lowery on Wednesday, June 10, 2020).

[0116] Figure 9 List of genes involved in homologous recombination repair (HR) pathway.

[0117] A summary of genes from Toh and Ngeow, 2021, Kim et al., 2021, Yamamoto and Hirasawa, 2021, and HRD signature genes from Peng et al., 2014.

[0118] Figure 10 Synergistic effect of ALC1i-101 and trametinib in MiaPaCa2 CDX experiments. Detailed Implementation

[0119] Before describing the invention in detail below, it should be understood that the invention is not limited to the specific methods, schemes, and reagents described herein, as these can be modified. It should also 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 invention, which will be defined only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0120] Numerous references are cited throughout this specification. Every reference cited herein, whether above or below (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), is incorporated herein by reference in its entirety. Nothing herein should be construed as an admission that the invention is not entitled to any prior disclosure due to prior invention. Some documents cited herein are characterized by being “incorporated by reference.” In the event of a conflict between the definitions or teachings of such incorporated references and those set forth in this specification, the text of this specification shall prevail.

[0121] The elements of the invention will be described below. These elements are listed using specific embodiments; however, it should be understood that these specific embodiments can be combined in any manner and in any number to produce other embodiments. The differently described embodiments and preferred embodiments should not be construed as limiting the invention to only the explicitly described embodiments. This specification should be understood to support and cover embodiments combining the explicitly described embodiments with any number of disclosed and / or preferred elements. Furthermore, unless the context otherwise indicates, any arrangement and combination of the elements described herein should be considered in the specification of this application.

[0122] definition

[0123] To carry out this invention, unless otherwise instructed, conventional methods of chemical, biochemical, and recombinant DNA techniques as explained in the literature in the art shall be employed (see, for example, Molecular Cloning: A Laboratory Manual, 2nd edition, edited by J. Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0124] The following provides definitions for some terms that are frequently used in this specification. These terms will have their respective defined and preferred meanings in the remainder of this specification in each instance of their use.

[0125] Unless the context clearly specifies otherwise, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural indicators.

[0126] The term "Cromo domain-helicase-DNA-binding protein 1-like protein" (abbreviated CHD1L) refers to a protein also known as ALC1. The amino acid sequence of human ALC1 is as specified in SEQ ID NO: 1, as is known in the art, for example, as specified in WO2022 / 117782 A1. The 897-amino acid-residue-long protein consists of an N-terminal Snf2-like DNA-dependent ATPase domain spanning amino acid residues 40 to 513, containing a conserved helicase motif crucial 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). An allosteric binding pocket is spatially separated from the ALC1 portion involved in ATP binding. Following the ATPase domain is a linker region ranging from amino acid residues 514 to 703 (containing a putative coiled-coil region (amino acid residues 638 to 675)) and a C-terminal macrodomain (amino acid residues 704 to 897). The macrodomain has been shown to interact directly with the ATPase domain, thereby inhibiting its catalytic function (Lehmann et al., 2017; Singh et al., 2017). This interaction is released upon binding of the poly(ADP-ribose) to the macrodomain, leading to activation of the chromatin remodeling enzyme.

[0127] Preferably, the terms used herein are as defined in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, edited by Leuenberger, HGW, Nagel, B. and Kölbl, H. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.

[0128] As used in the context of this invention, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon chain. Preferably, the chain comprises 1 to 10 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, nonyl, or decyl. The alkyl group may optionally be substituted.

[0129] As used in the context of this invention, the term "heteroalkyl" refers to a saturated straight-chain or branched hydrocarbon chain. Preferably, the chain comprises 1 to 9 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9) carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, and nonyl, which are broken once or more by the same or different heteroatoms, for example, 1, 2, 3, 4, or 5 times. Preferably, the heteroatoms are selected from O, S, and N, for example, -(CH2). n -X-(CH2) m CH3, where n = 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, m = 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, and X = S, O or NR', where R' = H or a hydrocarbon (e.g., C1 to C6 alkyl). Specifically, "heteroalkyl" refers to O-CH3, -OC2H5, -CH2-O-CH3, -CH2-O-C2H5, -CH2-O-C3H7, -CH2-O-C4H9, -CH2-O-C5H 11 Examples of alkyl groups include -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-O-C3H7, and -C2H4-O-C4H9. Heteroalkyl groups are optionally substituted.

[0130] The term "haloalkyl" refers to a saturated straight-chain or branched hydrocarbon chain in which one or more hydrogen atoms are replaced by halogen atoms, such as fluorine, chlorine, bromine or iodine. Preferably, the chain contains 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms. Specifically, "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. The haloalkyl group may be optionally substituted.

[0131] In the context of this invention, the term "5-membered, 6-membered, or 7-membered carbon ring" is used to refer to such "cycloalkyl", "cycloalkenyl", or "aryl" rings in which 5, 6, or 7 carbon atoms form a ring.

[0132] The term "cycloalkyl" includes cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups are optionally substituted.

[0133] The term "cycloalkenyl" includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups are optionally substituted.

[0134] The term "aryl" refers to a polyunsaturated, typically aromatic, hydrocarbon group, which can be a monocyclic or fused together or covalently linked polycyclic ring (up to three rings). Preferably, the aryl group contains 6 to 10 carbon atoms, i.e., C646. 6-10 Aryl group. In a preferred embodiment, the aryl group is phenyl (which is most preferred) or naphthyl. The aryl group may optionally be substituted.

[0135] In the context of this invention, the term "5-membered, 6-membered or 7-membered heterocyclic" is used to refer to such a monocyclic "5-membered, 6-membered or 7-membered heterocyclic alkyl" or monocyclic "5-membered, 6-membered or 7-membered heteroaryl", wherein 5, 6 or 7 atoms form a ring.

[0136] The term "5-, 6-, or 7-membered heterocyclic alkyl" refers to a saturated monocyclic ring in which at least one carbon atom is replaced by one or two (for a five-membered ring), or one, two, or three (for a six-membered ring), or one, two, three, or four (for a seven-membered ring) identical or different heteroatoms (preferably selected from O, N, and S). Preferred examples of heterocyclic alkyl groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, or 2-piperazinyl. The heterocyclic alkyl group may optionally be substituted.

[0137] As used in the context of this invention, the term "heteroaryl" refers to a 5-, 6-, or 7-membered aromatic monocyclic ring in which at least one carbon atom is replaced by 1, 2, or 3 (for 5-membered rings) or 1, 2, 3, or 4 (for 6-membered rings) identical or different heteroatoms (preferably selected from O, N, and S). Preferred examples of heteroaryl groups are furanyl, thiophene, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrroleyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, and 1,3,5-triazinyl. The heteroaryl group may be optionally substituted.

[0138] The term “arylalkyl” corresponds to an arylalkyl residue, that is, an alkyl group substituted with an aryl group as defined above.

[0139] The term "independently" means that the groups can be the same or different if two or more groups can be chosen independently of each other.

[0140] Unless otherwise specified, the term "optionally substituted" in each case refers to halogens (especially F, Cl, Br, or I), -NO2, -CN, -OR''', -NR'R'', -COOR''', -CONR'R'', -NR''COR'', -NR''COR''', -NR'CONR'R'', -NR'SO2E, -COR'''; -SO2NR'R'', -OOCR''', -CR'''R''''OH, -R'''OH, and -E;

[0141] R' and R'' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and heteroaryl, or together to form heteroaryl or heterocycloalkyl;

[0142] R''' and R'''' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl and -NR'R'';

[0143] E is selected from alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, aliphatic ring system, aryl and heteroaryl; optionally substituted.

[0144] "Pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia (United States Pharmacopeia-33 / National Formulary-28 Reissue, published by United States Pharmacopeia Convention, Inc., Rockville, Maryland, April 2010) or other recognized pharmacopoeias for use in animals, and more particularly in humans.

[0145] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts, which can be formed, for example, by mixing a solution of the compounds described herein or their derivatives 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, in cases where the compounds of the present invention have an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium, and amine cations formed using counter anions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates, and aryl sulfonates)).Illustrative examples of pharmaceutically acceptable salts include, but are not limited to: acetates, adipic acid salts, alginates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium edetate, camphorates, camphorsulfonates, camsylates, carbonates, chlorides, citrates, clavulanates, cyclopentanepropionate, digluconate, dihydrochlorides, dodecyl sulfates, edetate, ethanedisulfonate, etopoate, ethanesulfonate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphates, glycolylarsanilates, hemisulfates, heptahydrates, hexanoates, hexylresorcinol salts, hydrabamine, hydrobromide, and salts. Salts, hydroiodates, 2-hydroxyethanesulfonate, hydroxynaphthylcarboxylate, iodides, isothiosulfates, lactates, lacturonates, laurates, lauryl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methanesulfonates, methyl sulfates, mucilages, 2-naphthalenesulfonate, naphthalenesulfonate, nicotinate, nitrates, N-methylglucosamine ammonium salts, oleates, oxalates, dihydroxynaphthylcarboxylate (p Amoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / bisphosphate, picrate, neopentanoate, polygalacturonate, propionate, salicylate, stearate, sulfate, hypoacetate, succinate, tannic acid salt, tartrate, teoclate, toluenesulfonate, triethyliodide, undecanoate, valerate, etc. (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into basic addition salts or acid addition salts.

[0146] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (such as solubility in polar solvents), but in other respects, for the purposes of this invention, the salt and the parent form of the compound are equivalent.

[0147] In addition to the salt form, the present invention also provides compounds in the form of prodrugs. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide formula (I) or formula (II), especially... Figure 1 The compounds shown are those compounds. Prodrugs are active or inactive compounds that, after administration to a patient, are chemically modified into the compounds of the present invention through physiological processes in vivo (such as hydrolysis, metabolism, etc.). Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes, prodrugs can be slowly converted into the compounds of the present invention. The suitability and techniques involved in the preparation and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson LA and Tunek A. (1988) Drug Metabolism Reviews 19(2): 165-194 and Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985). Examples of masked carboxylate anions include various esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g., neopentyloxymethyl). Amines have been masked as arylcarbonyloxymethyl-substituted derivatives, which are cleaved in vivo by esterases, releasing the free drug and formaldehyde (Bundgaard H. et al. (1989) J. Med. Chem. 32(12): 2503-2507). In addition, drugs containing acidic NH groups (e.g., imidazole, imide, indole, etc.) have been masked with N-acyloxymethyl (Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985)). Hydroxyl groups have been masked as esters and ethers. EP 0 039 051 A2 discloses the Mannich base hydroxamic acid prodrug, its preparation, and its use.

[0148] The compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more sites among the atoms constituting such compounds. For example, radioactive isotopes such as tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling of the compounds. All isotopic variants of the compounds of the present invention, whether or not radioactive, are intended to be covered within the scope of the present invention.

[0149] As used in this article, when referring to substituents of aryl groups, "para" means that the substituent occupies the position opposite to the position where the aryl group is connected to the main chain of the compound.

[0150] As used herein, "patient" means any mammal or bird that may benefit from treatment with the compounds described herein. Preferably, "patient" is selected from laboratory animals, livestock, or primates (including chimpanzees and humans). Particularly preferred is that "patient" is a human.

[0151] As used herein, “treat,” “treating,” or “treatment” or improvement of a disease or disorder means, respectively, achieving one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing the development of symptoms characteristic of one or more disorders being treated; (c) suppressing the worsening of symptoms characteristic of one or more disorders being treated; (d) limiting or preventing the recurrence of said one or more disorders in a patient who previously had one or more disorders; and (e) limiting or preventing the recurrence of symptoms in a patient who previously had symptoms of one or more disorders.

[0152] As used herein, “prevent,” “preventing,” “prevention,” or “prophylaxis” for a disease or disorder means preventing the occurrence of the disorder in a subject for a certain period of time. For example, if a compound described herein is administered to a subject for the purpose of preventing a disease or disorder, the disease or disorder is prevented from occurring at least on the day of administration and preferably also for one or more days after the day of administration (e.g., 1 to 30 days; or 2 to 28 days; or 3 to 21 days; or 4 to 14 days; or 5 to 10 days).

[0153] The "pharmaceutical composition" according to the invention can exist as a composition in which different active ingredients and diluents and / or carriers are mixed with each other; or it can be in the form of a combination formulation in which the active ingredients exist in some or completely different forms. An example of such a combination or combination formulation is a kit.

[0154] "Effective dose" is the amount of a therapeutic agent sufficient to achieve the intended purpose. The effective dose of a given therapeutic agent will vary depending on factors such as the nature of the agent, the route of administration, the size and species of the animal receiving the agent, and the purpose of administration. The effective dose in each individual case can be determined empirically by a skilled person using methods proven in the art.

[0155] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or medium that is administered with a therapeutic agent. Such drug carriers can be sterile liquids, such as saline solutions in water, and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Saline solutions are preferred carriers when the drug composition is administered intravenously. Saline solutions, as well as aqueous dextran and glycerol solutions, can also be used as liquid carriers, particularly for injectable solutions. Suitable drug excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk, glycerol, propylene glycol, water, ethanol, etc. If desired, the composition may also contain small amounts of wetting agents, emulsifiers, or pH buffers. These compositions can be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. The composition can be formulated as a suppository using conventional binders and carriers (such as triglycerides). The compounds of the present invention can be formulated in a neutral or salt form. Pharmaceutically acceptable salts include salts formed with free amino groups, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc.; and salts formed with free carboxyl groups, such as those derived from sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc. Examples of suitable pharmaceutical carriers are described in EW Martin's "Remington's Pharmaceutical Sciences". Such compositions contain a therapeutically effective amount of the compound, preferably in a purified form, along with a suitable amount of carrier, to provide a form suitable for appropriate administration to the patient. The formulation should conform to the administration method.

[0156]

[0157] Embodiments of the present invention

[0158] The inventors have identified and characterized ALC1 inhibitors that exhibit allosteric regulation of ALC1 nucleosome sliding activity. These compounds specifically bind to the allosteric pocket and are able to inhibit ALC1 activity. Compounds that bind to the ALC1 ATPase site and block ATPase activity must compete with ATP for binding to the ATPase site. The ability of these compounds to kill different tumor cell lines, one of which is BRCA-deficient, has been tested.

[0159] The inventors have determined that, when combined with inhibitors of several classes of cancer drugs, namely inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or with mitomycin C, paclitaxel, ionizing radiation, or antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors, the allosteric inhibitors of ALC1 (CHD1L) (especially the allosteric inhibitors of ALC1 (CHD1L) of formulas (I) and (II)) exhibit enhancing effects, preferably synergistic effects, in the treatment of proliferative diseases.

[0160] Furthermore, it has been found that the ALC1 inhibitor of formula (II) exhibits a synergistic effect in the treatment of pancreatic cancer or fallopian tube cancer when combined with a PARP inhibitor.

[0161] The inventors considered the following basic principle: ALC1 inhibitors, as known classes of cancer drugs, can 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 antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors. However, tests with known ALC1 inhibitors have not shown superadditive efficacy against cancer cell lines. This invention is based on the surprising discovery that 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 antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors, the specific allosteric ALC1 inhibitors, preferably those of formulas (I) and (II), exhibit synergistic antiproliferative activity. Therefore, these combinations are expected to be suitable for treating proliferative diseases.

[0162] The ALC1 inhibitors used according to the invention, preferably those characterized in formulas (I) and (II) (the latter being known in the art (WO 2022 / 117782 A1)), exhibit allosteric regulation of the nucleosome sliding activity of ALC1. These compounds specifically bind to the allosteric pocket and are able to inhibit ALC1 activity. Compounds that bind to the ATPase site of ALC1 and block ATPase activity must compete with ATP for binding to the ATPase site. Since cellular ATP concentrations are in the range of 1 to 10 mM (depending on the cell compartment), very high binding affinity is required in the low nanomolar range to successfully prevent ATP from binding to the ATPase site of ALC1. The allosteric inhibitors of ALC1 used according to the invention (especially those characterized in formulas (I) and (II)) do not have this limitation because they do not necessarily prevent ATP binding, but rather inhibit ALC1 activity through different mechanisms. The inventors have identified ALC1 inhibitors capable of specifically binding to the allosteric pocket of ALC1. Whether these specific ALC1 inhibitors will provide synergistic effects with other classes of cancer drugs remains a question that has not yet been answered in the field.

[0163] In a first aspect, the present invention relates to an allosteric inhibitor of cromomorphin-helicase-DNA binding protein 1-like protein (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid segment spanning amino acid residues 101 to 219 of SEQ ID NO: 1, said allosteric inhibitor being used in combination with the following to treat or improve proliferative diseases in patients, and / or to enhance the efficacy of the following in the treatment of proliferative diseases:

[0164] a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, or

[0165] b) Mitomycin C, paclitaxel,

[0166] c) Ionizing radiation, or

[0167] d) Antibody drug conjugates that have tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab, dedabrotuzumab, or gosetuzumab).

[0168] In this context, the term "specific binding" indicates that the compound binds to K+ of full-length human ALC1 having the amino acid sequence according to SEQ ID NO: 1. DThe Km is 200 µM or lower, preferably 100 µM, more preferably 50 µM, even more preferably 10 µM or lower, even more preferably 5 µM or lower, and even more preferably 1 µM and even more preferably 500 nM or lower. Those skilled in the art will readily understand how to measure the dissociation constant of small molecules with proteins, including surface plasmon resonance. Preferably, the Km of the compound of the present invention is... D The measurement was performed by immobilizing full-length human ALC1 on a chip surface, followed by applying the compound to the immobilized protein. Preferably, the measurement was conducted at 37ºC.

[0169] In a preferred embodiment of the invention, the allosteric inhibitor of ALC1 used according to the invention exhibits an IC50 value 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 in a FRET-based nucleosome remodeling assay. This is as disclosed in WO 2022 / 117782 A1 for determining K as described herein. D and IC 50 .

[0170] Not every amino acid within the amino acid segment spanning amino acid residues 101 to 219 of SEQ ID NO: 1 forms a surface of an alternative pocket of ALC1 that can be used to bind with the compound used according to the invention. This is due to the fact that some amino acids are embedded in the pocket and are difficult to access, while others are not even part of the pocket but are located on the inner or outer surface of ALC1. Therefore, in a preferred embodiment, the allosteric binding pocket that specifically binds to the ALC1 inhibitor used according to the present invention comprises, or is composed of, the 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, and more preferably, the binding pocket comprises SEQ ID NO: 1. The ALC1 allosteric binding pockets are composed of Y153, C156, L157, A160, L163, V173, E175, R178, L186, H187, L190, F193, L200, and E212. Skilled artisans can model the allosteric binding pocket of ALC1 based on homology with other chromatin remodeling enzymes. Such models with and without the compounds used in this invention are also depicted in WO 2022 / 117782 A1. WO 2022 / 117782 A1 depicts how artisans can visualize the fit of a given compound to the allosteric binding pocket and thus provides further guidance on selecting compounds that meet the spatial, hydrophobic and hydrophilic, and charge requirements of the pocket. Figure 20 of WO 2022 / 117782 A1 provides a minimal set of structural coordinates of the amino acids of ALC1 involved in binding with the compounds of this invention. In other words, by using the detailed teachings given in WO 2022 / 117782 A1, it can be determined whether the inhibitor specifically binds to the allosteric binding pocket formed by the amino acid segment spanning amino acid residues 101 to 219 of SEQ ID NO: 1.

[0171] Based on their orientation within the pocket, different amino acids accessible on the pocket surface can form different non-covalent bonds, particularly hydrogen bonds, ionic interactions, van der Waals interactions, and hydrophobic interactions. Therefore, in a preferred embodiment, the inhibitor used according to the invention allosterically binds to one or more amino acids in the pocket, preferably to the backbone of ALC1 amino acids L157, A160, K164, V173, D174, H177, R178, L179, L186, N208, and / or E212, and / or ALC1 amino acids L101, Y153, C156, L157, A160, and L163. One or more of the side chains of E175, R178, L179, L186, H187, L190, F193, T202, N208, E212 or L213, more preferably forming one or more non-covalent bonds with the main chains of D174, H177 and R178 of ALC1 and the side chains of Y153, E175, R178, H187, T202, N208 and / or E212 of ALC1.

[0172] In a preferred embodiment, the ALC1 inhibitor used according to the present invention binds non-covalently:

[0173] (i) The aromatic ring of the side chain of amino acid Y153 of ALC1 that interacts face-to-face or side-to-side with aromatic carbocyclic or heterocyclic substituents or forms cationic-π, polar-π or halogen-π interactions with polar, charged or carbon-halogen substituents.

[0174] (ii) The terminal oxygen of the side chain of amino acid Y153 of ALC1 with a hydrogen bond-donating group.

[0175] (iii) Carbonyl oxygen of the main chain of H177 having a carbon halogen or hydrogen bond donor group;

[0176] (iv) Carbonyl oxygen of the main chain of D174 having a carbon halogen or hydrogen bond donor group;

[0177] (v) Side chains of E175 having hydrogen bond donor or acceptor groups;

[0178] (vi) Side chains of R178 having hydrogen bond donor or acceptor groups;

[0179] (vii) Main-chain carbonyl oxygen of R178 having a carbon halogen or hydrogen bond donor group;

[0180] (viii) H187 side chains that interact face-to-face or side-to-side with aromatic carbocyclic or heterocyclic substituents, or form cationic-π, polar-π, or halogen-π interactions with polar, charged, or carbon-halogen substituents, or have hydrogen bond donor or acceptor groups.

[0181] (ix) Side chains of T202 having hydrogen bond donor or acceptor groups;

[0182] (x) a side chain of N208 having hydrogen bond donor or acceptor groups; and

[0183] (xi) Side chains of E212 having hydrogen bond donor or acceptor groups.

[0184] In a preferred embodiment, the ALC1 inhibitor (ALC1i) used according to the present invention is the ALC1 inhibitor (ALC1i) according to formula (II).

[0185]

[0186] Equation (II)

[0187] in

[0188] (i) R5 contains aromatic rings π-stacked with Y153; and / or

[0189] (ii) N is a hydrogen bond acceptor group of the terminal OH group of Y153; and / or

[0190] (iii) R1 contains a group that serves as a hydrogen bond donor group for the main-chain carbonyl oxygen to H177; and / or

[0191] (iv) R3 contains a carbon halogen or hydrogen bond donor group bonded to the carbonyl oxygen of the D174 backbone; and / or

[0192] (v) R1 and R2 together form an aromatic or heteroaromatic monocyclic ring, particularly at or near the R1 position, comprising a hydrogen bond donor or acceptor group, which can act as a hydrogen bond donor or acceptor group to the side chains of E175 and / or R178; and / or

[0193] (vi) R1 and R2 together form a substituted carbon monocyclic or heterocyclic ring, preferably containing a hydrogen bond donor or acceptor group at or near the R1 position, wherein the hydrogen bond donor or acceptor group is a hydrogen bond donor or acceptor group to the side chain of R178; and / or

[0194] (vii) R3 comprises an aromatic ring, which is π-stacked with the aromatic ring H187, or is an electron-deficient substituent, particularly at sites where a polar -π or cation -π interaction is formed with the aromatic ring of H187; and / or

[0195] (viii) R1 and R2 together form an aromatic or heteroaromatic monocyclic ring, particularly at or near the R2 position, comprising a hydrogen bond donor or acceptor group, which can act as a hydrogen bond donor or acceptor group to the side chains of T202 and / or N208; and / or

[0196] (ix)R4 is H or -C 1-3 -alkyl group, preferably H; and / or

[0197] (x)R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1, or 2, preferably 0 or 1, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic or adamantyl alkyl group, optionally substituted, preferably substituted by 1, 2, 3, or 4 independently selected substituents from: -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents forming a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; and / or

[0198] (xi)R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A Preferably, R4 and R5 together form C 5-7 -cycloalkyl; and / or

[0199] (xii)X is N or S; and / or

[0200] (xiii) A is C or N;

[0201] Or its pharmaceutically acceptable salts, isomers, solvates, chemically protected forms, and prodrugs.

[0202] In a preferred embodiment, the ALC1 inhibitor (ALC1i) used according to the present invention is an ALC1 inhibitor (ALC1i) according to formula (I).

[0203]

[0204] Formula (I)

[0205] in

[0206] A5 and A8 are each independently selected from N or CH;

[0207] A6 is selected from N or CH, or when A6 participates in a cyclic carbocyclic or heterocyclic Z, especially a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring, then A6 is C;

[0208] A7 is selected from N or CH, or when A7 participates in a cyclic carbocyclic or heterocyclic Z, especially a 5-membered, 6-membered or 7-membered carbocyclic or heterocyclic ring, then A7 is C;

[0209] L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4;

[0210] L3 is selected from CH2-R9, -CF2-R9, -CH2-CH2-R9, -CH2-CF2-R9, -CH2-CH2-CH2-R9, -O-R9, -NH-R9, -N=R9;

[0211] or

[0212] L2 and L3, together with A8 to which they are connected, form 5- or 6-membered heterocycles that are replaced by R4 and / or R9.

[0213] L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N, and NH, or it may not exist;

[0214] Z is a 5-, 6-, or 7-membered carbon ring or heterocycle, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0215] Furthermore, it can circulate to the central core or connect via covalent bonds.

[0216] R4 is a 5-, 6-, or 7-membered carbon ring or heterocycle, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH;

[0217] R9 is a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe;

[0218] R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe;

[0219] Or R6 is H;

[0220] or

[0221] When A7 participates in a cyclic carbocyclic ring or heterocyclic ring Z, A5 and A6 are independently selected from -N or -CH, and A8 is selected from -N, -CH, -CH2-N, -CH2-CH or -NH-CH;

[0222] Or a pharmaceutically acceptable salt, isomer, solvate, chemically protected form or prodrug thereof for use with inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, with mitomycin C, paclitaxel, antibody-drug conjugates having tumor-specific antibodies conjugated to TOP1 inhibitors (such as trastuzumab), or in combination with ionizing radiation to treat or improve proliferative diseases in patients.

[0223] Preferred embodiments of ALC1 inhibitors (ALC1i) according to formula (I)

[0224] According to formula (I), ALC1i showed >50% inhibition at concentrations of 250 µM or below, with IC50 being the preferred option. 50 < 250 µM, and more preferably < 25 µM. IC is preferably measured in FRET-based nucleosome remodeling assays as described in WO 2022 / 117782 A1. 50 .

[0225] EC of ALC1i according to equation (I) 50 Preferably < 250 µM, more preferably < 50 µM; and even more preferably < 10 µM. EC is preferably measured using SRB-based readings in cell proliferation assays as described in WO 2022 / 117782 A1. 50 .

[0226] Unless otherwise specified, residues with normal (i.e., non-subscripted) integers refer to compounds of formula (I), and residues with subscripted integers refer to compounds of formula (II).

[0227] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0228] A5 and A6 are N; and

[0229] A7 participates in cyclic carbon rings or heterocyclic rings Z, particularly 5-membered, 6-membered or 7-membered carbon rings or heterocyclic rings Z, preferably carbon ring Z, particularly 5-membered, 6-membered or 7-membered carbon ring Z, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and -NO2.

[0230] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0231] A5 and A6 are N;

[0232] A7 participates in cyclic carbocyclic or heterocyclic Z, preferably carbocyclic Z, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0233] A8 is -CH2-N, -CH2-CH or -NH-CH, with -NH-CH being preferred.

[0234] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0235] A5 is N, and A8 is -N or -CH.

[0236] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0237] A5 is N, and A8 is -N or -CH; and

[0238] A6 participates in cyclic carbon rings or heterocyclic rings, preferably carbon rings Z.

[0239] In a particularly preferred embodiment, A5, A7, and A8 are N.

[0240] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2.

[0241] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 participates in the cyclic carbon ring Z, particularly a 5-, 6-, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2.

[0242] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0243] L2 is selected from -CH2-R4, -CH2-CH2-R4, and -CH2-CH2-CH2-R4.

[0244] In one implementation scheme, the preferred option is:

[0245] L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, and -NH-R4; and

[0246] R4 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, preferably a 5- or 6-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH.

[0247] In one implementation scheme, the preferred option is:

[0248] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9.

[0249] In one implementation scheme, the preferred option is:

[0250] L3 is selected from -CH2-R9, -CH2-CH2-R9, and -CH2-CF2-R9; and

[0251] R9 is a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbon ring or heterocycle, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0252] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0253] L2 and L3, together with A8 which they are connected to, form 5- or 6-membered heterocycles that are replaced by R4 and R9.

[0254] In one implementation scheme, the preferred option is:

[0255] L2 and L3, together with A8 which they are connected to, form 5- or 6-membered heterocycles that are replaced by R4 and R9.

[0256] R4 is hydrogen, methyl, or COOH; and

[0257] R9 is any 4-, 5-, 6-, or 7-membered carbon ring or heterocycle, preferably phenyl or 5- or 6-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe.

[0258] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0259] L4 does not exist.

[0260] In a particularly preferred embodiment, A5, A7, and A8 are N; and

[0261] L4 does not exist.

[0262] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0263] L4 does not exist.

[0264] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0265] L4 does not exist.

[0266] In a particularly preferred embodiment, A5, A7, and A8 are N; and

[0267] L4 does not exist.

[0268] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0269] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0270] L4 does not exist.

[0271] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

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

[0273] L4 does not exist.

[0274] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0275] In a particularly preferred embodiment, A5, A7, and A8 are N; and

[0276] L4 does not exist.

[0277] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0278] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0279] L4 does not exist; and

[0280] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0281] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0282] L4 does not exist; and

[0283] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0284] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0285] L4 does not exist; and

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

[0287] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0288] L4 does not exist; and

[0289] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0290] In one implementation scheme, the preferred option is:

[0291] R4 is hydrogen, methyl, COOH, or tetrazolium.

[0292] In one implementation scheme, the preferred option is:

[0293] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4; and

[0294] R4 is hydrogen, methyl, COOH, or tetrazolium.

[0295] In one implementation scheme, the preferred option is:

[0296] R9 is any 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbon ring or heterocycle, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe.

[0297] In one implementation scheme, the preferred option is:

[0298] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0299] In one implementation scheme, the preferred option is:

[0300] L3 is selected from -CH2-R9, -CH2-CH2-R9, and -CH2-CF2-R9; and

[0301] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0302] In one implementation scheme, the preferred option is:

[0303] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe;

[0304] Or R6 is H.

[0305] In one implementation scheme, the preferred option is:

[0306] L4 does not exist; and

[0307] R6 is a 5- or 6-membered carbon ring or heterocycle, preferably a 6-membered carbon ring or heterocycle, optionally substituted by one, two or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0308] In the above implementation scheme, the preferred option is:

[0309] Z is a 6-membered aryl, or a 5- or 6-membered heteroaryl, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2.

[0310] In one implementation scheme, the preferred option is:

[0311] A5 is N;

[0312] One of A6 and A7 is CH, and the other is N; or one of A6 and A7 is C and participates in cyclic carbocyclic or heterocyclic Z, and the other is N;

[0313] A8 is either N or CH;

[0314] L2, L3, and L4 are independently selected from CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N, and NH, or they are not present, or L2 and L3 together with the A8 they are attached to form a 5- or 6-membered heterocycle substituted by R4 and R9.

[0315] Z is any 5-, 6-, or 7-membered carbon ring or heterocycle, and may be cyclized to the central core or connected via covalent bonds, and may optionally be substituted by one, two, or three (preferably one) substituents selected from -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0316] R4 is any 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe.

[0317] Or R4 can be hydrogen, methyl, or COOH;

[0318] R9 is a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe.

[0319] R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0320] Or R6 is H

[0321] or

[0322] When A7 participates in cyclic carbon or heterocyclic 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;

[0323] Among them, R4, R9, and R6.

[0324] In one implementation scheme, the preferred option is:

[0325] A5 is N;

[0326] One of A6 and A7 is C and participates in cyclic carbocyclic or heterocyclic Z, and the other is N;

[0327] A8 is N;

[0328] L2 is CH2-CH2, and L3 is CH2-CH2 or CH2-CF2, or L2 and L3 together with the A8 they are attached to form a 5- or 6-membered heterocycle (preferably piperidine or pyrrolidine) substituted by R4 and R9.

[0329] L4 does not exist;

[0330] Z is a 6-membered carbon ring or heterocycle cyclized to the central core, wherein Z is optionally substituted by one, two or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and NO2;

[0331] R4 is either COOH or CH2N4;

[0332] R9 is a 4-, 5-, 6-, 7-, or 10-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and

[0333] R6 is a 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0334] Or R6 is H.

[0335] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (I):

[0336] Each of A5, A7, and A8 is N;

[0337] A6 is C and participates in a cyclic carbon ring or heterocycle Z, preferably a 5-membered, 6-membered, or 7-membered carbon ring or heterocycle, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe;

[0338] L2 is CH2-CH2-R4;

[0339] L3 is CH2-CH2-R4 or -CH2-CF2-R9;

[0340] Alternatively, L2 and L3 together with A8 to which they are attached can form a piperidine ring or a pyrrolidine ring substituted by R4 and R9.

[0341] L4 does not exist;

[0342] Z is a phenyl or cyclohexyl group cyclized to the central core, wherein Z is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -OH, Me, -CF3, -OMe, and -NO2.

[0343] R4 is either COOH or tetrazolium;

[0344] R9 is phenyl, cyclobutyl, cyclopentyl or adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -CF3, Me, -CH2-CF3 and -OMe;

[0345] R6 is a 6-membered carbon ring or heterocycle optionally substituted with one, two, or three, preferably one, substituent, preferably phenyl or cyclohexyl, more preferably phenyl, wherein the substituent is selected from Br, -Cl, -F, Me, -CF3, -OMe, and -NO2.

[0346] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0347] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0348] R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; and

[0349] L4 does not exist.

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

[0351] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0352] R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; and

[0353] L4 does not exist.

[0354] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0355] L4 does not exist.

[0356] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0357] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0358] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0359] L4 does not exist; and

[0360] R6 is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0361] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0362] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0363] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0364] L4 does not exist; and

[0365] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0366] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0367] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0368] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0369] L4 does not exist; and

[0370] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0371] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0372] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0373] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0374] L4 does not exist; and

[0375] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0376] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0377] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0378] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0379] L4 does not exist; and

[0380] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0381] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0382] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0383] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0384] L4 does not exist; and

[0385] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0386] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0387] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0388] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0389] L4 does not exist; and

[0390] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0391] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0392] L2 is -CH2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4;

[0393] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0394] L4 does not exist; and

[0395] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0396] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0397] L4 does not exist; and

[0398] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0399] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0400] L4 does not exist; and

[0401] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0402] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0403] L4 does not exist; and

[0404] R9 is a C5 to C7 cycloalkyl (i.e., C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0405] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0406] L4 does not exist;

[0407] R9 is a C5 to C7 cycloalkyl (i.e., C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0408] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0409] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0410] L4 does not exist;

[0411] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0412] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0413] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0414] L4 does not exist;

[0415] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0416] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0417] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0418] L4 does not exist;

[0419] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0420] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0421] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0422] L4 does not exist;

[0423] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0424] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0425] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0426] L4 does not exist;

[0427] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

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

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

[0430] L4 does not exist;

[0431] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0432] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0433] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0434] L4 does not exist;

[0435] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0436] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0437] In a particularly preferred embodiment, A5, A7, and A8 are N; and

[0438] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0439] L4 does not exist; and

[0440] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0441] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0442] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0443] L4 does not exist; and

[0444] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0445] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0446] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0447] L4 does not exist; and

[0448] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0449] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0450] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0451] L4 does not exist;

[0452] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0453] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0454] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0455] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0456] L4 does not exist; and

[0457] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0458] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0459] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0460] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0461] L4 does not exist; and

[0462] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -C F3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl alkyl substituted with one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe. R6 is a 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0463] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0464] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0465] L4 does not exist;

[0466] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0467] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

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

[0469] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0470] L4 does not exist;

[0471] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0472] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0473] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0474] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0475] L4 does not exist;

[0476] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0477] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0478] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0479] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0480] L4 does not exist; and

[0481] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0482] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0483] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0484] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0485] L4 does not exist;

[0486] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0487] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0488] In a particularly preferred embodiment, A5, A7, and A8 are N; and

[0489] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0490] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0491] L4 does not exist; and

[0492] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0493] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0494] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0495] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0496] L4 does not exist; and

[0497] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0498] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0499] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0500] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0501] L4 does not exist; and

[0502] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

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

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

[0505] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0506] L4 does not exist;

[0507] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0508] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

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

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

[0511] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0512] L4 does not exist; and

[0513] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0514] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

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

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

[0517] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0518] L4 does not exist; and

[0519] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -C F3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl alkyl substituted with one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe. R6 is a 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0520] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0521] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0522] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0523] L4 does not exist;

[0524] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0525] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0526] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0527] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0528] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0529] L4 does not exist;

[0530] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0531] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0532] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0533] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0534] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0535] L4 does not exist;

[0536] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0537] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0538] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0539] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0540] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0541] L4 does not exist; and

[0542] R9 is a C5 to C7 cycloalkyl, C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0543] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0544] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0545] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0546] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0547] L4 does not exist;

[0548] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0549] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0550] In a particularly preferred embodiment, A5, A7, and A8 are N; and

[0551] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0552] L4 does not exist; and

[0553] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0554] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

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

[0556] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0557] L4 does not exist; and

[0558] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0559] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0560] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0561] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0562] L4 does not exist; and

[0563] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0564] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0565] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0566] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0567] L4 does not exist;

[0568] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0569] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0570] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0571] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0572] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0573] L4 does not exist; and

[0574] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0575] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0576] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0577] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0578] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0579] L4 does not exist; and

[0580] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0581] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -C F3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl alkyl substituted with one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe. R6 is a 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0582] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0583] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0584] L4 does not exist;

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

[0586] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0587] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

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

[0589] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0590] L4 does not exist;

[0591] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0592] R9C4 to C7-cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10-spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0593] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0594] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0595] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0596] L4 does not exist;

[0597] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0598] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0599] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0600] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0601] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0602] L4 does not exist; and

[0603] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0604] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0605] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0606] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0607] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0608] L4 does not exist;

[0609] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0610] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0611] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0612] In a particularly preferred embodiment, A5, A7, and A8 are N; and

[0613] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0614] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0615] L4 does not exist; and

[0616] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0617] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0618] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0619] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0620] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0621] L4 does not exist; and

[0622] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0623] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0624] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0625] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0626] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0627] L4 does not exist; and

[0628] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0629] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted with one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted with one or two substituents, said substituents being selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe.

[0630] In a particularly preferred embodiment, A5, A7, and A8 are N;

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

[0632] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0633] L4 does not exist;

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

[0635] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0636] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

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

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

[0639] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0640] L4 does not exist; and

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

[0642] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0643] R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

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

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

[0646] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0647] L4 does not exist; and

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

[0649] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -C F3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl alkyl substituted with one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe. R6 is a 6-membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two or three, preferably one substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe.

[0650] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0651] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0652] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0653] L4 does not exist;

[0654] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0655] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0656] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0657] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0658] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0659] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0660] L4 does not exist;

[0661] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0662] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0663] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0664] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0665] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0666] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0667] L4 does not exist;

[0668] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0669] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0670] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0671] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0672] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0673] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0674] L4 does not exist; and

[0675] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0676] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe;

[0677] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0678] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbide ring Z, particularly a 5-, 6-, or 7-membered carbide ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and

[0679] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0680] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0681] L4 does not exist;

[0682] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0683] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0684] R6 is a phenyl group, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe.

[0685] In a particularly preferred embodiment of the above implementation scheme:

[0686] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0687] In a particularly preferred embodiment of the above implementation scheme:

[0688] L4 does not exist; and

[0689] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0690] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0691] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0692] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0693] L4 does not exist;

[0694] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0695] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0696] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0697] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0698] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0699] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0700] L4 does not exist;

[0701] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0702] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0703] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0704] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0705] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0706] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0707] L4 does not exist;

[0708] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0709] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0710] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0711] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0712] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0713] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0714] L4 does not exist;

[0715] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0716] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0717] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0718] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0719] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0720] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0721] L4 does not exist;

[0722] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0723] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0724] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0725] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0726] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0727] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0728] L4 does not exist;

[0729] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0730] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0731] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0732] In a particularly preferred embodiment, A5, A7, and A8 are N;

[0733] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0734] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0735] L4 does not exist;

[0736] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0737] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0738] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0739] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in a cyclic carbocyclic or heterocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic Z, preferably a carbocyclic Z, particularly a 5-membered, 6-membered, or 7-membered carbocyclic Z, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0740] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0741] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0742] L4 does not exist;

[0743] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0744] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0745] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0746] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, optionally substituted by one, two, or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0747] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0748] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0749] L4 does not exist;

[0750] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0751] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0752] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0753] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0754] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0755] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0756] L4 does not exist;

[0757] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0758] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0759] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0760] In a particularly preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the cyclic carbon ring Z, particularly a 5-membered, 6-membered, or 7-membered carbon ring Z, preferably phenyl, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2;

[0761] L2 is selected from -CH2-R4, -CH2-CH2-R4 and -CH2-CH2-CH2-R4;

[0762] L3 is selected from -CH2-R9, -CH2-CH2-R9 and -CH2-CF2-R9;

[0763] L4 does not exist;

[0764] R4 is hydrogen, methyl, COOH or tetrazolium, preferably COOH;

[0765] R9 is a C4 to C7 cycloalkyl (i.e., C4-, C5-, C6-, or C7-cycloalkyl), C6 to C 10 -Bicycloalkyl (i.e., C6-, C7-, C8-, C9-, or C 10 -bicycloalkyl), C6 to C6 10 -spiroalkyl (i.e., C6-, C7-, C8-, C9-, or C 10-spiroalkyl), phenyl, 5- or 6-membered heteroaryl, adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromophenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl or adamantyl, optionally substituted by one, two or three, preferably one selected from the following substituents: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe, more preferably unsubstituted phenyl or adamantyl substituted by one or two substituents, wherein the substituents are selected from -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; and

[0766] R6 is a phenyl group ortho-substituted with a substituent selected from -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe and -SMe, preferably -Br, -Cl, -F, -I, and more preferably Br.

[0767] In a particularly preferred embodiment, the ALC1 inhibitor (ALC1i) of formula (I) according to the first and other aspects of the present invention has the following characteristics: Figure 1 The specific structure shown.

[0768] In a first aspect, in a preferred embodiment, the ALC1 inhibitor (ALC1i) used according to the invention is an ALC1 inhibitor (ALC1i) according to formula (II):

[0769]

[0770] Equation (II)

[0771] and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which:

[0772] X is N or S;

[0773] A is C or N;

[0774] R1 is -CO-OR6, -CO-R7, or -CO-NR6R A Preferably, R1 is -CO-OR6;

[0775] R2 can be -R7, -NHR8, -O-R7, -CO-R7, Br, or -C. 3-8 -cycloalkyl (preferably cyclopropyl) or -C 4-8 - Cycloalkenyl (preferably cyclohexenyl);

[0776] or

[0777] R1 and R2 together form a 5-, 6-, or 7-membered carbon ring or heterocycle, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl, =O, [-O-CH2-CH2]-NH-CH(OH)-O-tBu;

[0778] R3 can be H, =O, -OH, -O-R7, -R7, or -(CH2). m -L, where m is 0, 1, or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl, -hydroxy C 1-3 -alkyl and =O;

[0779] R4 is H or -C 1-3 -alkyl group, preferably H;

[0780] R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1, or 2, preferably 0 or 1, and L is a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic, adamantyl, or C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably substituted by 1, 2, 3 or 4 independently selected from the following substituents: -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-membered, 6-membered or 7-membered carbon ring or heterocycle;

[0781] or

[0782] R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which may optionally be substituted, preferably by one, two, or three independent substituents selected from the following: -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;

[0783] R6 is H, or optionally substituted -C. 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6-Alynyl group, preferably R6 is H;

[0784] R7 is -C 1-3 -alkyl, -C 2-3 -Alkenyl, -C 2-3 -Alynyl group, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3;

[0785] R8 is H or C 1-6 -alkyl, preferably H,

[0786] R9 is optionally substituted with 1, 2, or 3 substituents selected from -C 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6 -alkynyl group, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine, or pyrazole): -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl group (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl group (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably -CH3, ethyl, propyl, tert-butyl, or pentyl), -C 1-3 - Haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocyclic (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl group (preferably -OCH3), -OC 1-3 -alkyl-OC 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or when R9 is -C 1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form optionally substituted 5-, 6-, or 7-membered carbon rings or heterocycles;

[0787] R A It is an H, a carbocyclic or heterocyclic ring, which is optionally substituted, preferably substituted by one, two or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2).o -R9, -SO2NH2 and =O, where o is 0 or 1.

[0788] Preferred embodiments of the ALC1 inhibitor (ALC1i) according to formula (II)

[0789] According to formula (II), ALC1i showed >50% inhibition at concentrations of 250 µM or below, with IC50 being the preferred option. 50 <250 µM, and more preferably <25 µM. IC is preferably measured in FRET-based nucleosome remodeling assays as described in WO 2022 / 117782 A1. 50 .

[0790] EC of ALC1i according to equation (II) 50 Preferably < 250 µM, more preferably < 50 µM; and even more preferably < 10 µM. EC is preferably measured using SRB-based readings in cell proliferation assays as described in WO 2022 / 117782 A1. 50 .

[0791] When X is N in equation (II), this includes the option that X is NH, and / or R4 may not exist when A is N.

[0792] In the implementation scheme, preferably, in the ALC1 inhibitor (ALC1i) according to formula (II):

[0793] X is N or S;

[0794] A is C or N;

[0795] R1 is -CO-OR6, -CO-R7, or -CO-NR6R A Preferably, R1 is -CO-OR6;

[0796] R2 can be -R7, -NHR8, -O-R7, -CO-R7, Br, or -C. 3-8 -cycloalkyl (preferably cyclopropyl) or -C 4-8 - Cycloalkenyl (preferably cyclohexenyl);

[0797] or

[0798] R1 and R2 together form a 5-, 6-, or 7-membered carbon ring or heterocycle, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl, =O, [-O-CH2-CH2]-NH-CH(OH)-O-tBu;

[0799] R3 can be H, =O, -OH, -O-R7, -R7, or -(CH2). m -L, where m is 0, 1, or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl, -hydroxy C 1-3 -alkyl and =O;

[0800] R4 is H or -C 1-3 -alkyl group, preferably H;

[0801] R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1, or 2, preferably 0 or 1, and L is a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic, adamantyl, or C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably substituted by 1, 2, 3 or 4 independently selected from the following substituents: -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-membered, 6-membered or 7-membered carbon ring or heterocycle;

[0802] or

[0803] R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which may optionally be substituted, preferably by one, two, or three independent substituents selected from the following: -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;

[0804] R6 is H, or optionally substituted -C. 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6 -Alynyl group, preferably R6 is H;

[0805] R7 is -C 1-3 -alkyl, -C 2-3 -Alkenyl, -C 2-3 -Alynyl group, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3;

[0806] R8 is H or C 1-6 -alkyl, preferably H,

[0807] R9 is optionally substituted with 1, 2, or 3 substituents selected from -C 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6 -alkynyl group, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine, or pyrazole): -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl group (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl group (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably -CH3, ethyl, propyl, tert-butyl, or pentyl), -C 1-3 - Haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocyclic (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl group (preferably -OCH3), -OC 1-3 -alkyl-OC 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or when R9 is -C 1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form optionally substituted 5-, 6-, or 7-membered carbon rings or heterocycles;

[0808] R A It is an H, a carbocyclic or heterocyclic ring, which is optionally substituted, preferably substituted by one, two or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2). o -R9, -SO2NH2 and =O, where o is 0 or 1.

[0809] According to the present invention, preferably, in the ALC1 inhibitor (ALC1i) according to formula (II):

[0810] X is N or S;

[0811] A is C or N;

[0812] R1 is -CO-OR6, -CO-R7, or -CO-NR6R A Preferably, R1 is -CO-OR6;

[0813] R2 is -R7, -NHR8, -O-R7, -CO-R7;

[0814] or

[0815] R1 and R2 together form a 5-, 6-, or 7-membered carbon ring or heterocycle, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O;

[0816] R3 can be H, =O, -OH, -O-R7, -R7, or -(CH2). m -L, where m is 0, 1, or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl, -hydroxy C 1-3 -alkyl and =O;

[0817] R4 is H or -C 1-3 -alkyl group, preferably H;

[0818] R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6- or 7-membered carbon ring or heterocyclic or adamantyl alkyl group, which is optionally substituted, preferably substituted by 1, 2, 3 or 4 independent substituents selected from the following: -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 carbon ring or heterocyclic;

[0819] or

[0820] R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which may optionally be substituted, preferably by one, two, or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A Preferably, R4 and R5 together form C 5-7 -cycloalkyl;

[0821] R6 is H, with optional substituted -C. 1-6 -alkyl refers to C1-, C2-, C3-, C4-, C5-, or C6-alkyl, -C 2-6 -Alkenyl refers to C2-, C3-, C4-, C5-, or C6-alkenyl, --C 2-6 -Alynyl group refers to C2-, C3-, C4-, C5-, or C6-alkynyl group, preferably R6 is H;

[0822] R7 is -C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, namely the C2- or C3-alkynyl group, is optionally substituted, preferably substituted by one, two or three substituents independently selected from the following: -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3;

[0823] R8 is H or C 1-6 -alkyl, preferably H,

[0824] R9 is optionally substituted with 1, 2, or 3 substituents selected from -C 1-6 -alkyl refers to C1-, C2-, C3-, C4-, C5-, or C6-alkyl, -C 2-6 -Alkenyl refers to C2-, C3-, C4-, C5-, or C6-alkenyl, --C 2-6 -Alynyl group refers to C2-, C3-, C4-, C5-, or C6-alkynyl group, or -C 1-6 -alkyl-aryl refers to C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl: -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3;

[0825] R A It is an H, a carbocyclic or heterocyclic ring, which is optionally substituted, preferably substituted by one, two or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2). o -R9, -SO2NH2 and =O, where o is 0 or 1.

[0826] In a preferred embodiment of the invention, X is N.

[0827] In a preferred embodiment of the present invention, A is C.

[0828] In a preferred embodiment of the present invention, R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3-alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, and preferably R6 is H;

[0829] In a preferred embodiment of the present invention, R1 is -CO-OH.

[0830] In a preferred embodiment of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, and preferably R6 is H.

[0831] In a preferred embodiment of the invention, A is C and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, and preferably R6 is H.

[0832] In a preferred embodiment of the invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, and preferably R6 is H.

[0833] In a preferred embodiment of the invention, X is N, A is C, and R1 is -CO-OH or -CO-NH2.

[0834] In a preferred embodiment of the invention, R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H.

[0835] In a preferred embodiment of the invention, X is N and R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H.

[0836] In a preferred embodiment of the invention, A is C and R2 is -NHR8, where R8 is H or C.1-6 -alkyl, preferably H.

[0837] In a preferred embodiment of the present invention, R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H.

[0838] In a preferred embodiment of the invention, R1 is -CO-OH and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H.

[0839] In a preferred embodiment of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H.

[0840] In a preferred embodiment of the invention, A is C and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H.

[0841] In a preferred embodiment of the invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C1-6 -alkyl, preferably H.

[0842] In a preferred embodiment of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2, and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H.

[0843] In a preferred embodiment of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O.

[0844] In a preferred embodiment of the invention, X is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O.

[0845] In a preferred embodiment of the invention, A is C and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O.

[0846] In a preferred embodiment of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O.

[0847] In a preferred embodiment of the invention, R1 and R2 together form uracil or 3-deazouracil.

[0848] In a preferred embodiment of the invention, X is N, and R1 and R2 together form uracil or 3-deazouracil.

[0849] In a preferred embodiment of the invention, A is C, and R1 and R2 together form uracil or 3-deazouracil.

[0850] In a preferred embodiment of the invention, X is N, A is C, and R1 and R2 together form uracil or 3-deazouracil.

[0851] In a preferred embodiment of the invention, R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0852] In a preferred embodiment of the invention, R1 is -CO-OH and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0853] In a preferred embodiment of the present invention, X is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, C3-, -alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0854] In a preferred embodiment of the present invention, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3-Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0855] In a preferred embodiment of the present invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0856] 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, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0857] In a preferred embodiment of the invention, R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m-L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0858] In a preferred embodiment of the invention, X is N, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0859] In a preferred embodiment of the invention, A is C, and R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0860] In a preferred embodiment of the present invention, R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, C3-, -alkyl, -C 2-3 -Alkenyl refers to C2-, C3-, and -Alkenyl groups, -C 2-3-Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0861] In a preferred embodiment of the invention, R1 is -CO-OH and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0862] In a preferred embodiment of the present invention, X is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0863] In a preferred embodiment of the present invention, A is C, and R1 is -CO-OR6 or -CO-NR6R. APreferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0864] In a preferred embodiment of the present invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0865] In a preferred embodiment of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3-alkyl and -hydroxy C 1-3 -alkyl.

[0866] In a preferred embodiment of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0867] In a preferred embodiment of the invention, X is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0868] In a preferred embodiment of the invention, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3-alkyl and -hydroxy C 1-3 -alkyl.

[0869] In a preferred embodiment of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0870] In a preferred embodiment of the invention, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0871] In a preferred embodiment of the invention, X is N, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3-alkyl and -hydroxy C 1-3 -alkyl.

[0872] In a preferred embodiment of the invention, A is C, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0873] In a preferred embodiment of the invention, X is N, A is C, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0874] In a preferred embodiment of the present invention, R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0875] In a preferred embodiment of the invention, R1 is -CO-OH and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0876] In a preferred embodiment of the present invention, X is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0877] In a preferred embodiment of the present invention, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0878] In a preferred embodiment of the present invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m-L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0879] In a preferred embodiment of the present invention, X is N, A is C, R1 is -CO-OH or -CO-NH2, and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0880] In a preferred embodiment of the invention, R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0881] In a preferred embodiment of the invention, X is N, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0882] In a preferred embodiment of the invention, A is C, and R2 is -NHR8, where R8 is H or C. 1-6-alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0883] In a preferred embodiment of the present invention, R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, C3-, -alkyl, -C 2-3 -Alkenyl refers to C2-, C3-, and -Alkenyl groups, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0884] In a preferred embodiment of the present invention, R1 is -CO-OH, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0885] In a preferred embodiment of the present invention, X is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3-alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0886] In a preferred embodiment of the present invention, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0887] In a preferred embodiment of the present invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3-alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0888] In a preferred embodiment of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2, and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0889] In a preferred embodiment of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0890] In a preferred embodiment of the invention, X is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0891] In a preferred embodiment of the invention, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m-L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0892] In a preferred embodiment of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0893] In a preferred embodiment of the invention, R1 and R2 together form uracil or 3-deazouracil, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m-L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0894] In a preferred embodiment of the invention, X is N, and R1 and R2 together form uracil or 3-deazouracil, and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0895] In a preferred embodiment of the invention, A is C, R1 and R2 together form uracil or 3-deazouracil, and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C1-3 -alkyl.

[0896] In a preferred embodiment of the invention, X is N, A is C, R1 and R2 together form uracil or 3-deazouracil, and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0897] In a preferred embodiment of the present invention, R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0898] In a preferred embodiment of the invention, R1 is -CO-OH, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H, or CF3.

[0899] In a preferred embodiment of the present invention, X is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0900] In a preferred embodiment of the present invention, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0901] In a preferred embodiment of the present invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3-alkyl refers to C1-, C2-, C3-, -alkyl, -C 2-3 -Alkenyl refers to C2-, C3-, and -Alkenyl groups, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0902] 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, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H, or CF3.

[0903] In a preferred embodiment of the invention, R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0904] In a preferred embodiment of the invention, X is N, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0905] In a preferred embodiment of the invention, A is C, and R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0906] In a preferred embodiment of the present invention, R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0907] In a preferred embodiment of the present invention, R1 is -CO-OH, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0908] In a preferred embodiment of the present invention, X is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0909] In a preferred embodiment of the present invention, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0910] In a preferred embodiment of the present invention, X is N, A is C, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0911] In a preferred embodiment of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2, and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0912] In a preferred embodiment of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0913] In a preferred embodiment of the invention, X is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0914] In a preferred embodiment of the invention, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0915] In a preferred embodiment of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0916] In a preferred embodiment of the invention, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H, or CF3.

[0917] In a preferred embodiment of the invention, X is N, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0918] In a preferred embodiment of the invention, A is C, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0919] In a preferred embodiment of the invention, X is N, A is C, and R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H, or CF3.

[0920] In a preferred embodiment of the invention, A is N and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, and preferably R6 is H.

[0921] In a preferred embodiment of the invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, and preferably R6 is H.

[0922] In a preferred embodiment of the invention, X is N, A is N, and R1 is -CO-OH or -CO-NH2.

[0923] In a preferred embodiment of the invention, A is N and R2 is -NHR8, where R8 is H or C. 1-6 -alkyl, preferably H.

[0924] In a preferred embodiment of the invention, A is N and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H.

[0925] In a preferred embodiment of the invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H.

[0926] In a preferred embodiment of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H.

[0927] In a preferred embodiment of the invention, A is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O.

[0928] In a preferred embodiment of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O.

[0929] In a preferred embodiment of the invention, A is N and R1 and R2 together form uracil or 3-deazouracil.

[0930] In a preferred embodiment of the invention, X is N, A is N, and R1 and R2 together form uracil or 3-deazouracil.

[0931] In a preferred embodiment of the present invention, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, -R7, or -(CH2). m-L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0932] In a preferred embodiment of the present invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0933] In a preferred embodiment of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0934] In a preferred embodiment of the invention, A is N, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C1-3 -alkyl.

[0935] In a preferred embodiment of the present invention, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0936] In a preferred embodiment of the present invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0937] In a preferred embodiment of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, -R7 or -(CH2). m-L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0938] In a preferred embodiment of the invention, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0939] In a preferred embodiment of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7 or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0940] In a preferred embodiment of the invention, A is N, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, -R7, or -(CH2). m-L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0941] In a preferred embodiment of the invention, X is N, A is N, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, -R7, or -(CH2). m -L, where m is 0, and L is a phenyl or a 5-, 6-, or 7-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0942] In a preferred embodiment of the present invention, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0943] In a preferred embodiment of the present invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -The alkynyl group, i.e., C2- or C3-, is optionally substituted, preferably R6 is H and R3 is -C. 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2)m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0944] In a preferred embodiment of the present invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0945] In a preferred embodiment of the invention, A is N, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0946] In a preferred embodiment of the present invention, R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, C3-, -alkyl, -C 2-3 -Alkenyl refers to C2-, C3-, and -Alkenyl groups, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m-L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0947] In a preferred embodiment of the present invention, R1 is -CO-OH, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0948] In a preferred embodiment of the present invention, X is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0949] In a preferred embodiment of the present invention, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3-Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0950] In a preferred embodiment of the present invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0951] In a preferred embodiment of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0952] In a preferred embodiment of the invention, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0953] In a preferred embodiment of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m-L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0954] In a preferred embodiment of the invention, A is N, R1 and R2 together form uracil or 3-deazouracil, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0955] In a preferred embodiment of the invention, X is N, A is N, R1 and R2 together form uracil or 3-deazouracil, and R3 is -C 1-3 -alkyl refers to C1-, C2-, C3-alkyl or -(CH2) m -L, where m is 0, and L is a phenyl or a 5-membered heteroaryl group, preferably phenyl, wherein the phenyl or heteroaryl group is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl and -hydroxy C 1-3 -alkyl.

[0956] In a preferred embodiment of the present invention, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3-Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0957] In a preferred embodiment of the present invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0958] In a preferred embodiment of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H, or CF3.

[0959] In a preferred embodiment of the invention, A is N, R2 is -NHR8, and R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0960] In a preferred embodiment of the present invention, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3 -Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0961] In a preferred embodiment of the present invention, X is N, A is N, and R1 is -CO-OR6 or -CO-NR6R. A Preferably, R6 is H,-C 1-3 -alkyl refers to C1-, C2-, or C3-alkyl, -C 2-3 -Alkenyl refers to C2- or C3-alkenyl, -C 2-3-Alynyl group, i.e., C2- or C3- optionally substituted, preferably R6 is H and R2 is -NHR8, wherein R8 is H or C 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0962] In a preferred embodiment of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R2 is -NHR8, wherein R8 is H or C. 1-6 -alkyl, preferably H, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0963] In a preferred embodiment of the invention, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0964] In a preferred embodiment of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably substituted by 1, 2, or 3 substituents independently selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl and =O, preferably -OH and =O, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0965] In a preferred embodiment of the invention, A is N, R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3.

[0966] In a preferred embodiment of the invention, X is N, A is N, and R1 and R2 together form uracil or 3-deazouracil, and R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H, or CF3.

[0967] In a preferred embodiment of the invention, R5 is -(CH2). m-L, where m is 0 or 1, or -(CH2)-(CH=CH)-L, and L is phenyl or 5 or 6-membered heteroaryl or adamantyl, which is optionally substituted, preferably substituted by 1, 2 or 3 independent substituents selected from the following: -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9 and =O, or two adjacent substituents form a 5-membered, 6-membered or 7-membered carbon ring or heterocycle.

[0968] In a preferred embodiment of the invention, R4 and R5 together form a 5- or 6-membered unsubstituted or monosubstituted heterocyclic alkyl group, preferably with =CH-R at the R4 position. A replace.

[0969] In a preferred embodiment of the present invention, R A It is a substituted carbocyclic ring having one or two independent substituents selected from the following: -Br, -Cl, -F, -O-(CH2). o -R9 or -SCH3, where o is 0 or 1.

[0970] In a preferred embodiment of the invention, R4 and R5 together form a 5- or 6-membered unsubstituted or monosubstituted heterocyclic alkyl group, preferably with =CH-R at the R4 position. A Replace, where R A It is a substituted carbocyclic ring having one or two independent substituents selected from the following: -Br, -Cl, -F, -O-(CH2). o -R9 or -SCH3, where o is 0 or 1.

[0971] In a preferred embodiment of the invention, R9 is a -C group optionally substituted with one or two substituents selected from -Cl, -CH3, -OCH3, or -SCH3. 1-4 -alkyl refers to C1-, C2-, C3-, or C4-alkyl, -C 2-4 -Alkenyl refers to C2-, C3-, or C4-alkenyl, or -C 1-6 -alkyl-aryl refers to C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl.

[0972] In a preferred embodiment of the invention, R5 is -(CH2). m-L, where m is 0 or 1, or -(CH2)-(CH=CH)-L, and L is a phenyl or 5- or 6-membered heteroaryl or adamantyl group, optionally substituted, preferably substituted by 1, 2 or 3 independent substituents selected from: -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9 and =O, or two adjacent substituents forming a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, wherein R9 is a -C ring optionally substituted by 1 or 2 substituents selected from -Cl, -CH3, -OCH3 or -SCH3. 1-4 -alkyl refers to C1-, C2-, C3-, or C4-alkyl, -C 2-4 -Alkenyl refers to C2-, C3-, or C4-alkenyl, or -C 1-6 -alkyl-aryl refers to C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl.

[0973] In a particularly preferred embodiment of the invention, ALC1i has the structure of formula (IIa):

[0974]

[0975] Formula (IIa)

[0976] and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which:

[0977] A is C or N;

[0978] R1 is -COOH

[0979] R2 is -CH3 or -NH2

[0980] or

[0981] R1 and R2 together form uracil or 3-deazouracil;

[0982] R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, CF2H or CF3;

[0983] R4 is H

[0984] R5 is -L or -CH2-(CH=CH)-L, where L is a 6-membered carbon ring or heterocycle or adamantyl alkyl group optionally substituted by one or two independent substituents selected from the following: -OH, -NO2, -Br, -Cl, -F, CH3, -O-R9 and =O, or two adjacent substituents forming a 5 or 6-membered heterocycle.

[0985] or

[0986] R4 and R5 together form a 5- or 6-membered unsubstituted or monosubstituted heterocyclic alkyl group, preferably with =CH-R at the R4 position. A replace;

[0987] R9 is a -C group optionally substituted with one or two substituents selected from -Cl, -CH3, -OCH3, or -SCH3. 1-4 -alkyl refers to C1-, C2-, C3-, or C4-alkyl, -C 2-4 -Alkenyl refers to C2-, C3-, or C4-alkenyl, or -C 1-6 -alkyl-aryl refers to C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl;

[0988] R A It is a substituted carbocyclic ring having one or two independent substituents selected from the following: -Br, -Cl, -F, -O-(CH2). o -R9 or -SCH3, where o is 0 or 1.

[0989] In a particularly preferred embodiment, the ALC1i of the present invention has the following characteristics: Figure 1 The specific structure shown.

[0990] According to the present invention, ALC1i can be used in combination with inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, or in combination with mitomycin C, paclitaxel, ionizing radiation, or in combination with an antibody-drug conjugate having a tumor-specific antibody conjugated to a TOP1 inhibitor.

[0991] Topoisomerase I (TOPI) is involved in the relaxation of supercoiled DNA. It removes the helical constraints that would otherwise hinder DNA replication and transcription. Suitable inhibitors of topoisomerase I are known in the art and are commercially available. Examples used according to the invention are irinotecan, SN-38, topotecan, camptothecin (NSC-100880) or derivatives thereof, such as hydroxycamptothecin, 7-ethylcamptothecin or 9-aminocamptothecin, rubitecan, Genz-644282 (CAS No. 529488-28-6), belotetan (CKD-602) hydrochloride or β-lapaquinone. Irinotecan, SN-38 or topotecan are preferred, with irinotecan (preferably in the form of its active metabolite SN-38) being most preferred.

[0992] Topoisomerase II (TOPII) controls DNA tangling and supercoiling. It allows one double helix to pass through another double helix, unwinding DNA by simultaneously cleaving both strands of the DNA helix. Suitable inhibitors of topoisomerase II are known in the art and are commercially available. Examples of inhibitors of topoisomerase II used according to the present invention are teniposide, etoposide, anthracyclines such as arubicin, epirubicin, idarubicin, doxorubicin, doxorubicin, daunomycin, pirarubicin (NSC-333054), zolarubicin, arubicin, or erythromycin, aminonatifide, mitoxantrone (NSC-301739), pisacosan maleate, dexazosin, rosehip hydrochloride, haginin E, etoposide (VP-16), voroxantrone hydrochloride (SNS-595), and acridine. Teniposide and etoposide are preferred.

[0993] Ataxia-telangiectasia mutant (ATM) is a serine / threonine protein kinase belonging to the phosphatidylinositol 3-kinase-associated kinase (PIKK) family of protein kinases. Suitable ATM inhibitors are known in the art and are commercially available. Examples of ATM inhibitors used in accordance with the present 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), and 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.

[0994] ATR (Ataxia-telangiectasia mutation (ATM) and Rad3-associated protein kinase) is a serine / threonine protein kinase. Suitable ATR inhibitors are known in the art and are commercially available. Examples of ATR inhibitors used according to the present invention are cilazetide (AZD6738) (CAS No. 1352226-88-0), elixetide, VX-803 (M4344) (CAS No. 1613191-99-3), AZ20 (CAS No. 1233339-22-4), ETP-46464 (CAS No. 1345675-02-6), bezocelide (VE-822) (CAS No. 1232416-25-9), datolis (BEZ235) (CAS No. 915019-65-7), VE-821 (CAS No. 1232410-49-9), schisandrin B (Sch B) (CAS No. 61281-37-6), and HAMNO (NSC-111847) (CAS No. 138736-73-9). 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). Ciracetide and Elisetide are preferred.

[0995] WEE1 G2 checkpoint kinases play a crucial role in cell cycle regulation and DNA damage recognition / repair. Suitable WEE1 inhibitors are known in the art and are commercially available. Examples of WEE1 inhibitors used according to the present invention are adaceltetracycline (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). Adaceltetracycline is preferred.

[0996] Bromo domains are an evolutionarily conserved family of motifs that bind acetylated lysine residues to histone tails and recruit transcriptional mechanisms that promote the transcription of target genes. Inhibitors of bromo domains (BET inhibitors) are known in the art and are commercially available. Examples of BRD inhibitors used according to the present 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), and CPI-0610 (CAS No. 1380087-89-7, see, for example, 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.

[0997] MEK is a component of the MAP kinase signaling pathway. MEK acts as a dual-specific kinase, phosphorylating both serine / threonine and tyrosine residues. It specifically activates extracellular signal-regulated kinases (ERKs) through phosphorylation, which then continue to regulate various targets within the cell, thereby influencing processes such as growth, proliferation, differentiation, and survival. Examples of MEK inhibitors used according to the present invention are trametinib (CAS No. 871700-17-3), cobimetinib (CAS No. 934660-93-2), bimetinib (CAS No. 606143-89-9), and selumetinib (CAS No. 606143-52-6).

[0998] In a second aspect, the present invention relates to an ALC1i according to formula (II) as described above, said ALC1i being used in combination with a PARP inhibitor for the treatment or improvement of pancreatic or fallopian tube cancer in patients, or for enhancing the efficacy of the PARP inhibitor in the treatment or improvement of pancreatic or fallopian tube cancer in patients. The preferred embodiments described herein with respect to the first aspect are also preferred for the second aspect, particularly the definitions of ALC1i and PARP inhibitors according to formula (II).

[0999] In a preferred embodiment, (i) ALC1i according to formula (II) enhances the cancer cell killing efficacy of PARPi, (ii) administers a reduced amount of PARPi, and / or (iii) avoids PARPi resistance.

[1000] That is, the present invention also relates to ALC1i according to formula (II), said ALC1i being used in combination with a PARP inhibitor to treat or improve pancreatic cancer (preferably) or fallopian tube cancer in patients. Typically, PARP inhibitors (PARPi) are known in the art and are commercially available. Nucleopolyadenosine polymerase (PARP) is an early key factor in the DNA damage response (DDR) to identify single-strand breaks and double-strand breaks (SSB / DSB). The metabolite NAD+ is used... + PARP-1 and PARP-2 add poly-ADP-ribose (PAR) chains to chromatin components and factors belonging to DDR, while PARP-3 targets chromatin components via mono-ADP-ribosylation. By recognizing DNA damage-induced structures that undergo specific alterations, PARPs are recruited to the DNA damage site, which activates their PARation activity, thereby modulating their activity and that of other DDR and chromatin proteins, thus promoting DDR (Ray Chaudhuri and Nussenzweig, 2017).

[1001] This catalytic activity can be detected by NAD. +Analog inhibition has become particularly interesting and clinically available for genetically determined cancers. Notably, so-called PARP inhibitors (PARPi) are used to treat homologous recombination (HR)-deficient cancers and other cancers by targeting synthetic lethality in cases of BRCA1 or BRCA2 deficiency. This is thought to occur by reducing PARP activity and / or by biochemically “capturing” PARP-1 / 2 / 3 on chromatin (Murai et al., 2012, 2014). While “capturing” remains poorly defined molecularly, the term defines the enhanced recruitment, association, and / or retention of PARP-1 / 2 / 3 enzymes on damaged chromatin, typically induced by treatment of PARP-1 enzymes with a PARP inhibitor (PARPi) or by a reduction in the release of PARP-1 / 2 / 3 enzymes after their initial recruitment (which leads to prolonged retention). Biochemically, this manifests itself as enhanced homeostatic association / retention / binding (“capturing”) of PARP enzymes with damaged genomic regions / locuses.

[1002] With the clinical advent of PARPi, PARP-1 has become a powerful target for an increasing number of cancers, including in combination with immuno-oncology therapies (such as the Lynparza / Keytruda trial), to name just a few. Furthermore, first-line PARPi therapy and its application in cases other than germline BRCA-1 / 2 mutations are becoming possible.

[1003] In the preferred embodiment, PARPi:

[1004] (i) The PARPi that reduces PARP activity is selected from small interfering RNAs, and

[1005] (ii) The PARP1 inhibitors are selected from the following compounds:

[1006] (a) Equation (III)

[1007]

[1008] (III)

[1009] and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which:

[1010] III A and III B together represents an arbitrarily substituted fused aromatic ring;

[1011] X III It is NR X or CR X R Y ;

[1012] If XIII =NR X If n is 1 or 2, and if X III = CR X R Y If n is l;

[1013] R X Selected from H, or arbitrarily substituted C l-20 Alkyl, C 5-20 Aryl, C 3-20 Heterocyclic groups, amide groups, thioamide groups, ester groups, acyl groups, and sulfonyl groups;

[1014] R Y Selected from H, hydroxyl, and amino groups;

[1015] Or R X and R Y Able to form spiral-C together 3-7 cycloalkyl or heterocyclic groups;

[1016] R C1 and R C2 Independently selected from hydrogen and C l-4 Alkyl, or when X III It is CR X R Y At that time, R C1 R C2 R X and R Y Together with the carbon atoms to which they are attached, they can form optionally substituted fused aromatic rings; and

[1017] R III Selected from H and halogenated groups;

[1018] as well as

[1019] (b) Formula (IV)

[1020]

[1021] (IV)

[1022] and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which:

[1023] IV Y and IV Z is selected independently from:

[1024] 1. Can be chosen from 1, 2 or 3 IV R6-substituted aryl groups;

[1025] 2. Can be selected from 1, 2 or 3 IV R6-substituted heteroaryl groups;

[1026] 3. Substituents independently selected from the following: hydrogen, alkenyl (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70, C70, C7 2-6 -alkenyl), alkoxy (e.g., C-alkene), alkoxy group (e.g., C-alkene), 1-6 -alkoxy), alkoxyalkyl (e.g., C 1-6 -alkoxy-C 1-6 -alkyl), alkoxycarbonyl (e.g., C10) 1-6 -alkoxy-carbonyl), alkoxycarbonyl alkyl (e.g., C 1-6 -alkoxy-carbonyl-C 1-6 -alkyl), alkyl (e.g., C10) 1-6 -alkyl), alkynyl (e.g., C-alkyl), 2-6 -alkynyl), arylalkyl (e.g., aryl-C) 1-6 -alkyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), cycloalkylalkyl (e.g., C10) 3-8 -cycloalkyl-C 1-6 -alkyl), haloalkyl (e.g., C10) 1-6 -haloalkyl), hydroxyalkylene (e.g., hydroxy-C) 1-6 -alkylene), oxoyl, heterocyclic alkyl (e.g., C10) 2-8 -heterocyclic alkyl), heterocyclic alkyl alkyl (e.g., C 2-8 -heterocyclic alkyl-C 1-6 -alkyl), alkyl carbonyl (e.g., C10) 1-6 -alkyl-carbonyl), arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl (e.g., C10) 1-6 -alkyl-sulfonyl), arylsulfonyl, heteroarylsulfonyl, (R A R B )alkylene (e.g. (R) A R B )-C 1-6 -alkylene), (NR) A R B Carbonyl group, (NR) A R B ) carbonyl alkylene (e.g., (NR) A R B carbonyl-C 1-6 -alkylene), (NR) A R B )sulfonyl and (R A R B ) sulfonylalkylene (e.g., (R A R B )sulfonyl-C 1-6 -alkylene);

[1027] Each of them IV R6 is selected from OH, NO2, CN, Br, Cl, F, I, C 1-6-alkyl, C 3-8 -cycloalkyl, C 2-8 - Heterocyclic alkyl, C 2-6 -Alkenyl, alkoxy (e.g., C) 1-6 -alkoxy), alkoxyalkyl (e.g., C 1-6 -alkoxy-C 1-6 -alkyl), alkoxycarbonyl (e.g., C10) 1-6 -alkoxy-carbonyl), alkoxycarbonyl alkyl (e.g., C 1-6 -alkoxy-carbonyl-C 1-6 -alkyl), C 2-6- alkynyl, aryl, arylalkyl (e.g., aryl-C) 1-6 -alkyl), C 3-8 -cycloalkylalkyl (e.g., C10) 3-8 -cycloalkyl-C 1-6 -alkyl), haloalkoxy (e.g., C10) 1-6 -haloalkoxy), haloalkyl (e.g., C10) 1-6 -haloalkyl), hydroxyalkylene (e.g., hydroxy-C) 1-6 -alkylene), oxo group, heteroaryl, heteroarylalkoxy (e.g., heteroaryl-C) 1-6 -alkoxy), heteroaryloxy, heteroarylthio, heteroarylalkylthio (e.g., heteroaryl-C), heteroaryl-C 1-6 -alkylthio), heterocyclic alkoxy (e.g., C10) 2-8 -heterocyclic alkoxy), C 2-8 - Heterocyclic alkylthio group, heterocyclic oxy group, heterocyclic thio group, NR A R B 、(R A R B C 1-6 -alkylene, (NR) A R B carbonyl group, (R) A R B ) carbonyl alkylene (e.g. (R A R B carbonyl-C 1-6 -alkylene), (NR) A R B )sulfonyl and (NR A R B ) sulfonylalkylene (e.g., (NR) A R B )sulfonyl-C 1-6 -alkylene);

[1028] IV R1、 IV R2 and IV R3 is independently selected from hydrogen, halogen, alkenyl (e.g., C). 2-6-alkenyl), alkoxy (e.g., C-alkene), alkoxy group (e.g., C-alkene), 1-6 -alkoxy), alkoxycarbonyl (e.g., C 1-6 -alkoxy-carbonyl), alkyl (e.g., C10) 1-6 -alkyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), alkynyl (e.g., C10) 2-6 -alkynyl), cyano, haloalkoxy (e.g., C10), 1-6 -haloalkoxy), haloalkyl (e.g., C10) 1-6 -haloalkyl), hydroxyl, hydroxyalkylene (e.g., hydroxy-C) 1-6 -alkylene), nitro, NR A R B NR A R B Alkylenes (e.g., NR) A R B C 1-6 -alkylene) and (R A R B Carbonyl group;

[1029] IV A and IV B is selected independently from hydrogen, Br, Cl, F, I, OH, and C. 1-6 -alkyl, C 3-8 -cycloalkyl, alkoxy (e.g., C10) 1-6 -alkoxy), alkoxyalkyl (e.g., C 1-6 -alkoxy-C 1-6 -alkyl), where C 1-6- Alkyl, C 3-8 -The cycloalkyl, alkoxy, or alkoxyalkyl group is optionally substituted by at least one substituent selected from the following: OH, NO2, CN, Br, Cl, F, I, C 1-6- Alkyl and C 3-8 -cycloalkyl, wherein IV B is not OH;

[1030] R A and R B Independently selected from hydrogen, alkyl (e.g., C10) 1-6 -alkyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl) and alkyl carbonyl (e.g., C10) 1-6 -alkyl-carbonyl); or R A and R B Together with the atoms to which they are attached, they form 3- to 10-membered heterocycles, optionally having one to three heteroatoms or heterofunctional groups selected from the following: -O-, -NH, -N(C 1-6-alkyl)-, -NCO(C1-6-alkyl)-, -N(aryl)-, -N(aryl-C1-6-alkyl-), -N(substituted -aryl-C 1-6 -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C 1-6 Alkyl-)- and -S- or S(O)q-, wherein q is 1 or 2, and the 3- to 10-membered heterocycle is optionally substituted by one or more substituents;

[1031] IV R4 and IV R5 is independently selected from hydrogen, alkyl (e.g., C) 1-6 -alkyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), alkoxyalkyl (e.g., C10) 1-6 -alkoxy-C 1-6 -alkyl), haloalkyl (e.g., C10) 1-6 -haloalkyl), hydroxyalkylene (e.g., hydroxy-C) 1-6 -alkylene) and (NR A R B )alkylene (e.g., NR) A R B C 1-6 -alkylene);

[1032] (iii) The PARP1 and PARP2 inhibitors are selected from the following compounds:

[1033] (a) Equation (V)

[1034]

[1035] (V)

[1036] and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which:

[1037] V R1 is either hydrogen or fluorine; and

[1038] V R2 is either hydrogen or fluorine;

[1039] as well as

[1040] (b) Formula (VI)

[1041]

[1042] (VI)

[1043] and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which:

[1044] VI R1、 VI R2 and VI R3 is independently selected from hydrogen, alkenyl (e.g., C), and other groups. 1-6 -alkenyl), alkoxy (e.g., C-alkene), alkoxy group (e.g., C-alkene), 1-6 -alkoxy), alkoxycarbonyl (e.g., C 1-6 -alkoxycarbonyl), alkyl (e.g., C10) 1-6 -alkyl), alkynyl (e.g., C-alkyl), 1-6 -alkynyl), cyano, haloalkoxy (e.g., C10), 1-6 -haloalkoxy), haloalkyl (e.g., C10) 1-6 -haloalkyl), halogen, hydroxyl, hydroxyalkyl (e.g., C10) 1-6 -hydroxyalkyl), nitro, NR A R B and (NR) A R B Carbonyl group;

[1045] VI A is a non-aromatic 4-, 5-, 6-, 7-, or 8-membered ring containing 1 or 2 nitrogen atoms and optionally one sulfur or oxygen atom, wherein the non-aromatic ring is optionally substituted by 1, 2, or 3 substituents selected from the following: alkenyl (e.g., C... 1-6 -alkenyl), alkoxy (e.g., C-alkene), alkoxy group (e.g., C-alkene), 1-6 -alkoxy), alkoxyalkyl (e.g., C 1-6 -alkoxy-C 1-6 -alkyl), alkoxycarbonyl (e.g., C10) 1-6 -alkoxycarbonyl), alkoxycarbonyl alkyl (e.g., C 1-6 -alkoxycarbonyl-C 1-6 -alkyl), alkyl (e.g., C10) 1-6 -alkyl), alkynyl (e.g., C-alkyl), 1-6 -alkynyl), aryl, arylalkyl (e.g., aryl-C) 1-6 -alkyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), cycloalkylalkyl (e.g., C10) 3-8 -cycloalkyl-C 1-6 -alkyl), cyano, haloalkoxy (e.g., C14), 1-6 -haloalkoxy), haloalkyl (e.g., C10) 1-6 -haloalkyl), halogen, heterocyclic, heterocyclic alkyl (e.g., heterocyclic-C) 1-6 -alkyl), heteroaryl, heteroarylalkyl (e.g., heteroaryl-C) 1-6 -alkyl), hydroxyl, hydroxyalkyl (e.g., C10) 1-6 -hydroxyalkyl), nitro, NR C R D 、(NRC R D )alkyl (e.g., (NR) C R D )-C 1-6 -alkyl), (NR C R D Carbonyl group, (NR) C R D Carbonyl alkyl (e.g., (NR) C R D carbonyl-C 1-6 -alkyl) and (NR C R D )sulfonyl group; and

[1046] R A R B R C and R D Independently selected from hydrogen, alkyl (e.g., C10) 1-6 -alkyl) and alkyl carbonyl (e.g., C10) 1-6 -alkylcarbonyl).

[1047] (iv) PARP1, PARP2 and PARP3 inhibitors are compounds of formula (VII).

[1048]

[1049] (VII)

[1050] and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which:

[1051] VII R1 is: H; halogen; cyano; optionally substituted alkyl group (e.g., C1). 1-6 -alkyl), alkenyl (e.g., C- ...) 2-6 -alkenyl), alkynyl (e.g., C-yl), 2-6 -alkynyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), heterocycloalkyl (e.g., C10) 2-8 -heterocyclic alkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogens, hydroxyl, nitro, and amino, unsubstituted or substituted with one or more substituents selected from halogens, hydroxyl, nitro, carboxyl, and optionally substituted amino and ether groups (such as O-aryl) alkoxy (e.g., C 1-6 -alkoxy), alkyl (e.g., C10) 1-6 -alkyl) and aryl); or -C(O)-R 10 , where R 10 Yes: H; optionally substituted alkyl group (e.g., C 1-6 -alkyl), alkenyl (e.g., C- ...)1-6 -alkenyl), alkynyl (e.g., C-yl), 1-6 -alkynyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), heterocycloalkyl (e.g., C10) 2-8 - Heterocyclic alkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogens, hydroxyl, nitro, amino, and unsubstituted or substituted with one or more substituents selected from halogens, hydroxyl, nitro, and amino, and alkyl (e.g., C14) 1-6 -alkyl) and aryl); or OR 100 or NR 100 R 110 , where R 100 and R 110 Each is independently H or optionally substituted alkyl group (e.g. C). 1-6 -alkyl), alkenyl (e.g., C- ...) 2-6 -alkenyl), alkynyl (e.g., C-yl), 2-6 -alkynyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), heterocycloalkyl (e.g., C10) 2-8 -heterocyclic alkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents, said one or more substituents being selected from unsubstituted or substituted alkyl groups (e.g., C10-12 ... 1-6 -alkyl), alkenyl (e.g., C- ...) 2-6 -alkenyl), alkynyl (e.g., C-yl), 2-6 -alkynyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), heterocycloalkyl (e.g., C10) 2-8 -heterocyclic alkyl), aryl and heteroaryl, wherein the one or more substituents are selected from halogens, hydroxyl, nitro, amino, and unsubstituted alkyl groups or alkyl groups substituted with one or more substituents selected from halogens, hydroxyl, nitro and optionally substituted amino groups (e.g. C10). 1-6 -alkyl) and aryl);

[1052] VII R2 is H or an alkyl group (e.g., C). 1-6 -alkyl);

[1053] VII R3 is H or an alkyl group (e.g., C). 1-6 -alkyl);

[1054] VII R4 is H, halogen, or alkyl (e.g., C). 1-6 -alkyl);

[1055] VII X is O or S;

[1056] Y is (C)VII R5 VII R6)(C VII R7 VII R8) n or NC ( VII R5), where:

[1057] n is 0 or 1;

[1058] VII R5 and VII R6 is independently H or optionally substituted alkyl group (e.g., C). 1-6 -alkyl), alkenyl (e.g., C- ...) 2-6 -alkenyl), alkynyl (e.g., C-yl), 2-6 -alkynyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), heterocycloalkyl (e.g., C10) 2-8 - Heterocyclic alkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogens, hydroxyl, nitro, amino), and lower alkyl groups (e.g., C10, 20, 30, 40, 5 ... 1-4 -alkyl), lower alkoxy groups (e.g., C10) 1-4 -alkoxy) or aryl); and

[1059] VII R7 and VII R8 is independently H or optionally substituted alkyl (e.g., C). 1-6 -alkyl), alkenyl (e.g., C- ...) 2-6 -alkenyl), alkynyl (e.g., C-yl), 2-6 -alkynyl), cycloalkyl (e.g., C10) 3-8 -cycloalkyl), heterocycloalkyl (e.g., C10) 2-8 - Heterocyclic alkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from halogens, hydroxyl, nitro, amino), and lower alkyl groups (e.g., C10, 20, 30, 40, 5 ... 1-4 -alkyl), lower alkoxy groups (e.g., C10) 1-4 -alkoxy) and aryl);

[1060] Among them when VII R1、 VII R4 VII R5 VII R6 and VII When each of R7 is H VII R8 is not an unsubstituted phenyl group.

[1061] In a preferred embodiment of the invention, PARPi is selected from AZD-5305, olaparib, tarapazopanib, nirapazanib, pamipanib, rucapazanib, and velipazanib, and particularly from olaparib, tarapazopanib, nirapazanib, pamipanib, rucapazanib, and velipazanib.

[1062] In a preferred embodiment of the present invention, ALC1i is administered simultaneously or sequentially with an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, MEK or PARP, or mitomycin C, paclitaxel, ionizing radiation or an antibody-drug conjugate having a tumor-specific antibody conjugated to a TOP1 inhibitor.

[1063] In a third aspect, the present invention relates to a pharmaceutical composition comprising, as specified in the first aspect of the invention, an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, or mitomycin C, or paclitaxel, or an antibody-pharmaceutical conjugate having a tumor-specific antibody conjugated to a TOP1 inhibitor, preferably for the treatment and / or improvement of proliferative diseases, preferably cancer.

[1064] In a fourth aspect, the present invention relates to a kit comprising ALC1i as described herein, and instructions for use in combination with inhibitors 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 having a tumor-specific antibody conjugated to a TOP1 inhibitor, or comprising inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, or mitomycin C. Or paclitaxel, or an antibody-drug conjugate having a tumor-specific antibody conjugated to a TOP1 inhibitor, and a package insert containing an ALC1i as defined herein, or a separately packaged ALC1i as defined herein, and an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD and / or MEK, or mitomycin C, paclitaxel, or an antibody-drug conjugate having a tumor-specific antibody conjugated to a TOP1 inhibitor, and optionally a package insert, for the treatment or improvement of proliferative diseases, preferably cancer.

[1065] In a preferred embodiment of all aspects of the invention, the ALC1i used is a compound of formula (I) or formula (II), more preferably having the following characteristics: Figure 1 The compound with the structure shown, or its isomers, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs. Preferred pharmaceutically acceptable salts are sodium salts.

[1066] In a preferred embodiment, ALC1i as defined above, pharmaceutical compositions as defined above, and / or kits as defined above are used to treat or improve proliferative diseases, preferably cancer, more preferably proliferative diseases selected from BRCA-1 and / or BRCA-2 deficient tumors, and / or proliferative diseases selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, or pancreatic cancer.

[1067] BRCA1 and BRCA2 proteins are involved in both promoting homologous recombination (HR)-mediated DNA repair and controlling the stability of stalled replication forks. Many tumor types, including, for example, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, and uveal melanoma, often have underlying defects in BRCA1 or BRCA2 activity. These defects are usually due to germline or somatic mutations in the BRCA1 or BRCA2 genes. These tumors with underlying HR repair defects are generally sensitive to PARP inhibitors. However, over time, they develop resistance to PARP inhibitors. For the treatment of such tumors, the use of ALC1i according to the present invention, whether alone or in combination with PARP inhibitors, is particularly suitable. In a preferred embodiment of the ALC1i used according to the present invention or the pharmaceutical composition or kit according to the present invention, the proliferative disease is selected from cancers.

[1068] As used herein, the term “cancer” (preferably a tumor (also called a vegetation), particularly a solid tumor) refers to cells capable of autonomous growth. Examples of such cells include cells exhibiting an abnormal state or condition characterized by rapid proliferative cell growth. This term implies cancerous growth, such as tumors; cells, tissues, or organs involved in carcinogenic processes, metastatic tissues, and malignant transformations, regardless of their histopathological type or stage of invasion. It also includes malignant tumors of various organ systems, such as the respiratory, cardiovascular, renal, reproductive, hematopoietic, nervous, hepatic, gastrointestinal, and endocrine systems; and adenocarcinomas, which include malignant tumors such as most colon cancers, renal cell carcinomas, prostate and / or testicular tumors, non-small cell lung cancer, and small bowel cancer. “Naturally occurring” cancer includes any cancer that is not experimentally induced by implanting cancer cells into a subject, and includes, for example, spontaneously occurring cancer, cancer resulting from a patient’s exposure to one or more carcinogens, cancer resulting from the insertion of a transgenic oncogene or the knockout of a tumor suppressor gene, and cancer resulting from infection (e.g., viral infection). T...

Claims

1. An allosteric inhibitor of a cromodomain-helicase-DNA binding protein 1-like protein (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid segment spanning amino acid residues 101 to 219 of SEQ ID NO: 1, the allosteric inhibitor being used in combination with the following to treat or improve proliferative diseases in patients, and / or to enhance the efficacy of the following in the treatment of proliferative diseases: a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and / or MEK. b) Mitomycin C or paclitaxel c) Ionizing radiation, or d) Antibody-drug conjugates containing tumor-specific antibodies conjugated to TOP1 inhibitors.

2. The ALC1 allosteric inhibitor for the stated purpose according to claim 1, wherein the allosteric binding pocket comprises or is composed 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 SEQ ID NO: 1, preferably comprising SEQ ID NO: 1 is composed of Y153, C156, L157, A160, L163, V173, E175, R178, L186, H187, L190, F193, L200 and E212 or thereof.

3. The ALC1 inhibitor (ALC1i) for the stated purpose according to claim 1 or 2, wherein the ALC1 inhibitor (ALC1i) is based on formula (I). (I) and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which (i) A5 and A8 are each independently selected from N or CH; (ii) A6 is selected from N or CH, or when A6 participates in a cyclic carbocyclic or heterocyclic Z, then A6 is C; (iii) A7 is selected from N or CH, or when A7 participates in a cyclic carbocyclic or heterocyclic Z, then A7 is C; (iv) L2 is selected from -CH2-R4, -CF2-R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, -O-R4, -NH-R4, -N=R4; (v)L3 is selected from CH2-R9, -CF2-R9, -CH2-CH2-R9, -CH2-CF2-R9, -CH2-CH2-CH2-R9, -O-R9, -NH-R9, -N=R9; or (vi) L2 and L3 together with A8 to which they are connected form a 5- or 6-membered heterocycle replaced by R4 and / or R9; (vii)L4 is CH2, -CF2-, CH2-CH2, CH2-CH2-CH2, O, N, and NH, or it does not exist; (viii) Z is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and can be cyclized to the central core or linked via a covalent bond. (ix) R4 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH; (x)R9 is a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered carbocyclic or heterocyclic ring, which is optionally substituted by one, two or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe and -SMe; (xi)R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe; (xii) or R6 is H; or (xiii) When A7 participates in a cyclic carbocyclic or heterocyclic Z, 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 according to equation (II) (II) and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which (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 carbon ring or heterocycle, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -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, where m is 0, 1, or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from: -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 group, preferably H; (viii) R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1, or 2, preferably 0 or 1, and L is a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic, adamantyl, or C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably substituted by 1, 2, 3 or 4 independently selected from the following substituents: -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-membered, 6-membered or 7-membered carbon ring or heterocycle; or (ix) R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -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 -Alynyl group, which is optionally substituted, preferably R6 is H; (xi)R7 is -C 1-3 -alkyl, -C 2-3 -Alkenyl, -C 2-3 -Alynyl group, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3; (xii)R8 is H or C 1-6 -alkyl, preferably H, (xiii)R9 is -C 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6 -alkynyl group, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazolium, 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: -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl group (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl group (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably -CH3, ethyl, propyl, tert-butyl, or pentyl), -C 1-3 - Haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocyclic (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl group (preferably -OCH3), -OC 1-3 -alkyl-OC 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or when R9 is -C 1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form optionally substituted 5-, 6-, or 7-membered carbon rings or heterocycles; (xiv)R A It is an H, a carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by one, two or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2). o -R9, -SO2NH2 and =O, where o is 0 or 1.

4. An ALC1 inhibitor (ALC1i) according to formula (II) (II) and its isomers, salts, solvates, chemically protected forms, and prodrugs, among which (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 carbon ring or heterocycle, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -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, where m is 0, 1, or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from: -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 group, preferably H; (viii) R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1, or 2, preferably 0 or 1, and L is a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic, adamantyl, or C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably substituted by 1, 2, 3 or 4 independently selected from the following substituents: -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-membered, 6-membered or 7-membered carbon ring or heterocycle; or (ix) R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -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 -Alynyl group, which is optionally substituted, preferably R6 is H; (xi)R7 is -C 1-3 -alkyl, -C 2-3 -Alkenyl, -C 2-3 -Alynyl group, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3; (xii)R8 is H or C 1-6 -alkyl, preferably H, (xiii)R9 is -C 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6 -alkynyl group, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazolium, 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: -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl group (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl group (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably -CH3, ethyl, propyl, tert-butyl, or pentyl), -C 1-3 - Haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocyclic (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl group (preferably -OCH3), -OC 1-3 -alkyl-OC 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or when R9 is -C 1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form optionally substituted 5-, 6-, or 7-membered carbon rings or heterocycles; (xiv)R A It is an H, a carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by one, two or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2). o -R9, -SO2NH2, and =O, where o is 0 or 1. Used in combination with PARP inhibitors to treat or improve pancreatic or fallopian tube cancer in patients, or to enhance the efficacy of PARP inhibitors in treating or improving pancreatic or fallopian tube cancer in patients.

5. The ALC1i for the said purpose according to any one of claims 1 to 5, wherein the ALC1i has the structure of formula (I), wherein A5 is N; One of A6 and A7 is CH, and the other is N; or one of A6 and A7 is C and participates in cyclic carbocyclic or heterocyclic Z, and the other is N; A8 is N or CH. or A5 is N; One of A6 and A7 is C and participates in a 5-membered, 6-membered or 7-membered cyclic carbocyclic or heterocyclic ring, preferably a 5-membered or 6-membered aryl or heteroaryl Z, and the other is N; A8 is N; L2 is CH2-CH2-R4, and L3 is CH2-CH2-R9 or CH2-CF2-R9, or L2 and L3 together with the A8 they are attached to form a 5- or 6-membered heterocycle substituted with R4 and R9, preferably piperidinyl or pyrrolidinyl. L4 does not exist; Z is any 6-membered carbon ring or heterocycle cyclized to the central core, preferably a 6-membered aryl or heteroaryl, wherein Z is optionally substituted by one, two or three, preferably one of the following substituents: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe and NO2; R4 is either COOH or tetrazolium; R9 is any 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; and R6 is any 5- or 6-membered carbocyclic or heterocyclic ring, optionally substituted by one, two, or three (preferably one) substituents selected from the following: -Br, -Cl, -F, -I, -OH, -NO2, Me, -CF3, Et, -OMe, and -SMe, or R6 is H. Alternatively, the ALC1i may have the structure of formula (II), wherein: X is N or S; A is C or N; R1 is -CO-OR6, -CO-R7, or -CO-NR6R A Preferably, R1 is -CO-OR6; R2 can be -R7, -NHR8, -O-R7, -CO-R7, Br, or -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 carbon ring or heterocycle, which is optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC. 1-3 -alkyl, =O and [-O-CH2-CH2]-NH-CH(OH)-O-tBu; R3 can be H, =O, -OH, -O-R7, -R7, or -(CH2). m -L, where m is 0, 1, or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by 1, 2, or 3 independent substituents selected from: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 -alkyl, -hydroxy C 1-3 -alkyl and =O; R4 is H or -C 1-3 -alkyl group, preferably H; R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1, or 2, preferably 0 or 1, and L is a 5-membered, 6-membered, or 7-membered carbocyclic or heterocyclic, adamantyl, or C 1-4 -alkyl or -N(CH3)2, optionally substituted, preferably substituted by 1, 2, 3 or 4 independently selected from the following substituents: -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-membered, 6-membered or 7-membered carbon ring or heterocycle; or R4 and R5 together form a 5-, 6-, or 7-membered carbon ring, which may optionally be substituted, preferably by one, two, or three independent substituents selected from the following: -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, -C 2-6 -Alkenyl, -C 2-6 -Alynyl group, which is optionally substituted, preferably R6 is H; R7 is -C 1-3 -alkyl, -C 2-3 -Alkenyl, -C 2-3 -Alynyl group, which is optionally substituted, preferably substituted by 1, 2 or 3 substituents independently selected from the following: -Br, -Cl, -F, -I, -CH3, -OCH3 or -SCH3; R8 is H or C 1-6 -alkyl, preferably H, R9 is -C 1-6 -alkyl, -C 2-6 -Alkenyl, -C 2-6 -alkynyl group, -C 1-6 -alkyl-aryl or C 1-6 -alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazolium, 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: -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 -alkyl group (preferably -CONH-CH3), -NH-CO-C 1-3 -alkyl group (preferably -NH-CO-CH3), -C 1-6 -alkyl (preferably -CH3, ethyl, propyl, tert-butyl, or pentyl), -C 1-3 - Haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocyclic (preferably cyclopropyl, cyclohexyl or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 -alkyl group (preferably -OCH3), -OC 1-3 -alkyl-OC 1-3 -alkyl (preferably -O-CH2-O-CH3), -SCH3, or when R9 is -C 1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form optionally substituted 5-, 6-, or 7-membered carbon rings or heterocycles; R A It is an H, a carbocyclic or heterocyclic ring, optionally substituted, preferably substituted by one, two or three independent substituents selected from the following: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2). o -R9, -SO2NH2 and =O, where o is 0 or 1.

6. The ALC1i for the said purpose according to any one of claims 1 to 5, wherein the ALC1i has the structure of formula (I), wherein Each of A5, A7, and A8 is N; A6 is C and participates in cyclic carbocyclic or heterocyclic 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 does not exist; Z is a phenyl or cyclohexyl group cyclized to the central core, wherein Z is optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -F, -OH, Me, -CF3, -OMe, and -NO2. R4 is either COOH or tetrazolium; R9 is phenyl, cyclobutyl, cyclopentyl, or adamantyl, optionally substituted by one, two, or three, preferably one, substituent selected from the following: -Br, -Cl, -CF3, Me, -CH2-CF3, and -OMe; R6 is any 6-membered carbon ring or heterocycle (preferably phenyl or cyclohexyl; more preferably phenyl), which is optionally substituted by one, two or three, preferably one, substituent selected from the following: Br, -Cl, -F, Me, -CF3, -OMe and -NO2.

7. The ALC1i for the said purpose according to any one of claims 1 to 6, wherein the ALC1i is selected from: Its isomers, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs.

8. The ALC1i for the stated purpose according to any one of claims 1 to 7, wherein the ALC1i is administered simultaneously or sequentially with an inhibitor of the topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK, BRD or PARP, or mitomycin C, paclitaxel or an antibody-drug conjugate having a tumor-specific antibody conjugated to a TOP1 inhibitor, such as trastuzumab, dedabrotuzumab or gosetuzumab.

9. The ALC1i for the purpose according to any one of claims 1 to 8, wherein the proliferative disease is selected from HR-deficient cancers, preferably BRCA-1 and / or BRCA-2 deficient tumors, 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.

10. A pharmaceutical composition comprising ALC1i according to any one of claims 1 to 7, and a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, and / or BRD, MEK. b) Mitomycin C or paclitaxel, or c) Antibody-drug conjugates containing tumor-specific antibodies conjugated to TOP1 inhibitors.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is used to treat or improve proliferative diseases, preferably, the proliferative diseases are selected from HR-deficient cancers, more preferably BRCA-1 and / or BRCA-2 deficient tumors, and / or the proliferative diseases are selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer, or pancreatic cancer.

12. A kit, the kit comprising: (i) ALC1i according to any one of claims 1 to 7, and the combination thereof with a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK, and / or BRD, b) Mitomycin C or paclitaxel, or c) Ionizing radiation; or d) The product information for an antibody-drug conjugate combination containing a tumor-specific antibody conjugated to a TOP1 inhibitor, or (ii) includes: a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK and / or BRD, or b) Mitomycin C, paclitaxel, or antibody-drug conjugates containing tumor-specific antibodies conjugated to TOP1 inhibitors. And a description of its combination with ALC1i according to any one of claims 1 to 5, or (iii) Containing individually packaged ALC1i according to any one of claims 1 to 5, and a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK and / or BRD, or b) Mitomycin C or paclitaxel, or c) Antibody-drug conjugates containing tumor-specific antibodies conjugated to TOP1 inhibitors. Optionally, and as a instruction manual for the treatment or improvement of proliferative diseases.

13. The kit according to claim 12, wherein the kit is used to treat or improve proliferative diseases, preferably, the proliferative diseases are selected from HR-deficient cancers, more preferably BRCA-1 and / or BRCA-2 deficient tumors, and / or the proliferative diseases are selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer or pancreatic cancer.

14. The ALC1i for the stated purpose according to any one of claims 1 to 9, the pharmaceutical composition according to claim 10 or 11, or the kit according to claim 12 or 13, wherein the ALC1i is combined with any one of the following: adasetin, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, cilasetide, elixetide, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, taprazole, detrastuzumab, dedabrotuzumab, and / or gosetuzumab.

15. A pharmaceutical composition comprising ALC1i-101 or a salt thereof and trastuzumab, said pharmaceutical composition for treating or improving proliferative diseases, preferably, said proliferative diseases are selected from HR-deficient cancers, more preferably BRCA-1 and / or BRCA-2-deficient cancers, and / or said proliferative diseases are 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, said pharmaceutical composition for treating advanced or metastatic cancer with homologous recombination defect (HRD) mutations.

17. The ALC1i for the stated use according to any one of claims 1 to 9, the pharmaceutical composition according to claim 10, 11, 15 or 16, or the kit according to claim 12 or 13, wherein the patient to be treated is receiving or has received trastuzumab and preferably shows or has not shown at least a partial response after several treatment cycles.

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