TW202535405A - Alc1 inhibitors for use in treating cancer by potentiating the effects of several classes of approved cancer drugs - Google Patents

Abstract

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

Description

ALC1 inhibitors used to treat cancer by enhancing the effects of several approved drugs.

This invention relates to the use of small molecule compounds that ectopically inhibit ALC1 (CHD1L) (particularly ectopic inhibitors of two types, formula (I) and formula (II) of ALC1 (CHD1L)) that demonstrate enhanced (preferably additive) therapeutic effects on proliferative diseases when combined with several classes of cancer drugs (i.e., inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK), or when combined with mitomycin C, paclitaxel, free radiation, or with antibody drug conjugates having tumor-specific antibodies that bind to TOP1 inhibitors. Furthermore, the ALC1 inhibitor of Equation (II) of this invention exhibits a synergistic effect in the treatment of pancreatic cancer or fallopian tube cancer when combined with a PARP inhibitor (poly(ADP-ribose)-polymerase inhibitor (PARPi)). Due to its synergistic effect with these inhibitor classes, the ALC1 inhibitor enhances the cancer-killing properties of these inhibitors, thereby enabling treatment methods for ALC1 amplification into an oncogene and/or for cancers in which homologous recombination deletion (HRD) cancers are present. Furthermore, these ALC1 inhibitors may overcome inhibitor resistance mechanisms and enable alternative treatments for germline or acquired BRCA1/BRCA2 deficiencies (including tumors defined by "BRCAness" or other variations in the DNA repair network). Importantly, the toxicity mechanisms of these drugs do not overlap with those of ALC1 inhibitors, and therefore synergistic toxicity is not expected.

Invention Background

Cancer is generally divided into two categories: blood cancers and solid cancers. Solid cancers can occur in almost any part of the body, leading to pancreatic cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer, among others. While some treatments include targeted drugs such as Gleevec or Herceptin, most cancers are still treated with chemotherapy or radiation therapy. Because chemotherapy is not a targeted therapy, the biggest problems with traditional chemotherapy agents are, on the one hand, the side effects caused by cytotoxicity, and on the other hand, the development of drug resistance. Although there may be an initial successful response to chemotherapy agents, the latter is ultimately a major factor leading to treatment failure. Therefore, in order to overcome the limitations of these chemotherapy agents, it is necessary to develop new targeted therapies that specifically interfere with cancer cell proliferation.

While combinations of cancer drugs have proven successful in many cases in oncology, there are exceptions, and it is impossible to predict whether two different drugs will work synergistically in the treatment of proliferative diseases. Therefore, there is an urgent medical need to develop novel combination therapies, which combine chemotherapy agents with established efficacy against cancer with novel anticancer drugs that enhance existing treatment regimens.

Unwilling to be bound by any theory, the inventors believe the fundamental reason is that 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 established cancer drugs (i.e., mitomycin C or paclitaxel), or with free radiation, or with antibody-drug conjugates of tumor-specific antibodies that conjugate with TOP1 inhibitors. However, combinations of some representative drugs of these classes of known cancer drugs with known ALC1 inhibitors have not shown synergistic effects.

This invention is based on the following surprising discovery that certain ALC1 inhibitors, namely those that specifically bind to an ectopic binding pocket formed by an amino acid extension spanning amino acid residues 101 to 219 of SEQ ID NO:1, particularly those formulas (I) and (II), exhibit synergistic antiproliferative activity when combined with several known cancer drugs (i.e., inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, MEK), or when combined with certain established cancer drugs (i.e., mitomycin C or paclitaxel), or when combined with free radiation, or when combined with antibody-drug conjugates of tumor-specific antibodies bound to TOP1 inhibitors. Therefore, these combinations are expected to be particularly suitable for treating proliferative diseases.

At least in certain combinations, ALC1 inhibitors combined with other cancer drugs can lead to additive effects beyond expectations, for the following reasons. Activation of DNA damage pathways leads to the replenishment of numerous proteins into damaged chromatin, notably specific chromatin remodeling enzymes, including the nucleosome remodeling agent ALC1 (CHD1L) containing a macrodomain (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017). The metadomain typically binds to ADP-ribose, oligo-ADP-ribose, and poly-ADP-ribose (PAR) (Karras et al., 2005). Therefore, proteins containing the metadomain respond to and recruit PARP activation sites on the genome, including during DNA damage and in association with cancer. Importantly, PAR or oligo-ADP-ribose bound to the metadomain of ALC1 strongly initiates chromatin remodeling activity (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017), revealing ALC1 as an ectopically regulated chromatin remodeling enzyme, making it the first and one of the very few enzymes whose catalytic activity is directly regulated by PAR. In addition, ALC1 is a proven oncogene and is often amplified along with PARP1 in BRCA1/2-deficient ovarian and breast cancer samples.

This technique includes, for example, some ALC1i described by Abbott et al. in 2020 (Abbott et al., 2020). This document reveals inhibitors of CHD1L and their in vitro antitumor activity. Two of the most active ALC1i described, namely "Compound 1" and "Compound 3", have the following chemical structures: Compound 1 Compound 3

WO 2022/117782 A1 reveals specific ALC1 inhibitors. In BRCA-negative breast cancer cell lines, they exhibit at least additive effects when combined with PARP inhibitors.

The inventors tested known ALC1 inhibitors (i.e., compounds 1 and 3 as shown above) in combination with a known commercially available ATR inhibitor (i.e., elimusertib) and with a known and commercially available PARP inhibitor, olaparib. Contrary to the above basic reasoning, in vitro, only additive effects were observed against anticancer cell lines. However, extensive further research has shown that certain ALC1 inhibitors, particularly those having structures according to formulas (I) and (II), specifically bind to an ectopic binding pocket formed by the extension of amino acids spanning amino acid residues 101 to 219 of SEQ ID NO:1, and which inhibit ALC1 ATPase function and/or nucleosome remodeling function, exhibit synergistic effects with and enhance the following combinations: a) certain compounds from several classes of cancer drugs, namely, inhibitors of topoisomerase I (e.g., topotecan) and inhibitors of topoisomerase II (e.g., teniposide). Inhibitors of ATM (e.g., AZ-32, AZD-1056, or AZD-1390) Inhibitors of ATR (e.g., ceralasertib, elimusertib) Inhibitors of WEE1 (e.g., adavosertib) Inhibitors of BRD (e.g., BAY-299 or ABBV-744) MEK inhibitors (e.g., trametinib), b) specific established cancer drugs, namely mitochondrial C or paclitaxel, c) free radiation, and d) antibody-drug conjugates of tumor-specific antibodies that bind to TOP1 inhibitors (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan).

Furthermore, certain ALC1 inhibitors with structures according to formula (II) have been found to inhibit ALC1 ATPase function and/or nucleosome remodeling function, and enhance the anti-pancreatic or fallopian tube cancer cell lines of PARP inhibitors (e.g., AZD-5305, niraparib, olaparib, pamiparib, rucaparib, talazoparib, and veliparib). Therefore, the combination of this specific ALC1 inhibitor and a PARP inhibitor has been found to be particularly suitable for the treatment of pancreatic or fallopian tube cancer.

Therefore, the inventors believe that ALC1 inhibition by specific ALC1 inhibitors inhibits effective DNA repair by making chromatin more difficult to access DNA repair enzymes. Even at lower doses, this leads to enhanced cancer cell killing and/or reduced off-target effects of chemotherapy agents or cancer drugs, and thus reduced cytotoxicity in non-cancer cells. The ALC1 inhibitors used according to the invention (especially the inhibitors of formulas (I) and (II)) can also mediate the sensitization of compounds a), b), and d) listed above.

The inventors further anticipate that manipulating ALC1 activity using the ALC1 inhibitors used according to the invention can induce a strong antiproliferative effect, and is also sufficient to disregard acquired resistance to the above-mentioned compounds a), b), and d), as well as PARP1 and PARP2 inhibition. Therefore, the ALC1 inhibitors of the invention (especially the inhibitors of formulas (I) and (II)) in combination with compounds a), b), and d), PARP1 and/or PARP2 inhibitors can be used for the treatment of oncology (including relapse and progression in advanced clinical stages).

In view of the above-mentioned relevance of specific ALC1 inhibitors used according to the present invention (particularly specific ALC1 inhibitors of formulas (I) and (II)) to cancer (particularly cancers suitable for treatment with the following): adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib The present invention provides a novel combination regimen for the treatment or improvement of proliferative diseases, preferably neoplastic diseases, particularly those characterized by loss of sensitivity to the aforementioned chemotherapy therapies, including bismuth subcitrate (B1), paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and/or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan.

Furthermore, the inventors have determined that the use of an ALC1 inhibitor according to the invention (particularly characterized by formulas (I) and (II)) in combination with the following: adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, and paclitaxel... Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, or talazoparib, and trastuzumab (derutecan) deruxtecan, adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, talazoparib, trastuzumab deruxtecan, and datopomab deruxtecan. The effects of deruxtecan and sacituzumab govitecan were all surprisingly enhanced.

Therefore, the ALC1 inhibitors used in this invention (particularly characterized by formulas (I) and (II) and adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, or talazoparib, and trastuzumab (delutec) are used in this invention. deruxtecan, datopomab deruxtecan, or sacituzumab gavitecan The use of govitecan in combination provides, in particular, an effective treatment for cancer, suitable for use with a combination of adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotetcan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and/or talazoparib, as well as trastuzumab (delutec). deruxtecan, datopomab deruxtecan, or sacituzumab gavitecan (ii) chemotherapy regimens including adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and/or talazoparib, as well as trastuzumab (delutec). deruxtecan, datopomab deruxtecan, or sacituzumab gavitecan (iii) Neglecting adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and/or talazoparib, as well as trastuzumab deruxtecan and datopotamab deruxtecan. deruxtecan), or sacituzumab (glavotecan) (iv) and/or allow reduction of adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, and/or talazoparib, as well as trastuzumab (delutec). The dosage of deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan, when administered, collectively leads to improved anticancer efficacy and fewer adverse side effects.

Invention Overview

In the first state, the invention relates to an ectopic inhibitor of a chromodomain-helicase-DNA-binding protein 1-like (ALC1) protein, wherein the inhibitor specifically binds to an ectopic binding pocket formed by stretching amino acids spanning amino acid residues 101 to 219 of SEQ ID NO:1, preferably an inhibitor of ALC1 (ALC1i) according to formula (I). Formula (I) or its pharmaceutically acceptable salts, isomers, solvents, chemically protected forms, and prodrugs, wherein A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or when A6 participates in annulated carbocyclic or heterocyclic Z, then A6 is C; A7 is selected from N or CH, or when A7 participates in annulated carbocyclic or heterocyclic Z, then A7 is C; L2 is selected from the following groups: -CH2 _- R4, _–CF2 -R4, _{-CH2- CH2} -R4, -CH2 _{- CH2} - _CH2 -R4, -O-R4, -NH-R4, -N=R4; L3 is selected from the following groups: _CH2 -R5, –CF2-R5, –CF2-R4 ... ₂ – R5, _{-CH2- CH2} -R5, _-CH2 -CF2 _- R5, -CH2 _{- CH2} - _CH2 -R5, -O-R5, -NH-R5, -N=R5; or L2 and L3 together with the A8 to which they are attached form a 5- or 6-membered heterocycle substituted with R4 and/or R9; L4 is _CH2 , _–CF2- , _CH2 - _CH2 , _CH2 - _CH2 - _CH2 , O, N, and NH, or is absent; Z is a 5-, 6-, or 7-membered carbon ring or heterocycle, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and -NO2 _. It can form a ring with the central core or be covalently linked. R4 is a 5-, 6-, or 7-membered carbon ring or heterocyclic ring, which may be substituted as needed by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, _-CF3 , Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH; R5 is a 4-, 5-, 6-, 7-, 8-, 9-, or ₁₀ -membered carbon ring or heterocyclic ring, which may be substituted as needed by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, -CF3 Et, -OMe, and -SMe; R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which, as needed, is substituted by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO₂ , Me, _-CF₃ , Et, -OMe, and -SMe; or R6 is H; or when A7 participates in the annulated carbocyclic 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; or an inhibitor of ALC1 according to formula (II): Formula (II) or its pharmaceutically acceptable salt, isomer, solvent, chemically protected form, and precursor, wherein: X is N or S; A is C or N; _R1 is –CO- _OR6 , -CO- _R7 , or -CO- _NR6RA , preferably _{R1 is} –CO- _OR6 ; _R2 is _-R7 , _-NHR8 , _-OR7 , _-COR7 , Br, _-C3-8 -cycloalkyl (preferably cyclopropyl), or _–C4-8 -cycloenyl (preferably cyclohexenyl); or _R1 and R _Together, they form a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the following groups: -OH, -NO₂, -CN, -Br, -Cl, -F, -I, -OC, _1-3 -alkyl, =O, [-O- _CH₂ - _CH₂ ]-NH-CH(OH)-O-tBu; _R₃ is H, =O, -OH, _-OR₇ , _-R₇ , or –( _CH₂ ) _m -L, where m is 0, 1, or 2, and L is a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the following groups: -OH, _-NO₂ R1 is -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, _-hydroxyC1-3 -alkyl, and =O; _R4 is H or _-C1-3 -alkyl, 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, 6, or 7-membered carbocyclic or heterocyclic, adamantine, _C1-4 -alkyl, or -N( _CH3 ) ₂ , substituted as desired, preferably substituted by 1, ₂ , 3, or 4 substituents independently selected from the following group: -OH, -NO2, -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 =O, and [-O- _CH₂ - _CH₂ ] _q -NH-biotin, where q is 1, 2, 3, or 4, or two adjacent substituents form a 5, 6, or 7-membered carbon ring or heterocyclic ring; or _R₄ and _R₅ together form a 5, 6, or 7-membered carbon ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the group consisting of: -OH, -NO₂, -CN, -Br, -Cl, -F, -I, _-OR₉ , _-R₉ , =CH- _RA , and _{–CH₂- RA} , preferably _R₄ and _R₅ together form a C₅ _-7 -cycloalkyl; _R₆ is H, -C₁ _-6 -alkyl, -C₂ _-6 -alkenyl, -C₂- ₆ -alkyl ... -Alynyl group, which may be substituted as desired, preferably _R6 is H; _R7 is _-C1-3 -alkyl, _-C2-3 -alkenyl, _-C2-3 -alkynyl group, which may be substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -Br, -Cl, _-F , -I, -CH3, _-OCH3 , or _-SCH3 ; _R8 is H or _C1-6 -alkyl group, preferably H; _R9 is _-C1-6 -alkyl, _-C2-6 -alkenyl, _-C2-6 -alkynyl, _-C1-6 -alkyl-aryl, or _C1-6 -alkyl-heteroaryl (preferably isothiazolium, thiazolium, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-thiadiazole, pyridine, or pyrazole), wherein the alkyl-heteroaryl group is, as desired, substituted by one, two, or three substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-NO₂ , -CN, -CONH₂, -CONH- _{C₁ -3 -} alkyl (preferably –CONH-CH₃), -NH-CO-C₁- ₃ -alkyl (preferably -NH-CO- _CH₃ ), -C₁- ₆ -alkyl (preferably _-CH₃ , ethyl, propyl, tri-butyl, or pentyl), -C₁- ₃ -halogen (preferably -CF₃). ₃ , or _-CHF2 ), -O- _CHF2 , -O- _CF3 , carbocyclic (preferably cyclopropyl, cyclohexyl, or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably –CO-(1-pyrrolidyl)), _-SO2 - _CH3 , _-SO2- N( _CH3 ) ₂ , _-OC1-4 -alkyl (preferably _-OCH3 ), _-OC1-3 -alkyl- _OC1-3 -alkyl (preferably –O- _CH2 -O- _CH3 ), _-SCH3 , or when _R9 is _-C1-6 -alkyl-aryl, then the two adjacent substituents on the aryl moiety can form a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which are substituted as needed; _RA is H, carbocyclic, or heterocyclic, which are substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the following group: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-R9 , -O- _R7 , -O-( _CH2 ) _OR9 , _{-SO2NH2 ,} and =O, where o is 0 or 1. It is used in combination with the following for the treatment or improvement of proliferative diseases in patients, preferably cancer, a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK; b) mitomycin C or paclitaxel; c) free radiation; or d) antibody-drug conjugates of tumor-specific antibodies bound to TOP1 inhibitors (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan); and/or for enhancing efficacy in patients with proliferative diseases (preferably cancers), a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK; b) mitomycin C or paclitaxel; c) free radiation; or d) antibody-drug conjugates of tumor-specific antibodies conjugated to TOP1 inhibitors (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan).

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

In the third embodiment, the invention relates to a pharmaceutical composition comprising ALC1i as defined herein and a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, b) mitomycin C, paclitaxel, or c) an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan).

In the fourth embodiment, the invention relates to a kit of parts comprising, as described herein, an ALC1i and instructions for use in combination with, a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK; b) mitomycin C, or paclitaxel; c) free radiation; or d) an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan); or comprising a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK; b) mitomycin C or paclitaxel; or c) antibody-drug conjugates of tumor-specific antibodies conjugated to a TOP1 inhibitor (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan); and instructions for use combining them with an ALC1i as defined herein, or containing separately packaged ALC1i as defined herein and a) Inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK; b) mitochondrial C or paclitaxel; or c) antibody-drug conjugates of tumor-specific antibodies conjugated to a TOP1 inhibitor (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan), as needed, with instructions for use for the treatment or improvement of a disease (preferably cancer).

Detailed description of the invention

Before the invention is described in detail below, it should be understood that the invention is not limited to the specific methods, protocols, and reagents described herein, as these are subject to variation. It should also be understood that the terminology used herein is for illustrative purposes only and is not intended to limit the scope of the invention, which is limited only by the scope of the appended patent applications. Unless otherwise stated, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

This specification cites numerous references in full. All references cited herein (including all patents, patent applications, scientific publications, manufacturer's manuals, user manuals, etc.), whether preceding or following, are hereby incorporated in full. Nothing in this document shall be construed as an acceptance that this invention is not entitled to any prior art that predates that disclosure. Some of the references cited herein are characterized as being "incorporated by reference." In the event of any conflict between the definitions or teachings of such incorporated references and those listed in this specification, the content of this specification shall prevail.

The elements of the present invention will be described below. These elements are listed with specific embodiments; however, it should be understood that they can be combined in any manner and in any number to create additional embodiments. Examples and preferred embodiments of the various descriptions should not constitute a limitation of the invention to the embodiments explicitly described. It should be understood that this description supports and encompasses combinations of embodiments explicitly described with any number of disclosed and/or preferred elements. Furthermore, any arrangement and combination of all the elements described in this application should be considered as disclosed in the description of this application, unless the context otherwise requires. Definitions

In order to practice this invention, unless otherwise stated, the conventional methods of chemistry, biochemistry, and recombinant DNA technology as explained in the literature of the field shall be adopted (see, for example: Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

The following provides definitions for some terms that are frequently used in this manual. These terms, in their respective uses, have their own defined and preferred meanings in the remainder of this manual.

As used in this specification and the scope of the attached patent application, the singular forms "a(a)", "an" and "the" include the plural references, unless the contents expressly state otherwise.

The abbreviation CHD1L, "chromodomain-helicase-DNA-binding protein 1-like," refers to a protein also known as ALC1. The amino acid sequence of human ALC1 is specified as SEQ ID NO:1, as known in this art, for example, as specified in WO2022/117782 A1. This 897-amino acid residue-length protein consists of an N-terminal Snf2-like DNA-dependent ATPase domain spanning amino acid residues 40 to 513, containing a preserved helicase motif crucial for catalysis (Flaus et al., 2006). This domain is composed of two RecA-like lobes, located in the amino acid residue ranges of 48 to 261 and 351 to 513, respectively. The ectopic binding pocket is spatially separated from the portion of ALC1 involved in ATP binding. The ATPase domain is followed by a linker region ranging from amino acid residues 514 to 703, containing a hypothesized coiled-coil region (amino acid residues 638 to 675) and a C-terminal macrodomain (amino acid residues 704 to 897). This 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 poly(ADP-ribose) binding to the macrodomain, leading to activation of chromatin remodeling enzymes.

Preferably, the terms used in this paper are defined as described in "A multilingual glossary of biotechnological terms:(IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Kölbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.

The term "alkyl" as used in the context of this invention refers to a saturated straight-chain or branched hydrocarbon chain. Preferably, the chain comprises 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as methyl, ethylpropyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, di-butyl, or tri-butyl), pentyl, hexyl, heptyl, octyl, nonyl, or decyl. The alkyl group is substituted as desired.

The term "heteroalkyl" as used in the context of this invention refers to a saturated straight-chain or branched hydrocarbon chain. Preferably, the chain comprises 1 to 9 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, di-butyl, or tri-butyl, pentyl, hexyl, heptyl, octyl, or nonyl, which are interrupted one or more times 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 ) _mCH3 , and 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' and R' = H or hydrocarbon (e.g., _C1 to _C6 alkyl). Specifically, " _heteroalkyl " refers _to O- _CH3 , _-OC2H5 , _-CH2 - _{O - CH3} , _-CH2 - _OC2H5 , -CH2 _{- OC3H7 ,} -CH2-OC4H9, _-CH2 - _OC5H11 , _C2H4 - _O -CH3 _{, -C2H4 - OC2H5 , -C2H4-OC3H7 , -C2H4 - OC4H9 , etc. Heteroalkyl is substituted as needed} .

The term "halogenated" 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 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In _particular , " _{haloalkyl "} means _-CH2F , _{-CHF2 , -CF3 , -C2H4F} , _{-C2H3F2 , C2H2F3 , -C2HF4 , -C2F5 , -C3H6F , -C3H5F2 , -C3H4F3 , -C3} H ₃ F ₄ , -C ₃ H ₂ F ₅ , -C ₃ HF ₆ , -C ₃ F ₇ , CH ₂ Cl , -CHCl ₂ , -CCl ₃ , -C ₂ H ₄ Cl , -C ₂ H ₃ Cl ₂ , C ₂ H ₂ Cl ₃ , -C ₂ HCl ₄ , C ₂ Cl ₅ , -C ₃ H ₆ Cl, -C ₃ H ₅ Cl _{2. -C3H4Cl3 , -C3H3Cl4 , -C3H2Cl5 , -C3HCl6} , _{and -C3Cl7 . Halogenated} groups are substituted as _{needed .}

The term "5, 6, or 7-membered carbon ring" is used in the context of this invention to refer to a "cycloalkyl", "cycloalkenyl", or "aryl" having 5, 6, or 7 carbon atoms forming the ring.

The term "cycloalkyl" includes cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups are substituted as needed.

The term "cycloalkenyl" includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups are substituted as needed.

The term "aryl" refers to a multi-unsaturated, usually aromatic hydrocarbon, which can be a monocyclic or fused together or covalently linked polycyclic (up to three) rings. Preferably, the aryl group contains 6 to 10 carbon atoms, i.e., _C6-10 aryl. In a preferred embodiment, the aryl group is phenyl, which is most preferred, or naphthyl. The aryl group may be substituted as desired.

The term "5, 6, or 7-membered heterocyclic" is used in the context of this invention to refer to a monocyclic "5, 6, or 7-membered heterocyclic alkyl" or monocyclic "5, 6, or 7-membered heteroaryl" having 5, 6, or 7 carbon atoms forming the ring.

The term "5, 6, or 7-membered heterocycloalkyl" refers to a saturated monocyclic ring in which at least one carbon atom is replaced by one or two (for five-membered rings), or one, two, or three (for six-membered rings), or one, two, three, or four (for seven-membered rings) identical or different heteroatoms (preferably O, N, and S). Preferred examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperidyl, or 2-piperidyl. Heterocyclic compounds are substituted as needed.

The term "heteroaryl" as used in the context of this invention refers to a 5, 6, or 7-membered aromatic monocyclic ring in which at least one carbon atom is replaced by 1, 2, or 3 (for 5-membered rings) or 1, 2, 3, or 4 (for 6-membered rings) identical or different heteroatoms (preferably O, N, and S). Preferred examples of heteroaryl groups include furanyl, thienyl, acezolyl, isoacezolyl, 1,2,4-acediazolyl, 1,2,3-acediazolyl, pyrroleyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyracloyl, 1,2,3-triracloyl, 1,2,4-triracloyl, and 1,3,5-triracloyl. The heteroaryl group is substituted as desired.

The term "arylalkyl" corresponds to arylalkyl residue, which is an alkyl group that has been substituted with aryl as defined above.

If two or more groups can be chosen independently, the term "independently" means that the groups can be the same or different.

The term "substituted as needed" in all cases, unless further specified, 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;

R' and R'' are each independently selected from the following groups: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl or together to form heteroaryl or heterocycloalkyl;

R''' and R'''' are each independently selected from the following groups: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R'';

E series are selected from the following groups: alkyl, alkenyl, alkynylcycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, alicyclic system, aryl and heteroaryl; substituted as required.

"Pharmaceutical acceptable" means approved by a federal or governmental regulatory agency or listed in the United States Pharmacopeia (United States Pharmacopeia-33/National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., April 2010) or other pharmacopoeias generally accepted for use in animals and more specifically for use in humans.

The term "medically acceptable salt" refers to the salt of the compound of the invention. Suitable pharmaceutically acceptable salts of the compound of the invention include acid addition salts, which can be formed, for example, by mixing a solution of the compound described herein or its 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 the case where the compound of the invention has an acidic moiety, its suitable pharmaceutically acceptable salt may include alkaline metal salts (e.g., sodium salts or potassium salts); alkaline earth metal salts (e.g., calcium salts or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium, and amine cations formed using counter anions such as halogens, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates, and aryl sulfonates). Explanatory examples of pharmaceutically acceptable salts include, but are not limited to: acetates, adipic acid salts, alginates, ascorbic acid salts, aspartate salts, benzenesulfonate salts, benzoate salts, bicarbonates, bisulfates, bitartrate salts, borates, bromides, butyrates, calcium ethylenediaminetetraacetate, camphorates, camphorsulfonate, camsylate, carbonates, chlorides, citrates, clavulanates, cyclopentanepropionate, diglucuronide, dihydrochloride, dodecyl sulfate, edetate, and edisylate. Lauryl sulfate, estolate, ethanesulfonate, formate, fumarate, glucono-heptarate, glucono-heptarate, gluconate, glutamate, glyceryl phosphate, glycolylarsanilate, hemisulfate, heptarate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodate, 2-hydroxyethanesulfonate, hydroxynaphthylcarboxylate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate Salts, malates, maleate, malonic acid, mandelates, methanesulfonates, methanesulfonates, methyl sulfates, mucilages, 2-naphthalenesulfonates, naphthalenesulfonates, nicotinates, nitrates, N-methylglucosamine ammonium salts, oleates, oxalates, embonate (bis(hydroxynaphthalene)), palmitate, pantothenate, jelly salts, persulfates, 3-phenylpropionate Phosphates/bisphosphates, picrates, pentylaminoates, polygalacturonic acids, propionates, salicates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, teoclates, toluenesulfonates, triethyliodide, undecanoates, valerates, etc. (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of this invention possess both basic and acidic functionalities, enabling the conversion of the compound into base or acid addition salts.

The neutral form of a 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 otherwise, for the purposes of this invention, these salts are equivalent to the parent form of the compound.

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 those compounds that readily undergo chemical changes under physiological conditions to provide compounds of formula (I) or formula (II), and particularly the compounds shown in Figure 1. The prodrug is an active or inactive compound that, upon administration to a patient, chemically modifies the compound of the present invention through in vivo physiological processes (such as hydrolysis, metabolism, etc.). Furthermore, the prodrug can be converted into the compound of the present invention by chemical or biochemical methods in an in vitro environment. For example, when the prodrug is placed in a transdermal patch reservoir containing a suitable enzyme, it can be slowly converted into the compound of the present invention. The suitability and techniques relating to the manufacture and use of the prodrug are well known to those skilled in the art. For a general discussion of ester-based predrugs, see Svensson L.A. and Tunek A. (1988) Drug Metabolism Reviews 19(2): 165-194 and Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985). Examples of 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., p-pentyloxymethyl). Amines have been masked into arylcarbonyloxymethyl-substituted derivatives, which are cleaved by esterases in vivo, releasing free drugs and formaldehyde (Bundgaard H. et al. (1989) J. Med. Chem. 32(12): 2503-2507). Furthermore, drugs containing acidic NH groups (such as imidazoles, imines, indoles, etc.) have been masked with N-acetylated methyl groups (Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985)). Hydroxyl groups have been masked into esters and ethers. EP 0 039 051 A2 discloses a mannich-base isohydroxime precursor, its preparation, and its uses.

The compounds of the present invention may also contain atomic isotopes in non-natural proportions on one or more atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). All isotopic variants of the compounds of the present invention, whether or not radioactive, are intended to be included within the scope of the present invention.

As used in this article, when referring to a substituent of an aryl group, "para" means that the substituent occupies the position opposite to the position where the aryl group is attached to the main chain of the compound.

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

As used herein, “treat,” “treating,” or “treatment (treatment)” or “improvement” for a disease or ailment means, respectively, to accomplish one or more of the following: (a) to reduce the severity of the ailment; (b) to limit or prevent the development of the characteristic symptoms of the treated ailment; (c) to suppress the worsening of the characteristic symptoms of the treated ailment; (d) to limit or prevent the recurrence of the ailment in a patient who has previously had the ailment; and (e) to limit or prevent the recurrence of symptoms in a patient who has previously had symptoms of the ailment.

As used herein, the terms "prevent," "preventing," "prevention," or "prophylaxis" for a disease or symptom mean that an individual is prevented from developing the symptom for a certain period of time. For example, if the compound described herein is administered to an individual for the purpose of preventing a disease or symptom, the occurrence of the disease or symptom is prevented at least on the day of administration and preferably 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).

The "pharmaceutical composition" according to the present invention may exist in the form of a composition in which different active ingredients are mixed with diluents and/or carriers, or may be in the form of a combination formulation in which the active ingredients exist in some or completely different forms. Examples of such combinations or combination formulations are kits of parts.

"Effective dose" is the amount of a treatment agent sufficient to achieve the desired effect. The effective dose of a given treatment 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 treatment agent, and the purpose of administration. In each individual case, the effective dose can be determined by an expert in the technique based on experience and the methods established by the technique.

As used herein, the term "carrier" refers to a therapeutic agent and any diluent, adjuvant, excipient, or mediator administered with it. Such pharmaceutical carriers can be sterile liquids, such as saline solutions of 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 pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of dextran and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice flour, chalk, silicone, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. If necessary, the composition may also contain small amounts of humectants or emulsifiers, or pH buffers. These compositions can be in the form of solutions, suspensions, emulsions, tablets, pellets, capsules, powders, sustained-release formulations, etc. The composition can be formulated into suppositories with conventional binders and carriers (such as triglycerides). The compounds of this invention can be formulated into neutral or saline forms. Pharmaceutically acceptable salts include those that form with free amino groups, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and those that form with free carboxyl groups, such as those derived from sodium, potassium, ammonium, calcium, iron hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc. Examples of suitable pharmaceutical delivery systems are described in E. W. Martin's "Remington's Pharmaceutical Sciences". These formulations will contain a medically effective amount of the compound, preferably in its purified form, and an appropriate delivery system to provide a form suitable for administration to the patient. The formulation should be appropriate for the mode of administration.

SEQ ID NO 1: Embodiments of the Invention

The inventors have identified and characterized ALC1 inhibitors that appear to be involved in the ectopic regulation of ALC1 nucleosome sliding activity. These compounds specifically bind to the ectopic pocket and inhibit ALC1 activity. These compounds, which bind to the ATPase site of ALC1 and block ATPase activity, must competitively bind to the ATPase site. The ability of these compounds to kill different tumor cell lines, one of which is BRCA-deficient, has been tested.

The inventors have identified ectopic inhibitors of ALC1 (CHD1L), particularly those of formulas (I) and (II), as enhancing (preferably synergistically acting) the treatment of proliferative diseases when combined with inhibitors of several classes of cancer drugs (i.e., inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, mitochondrial C, paclitaxel, antibody-drug conjugates of tumor-specific antibodies conjugated with free radiation, or TOP1 inhibitors).

Furthermore, it has been found that these inhibitors of ALC1 of formula (II), when combined with PARP inhibitors, exhibit synergistic effects in the treatment of pancreatic cancer or fallopian tube cancer.

The inventors believe the fundamental reason is that 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), with mitomycin C, or paclitaxel, with free radiation, or with tumor-specific antibodies conjugated to TOP1 inhibitors. However, tests using known ALC1i have shown that their efficacy against anti-cancer cell lines does not exceed additive effects. This invention is based on the surprising discovery that certain ectopic ALC1 inhibitors, preferably those of formulas (I) and (II), exhibit synergistic antiproliferative activity when combined with inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, with mitomycin C, or paclitaxel, with ionizing radiation, or with antibody-drug conjugates of tumor-specific antibodies conjugated to TOP1 inhibitors. Therefore, such combinations are expected to be suitable for the treatment of proliferative diseases.

ALC1 inhibitors, preferably those characterized by formulas (I) and (II), the latter known from the art (WO 2022/117782 A1), which are used according to the present invention, appear to participate in the ectopic regulation of the nucleosome sliding activity of ALC1. These compounds specifically bind to the ectopic 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 used to bind to the ATPase site. Since the concentration of cellular ATP varies from 1 to 10 mM depending on the cellular environment, extremely high binding affinity is required at low nanomor concentrations to successfully prevent ATP from binding to the ATPase site of ALC1. The ectopic inhibitors of ALC1 used in this invention, particularly those characterized by formulas (I) and (II), are not subject to this limitation because they do not necessarily prevent ATP binding but rather inhibit ALC1 activity through different preventive mechanisms. The inventors have identified ALC1 inhibitors capable of specifically binding to the ectopic pockets of ALC1. Whether these specific ALC1 inhibitors will synergize with other classes of anticancer drugs remains an open question and has not yet been answered.

In the first state, the invention relates to an ectopic inhibitor of a chromodomain-helicase-DNA-binding protein 1-like (ALC1) protein, wherein the inhibitor specifically binds to an ectopic binding pocket formed by stretching amino acids spanning amino acid residues 101 to 219 of SEQ ID NO:1, and is used in combination with the following for the treatment or improvement of proliferative diseases and/or to enhance the efficacy of treatment for proliferative diseases: a) inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or b) mitomycin C, paclitaxel, c) free radiation, or d) Antibody-drug conjugates of tumor-specific antibodies that bind to TOP1 inhibitors (e.g., trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan).

The term "specific binding," as used in the context, indicates that the compound has a K _{_D} of 200 µM or less, preferably 100 µM, more preferably 50 µM, more preferably 10 µM or less, more preferably 5 µM or less, even more preferably 1 µM, and even more preferably 500 nM or less for full-length human ALC1 having the amino acid sequence according to SEQ ID NO:1. Those skilled in the art are well aware of how to measure the dissociation constant of small molecules with respect to proteins, including surface plasma resonances. Preferably, the K_{_D} of the compound of the invention is measured by immobilizing full-length human ALC1 on a wafer surface and subsequently applying the compound to the immobilized protein. Preferably, the measurement is performed at 37°C.

In one preferred embodiment of the invention, the inhibitor of ectopic ALC1 used according to the invention exhibits an IC50 value of 500 µM or less, more 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 for FRET-based nucleosome remodeling analysis. _{The KD} and _IC50 described herein are determined as disclosed in WO 2022/117782 A1.

Not every amino acid within the amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO:1 forms a surface of an ectopic pocket of ALC1 that can be used to bind compounds used according to the present invention. This is because 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 inside or on the outer surface of ALC1. Therefore, in a preferred embodiment, the ectopic binding pocket of the ALC1 inhibitor used according to the present invention specifically binding to it comprises or consists of the following: amino acids L101, Y153, _C156 , L157, A160, L163, K164, V173, D174, E175, A176, H177, R178, L179, S183, L186, H187, T189, L190, F193, L200, L201, T202, N208, S209, E212, L213, L216, and F219 of SEQ ID NO:1. More preferably, the binding pocket comprises or consists of the following: SEQ ID NO:1. NO:1 includes Y153, _C156 , L157, A160, L163, V173, E175, R178, L186, H187, L190, F193, L200, and E212. The ectopic binding pocket of ALC1 can be modeled by the art based on homology with other chromatin remodeling enzymes. Such patterns are also described in WO2022/117782 A1, with and without the compounds used in this invention. WO2022/117782 A1 describes how the art can demonstrate the suitability of a given compound for use with the ectopic binding pocket, and thus provides further guidance on selecting compounds that meet the requirements for space, hydrophobicity, hydrophilicity, and charge within the binding pocket. The smallest set of structural coordinates of the amino acids of ALC1 that bind to the compounds of the present invention is provided in Figure 20 of WO2022/117782 A1. That is, using the detailed teachings given in WO2022/117782 A1, it can be determined whether the inhibitor specifically binds to the ectopic binding pocket formed by the amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO:1.

Depending on the orientation of the different amino acids accessible on the bag surface within the bag, they can form various 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 ectopically binds one or more amino acids of the bag, preferably to one or more of the main chains of ALC1 amino acids L157, A160, K164, V173, D174, H177, R178, L179, L186, N208, and/or E212, and/or ALC1 amino acids L101, Y153, C1 _... The side chains of 56, L157, A160, L163, E175, R178, L179, L186, H187, L190, F193, T202, N208, E212, or L213 preferably form non-covalent bonds with the main chains of ALC1 (D174, H177, and R178) and the side chains of ALC1 (Y153, E175, R178, H187, T202, N208, and/or E212).

In a preferred embodiment, the inhibitor of ALC1 used according to the invention is non-covalently bound to: (i) an aromatic ring on the side chain of amino acid Y153 of the ALC1 ring, which forms a cation-π, polar-π, or halogen-π interaction with an aromatic carbon ring or heterocyclic substituent at face-to-face or edge-to-face, or with a polar, charged, or carbohalogen substituent; (ii) a terminal oxygen group on the side chain of amino acid Y153 of ALC1 having a hydrogen-donating group; (iii) a carbonyl oxygen group on the main chain of H177 having a carbohalogen or hydrogen-donating group; (iv) (v) A carbonyl oxygen in a D174 main chain with a carbapenditure or hydrogen bond-donating group; (vi) A side chain with an E175 with a hydrogen bond-donating or accepting group; (vii) A side chain with an R178 with a hydrogen bond-donating or accepting group; (vii) A carbonyl oxygen in a main chain with an R178 carbapenditure or hydrogen bond-donating group; (viii) A side chain with an H187 ring that interacts face-to-face or side-to-face with an aromatic carbon ring or heterocyclic substituent, or forms a cation-π, polar-π, or halogen-π interaction with a polar, charged, or carbapenditure substituent or with a hydrogen bond-donating or accepting group; (ix) (ix) A sidechain with a T202 having a hydrogen bond give or accept group; and (x) A sidechain with an E212 having a hydrogen bond give or accept group.

In a preferred embodiment, the ALC1 inhibitor (ALC1i) used according to the present invention is the ALC1 inhibitor (ALC1i) according to formula (II). Formula (II) wherein (i) R ₅ comprises an aromatic ring, which is π-stacked with the aromatic ring of Y153; and/or (ii) N is a hydrogen bond acceptor group for the terminal OH of Y153; and/or (iii) R ₁ comprises a hydrogen bond donor group for the carbonyl oxygen of the main chain to H177; and/or (iv) R ₃ comprises a hydrogen bond donor group for a carbapenem or a carbonyl oxygen bound to the main chain of D174; and/or (v) R ₁ and R ₂ together form an aromatic or heteroaromatic monocycle comprising a hydrogen bond donor or acceptor group (especially at or adjacent to R ₁ ), which can serve as a hydrogen bond donor or acceptor group for the side chains of E175 and/or R178; and/or (vi) R _R1 and _R2 together form a substituted carbon ring or heterocyclic ring, which contains a hydrogen bond donor or acceptor group, preferably at or adjacent to _R1 , which is a hydrogen bond donor or acceptor group in the side chain to R178; and/or (vii) _R3 contains an aromatic ring, which is π-accreted with the aromatic ring H187 or is an electron-deficient substituent, especially at, forming a polar -π or cation -π interaction with the aromatic ring of H187; and/or (viii) _R1 and _R2 together form an aromatic or heteroaromatic monocyclic ring, which contains a hydrogen bond donor or acceptor group, especially at or adjacent to R178. Position ₂ , which can function as a hydrogen bond donor or acceptor group in the side chain of T202 and/or N208; and/or (ix) _R4 is H or _-C1-3 -alkyl, preferably H; and/or (x) _R5 is -( _CH2 ) _m -L, or -( _CH2 ) _m- (CH=CH)-L, wherein m is 0, 1, or 2, preferably 0 or 1, and L is a 5, 6, or 7-membered carbocyclic or heterocyclic, or adamantyl, substituted as desired, preferably substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 =O, or two adjacent substituents forming a 5, 6, or 7-membered carbocyclic or heterocyclic ring; and/or (xi) _R4 and _R5 together forming a 5, 6, or 7-membered carbocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OR9 , _-R9 , =CH- _RA , preferably _R4 and _R5 together forming a _C5-7 -cycloalkyl group; and/or (xii) X is N or S; and/or (xiii) A is C or N; or a pharmaceutically acceptable salt, isomer, solvent, chemically protected form, or precursor thereof.

In a preferred embodiment, the ALC1 inhibitor (ALC1i) used according to the present invention is the ALC1 inhibitor (ALC1i) according to formula (I). In formula (I), A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or when A6 participates in the annulated carbon ring or heterocyclic ring Z (especially 5, 6, or 7-membered carbon ring or heterocyclic ring), then A6 is C; A7 is selected from N or CH, or when A7 participates in the annulated carbon ring or heterocyclic ring Z (especially 5, 6, or 7-membered carbon ring or heterocyclic ring), then A7 is C; L2 is selected from the following groups: -CH2 _- R4, –CF2 _- R4, _-CH2 - _CH2 -R4, _{-CH2- CH2} - _CH2 -R4, -O-R4, -NH-R4, -N=R4; L3 The group is selected from the following groups: CH2-R9, –CF2– R9, -CH2-CH2- R9, -CH2-CF2-R9, _-CH2 - _{CH2- CH2-} R9, -O-R9, -NH-R9, -N=R9; or L2 and L3 together with the A8 to which they are attached form a 5- or 6-membered heterocycle substituted with R4 and/or R9; L4 is _CH2 , _–CF2- , _CH2 - _CH2 , _CH2 - _CH2 - _CH2 , O, N, and NH, or is absent; Z is a 5-, 6-, or 7-membered carbide ring or heterocycle, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the following groups: -Br, -Cl, -F, -I, -OH, Me, _-CF3 R4 is a 5-, 6-, or 7-membered carbon ring or heterocyclic ring, which may be substituted with one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, _-CF3 , _Me , Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH; R9 is a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered carbon ring or heterocyclic ring, which may be substituted with one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO₂ , Me, _-CF₃ , Et, -OMe, and -SMe; or R6 is H; or when A7 participates in the annulated carbocyclic or heterocyclic ring Z, then A5 and A6 are independently selected from -N or -CH and A8 is selected from -N, -CH, _-CH₂ , -N, _-CH₂. -CH, or -NH-CH; or a pharmaceutically acceptable salt, isomer, solvent, chemically protected form, or prodrug thereof; used in combination with inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, antibody-drug conjugates of tumor-specific antibodies conjugated with mitochondrial C, paclitaxel, or TOP1 inhibitors (such as trastuzumab deruxtecan), or in combination with free radiation to treat or improve proliferative disorders in patients. A preferred embodiment of an ALC1 inhibitor (ALC1i) according to formula (I) .

According to formula (I), ALC1i preferably shows an _IC50 of <250 µM when the inhibition rate is >50% at concentrations of 250 µM or below, and more preferably _IC50 of <25 µM. _IC50 is preferably measured by nucleosome remodeling analysis based on FRET as described in WO 2022/117782 A1.

According to formula (I), ALC1i preferably has _{an EC50} of < 250 µM, more preferably < 50 µM, and even more preferably < 10 µM. _{The EC50 is} preferably measured by cell proliferation analysis and SRB-based readings as described in WO 2022/117782 A1.

Unless otherwise specified, residues of normal integers (i.e., non-subscripted integers) are associated with compounds of formula (I), and residues of subscripted integers are associated with compounds of formula (II).

In one embodiment, preferably in the inhibitor (ALC1i) of ALC1 according to formula (I): A5 and A6 are N; and A7 participates in the annulated carbocyclic or heterocyclic Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic Z, preferably the carbocyclic Z, particularly a 5, 6, or 7-membered carbocyclic Z, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 .

In one embodiment, preferably in the inhibitor (ALC1i) of ALC1 according to formula (I): A5 and A6 are N; A7 participates in the annulated carbocyclic or heterocyclic ring, preferably carbocyclic Z, which is substituted as needed by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and A8 is _-CH2- N, _-CH2- CH, or -NH-CH, preferably -NH-CH.

In one embodiment, it is preferred that in the ALC1 inhibitor (ALC1i) according to formula (I): A5 is N and A8 is -N or -CH.

In one embodiment, it is preferred that in the inhibitor (ALC1i) of ALC1 according to formula (I): A5 is N and A8 is -N or -CH; and A6 participates in the annulated carbocyclic or heterocyclic ring, preferably carbocyclic Z.

In a preferred embodiment, A5, A7, and A8 are N.

In a preferred embodiment, A5, A7, and A8 are N and A6 participating in the annulated carbocyclic or heterocyclic Z, particularly 5, 6, or 7-membered carbocyclic or heterocyclic Z. Preferably, the carbocyclic Z, particularly 5, 6, or 7-membered carbocyclic Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and _-NO2 .

In a preferred embodiment, A5, A7, and A8 are N and A6 participating in the annulated carbocyclic ring Z, particularly 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and _-NO2 .

In one embodiment, it is preferred that in the ALC1 inhibitor (ALC1i) according to formula (I), L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, -CH2 _{- CH2} - _CH2 -R4.

In one embodiment, preferably, L2 is selected from the group consisting of: _-CH2- R4, _–CF2 -R4, _-CH2 - _CH2 -R4, _{-CH2- CH2} - _CH2 -R4, -NH-R4; and R4 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, preferably a 5- or 6-membered heteroaryl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-CF3 , Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH.

In one embodiment, it is preferred that L3 is selected from the following groups: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9.

In one embodiment, it is preferred that L3 is selected from the group consisting of: _-CH2- R9, _-CH2 - _CH2 -R9, _-CH2 - _CF2 -R9; and R9 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbon ring or heterocyclic ring, which is substituted as desired by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In one embodiment, it is preferred that in the inhibitor of ALC1 (ALC1i) according to formula (I): L2 and L3 together with the A8 to which they are linked form a 5- or 6-membered heterocycle substituted with R4 and R9.

In one embodiment, preferably, L2 and L3 together with the A8 to which they are linked form a 5- or 6-membered heterocyclic ring substituted with R4 and R9; R4 is hydrogen, methyl, or COOH; and R9 is a 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, preferably phenyl or a 5- or 6-membered heteroaryl group, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In one embodiment, it is preferable that in the ALC1 inhibitor (ALC1i) according to formula (I): L4 is not present.

In a preferred embodiment, A5, A7, and A8 are N; and L4 does not exist.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic Z. Preferably, the carbocyclic Z, particularly a 5, 6, or 7-membered carbocyclic Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L4 is absent.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L4 is absent.

In a preferred embodiment, A5, A7, and A8 are N; and L4 is absent. R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and -NO2; and _L4 R6 is not a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L4 is absent. R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; and L4 is absent. R6 is phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N, and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted, as desired, by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; and R6 is phenyl, which is substituted, as desired, by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, -CF3 _3. Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbide ring Z, particularly a 5, 6, or 7-membered carbide ring Z, preferably phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; and R6 is phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; and R6 is phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbide ring Z, particularly a 5, 6, or 7-membered carbide ring Z, preferably phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; and R6 is phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In one embodiment, it is preferred that R4 is hydrogen, methyl, COOH or tetrazolium.

In one embodiment, it is preferred that L2 is -CH2 _- R4, _{-CH2- CH2} -R4, or _-CH2 - _CH2 - _CH2 -R4; and R4 is hydrogen, methyl, COOH, or tetrazolium.

In one embodiment, it is preferred that R9 is any 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered carbon ring or heterocycle, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-CF3 , Me, Et, -OMe, and -SMe.

In one embodiment, preferably, R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , C7-, _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl _{, i.e., C6-, C7-, C8-, C9- , or C10 - spiroalkyl} ; a phenyl, a _5- or 6-membered heteroaryl, or a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In one embodiment, preferably, L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, _-CH2 - _CF2 -R9; and R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- or _C10- spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In one embodiment, it is preferred that R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, or R6 is H.

In one embodiment, preferably: L4 is absent; and R6 is a 5- or 6-membered carbocyclic or heterocyclic ring, preferably a 6-membered carbocyclic or heterocyclic ring, which is substituted as desired by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In the above embodiments, it is preferred that Z is a 6-membered aryl or a 5- or 6-membered heteroaryl, preferably phenyl, which is substituted as needed by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 .

In one embodiment, preferably: 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 annulated carbocyclic or heterocyclic Z and the other is N; A8 is N or CH; L2, L3, and L4 are independently selected from the following groups: _CH2 , _–CF2- , _CH2 - _CH2 , _CH2 - _CH2 - _CH2 O, N, and NH, or absent, or L2 and L3 together with the A8 they are linked to form a 5- or 6-membered heterocycle substituted with R4 and R9; Z is any 5-, 6-, or 7-membered carbocyclic or heterocyclic ring that can form a ring with the central nucleus or be covalently linked and, as desired, substituted with one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; R4 is any 5-, 6-, or 7-membered carbocyclic or heterocyclic ring that, as desired, is substituted with one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, _-CF3 R4 is a hydrogen, methyl, or COOH group; R9 is a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered carbocyclic or heterocyclic ring, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the following groups: -Br, -Cl, -F, -I, _-CF3 , Me, Et, -OMe, and -SMe; R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the following groups: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 Et, -OMe, and -SMe, or R6 is H, or when A7 participates in the annulated carbocyclic 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; wherein R4, R9, and R6.

In one embodiment, preferably: A5 is N; one of A6 and A7 is C and participates in the annulated carbocyclic or heterocyclic Z and the other is N; A8 is N; L2 is _CH2 - _CH2 and L3 is _CH2 - _CH2 or _CH2 - _CF2 ; or L2 and L3 together with the A8 to which they are attached form a 5- or 6-membered heterocyclic ring (preferably piperidine or pyrrolidine) substituted with R4 and R9; L4 is absent; Z is a 6-membered carbocyclic or heterocyclic ring forming a ring with the central nucleus, wherein Z is substituted as desired by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 R4 is COOH or _CH2N4 ; R9 is a 4-, 5-, _{6- ,} 7-, or 10-membered carbocyclic or heterocyclic ring, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a 5- or 6-membered carbocyclic or heterocyclic ring, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, or R6 is H.

In one embodiment, preferably in the inhibitor (ALC1i) of ALC1 according to formula (I): each of A5, A7, and A8 is N; A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, preferably 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is substituted as needed by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe; L2 is _CH2 - _CH2 -R4; L3 is _CH2 - _CH2 -R4 or _-CH2 - _CF2 -R9; or L2 and L3 together with A8 to which they are attached form a piperidine ring or pyrrolidine ring substituted with R4 and R9; L4 is absent; Z is a phenyl or cyclohexyl group forming a ring with the central nucleus, wherein Z is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -OH, Me, _-CF3 , -OMe, and -NO2; R4 is COOH or _tetrazolium ; R9 is a phenyl, cyclobutyl, cyclopentyl, or adamantyl group, substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, _-CF3 , _Me , -CH2- _CF3 R6 is a 6-membered carbon ring or heterocyclic ring, preferably phenyl or cyclohexyl; more preferably phenyl, which may be substituted as desired by one, two or three (preferably one) substituents selected from the group consisting of: Br, -Cl, -F, Me, _-CF3 , -OMe, and _{-NO2 .}

In a preferred embodiment, A5, A7, and A8 are N; L2 is -CH2 _- R4, _{-CH2- CH2} -R4, or _-CH2 - _CH2 - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; and L4 is absent.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic Z. Preferably, the carbocyclic Z, particularly a 5, 6, or 7-membered carbocyclic Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is -CH2 _- R4, _{-CH2- CH2} -R4, _-CH2 - _CH2 - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; and L4 is absent.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L4 is absent.

In a preferred embodiment, A5, A7, and A8 are N; L2 is -CH2 _- R4, _{-CH2- CH2} -R4, or _-CH2 - _CH2 - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 is absent; and R6 is phenyl or a 5-, 6-, or 7-membered heteroaryl group, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is -CH2 _- R4, _{-CH2- CH2} -R4, _{-CH2- CH2} - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 It does not exist; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is _-CH2- R4, _{-CH2- CH2} -R4, -CH2 _{- CH2} - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 It does not exist; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L2 is -CH2 _- R4, _{-CH2- CH2} -R4, or _-CH2 - _CH2 - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 is absent; and R6 is phenyl, which is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is -CH2 _- R4, _{-CH2- CH2} -R4, _{-CH2- CH2} - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 It does not exist; and R6 is a phenyl group, which is substituted as required by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is _-CH2- R4, _{-CH2- CH2} -R4, -CH2 _{- CH2} - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 It does not exist; and R6 is a phenyl group, which is substituted as required by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is _-CH2- R4, _{-CH2- CH2} -R4, -CH2 _{- CH2} - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 It does not exist; and R6 is a phenyl group, which is substituted as required by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is _-CH2- R4, _{-CH2- CH2} -R4, -CH2 _{- CH2} - _CH2 -R4; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; L4 It does not exist; and R6 is a phenyl group, which is substituted as required by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; a phenyl, a 5- or 6-membered heteroaryl, or a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl, or a _C6 to _C10 -biscycloalkyl, i.e., C6 _-... - _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituents are, as desired, one, two, or _three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, -CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; and R9 is _C5 to _C7 -cycloalkyl, i.e., _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -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, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L4 is absent; R9 is a _C5 to _C7 -cycloalkyl, i.e., _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; a phenyl, a 5- or ₆ -membered heteroaryl, or a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic Z. Preferably, the carbocyclic Z, particularly a 5, 6, or 7-membered carbocyclic Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl, or a _C6 to _C10 -bicycloalkyl, i.e., _C6- , C5-, C6 ... _7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or tetraalkyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to C ₁₀ -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammayl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl group, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , C9-, or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; a phenyl, a 5- or 6-membered heteroaryl, or a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, _-Cl , -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic Z. Preferably, the carbocyclic Z, particularly a 5, 6, or 7-membered carbocyclic Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl, or a _C6 to _C10 -bicycloalkyl, i.e., _C6- , C5-, C6 ... _7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or tetraalkyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to C ₁₀ -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to C ₁₀ -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L4 is absent; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to C ₁₀ -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2- R9. L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -bicycloalkyl; or a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _{C10- spiroalkyl .} -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic Z. Preferably, the carbocyclic Z, particularly a 5, 6, or 7-membered carbocyclic Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl group, i.e., C _4- , _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, tetraalkyl, wherein the substituents are, as desired, one, two, or three (preferably one) selected from the group consisting of: -Br, -Cl, -F, -I, Me, -CF _. Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2- CF2- _R9 ; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 - Bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; phenyl; 5- or 6-membered heteroaryl; adamantyl, wherein the substituents are, as desired, one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -bicycloalkyl; or a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _{C10- spiroalkyl .} -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammayl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl group, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic Z. Preferably, the carbocyclic Z, particularly a 5, 6, or 7-membered carbocyclic Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl group, i.e., C _4- , _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, tetraalkyl, wherein the substituents are, as desired, one, two, or three (preferably one) selected from the group consisting of: -Br, -Cl, -F, -I, Me, -CF _. Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; and 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 _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; phenyl; 5- or 6-membered heteroaryl; adamantyl, wherein the substituents are, as desired, one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, where R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -bicycloalkyl; or a _C6 to _C10 -spiroalkyl _, i.e., _C6- , _{C7- , C8-} , _C9- , or _C10- spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl group, i.e., C _4- , _C5- , _C6- , or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, tetraalkyl, wherein the substituents are, as desired, one, two, or three (preferably one) selected from the group consisting of: -Br, -Cl, -F, -I, Me, -CF _. Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; 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 _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; phenyl; 5- or 6-membered heteroaryl; adamantyl, wherein the substituents are, as desired, one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe: and R6 is a phenyl group, which is substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; and 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 _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; phenyl; 5- or 6-membered heteroaryl; adamantyl, wherein the substituents are, as desired, one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMeR6 are phenyl groups, which may be substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; 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 _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl; phenyl; 5- or 6-membered heteroaryl; adamantyl, wherein the substituents are, as desired, one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; and L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or C7-cycloalkyl; a C6 to _C10 - _{bicycloalkyl, i.e., C6- , C7-} , _C8- , _C9- , or _C10 -bicycloalkyl; or a _C6 to _C10 -spiroalkyl, i.e. _{, C6-} , _C7- , C8-, C9 _... -, _C9- or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, substituted by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , C9-, or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 - _spiroalkyl ; phenyl; a 5- or 6-membered heteroaryl; a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 It does not exist; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., C6-, C7-, _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl _{, i.e., C6-, C7-, C8-, C9- , or C10 - spiroalkyl ; a} phenyl, a 5- or 6-membered heteroaryl, or a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, or C7-cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _{C8- , C9- ,} or _C10 -bicycloalkyl; or _{a C6 to C10-spiroalkyl, i.e., C6- , C7- , C8-} , C9 _... -, _C9- or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, substituted by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammayl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl group, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , C9-, or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 - _spiroalkyl ; phenyl; a 5- or 6-membered heteroaryl; a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 It does not exist; and R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., C6-, C7-, _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl _{, i.e., C6-, C7-, C8-, C9- , or C10 - spiroalkyl ; a} phenyl, a 5- or 6-membered heteroaryl, or a tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, where R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, or C7-cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _{C8- , C9- ,} or _C10 -bicycloalkyl; or _{a C6 to C10-spiroalkyl, i.e., C6- , C7- , C8-} , C9 _... -, _C9- or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, substituted by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 No; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., C5-, _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , C7-, _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 - _spiroalkyl ; phenyl; 5- or 6-membered heteroaryl; or adamantyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the following group: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe: and R6 is a phenyl group, which is substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 Not present; and R9 is a _C5 to _C7 -cycloalkyl, _C4 to _C7 -cycloalkyl (i.e., _C4- , i.e., _C5- , _C6- , or _C7 -cycloalkyl), _C6 to _C10 -bicycloalkyl (i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl), C6 to _C10 -spiroalkyl (i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl), phenyl, 5- or ₆ -membered heteroaryl, or tetraalkyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, _Me , _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMeR6 are phenyl groups, which may be substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 No; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., C5-, _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , C7-, _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 - _spiroalkyl ; phenyl; 5- or 6-membered heteroaryl; or adamantyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the following group: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 -CF2 _- R9. L4 is absent; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., _C5- , _C6- , or _C7 -cycloalkyl; C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or C10-bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _{C10 - spiroalkyl} . -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 Not present; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., C6-, _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a _5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2- CF2- _R9 ; L4 is absent; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl group, i.e., _C4- , C5-, C6-, C7 _... - _C6- or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , C8-, _C9- or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- or _C10 -spiroalkyl, phenyl, 5- or ₆ -membered heteroaryl, adamantyl, wherein the substituents are, as desired, one, two or three (preferably one) selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; or a _C6 to _C10 -spiroalkyl, i.e. _{, C6-} , _C7- , _C8- , _C9- , or _C10 -spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammayl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl group, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 Not present; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., C6-, _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a _5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2- CF2- _R9 ; L4 is absent; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl group, i.e., _C4- , C5-, C6-, C7 _... - _C6- or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , C8-, _C9- or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- or _C10 -spiroalkyl, phenyl, 5- or ₆ -membered heteroaryl, adamantyl, wherein the substituents are, as desired, one, two or three (preferably one) selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, where R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; or a _C6 to _C10 -spiroalkyl, i.e. _{, C6-} , _C7- , _C8- , _C9- , or _C10 -spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e. _{, C6- , C7-} , _C8- , _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2- CF2- _R9 ; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, C7 ... _6- or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., C6-, _C7- , _C8- , _C9- or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, tetraalkyl, wherein the molecule is, as desired, substituted by one, two or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe: and R6 is a phenyl group, which is substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _-CH2 - _CH2 -R9, and _-CH2- CF2- _R9 ; L4 is absent; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl group, i.e., _C4- , C5-, C6-, C7 _... - _C6- or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , C8-, _C9- or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- or _C10 -spiroalkyl, phenyl, 5- or ₆ -membered heteroaryl, adamantyl, wherein the substituents are, as desired, one, two or three (preferably one) selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMeR6 are phenyl groups, which may be substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2- CF2- _R9 ; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., _C5-. - _C6- or _C7 -cycloalkyl, _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , C8-, _C9- or _C10 -bicycloalkyl, _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- or _C10 -spiroalkyl, phenyl, 5- or ₆ -membered heteroaryl, adamantyl, wherein the substituents are, as desired, one, two or three (preferably one) selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; and L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., _C5- , _C6- , or _C7 -cycloalkyl, C6 to _C10 -dicycloalkyl, i.e., _C6- , _{C7- , C8-} , _C9- , or _C10 -dicycloalkyl, C ₆ to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , i.e., _C5- , _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -cycloalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 Not present; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., C6-, _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a _5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably unsubstituted phenyl or adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, or C7-cycloalkyl, or C6 to _C10 -dicycloalkyl, i.e., C6-, C7-, _C8- , C9-, or _C10 -dicycloalkyl, or _C6- , _C7- , _C8- , C9-, or C10-dicycloalkyl, or C6-, C7-, _C8- , _C9- , or _C10 -dicycloalkyl, or C6-, C9 ... ₆ to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammayl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl group, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammayl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl group, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 Not present; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., C6-, _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a _5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, where R6 is a 6-membered aryl or a 5-, 6-, or 7-membered heteroaryl, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, or C7-cycloalkyl, or C6 to _C10 -dicycloalkyl, i.e., C6-, C7-, _C8- , C9-, or _C10 -dicycloalkyl, or _C6- , _C7- , _C8- , C9-, or C10-dicycloalkyl, or C6-, C7-, _C8- , _C9- , or _C10 -dicycloalkyl, or C6-, C9 ... ₆ to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2- R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammalian substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl, which may be substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe: and R6 is a phenyl group, which is substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 Not present; and R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., C6-, _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a _5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMeR6 are phenyl groups, which may be substituted as required by one, two, or three (preferably one) substituents selected from the following group: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; and L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2 _{- CH2-CH2-R4; L3 is selected from the group consisting of: -CH2-R9, -CH2 - CH2 - R9} , and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the phenyl group is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl group or a adamantyl group substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; and R6 is a phenyl group, which may be substituted as required by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe.

In one of the preferred embodiments described above: R6 is a phenyl group ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In one of the preferred embodiments described above: L4 is absent; and R6 is a phenyl group ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In a preferred embodiment, A5, A7, and A8 are N; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, or C7-cycloalkyl, or C6 to _C10 -dicycloalkyl, i.e., C6-, C7-, _C8- , C9-, or _C10 -dicycloalkyl, or _C6- , _C7- , _C8- , C9-, or C10-dicycloalkyl, or C6-, C7-, _C8- , _C9- , or _C10 -dicycloalkyl, or C6-, C9 ... ₆ to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammaalkyl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammaalkyl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2- _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2 - CH2} -R9, and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, more preferably an unsubstituted phenyl or a adamantyl substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 -Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and even better Br.

In a preferred embodiment, A5, A7, and A8 are N; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, or C7-cycloalkyl, or C6 to _C10 -dicycloalkyl, i.e., C6-, C7-, _C8- , C9-, or _C10 -dicycloalkyl, or _C6- , _C7- , _C8- , C9-, or C10-dicycloalkyl, or C6-, C7-, _C8- , _C9- , or _C10 -dicycloalkyl, or C6-, C9 ... ₆ to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammaalkyl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2- R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammaalkyl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2- _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2 - CH2} -R9, and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, more preferably an unsubstituted phenyl or a adamantyl substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 -Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and even better Br.

In a preferred embodiment, A5, A7, and A8 are N; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , C6-, or C7-cycloalkyl, or C6 to _C10 -dicycloalkyl, i.e., C6-, C7-, _C8- , C9-, or _C10 -dicycloalkyl, or _C6- , _C7- , _C8- , C9-, or C10-dicycloalkyl, or C6-, C7-, _C8- , _C9- , or _C10 -dicycloalkyl, or C6-, C9 ... ₆ to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammaalkyl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic or heterocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic or heterocyclic ring Z. Preferably, the carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _-CH2 - _CH2 -R4, and _-CH2 - _CH2 - _CH2 -R4; L3 is selected from the group consisting of: _-CH2 -R9, _{-CH2- CH2} -R9, and _-CH2 - _CF2- R9; L4 is absent; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -spiroalkyl. -spiroalkyl, phenyl, 5- or 6-membered heteroaryl, adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, wherein the substituent is, as desired, one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe, preferably unsubstituted phenyl or a dammaalkyl group substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and more preferably Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2- _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2 - CH2} -R9, and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, preferably an unsubstituted phenyl or a adamantyl substituted by one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted by a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 -Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and even better Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2- _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2 - CH2} -R9, and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, more preferably an unsubstituted phenyl or a adamantyl substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 -Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and even better Br.

In a preferred embodiment, A5, A7, and A8 are N and A6 is C and participates in the annulated carbocyclic ring Z, particularly a 5, 6, or 7-membered carbocyclic ring Z, preferably phenyl, which is optionally substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _-NO2 ; L2 is selected from the group consisting of: -CH2 _- R4, _{-CH2- CH2} -R4, and -CH2- _CH2 - _CH2 -R4; L3 is selected from the group consisting of: -CH2 _- R9, _{-CH2 - CH2} -R9, and _-CH2 - _CF2 -R9; L4 Not present; R4 is hydrogen, methyl, COOH, or tetrazolium, preferably COOH; R9 is a _C4 to _C7 -cycloalkyl, i.e., _C4- , _C5- , _C6- , or _C7 -cycloalkyl; a _C6 to _C10 -bicycloalkyl, i.e., _C6- , _C7- , _C8- , _C9- , or _C10 -bicycloalkyl; a _C6 to _C10 -spiroalkyl, i.e., _C6- , _C7- , C8-, _C9- , or _C10 -spiroalkyl; phenyl; a 5- or 6-membered heteroaryl; or a tetraalkyl, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: _-Br , -Cl, -F, -I, Me, _-CF3 Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, which, as desired, is substituted with one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe, more preferably an unsubstituted phenyl or a adamantyl substituted with one or two substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and R6 is a phenyl ortho-substituted with a substituent selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 -Me, _-CF3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, and -I, and even better Br.

In a preferred embodiment, the ALC1 inhibitor (ALC1i) of the first and other embodiments of the present invention according to formula (I) has a specific structure as shown in Figure 1.

In the first embodiment, and in a preferred embodiment, the ALC1 inhibitor (ALC1i) used according to the invention is the ALC1 inhibitor (ALC1i) according to formula (II) : Formula (II) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein: X is N or S; A is C or N; _R1 is –CO- _OR6 , -CO- _R7 , or -CO- _NR6RA , preferably _R1 is –CO- _OR6 ; _R2 is _-R7 , _-NHR8 , _-OR7 , _-COR7 , Br, _-C3-8 - _cycloalkyl (preferably cyclopropyl), or _–C4-8 -cycloenyl (preferably cyclohexenyl); or _R1 and R _Together, they form a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the following groups: -OH, -NO₂, -CN, -Br, -Cl, -F, -I, -OC, _1-3 -alkyl, =O, [-O- _CH₂ - _CH₂ ]-NH-CH(OH)-O-tBu; _R₃ is H, =O, -OH, _-OR₇ , _-R₇ , or –( _CH₂ ) _m -L, where m is 0, 1, or 2, and L is a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the following groups: -OH, _-NO₂ R1 is -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, _-hydroxyC1-3 -alkyl, and =O; _R4 is H or _-C1-3 -alkyl, 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, 6, or 7-membered carbocyclic or heterocyclic, adamantine, _C1-4 -alkyl, or -N( _CH3 ) ₂ , which is substituted as desired, preferably substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 =O, and [-O- _CH₂ - _CH₂ ] _q -NH-biotin, where q is 1, 2, 3, or 4, or two adjacent substituents form a 5, 6, or 7-membered carbon ring or heterocyclic ring; or _R₄ and _R₅ together form a 5, 6, or 7-membered carbon ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the group consisting of: -OH, -NO₂, -CN, -Br, -Cl, -F, -I, _-OR₉ , _-R₉ , =CH- _RA , and _–CH₂ - _RA , preferably _R₄ and _R₅ together form a C₅ _-7 -cycloalkyl group; _R₆ is H, -C₁ _-6 -alkyl, -C₂ _-6 -alkenyl, -C₂- _6- alkyl ... -Alynyl group, which may be substituted as desired, preferably _R6 is H; _R7 is _-C1-3 -alkyl, _-C2-3 -alkenyl, _-C2-3 -alkynyl group, which may be substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -Br, -Cl, _-F , -I, -CH3, _-OCH3 , or _-SCH3 ; _R8 is H or _C1-6 -alkyl group, preferably H; _R9 is _-C1-6 -alkyl, _-C2-6 -alkenyl, _-C2-6 -alkynyl, _-C1-6 -alkyl-aryl, or _C1-6 -alkyl-heteroaryl (preferably isothiazolium, thiazolium, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-thiadiazole, pyridine, or pyrazole), wherein the alkyl-heteroaryl group is, as desired, substituted by one, two, or three substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-NO₂ , -CN, -CONH₂, -CONH- _{C₁ -3 -} alkyl (preferably –CONH-CH₃), -NH-CO-C₁- ₃ -alkyl (preferably -NH-CO- _CH₃ ), -C₁- ₆ -alkyl (preferably _-CH₃ , ethyl, propyl, tri-butyl, or pentyl), -C₁- ₃ -halogen (preferably -CF₃). ₃ , or _-CHF2 ), -O- _CHF2 , -O- _CF3 , carbocyclic (preferably cyclopropyl, cyclohexyl, or phenyl), -O-carbocyclic (preferably phenoxy), heterocyclic (preferably pyrazolyl), -CO-heterocyclic (preferably –CO-(1-pyrrolidyl)), _-SO2 - _CH3 , _-SO2- N( _CH3 ) ₂ , _-OC1-4 -alkyl (preferably _-OCH3 ), _-OC1-3 -alkyl- _OC1-3 -alkyl (preferably –O- _CH2 -O- _CH3 ), _-SCH3 , or when _R9 is _-C1-6 In the case of -alkyl-aryl, the two adjacent substituents on the aryl moiety can form a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted as needed; _RA is H, a carbocyclic or heterocyclic ring, which may be substituted as needed, preferably by 1, 2, or 3 substituents independently selected from the following group: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-R9 , -O- _R7 , -O-( _CH2 ) _OR9 , _-SO2NH2 , and =O, where o is 0 or 1. A preferred embodiment of the ALC1 _inhibitor ( ALC1i) according to formula (II)

According to Formula (II), ALC1i preferably shows an _IC50 of <250 µM when the inhibition rate is >50% at concentrations of 250 µM or below, and more preferably _IC50 of <25 µM. _IC50 is preferably measured by nucleosome remodeling analysis based on FRET as described in WO 2022/117782 A1.

According to formula (II), ALC1i preferably has _{an EC50} of <250 µM, more preferably <50 µM, and even more preferably <10 µM. _{The EC50 is} preferably measured by cell proliferation analysis and SRB-based readings as described in WO 2022/117782 A1.

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.

In one embodiment, preferably in the ALC1 inhibitor (ALC1i) according to formula (II): X is N or S; A is C or N; _R1 is –CO- _OR6 , -CO- _R7 , or -CO- _NR6RA , preferably _R1 is –CO- _OR6 ; _R2 is _-R7 , _-NHR8 , _-OR7 , _-COR7 , Br, _-C3-8 -cycloalkyl (preferably cyclopropyl), or _-C4-8 -cycloenyl (preferably cyclohexenyl); or _R1 and _{R Together,} they form a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the following groups: -OH, -NO₂, -CN, -Br, -Cl, -F, -I, -OC, _1-3 -alkyl, =O, [-O- _CH₂ - _CH₂ ]-NH-CH(OH)-O-tBu; _R₃ is H, =O, -OH, _-OR₇ , _-R₇ , or –( _CH₂ ) _m -L, where m is 0, 1, or 2, and L is a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the following groups: -OH, _-NO₂ R1 is -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, _-hydroxyC1-3 -alkyl, and =O; _R4 is H or _-C1-3 -alkyl, 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, 6, or 7-membered carbocyclic or heterocyclic, adamantine, _C1-4 -alkyl, or -N( _CH3 ) ₂ , substituted as desired, preferably substituted by 1, ₂ , 3, or 4 substituents independently selected from the following group: -OH, -NO2, -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 =O, and [-O- _CH₂ - _CH₂ ] _q -NH-biotin, where q is 1, 2, 3, or 4, or two adjacent substituents form a 5, 6, or 7-membered carbon ring or heterocyclic ring; or _R₄ and _R₅ together form a 5, 6, or 7-membered carbon ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the group consisting of: -OH, -NO₂, -CN, -Br, -Cl, -F, -I, _-OR₉ , _-R₉ , =CH- _RA , and _{–CH₂- RA} , preferably _R₄ and _R₅ together form a C₅ _-7 -cycloalkyl; _R₆ is H, -C₁ _-6 -alkyl, -C₂ _-6 -alkenyl, -C₂- ₆ -alkyl ... -Alynyl group, which may be substituted as desired, preferably _R6 is H; _R7 is _-C1-3 -alkyl, _-C2-3 -alkenyl, _-C2-3 -alkynyl group, which may be substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -Br, -Cl, _-F , -I, -CH3, _-OCH3 , or _-SCH3 ; _R8 is H or _C1-6 -alkyl group, preferably H; _R9 is _-C1-6 -alkyl, _-C2-6 -alkenyl, _-C2-6 -alkynyl, _-C1-6 -alkyl-aryl, or _C1-6 -alkyl-heteroaryl (preferably isothiazolium, thiazolium, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-thiadiazole, pyridine, or pyrazole), wherein the alkyl-heteroaryl group is, as desired, substituted by one, two, or three substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-NO₂ , -CN, -CONH₂, -CONH- _{C₁ -3 -} alkyl (preferably –CONH-CH₃), -NH-CO-C₁- ₃ -alkyl (preferably -NH-CO- _CH₃ ), -C₁- ₆ -alkyl (preferably _-CH₃ , ethyl, propyl, tri-butyl, or pentyl), -C₁- ₃ -halogen (preferably -CF₃). ₃ , 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 , _-OC1-4 -alkyl (preferably _-OCH3 ), _-OC1-3 -alkyl- _OC1-3 -alkyl (preferably –O- _CH2 -O- _CH3 ), _-SCH3 , or when _R9 is _-C1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted as needed; _RA is H, a carbocyclic or heterocyclic ring, which may be substituted as needed, preferably by 1, 2, or 3 substituents independently selected from the following group: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-R9 , -O- _R7 , -O-( _CH2 ) _OR9 , _{-SO2NH2 ,} and =O, where o is 0 or 1.

According to the present invention, preferably in the ALC1 inhibitor (ALC1i) according to formula (II): X is N or S; A is C or N; _R1 is –CO- _OR6 , -CO- _R7 , or _{-CO - NR6RA} , preferably –CO- _OR6 ; _R2 is _-R7 , _-NHR8 , _-OR7 , _{-COR7; or R1 and R2 together form a 5, 6, or 7-membered carbon ring or heterocycle, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN , -Br ,} -Cl, -F, -I, _-OC1-3 -alkyl, and =O; _R3 is H, =O, -OH, _-OR7 R4 is _-R7 or –( _CH2 ) _m -L, where m is 0, 1, or 2, and L is a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, _-hydroxyC1-3 -alkyl, and =O; _R4 is H or _-C1-3 -alkyl, preferably H; _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 a diamond-shaped alkyl group, which is substituted as desired, preferably substituted by 1, ₂ , 3, or 4 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 , and =O, or two adjacent substituents forming a 5, 6, or 7-membered carbocyclic or heterocyclic ring; or _R4 and _R5 together forming a 5, 6, or 7-membered carbocyclic ring, which is substituted as desired, preferably substituted by 1, 2, or ₃ substituents independently selected from the group consisting of: -OH, -NO2 -CN, -Br, -Cl, -F, -I, _-OR9 , _-R9 , =CH- _RA , preferably _R4 and _R5 together form a _C5-7 -cycloalkyl group; _R6 is H, _-C1-6 - _alkyl (i.e., _C1- , _C2- , _C3- , _C4- , _C5- , or _C6 - _alkyl ), _-C2-6 - _alkenyl (i.e., C2-, C3-, C4-, C5-, or C6-alkenyl), _-C2-6 -ynyl (i.e., _C2- , _C3- , _C4- , _C5- , or _C6 -ynyl), which may be substituted as desired, preferably _R6 is H; _R7 is _-C1-3 -alkyl (i.e. _{, C1-} , _C2- , _{C3 -} alkyl), _-C2-3 -Alkenyl, i.e., _C2- , _C3 -alkenyl, -C2-, _C3 -ynyl, i.e., _C2- , _C3 -ynyl, may be substituted as desired, preferably substituted by one, two or three substituents independently selected from the following group: -Br, -Cl, -F, -I, _-CH3 , _-OCH3 , or _-SCH3 ; _R8 is H or _C1-6 -alkyl, preferably H; _R9 is _-C1-6 -alkyl, i.e., _C1- , _C2- , _C3- , _C4- , _C5- or _C6 -alkyl, _-C2-6 -alkenyl, i.e., C2-, _C3- , _C4- , _C5- or _C6 -alkenyl, -C2-6-ynyl, i.e., C2-, C3-, C4-, _C5- or C6-alkenyl, or _-C2-6 -ynyl, i.e., _C2- , _C3- , _C4- , _C5- Or _C6 -alkynyl, or _-C1-6 -alkyl-aryl, i.e., _C1- , _C2- , _C3- , _C4- , _C5- , or _C6 -alkyl-aryl, which is substituted as desired by 1, 2, or 3 substituents selected from the following groups: -Br, -Cl, -F, -I, _-CH3 , -OCH3, or -SCH3 _{. RA} is H, carbocyclic, or heterocyclic, which is substituted as desired, preferably substituted by ₁ , 2, or 3 substituents independently selected from the following groups: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-R9 , -O- _R7 , -O-( _CH2 ) _OR9 , _{-SO2NH2 ,} and =O, where o is 0 or 1.

In one preferred embodiment of the present invention, X is N.

In one preferred embodiment of the present invention, A is C.

In one preferred embodiment of the present invention, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl , i.e. _C1- , _C2- , _C3- , _-alkyl , _-C2-3 -alkenyl, i.e. C2- _{, C3-, -alkenyl, -C2-3-ynyl, i.e. C2-, C3- as needed ,} preferably _R6 is H;

In one preferred embodiment of the present invention, _R1 is –CO-OH.

In one preferred embodiment of the invention, X is N and _R1 is –CO- _OR6 or -CO-NR6RA, preferably _R6 is H, _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3- , _-alkyl , _-C2-3 -alkenyl, i.e. C2-, C3-alkenyl _{, -C2-, C3-ynyl, i.e. C2-, C3- as needed} , preferably _R6 is _H.

In one preferred embodiment of the present invention, A is C and _R1 is –CO- _OR6 or -CO-NR6RA, preferably _R6 is H, _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. _C2- , C3 _- alkenyl, _-C2- , _{C3-ynyl, i.e. C2-, C3- as} needed, preferably _R6 is H.

In one preferred embodiment of the present invention, X is N, A is C and _R1 is –CO-OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl , i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. C2- _{, C3-, -alkenyl, -C2-3-ynyl, i.e. C2-, C3- as needed , preferably R6} is H.

In one preferred embodiment of the present invention, X is N, A is C and _R1 is –CO-OH or –CO- _NH2 .

In one preferred embodiment of the invention, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the invention, X is N and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the invention, A is C and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the present invention, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl (i.e., _C1- , _C2- , C3-, -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _C3- , _-alken ), -C2-3-ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _{R2 is -NHR8} , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the invention, _R1 is –CO-OH and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the present invention, X is N and _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. _C2- , _C3 -alkenyl, -C2-, _C3 -yynyl, i.e. _C2- , _C3- as desired, preferably substituted, preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the present invention, A is C and _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. _C2- , _C3 -alkenyl, -C2-, _C3 -ynyl, i.e. _C2- , _C3- as desired, preferably substituted, preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the present invention, X is N, A is C and _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. C2-, C3-, -alkenyl, _-C2-3 -ynyl, i.e. _C2- , _C3- as desired, preferably substituted, preferably _R6 is _H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably _H.

In one 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 _C1-6 -alkyl, preferably H.

In one preferred embodiment of the invention, _R1 and _R2 together form a 6-membered aryl or heteroaryl partial alkynyl group, which is substituted as desired, preferably, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O.

In one preferred embodiment of the invention, X is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl partial alkynyl group, which is substituted as desired, preferably, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O.

In one preferred embodiment of the invention, A is C, and _R1 and _R2 together form a 6-membered aryl or heteroaryl partial alkynyl group, which is substituted as desired, preferably, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O.

In one preferred embodiment of the invention, X is N, A is C, and _R1 and _R2 together form a 6-membered aryl or heteroaryl partial alkynyl group, which is substituted as desired, preferably, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O.

In one preferred embodiment of the invention, _R1 and _R2 together form uracil or 3-deazouracil.

In one preferred embodiment of the invention, X is N, and _R1 and _R2 together form uracil or 3-deazouracil.

In one preferred embodiment of the invention, A is C, and _R1 and _R2 together form uracil or 3-deazouracil.

In one preferred embodiment of the invention, X is N, A is C, and _R1 and _R2 together form uracil or 3-deazouracil.

In one preferred embodiment of the invention, _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5, 6, or 7-membered heteroaryl group, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R1 is –CO-OH and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6, or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ , or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alken), -C2-3-ynyl (i.e. _{, C2-} , _C3- , substituted as desired), preferably _R6 is H and R3 is H, =O, _-OH , _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, _-NO2 -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl, and -hydroxyC _1-3 -alkyl.

In one preferred embodiment of the invention, A is C, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alkenyl), -C2-3-ynyne (i.e. _{, C2-} , _C3- , substituted as desired), preferably _R6 is H and R3 is H, =O, _-OH , _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, _-NO2 -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl, and -hydroxyC _1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is C, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3- , _{-alkyl), -C2-3-alkenyl (i.e., C2-, C3-, -alken), -C2-3-ynyl (i.e., C2-, C3- , substituted as needed )} , preferably _R6 is H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, -NO ₂ , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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, wherein m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H, and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6, or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H, and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5, 6, or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl, and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is C, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H, and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5, 6, or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl (i.e., _C1- , _C2- , _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-, _-alken ), or -C2-3-ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _{R2 is -NHR8} , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R1 is –CO-OH and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H, and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6, or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _C3 -alkenyl), -C2-3-ynyl (i.e. _{, C2- , C3-} , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H _{or C1-6} -alkyl, preferably H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, A is C, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _C3 -alkenyl), -C2-3-ynyl (i.e. _{, C2- , C3-} , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H _{or C1-6} -alkyl, preferably H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is C, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., _C2- , C3-, -alken), _-C2-3 -ynyl (i.e. _{, C2-} , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably _H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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 _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, ₂ , or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5, 6, or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and -hydroxyl _C1-3 -alkyl.

In one preferred embodiment of the invention, X is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5, 6, or 7-membered heteroaryl group, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl, and -hydroxyl C _1-3 -alkyl.

In one preferred embodiment of the invention, A is C, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5, 6, or 7-membered heteroaryl group, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl, and -hydroxyl C _1-3 -alkyl.

In one 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 substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5, 6, or 7-membered heteroaryl group, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl, and -hydroxyC _1-3 -alkyl.

In one 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, wherein m is 0 and L is phenyl or 5, 6, or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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, wherein m is 0 and L is phenyl or a 5, 6, or 7-membered heteroaryl group, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl, and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is _CR1 and _R2 together to form uracil or 3-deazouracil and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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, wherein m is O and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R1 is –CO-OH and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alken), -C2-3- _{ynyl (i.e., C2-, C3-, substituted as desired), preferably R6 is H and R3 is -C1-3-alkyl (i.e., C1-, C2- , C3 - alkyl ) , or – ( CH2} ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _{-NO 2} , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is C, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alken), -C2-3- _{ynyl (i.e., C2-, C3-, substituted as desired), preferably R6 is H and R3 is -C1-3-alkyl (i.e., C1-, C2- , C3 - alkyl ) , or – ( CH2} ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _{-NO 2} , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is C, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., _C2- , C3-, _-alken ), _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _R3 is _-C1-3 -alkyl (i.e., _{C1- , C2-} , _C3 -alkyl), or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, A is C, _R1 is –CO-OH or –CO- _NH2 , and _R3 is _–C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _–NO2 , –CN, –Br, –Cl, –F, –I, –O- _C1-3 -alkyl, and _{–hydroxyC1-3} -alkyl.

In one preferred embodiment of the invention, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is C, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl (i.e., _C1- , _C2- , _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-, -alken), or -C2-3-ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H, and _{R2 is -NHR8} , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e., _C1- , _C2- , _{C3 -} alkyl), or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R1 is –CO-OH, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alkenyl), _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e. _{, C1-} , _C2- , _C3 -alkyl), or –( _{CH2 ) m} -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, A is C, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alkenyl), _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e. _{, C1-} , _C2- , _C3 -alkyl), or –( _{CH2 ) m} -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is C, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., _C2- , C3-, -alken), _-C2-3 -ynyl (i.e. _{, C2-} , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3 -alkyl), _or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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 _C1-6 -alkyl, preferably H and _R3 is _–C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _–NO2 , –CN, –Br, –Cl, –F, –I, –O- _C1-3 -alkyl, and _{–hydroxyC1-3} -alkyl.

In one preferred embodiment of the invention, _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: _-NO2 -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: _-NO2 -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is C, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: _-NO2 -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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 substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m - _L , wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -NO2 -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R1 and _R2 together form uracil or 3-deazouracil and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, and _R1 and _R2 together form uracil or 3-deazouracil and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is C, _R1 and _R2 together form uracil or 3-deazouracil, and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _{-hydroxyC1-3-alkyl, and R3 is -C1-3 - alkyl} , i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, A is C, _R1 and _R2 together form uracil or 3-deazouracil and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, _-F , -I, -O-C1-3-alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, _R1 is –CO-OH and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, X is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _{C3-alkenyl), -C2-3-ynyl (i.e., C2-, C3- , substituted as needed} ), preferably _R6 is H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, A is C, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _{C3-alkenyl), -C2-3-ynyl (i.e., C2-, C3- , substituted as needed} ), preferably _R6 is H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the present invention, X is N, A is C, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., _C2- , C3-, _-alken ), _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _R3 is H, =O, -OH _, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one 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 .

In one preferred embodiment of the invention, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H, and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, X is N, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, A is C, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the present invention, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl (i.e., _C1- , _C2- , C3-, -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _C3- , _-alken ), -C2-3-ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _{R2 is -NHR8} , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, _R1 is –CO-OH, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the present invention, X is N, _R1 is –CO- _OR6 or _-CO - _NR6RA , preferably _R6 is H, _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3- , _-alkyl , _-C2-3 -alkenyl, i.e. C2-, _C3 -alkenyl, _-C2- , C3-yynyl, i.e. _C2- , _C3- as desired, preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and R3 is _H , =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, A is C, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _C3 -alkenyl), _-C2-3 -ynyl (i.e. _{, C2-} , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the present invention, X is N, A is C, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., C2-, C3-, -alken), _-C2-3 -ynyl (i.e. _{, C2-} , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably _H and _R3 is H, =O, -OH, phenylthio, phenyl, _3,4,5 -hydroxymethylphenyl, CF2H, or _CF3 .

In one 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 _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, X is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, A is C, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one 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 substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one 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 .

In one 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 .

In one 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 .

In one 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 .

In one preferred embodiment of the present invention, A is N and _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 -alkyl _, i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. _C2- , _C3 -alkenyl, _-C2- , C3-ynyl, i.e. _C2- , _C3- as needed, preferably _R6 is H.

In one preferred embodiment of the present invention, X is N, A is N and _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl , i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. C2- _{, C3-, -alkenyl, -C2-3-ynyl, i.e. C2-, C3- as needed , preferably R6} is H.

In one preferred embodiment of the present invention, X is N, A is N and _R1 is –CO-OH or –CO- _NH2 .

In one preferred embodiment of the present invention, A is N and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the present invention, A is N and _R1 is –CO- _OR6 or -CO- _{NR6RA .} Preferably, _R6 is H, _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alkenyl), or _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed ₎ . Preferably, _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one preferred embodiment of the present invention, X is N, A is N and _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl , i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl, i.e. C2-, _C3- , -alkenyl, _-C2-3 -ynyl, i.e. _C2- , _C3- as desired, preferably substituted, preferably _R6 is _H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H.

In one 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 _C1-6 -alkyl, preferably H.

In one preferred embodiment of the invention, A is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O.

In one 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 substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O.

In one preferred embodiment of the invention, A is N, and _R1 and _R2 together form uracil or 3-deazouracil.

In one preferred embodiment of the invention, X is N, A is N, and _R1 and _R2 together form uracil or 3-deazouracil.

In one preferred embodiment of the invention, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alken), -C2-3-ynyl (i.e. _{, C2-} , _C3- , substituted as desired), preferably _R6 is H and R3 is H, =O, _-OH , _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, _-NO2 -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl, and -hydroxyC _1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3- , _{-alkyl), -C2-3-alkenyl (i.e., C2-, C3-, -alken), -C2-3-ynyl (i.e., C2-, C3- , substituted as desired )} , preferably _R6 is H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, -NO ₂ , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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, wherein m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is N, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H, and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5, 6, or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _C3 -alkenyl), _-C2-3 -ynyl (i.e. _{, C2-} , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., C2-, C3-, -alken), _-C2-3 -ynyl (i.e. _{, C2-} , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably _H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5, 6 or 7 heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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 _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, ₂ or 3 substituents independently selected from the group consisting of: -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In a preferred embodiment of the present invention, A is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5, 6, or 7-membered heteroaryl group, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl and -hydroxyl C _1-3 -alkyl.

In one 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 substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are H, =O, -OH, _-R7 , or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or a 5, 6, or 7-membered heteroaryl group, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 -CN, -Br, -Cl, -F, -I, -O-C _1-3 -alkyl, and -hydroxyC _1-3 -alkyl.

In one 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, wherein m is 0 and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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, wherein m is O and L is phenyl or 5, 6 or 7-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alken), -C2-3- _{ynyl (i.e., C2-, C3-, substituted as desired), preferably R6 is H and R3 is -C1-3-alkyl (i.e., C1-, C2- , C3 - alkyl ) , or – ( CH2} ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _{-NO 2} , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., C2-, C3-, _-alken ), _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _R3 is _-C1-3 -alkyl (i.e., _{C1- , C2-} , _C3 -alkyl), or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, A is N, _R1 is –CO-OH or –CO- _NH2 , and _R3 is _–C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _–NO2 , –CN, –Br, –Cl, –F, –I, –O- _C1-3 -alkyl, and _{–hydroxyC1-3} -alkyl.

In one preferred embodiment of the invention, A is N, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, _R1 is –CO- _OR6 or -CO- _NR6RA , preferably _R6 is H, _-C1-3 - _alkyl (i.e., _C1- , _C2- , _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-, -alken), or -C2-3-ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H, and _{R2 is -NHR8} , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e., _C1- , _C2- , _{C3 -} alkyl), or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, _R1 is –CO-OH, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alkenyl), _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e. _{, C1-} , _C2- , _C3 -alkyl), or –( _{CH2 ) m} -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, A is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alkenyl), _-C2-3 -ynyl (i.e., _C2- , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e. _{, C1-} , _C2- , _C3 -alkyl), or –( _{CH2 ) m} -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the present invention, X is N, A is N, _R1 is –CO- _OR6 or –CO- _{NR6RA .} Preferably, _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl ( _{i.e., C2-, C3-, -alken), or -C2-3 -} ynyl (i.e. _{, C2- , C3-} , substituted as needed). Preferably, _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 are _-C1-3 -alkyl (i.e., _C1- , _C2- , _C3 -alkyl), or –( _CH2 ) _m . -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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 _C1-6 -alkyl, preferably H and _R3 is _–C1-3 -alkyl, i.e. _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: _-NO2 -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one 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 substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O. Preferably, -OH and =O and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m - _L , wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -NO2 -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl and _R3 are _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is N, _R1 and _R2 together form uracil or 3-deazouracil, and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _{-hydroxyC1-3-alkyl, and R3 is -C1-3 - alkyl} , i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, where m is 0 and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, X is N, A is N, _R1 and _R2 together form uracil or 3-deazouracil and _R3 is _-C1-3 -alkyl, i.e., _C1- , _C2- , _C3 -alkyl, or –( _CH2 ) _m -L, wherein m is O and L is phenyl or 5-membered heteroaryl, preferably phenyl, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: _-NO2 , -CN, -Br, -Cl, _-F , -I, -O-C1-3-alkyl, and _-hydroxyC1-3 -alkyl.

In one preferred embodiment of the invention, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , _{C3-alkenyl), -C2-3-ynyl (i.e., C2-, C3- , substituted as needed} ), preferably _R6 is H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the present invention, X is N, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl, i.e. _C1- , _C2- , _C3- , -alkyl, _-C2-3 -alkenyl _, i.e. C2-, C3-, -alkenyl, _-C2-3 -ynyl, i.e. _C2- , _C3- as desired, preferably _R6 is _H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one 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 .

In one preferred embodiment of the invention, A is N, _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the present invention, A is N, _R1 is –CO- _OR6 or -CO _{- NR6RA} , preferably _R6 is H, _-C1-3 -alkyl (i.e., _C1- , C2-, _C3- , -alkyl), _-C2-3 -alkenyl (i.e., _C2- , C3-alkenyl), _-C2-3 -ynyl (i.e. _{, C2- , C3-} , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H _{or C1-6} -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the present invention, X is N, A is N, _R1 is –CO- _OR6 or -CO- _{NR6RA ,} preferably _R6 is H, _-C1-3 -alkyl ₍ i.e., _C1- , _C2- , _C3- , -alkyl), -C2-3-alkenyl (i.e., C2-, C3-, -alken), _-C2-3 -ynyl (i.e. _{, C2-} , _C3- , substituted as needed), preferably _R6 is H and _R2 is _-NHR8 , wherein _R8 is H or _C1-6 -alkyl, preferably _H and _R3 is H, =O, -OH, phenylthio, phenyl, _3,4,5 -hydroxymethylphenyl, CF2H, or _CF3 .

In one 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 _C1-6 -alkyl, preferably H and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one preferred embodiment of the invention, A is N, and _R1 and _R2 together form a 6-membered aryl or heteroaryl moiety, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one 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 substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OC1-3 -alkyl, and =O, preferably -OH and =O and _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 .

In one 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 .

In one 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 .

In one 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 a 5, or 6-membered heteroaryl, or adamantyl, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 , and =O, or two adjacent substituents forming a 5, 6, or 7-membered carbocyclic or heterocyclic ring.

In one preferred embodiment of the invention, _R4 and _R5 together form a 5 or 6-membered unsubstituted or monosubstituted heterocycloalkyl group, preferably substituted at the _R4 position by =CH- _RA .

In one preferred embodiment of the invention, _RA is a carbon ring substituted with one or two substituents independently selected from the group consisting of: -Br, -Cl, -F, -O-( _CH2 ) _OR9 , or _-SCH3 , where o is 0 or 1.

In one preferred embodiment of the invention, _R4 and _R5 together form a 5 or 6-membered unsubstituted or monosubstituted heterocyclic alkyl group, preferably substituted at the _R4 position with =CH- _RA , wherein _RA is a carbocyclic ring substituted with one or two substituents independently selected from the group consisting of: -Br, -Cl, -F, -O-( _CH2 ) _OR9 , or _-SCH3 , wherein o is 0 or 1.

In one preferred embodiment of the invention, _R9 is _-C1-4 -alkyl, i.e., _C1- , _C2- , _C3- , or _C4 -alkyl; _-C2-4 -alkenyl, i.e., C2-, _C3- , or _C4 -alkenyl; or _-C1-6 -alkyl-aryl, i.e. _{, C1-} , _C2- , _C3- , _C4- , _C5- , or _C6 -alkyl-aryl, which may be substituted as desired by one or two substituents selected from the group consisting of: -Cl, _-CH3 , _-OCH3 , or _-SCH3 .

In one 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 a 5- or 6-membered heteroaryl or diamond alkyl group, which is substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 , and =O, or two adjacent substituents forming a 5, 6 or 7-membered carbon ring or heterocyclic ring, wherein _R9 is _-C1-4 -alkyl, i.e., _C1- , _C2- , _C3- , or _C4 -alkyl, _-C2-4 -alkenyl, i.e., C2-, C4-, _C5- , C6 ... _3- , or _C4 -alkenyl, or _-C1-6 -alkyl-aryl, i.e. _C1- , _C2- , _C3- , _C4- , _C5- , or _C6 -alkyl-aryl, which may be substituted as required by one or two substituents selected from the group consisting of: -Cl, _-CH3 , _-OCH3 , or _-SCH3 .

In one preferred embodiment of the present invention, ALC1i has the structure of formula (IIa): Formula (IIa) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein: A is C or N; _R1 is –COOH; _R2 is _-CH3 or _-NH2 , or _R1 and _R2 together form uracil or 3-deazouracil; _R3 is H, =O, -OH, phenylthio, phenyl, 3,4,5-hydroxymethylphenyl, _CF2H , or _CF3 ; _R4 is HR; _R5 is -L, or _-CH2- (CH=CH)-L, wherein L is a 6-membered carbocyclic or heterocyclic, or adamantyl, and is substituted as desired by one or two independent substituents selected from the following group: -OH, _-NO2 , -Br, -Cl, -F, _CH3 , _-OR9 =O, or two adjacent substituents forming a 5 or 6-membered heterocyclic ring; or _R4 and _R5 together forming a 5 or 6-membered unsubstituted or monosubstituted heterocyclic alkyl group, preferably substituted at the _R4 position with =CH- _RA ; _R9 is _-C1-4 -alkyl, i.e., _C1- , _C2- , _C3- , or _C4 -alkyl, _-C2-4 -alkenyl, i.e., _C2- , _C3- , or _C4 -alkenyl, or _-C1-6 -alkyl-aryl, i.e., _C1- , _{C2- ,} C3-, _C4- , _C5- , or _C6 -alkyl-aryl, substituted as needed with one or two substituents selected from the following group: -Cl, _-CH3 , _-OCH3 , or _-SCH3 ; R _A is a carbon ring substituted with one or two substituents independently selected from the following groups: -Br, -Cl, -F, -O-( _CH2 ) _OR9 , or _-SCH3 , where o is 0 or 1.

In a preferred embodiment, the ALC1i of the present invention has a specific structure as shown in Figure 1.

According to the present invention, ALC1i is used in combination with inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or with mitomycin C, paclitaxel, free radiation, or with TOP1 inhibitors and tumor-specific antibodies.

The enzyme topoisomerase I (TOPI) participates in the relaxation of supercoiled DNA. It removes the helical restrictions that hinder DNA replication and transcription. Suitable inhibitors of topoisomerase I are known to those skilled in the art and are commercially available. Examples used according to the present invention are irinotecan, SN-38, totopotecan, camptothecin (NSC-100880) or derivatives thereof, such as hydroxycamptothecin, 7-ethylcamptothecin, or 9-aminocamptothecin, rubitecan, Genz-644282 (CAS No. 529488-28-6), belotecan (CKD-602) hydrochloride, or β-lapachone. Irinotecan, SN-38, or topotecan are preferred, with irinotecan being the best (preferably in the form of its active metabolite SN-38).

Topoisomerase II (TOPII) controls DNA entanglement and supercoiling. It can untangle DNA by passing one double helix through another, simultaneously cutting both strands of the DNA helix. Suitable inhibitors of topoisomerase II are known to the art and are commercially available. Examples of topoisomerase II inhibitors used according to this invention include teniposide, etoposide, anthracyclic compounds such as aclarubicin, epirubicin, idarubicin, doxorubicin, daunorubicin, pirarubicin (NSC-333054), zorubicin, aclarubicin, caminomycin, amonafide, mitoxantrone (NSC-301739), and pixantrone maleate. Maleate, dexrazoxane, ellipticine hydrochloride, phenoxodiol (haginin E), etoposide (VP-16), voreloxin (SNS-595) hydrochloride, and amsacrine. Teniposide and etoposide are preferred.

Ataxia telangiectasia mutant (ATM) is a serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase-associated kinase (PIKK) family of protein kinases. Appropriate inhibitors of ATM are known to the art and are commercially available. Examples of ATM inhibitors used according to this invention include 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.

ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related kinase) is a serine/threonine protein kinase. Appropriate inhibitors of ATM are known to the art and are commercially available. Examples of ATR inhibitors used according to this invention include ceralasertib (AZD6738) (CAS No. 1352226-88-0), elimusertib, VX-803 (M4344) (CAS No. 1613191-99-3), AZ20 (CAS No. 1233339-22-4), ETP-46464 (CAS No. 1345675-02-6), Berzosertib (VE-822) (CAS No. 1232416-25-9), Dactolisib (BEZ235) (CAS No. 915019-65-7), VE-821 (CAS No. 1232410-49-9), and schisandrin B (Sch... B)(CAS No. 61281-37-6), HAMNO(NSC-111847)(CAS No. 138736-73-9), torin 2(CAS No. 1223001-51-1), CGK 733(CAS No. 905973-89-9), RP-3500(CAS No. 2417489-10-0), or SKLB-197(CAS No. 2713577-16-1). Ceralasertib and elimusertib are preferred.

WEE1 G2 checkpoint kinase plays a crucial role in cell cycle regulation and DNA damage recognition/repair. Suitable inhibitors of WEE1 are known to those skilled in the art and are commercially available. Examples of WEE1 inhibitors used according to the present invention are adavosertib (CAS No. 955365-80-7), Zn-C3 (CAS No. 2376146-48-2), PD0166285 (CAS No. 185039-89-8), or Debio 0123 (CAS No. 2243882-74-6). Adavosertib is preferred.

Bromodomains are a family of evolutionarily conserved motifs that bind to acetylated lysine in histone tails and promote target gene transcription by recruiting transcriptional mechanisms. Bromodomain inhibitors (BET inhibitors) are known to the art and are commercially available. Examples of BRD inhibitors used according to this 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), and OTX015 (CAS No. 20259). 0-98-5), I-BET151 (CAS No. 1300031-49-5), CPI-203 (CAS No. 1446144-04-2), PFI-1 (CAS No. 1403764-72-6), MS436 (CAS No. 1395084-25-9), CPI-0610 (CAS No. 1380087-89-7), see 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 better.

MEK is a component of the MAP kinase signaling pathway. As a dual-specific kinase, MEK phosphorylates serine/threonine and tyrosine residues. It specifically activates extracellular signal-regulated kinases (ERKs) through phosphorylation, and then further regulates various intracellular targets, affecting processes such as growth, proliferation, differentiation, and survival. Examples of MEK inhibitors used according to this invention include trametinib (CAS No. 871700-17-3), cobimetinib (CAS No. 934660-93-2), binimetinib (CAS No. 606143-89-9), and selumetinib (CAS No. 606143-52-6).

In the second embodiment, the invention relates to ALC1i according to formula (II) as described above, 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 a PARP inhibitor in the treatment or improvement of pancreatic or fallopian tube cancer in patients. The preferred embodiment described herein as the first embodiment is also preferred for the second embodiment, particularly according to the definitions of ALC1i and PARP inhibitors according to formula (II).

In a preferred embodiment, (i) the cancer-killing efficacy of PARPi is enhanced by ALC1i according to formula (II), (ii) a reduced dose of PARPi is administered, and/or (iii) PARPi resistance is ignored.

In other words, this invention also relates to ALC1i according to formula (II), in combination with an inhibitor of PARP for the treatment or improvement of pancreatic cancer (preferably) or fallopian tube cancer in patients. Typically, PARP inhibitors (PARPi) are known to those skilled in the art and are commercially available. For the identification of single-stranded and double-stranded breaks (SSB/DSB), poly(ADP-ribose) polymerase (PARP) is an early key factor in the DNA damage response (DDR). The poly(ADP-ribose) chain is added to chromatin components and factors belonging to DDR using the metabolites NAD ⁺ , PARP-1, and -2, while PARP-3 targets chromatin components via mono-ADP ribosylation. PARP is replenished to DNA damage regions by recognizing structures induced by specific DNA damage changes. It activates PARylation activity, which in turn regulates the activity of PARylation and other DDR and chromatin proteins, thus promoting DDR (Ray Chaudhuri and Nussenzweig, 2017).

This catalytic activity, which can be inhibited by NAD ⁺ analogues, is particularly interesting and clinically applicable to genetically defined cancers. In particular, in cases of BRCA1 or BRCA2 deficiency, so-called PARP inhibitors (PARPi) can be used to treat homologous recombination (HR) deficiency and other cancers through targeted synthesis of lethality. This is believed to occur by reducing PARP activity and/or by biochemically "capturing" PARP-1/2/3 on chromatin (Murai et al., 2012, 2014). Although the molecular definition of "capture" is not yet fully clear, the term refers to the enhanced recruitment, binding, and/or retention of PARP-1/2/3 enzymes in damaged chromatin. This is typically achieved by inducing PARP-1 enzyme activity through treatment with a PARP inhibitor (PARPi) or by reducing the release of PARP-1/2/3 enzymes after initial recruitment, resulting in prolonged retention. This is biochemically demonstrated by the enhanced steady-state binding/retention/entrapment ("capture") of PARP enzymes with damaged genomic regions/locuses.

With the clinical emergence of PARPi, PARP-1 has become a powerful target for an increasing number of cancers, including in combination with immuno-oncology therapies, such as the Lynparza/Keytruda trial, to name just a few. Furthermore, its application in first-line PARPi therapy for germline BRCA-1/2 mutations and in the external environment has become possible.

In a preferred embodiment, the PARPi: (i) reduces PARP activity by being selected from small interfering RNA molecules, and (ii) inhibits PARP1 by being selected from the group consisting of the following compounds: (a) Formula (III). (III) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein: ^III A and ^III B together represent a fused aromatic ring that is substituted as desired; X ^III is NR ^X or CR ^{X RY} ; if X ^III = NR ^X , then n is 1 or 2 and if X ^III = CR ^{X RY} , then n is 1; ^RX is selected from the group consisting of: H, substituted _C1-20 alkyl, _C5-20 aryl, _C3-20 heterocyclic, amide, thioamide, ester, amide, and sulfonyl; ^RY is selected from H, hydroxyl, amino; or ^RX and ^RY together may form a spiro- _C3-7 cycloalkyl or heterocyclic group; R ^C1 and R ^C2 is independently selected from the ^group consisting of: hydrogen and _C1-4 alkyl groups, or when ^XIII is ^CRXRY , ^RC1 , ^RC2 , ^RX , and ^RY , together with the carbon atoms attached to them, to form a fused aromatic ring that is substituted as desired; and ^RIII is selected from H and halogen groups; and (b) formula (IV). (IV) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein: ^IV Y and ^IV Z are each independently selected from the group consisting of: 1. aryl groups substituted with 1, 2, or 3 ^IV R ₆ as desired; 2. heteroaryl groups substituted with 1, 2, or 3 ^IV R ₆ as desired; 3. substituents independently selected from the group consisting of: hydrogen, alkenyl 1 (e.g., _C2-6 -alkenyl), alkoxy (e.g., C1-6-alkoxy), alkoxyalkyl (e.g., _C1-6 -alkoxy- _C1-6 -alkyl), alkoxycarbonyl (e.g., _C1-6 -alkoxy-carbonyl), alkoxycarbonylalkyl (e.g., _C1-6 -alkoxy-carbonyl-C1-6-alkyl), alkyl ₍ e.g., _C1-6 -alkyl), alkynyl (e.g., _C2-6 -alkyl), and alkynyl (e.g., _C2-6 -alkyl). -alkynyl), arylalkyl (e.g., aryl- _C1-6 -alkyl), cycloalkyl (e.g., _C3-8 -cycloalkyl), cycloalkylalkyl (e.g., _C3-8 -cycloalkyl- _C1-6 -alkyl), halogen (e.g., C1-6-halogen), hydroxyalkyl (e.g., hydroxy- _C1-6 -hydroxyalkyl), lateraloxy, heterocycloalkyl (e.g., _{C2-8-heterocycloalkyl), heterocycloalkylalkyl (e.g., C2-8 - heterocycloalkyl} - _C1-6 -alkyl), alkylcarbonyl (e.g., _C1-6 -alkyl-carbonyl), arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl (e.g., _C1-6 -alkyl-sulfonyl), arylsulfonyl, heteroarylsulfonyl, ( _RARB ) alkylyl (e.g., ( _{RARB )} alkylyl _(B ) _-C1-6 -endenyl), (NR _{AR B} ) carbonyl, (NR AR B) carbonylendenyl (e.g., NR _{AR B} ) carbonyl- _C1-6 -endenyl), (NR _{AR B} ) sulfonyl, and (R _{AR B} ) sulfonylendenyl (e.g., (R _{AR B )} sulfonyl- _C1-6 -endenyl); wherein each ^IV R ₆ is selected from OH, NO ₂ , CN, _Br , Cl, F, I, _C1-6 -alkyl, _C3-8 -cycloalkyl, _C2-8 -heterocycloalkyl; _C2-6 -alkenyl, alkoxy (e.g., _C1-6 -alkoxy), alkoxyalkyl (e.g., _{C1-6-alkoxy-C1-6-alkyl), alkoxycarbonyl (e.g., C1-6 - alkoxy} -carbonyl), alkoxycarbonylalkyl (e.g., C1-6 _-... -alkoxy-carbonyl- _C1-6 -alkyl), _C2-6 -alkynyl, aryl, arylalkyl (e.g., aryl- _C1-6 -alkyl), _C3-8 -cycloalkylalkyl (e.g., _C3-8 -cycloalkyl- _C1-6 -alkyl), haloxy (e.g., _C1-6 -haloxy), halyl (e.g., _C1-6 -haloxy), hydroxyalkyl (e.g., hydroxy- _C1-6 -hydroxyalkyl), syloxy, heteroaryl, heteroarylalkoxy (e.g., heteroaryl- _C1-6 -alkoxy), heteroaryloxy, heteroarylthio, heteroarylalkylthio (e.g., heteroaryl- _C1-6 -alkylthio), heterocyclicalkoxy (e.g., _C2-8 -heterocyclicalkoxy), _C2-8 - Heterocyclic alkylthio, heterocyclic alkyl, heterocyclic alkyl, NR _RB , ( _{R RB)C1-6-endenylalkyl, (R RB)carbonyl, (R RB)carbonylendenylalkyl (e.g., R RB)carbonyl-C1-6-endenylalkyl), (R RB ) sulfonyl , and ( R RB ) sulfonylendenylalkyl ( e.g. , (R RB ) sulfonyl} - _C1-6 -endenylalkyl); ^IVR1 , ^IVR2 , and ^IVR3 are each independently selected from the group consisting of: _hydrogen , halogen, alkenyl (e.g., _C2-6 -alkenyl), alkoxy (e.g., C1-6-alkoxy), alkoxycarbonyl (e.g. _{, C1-6} -alkoxy-carbonyl), alkyl (e.g., _C1-6-6 -alkyl-carbonyl), and alkyl (e.g., _C1-6 -alkyl-carbonyl ₎ . -alkyl), cycloalkyl (e.g., _C3-8 -cycloalkyl), alkynyl (e.g., _C2-6 -alkynyl), cyano, haloxy (e.g., _C1-6 -haloxy), halyl (e.g., _C1-6 -haloxy), hydroxyl, hydroxylyl (e.g., hydroxyl- _C1-6 -hydroxyl), _nitro , NR _RB , _{NR RB} alkyl ( _{e.g., NR RB C1-6 -} hydroxyl), and ( _{RARB )} carbonyl; ^IVA and ^IVB are each independently selected from hydrogen, Br, Cl, F, I, OH, _C1-6 -alkyl, _C3-8- cycloalkyl, alkoxy (e.g., _C1-6 -alkoxy), alkoxyalkyl (e.g., _C1-6 -alkoxy- _C1-6 -alkyl), wherein _C1-6 -alkyl, C _3-8- cycloalkyl, alkoxy, and alkoxyalkyl are, as desired, substituted with at least one of the following substituents: OH, _NO₂ , CN, Br, Cl, F, I, C₁ _-6 -alkyl, and C₃ _-8 -cycloalkyl, wherein ^IV B is not OH; _RA and _RB are independently selected from the following groups: hydrogen, alkyl (e.g., C₁ _-6 -alkyl), cycloalkyl (e.g., C₃ _-8 -cycloalkyl), and alkylcarbonyl (e.g., C₁ _-6 -alkyl-carbonyl); or _RA and _RB, together with the atoms to which they are attached, form, as desired, 3-10 member heterocycles with one to three heteroatoms or heterofunctionalities selected from the following groups: -O-, -NH, -N(C₁ _-6 -alkyl)-, -NCO(C₁ _{- 6-} alkyl)-. -alkyl)-, -N(aryl)-, -N( _aryl - _C1-6 -alkyl-), -N(substituted aryl- _C1-6 -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- _C1 - _C6 -alkyl-)-, -N(substituted heteroaryl-C1-6-alkyl-)-, and -S- or S(O)q-, where q is 1 or 2 and 3-10 members of the heterocyclic system are substituted with one or more substituents as needed; ^IV R ₄ and ^IV R ₅ are each independently selected from the group consisting of: hydrogen, alkyl (e.g., _C1-6 -alkyl), cycloalkyl (e.g., _C3-8 -cycloalkyl), alkoxyalkyl (e.g., C1-6-alkoxy-C1-6-alkyl), _halogen (e.g., _C1-6 -alkyl- _{C1-6-alkyl), and alkyl (e.g., C1-6-alkyl-C1-6} -alkyl ₎ . -Halogen), hydroxylyl (e.g., hydroxyl- _C1-6 -endyl), and ( _{NRAR B} )endyl (e.g., _{NRAR B C1-6} -endyl); (iii) The inhibitors of PARP1 and PARP2 are selected from the group consisting of the following compounds: (a) Formula (V) (V) and its isomers, salts, solvent compounds, chemically protected forms, and precursors, wherein: ^VR1 is hydrogen or fluorine _; and ^VR2 is hydrogen or fluorine; _and (b) formula (VI). (VI) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein: ^VI _R1 , ^VI _R2 , and ^VI _R3 are independently selected from the group consisting of: hydrogen, alkenyl (e.g., _C1-6 -alkenyl), alkoxy (e.g., _C1-6 -alkoxy), alkoxycarbonyl (e.g., _C1-6 -alkoxycarbonyl), alkyl (e.g., _C1-6 -alkyl), alkynyl (e.g., _C1-6 -alkynyl), _cyano , halogenalkoxy (e.g., C1-6-halogenalkoxy), halogen (e.g., _C1-6 -halogenyl), halogen, hydroxyl, hydroxyalkyl (e.g., _C1-6 - _{hydroxyalkyl), nitro, NRAR B ,} and ( _{NRAR B} )carbonyl; ^VI A is a non-aromatic 4, 5, 6, 7, or 8-membered ring containing one or two nitrogen atoms and, if desired, one sulfur or oxygen atom, wherein the non-aromatic ring is, if desired, substituted with one, two, or three substituents selected from the group consisting of: alkenyl (e.g., _C1-6 -alkenyl), alkoxy (e.g., _C1-6 -alkoxy), alkoxyalkyl (e.g., _C1-6 -alkoxy- _C1-6 -alkyl), alkoxycarbonyl (e.g., _C1-6 -alkoxycarbonyl), _{alkoxycarbonylalkyl} (e.g., _C1-6 -alkoxycarbonyl-C1-6-alkyl), alkyl (e.g., C1-6-alkyl), ynyl (e.g., C1-6-ynyl), aryl, arylalkyl ( _e.g. , aryl- _C1-6 -alkyl), cycloalkyl (e.g., _C3-8 -cycloalkyl), cycloalkylalkyl ( _e.g. , _C3-8 -cycloalkyl-C1-6-alkyl). _1-6 -alkyl), cyano, halogenated alkoxy (e.g., _C1-6 -halogenated alkoxy), halogenated (e.g., _C1-6 -halogenated alkyl), halogen, heterocyclic, heterocyclic alkyl (e.g., heterocyclic- _C1-6 -alkyl), heteroaryl, heteroarylalkyl (e.g., heteroaryl- _C1-6 -alkyl), hydroxyl, hydroxyl (e.g., _C1-6 -hydroxyl), nitro, NRCR _D , (NRCR _D ) alkyl (e.g., (NRCR _D ) _-C1-6 -alkyl), (NRCR _D ) carbonyl, (NRCR _D ) carbonylalkyl (e.g., (NRCR _D ) carbonyl- _C1-6 -alkyl), and (NRCR _D ) sulfonyl; and _RA , _RB , RC, and R _D is independently selected from the following groups: hydrogen, alkyl (e.g., _C1-6 -alkyl), and alkylcarbonyl (e.g., _C1-6 -alkylcarbonyl). (iv) Its inhibitors PARP1, PARP2, and PARP3 are compounds of formula (VII). (VII) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein: ^VII R ₁ is: H; halogen; cyano; alkyl (e.g., _C1-6 -alkyl), alkenyl (e.g., _C2-6 -alkenyl), ynyl (e.g., _C2-6 -ynyl), cycloalkyl (e.g., _C3-8 -cycloalkyl), heterocycloalkyl (e.g., _C2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, and amino, alkoxy (e.g., _C1-6 -alkoxy), alkyl (e.g., _C1-6 -alkyl), ... -alkyl), and aryl, which are unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, carboxyl, and, where appropriate, substituted with amino and ether groups (such as O-aryl); or -C(O) _-R10 , wherein _R10 is: H; substituted with alkyl (e.g., _{C1-6-alkyl), alkenyl (e.g., C1-6-alkenyl), ynyl (e.g., C1-6} -ynyl), cycloalkyl (e.g., C3-8-cycloalkyl), heterocycloalkyl (e.g., C2-8-heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, amino, and alkyl (e.g., _C1-6 -alkyl), ... alkyl (e.g., _C3-8 -cycloalkyl), alkyl (e.g., _C3-8 -cycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, carboxyl, and, where appropriate, alkyl (e.g., _C1-6 -alkyl), alkyl (e.g., C3-8-cycloalkyl), alkyl (e.g., C3-8-cycloalkyl), alkyl (e.g., C3-8-cycloalkyl), alkyl (e.g., _C3-8 -cycloalkyl), -alkyl) and aryl, which are unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, and amino); or OR ₁₀₀ or NR ₁₀₀ R ₁₁₀ , wherein R ₁₀₀ and R ₁₁₀ are each independently H or, as desired, alkyl (e.g., _C1-6 -alkyl), alkenyl (e.g., _C2-6 -alkenyl), ynyl (e.g., _C2-6 -ynyl), cycloalkyl (e.g., C3-8-cycloalkyl), heterocycloalkyl (e.g., _C2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from: alkyl (e.g., _C1-6 -alkyl), alkenyl (e.g., _C2-6 -alkenyl), ynyl ( _e.g. , C2-6-ynyl), cycloalkyl (e.g., _C3-8- ... _C3-8 -alkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from -cycloalkyl), heterocycloalkyl (e.g., _C2-8 -heterocycloalkyl), aryl, and heteroaryl, unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, amino, and alkyl (e.g., _C1-6 -alkyl) and aryl unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, and substituted amino as desired); ^VII R ₂ is H or alkyl (e.g., _C1-6 -alkyl); ^VII R ₃ is H or alkyl (e.g., _C1-6 -alkyl); ^VII R ₄ is H, halogen, or alkyl (e.g., _C1-6 -alkyl); ^VII X is O or S; Y is (C ^VII R ₅ ^VII R ₆ )(C ^VII R ₇ ^VII R ₈ ) _n or NC ( ^VII R ₅ ), where n is 0 or 1; ^VII R ₅ and ^VII R ₆ are each independently H or, as desired, substituted alkyl (e.g., _C1-6 -alkyl), alkenyl (e.g., _C2-6 -alkenyl), ynyl (e.g., _C2-6 -ynyl), cycloalkyl (e.g., _C3-8 -cycloalkyl), heterocycloalkyl (e.g., _C2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, amino, and lower alkyl (e.g., _C1-4 -alkyl), lower alkoxy (e.g., _C1-4 -alkoxy), or aryl, unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, and amino); and ^VII R ₇ and ^VII R _8. Each of the following is independently H or, as desired, alkyl (e.g., _C1-6 -alkyl), alkenyl (e.g., _C2-6 -alkenyl), ynyl (e.g., _C2-6 -ynyl), cycloalkyl (e.g., _C3-8 -cycloalkyl), heterocycloalkyl (e.g., _C2-8 -heterocycloalkyl), aryl, or heteroaryl (e.g., unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, amino, and lower alkyl (e.g., _C1-4 -alkyl), lower alkoxy (e.g., _C1-4 -alkoxy), and aryl, unsubstituted or substituted with one or more substituents selected from: halogen, hydroxyl, nitro, and amino); wherein when ^VII _R1 , ^VII _R4 , ^VII _R5 , ^VII _R6 , and ^VII _R7 are each H, ^VII R ₈ is not an unsubstituted phenyl group.

In one preferred embodiment of the present invention, PARPi is selected from the group consisting of: AZD-5305, olaparib, talazoparib, niraparib, pamiparib, rucaparib, and veliparib, particularly the group consisting of: olaparib, talazoparib, niraparib, pamiparib, rucaparib, and veliparib.

In one preferred embodiment of the invention, ALC1i and an inhibitor of topu isomerase I, topu isomerase II, ATM, ATR, Wee1, BRD, MEK, or an inhibitor of PARP, or mitomycin C, paclitaxel, free radiation, or an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor are administered simultaneously or subsequently.

In the third state, the invention relates to a pharmaceutical composition comprising an inhibitor of ALC1i and topological isomerase I, topological isomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or mitomycin C, or paclitaxel, or an antibody-drug conjugate of a tumor-specific antibody conjugated with a TOP1 inhibitor, preferably for the treatment and/or improvement of proliferative diseases, preferably cancer.

In the fourth embodiment, the invention relates to a kit of parts comprising, as described herein, an instruction manual for combining ALC1i with an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or mitomycin C, or paclitaxel, or free radiation, or an antibody-drug conjugate containing a tumor-specific antibody conjugated with a TOP1 inhibitor, or an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or mitomycin C, or Instructions for use for the treatment or improvement of proliferative diseases (preferably cancer) may be provided, as needed, for the treatment or improvement of proliferative diseases (preferably cancer).

In a preferred embodiment of all embodiments of the present invention, the ALC1i used is a compound of formula (I) or formula (II), more preferably a compound having the structure shown in Figure 1, or an isomer thereof, a pharmaceutically acceptable salt, a solvent, a chemically protected form, or a prodrug. A preferred pharmaceutically acceptable salt is a sodium salt.

In a preferred embodiment, the assembly of ALC1i as defined above, the pharmaceutical composition as defined above, and/or the parts as defined above is for the treatment or improvement of proliferative diseases, preferably cancer, and more preferably proliferative diseases selected from: BRCA-1 and/or BRCA-2-deficient tumors, and/or the proliferative disease selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, or pancreatic cancer.

BRCA1 and BRCA2 proteins are involved in promoting homologous recombination (HR)-mediated DNA repair and controlling the stability of arrested 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 exhibit a potential loss of BRCA1 or BRCA2 activity. This loss is usually due to germline or somatic mutations in the BRCA1 or BRCA2 genes. These tumors, with a potential loss of HR repair, are generally sensitive to PARP inhibitors. However, they develop PARP inhibitor resistance over time. For the treatment of these tumors, the use of ALC1i according to the present invention is particularly suitable, whether used alone or in combination with PARP inhibitors. In a preferred embodiment of the ALC1i used according to the present invention, or of a pharmaceutical composition or kit according to the present invention, the proliferative disease is selected from cancer.

As used herein, the term "cancer," preferably tumor (also known as a neoplasm), and especially solid tumor, refers to cells capable of autonomous growth. Examples of such cells include those exhibiting abnormal conditions or characterized by rapid cell proliferation. The term implies the inclusion of cancerous growth, such as tumors; carcinogenic processes, metastatic tissues, and malignant transformations of cells, tissues, or organs, regardless of histopathological type or stage of invasion. This also includes malignant tumors of various organ systems (such as the respiratory, cardiovascular, renal, reproductive, hematopoietic, nervous, hepatic, gastrointestinal, and endocrine systems); and adenocarcinomas, including malignant tumors such as most colon cancers, renal cell carcinomas, prostate cancers and/or testicular tumors, non-small cell lung cancer, and small bowel cancer. "Naturally occurring" cancers include any cancer that is not experimentally induced by implanting cancer cells into an individual, such as spontaneously occurring cancers, cancers caused by patient exposure to carcinogens, cancers caused by the insertion of transgenic oncogenes or the knockout of tumor suppressor gene genes, and cancers caused by infections (such as viral infections). The term "cancer" is recognized in this technique as referring to a malignant tumor of epithelial or endocrine tissue. This term also includes carcinosarcoma, which comprises malignant tumors composed of both cancerous and sarcomatous tissue. "Adenocarcinoma" refers to a cancer originating from glandular tissue or tumor cells forming identifiable glandular structures. The term "sarcoma" is recognized in this technique as referring to a stromal-derived malignant tumor. The term "hematopoietic endothelial disease" includes diseases involving proliferative/endothelial cells of hematopoietic origin. Hematopoietic endothelial diseases can originate from myeloid, lymphoid, or erythroid cells, or their precursor cells.

In some embodiments of the present invention, the cancer includes breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), gastric cancer, gastroesophageal cancer, non-small cell lung cancer, bladder cancer, endometrial cancer, brain cancer (especially astrocytoma or glioma), cervical cancer, kidney cancer (especially RCC), thyroid cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanoma. In some embodiments, the cancer includes basal-like carcinoma, basal-like breast cancer, triple-negative breast cancer, high-grade cancer, or high-grade serous ovarian cancer cells. In one preferred embodiment of the various embodiments of the present invention, the cancer is breast cancer, prostate cancer, pancreatic cancer, fallopian tube cancer, colorectal cancer, hepatocellular carcinoma, or bone cancer (preferably osteosarcoma). In one preferred embodiment, the cancer is selected from the group consisting of: ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, castration-resistant prostate cancer, and pancreatic duct adenocarcinoma, especially metastatic ovarian cancer, metastatic fallopian tube cancer, metastatic primary peritoneal cancer, metastatic breast cancer, metastatic castration-resistant prostate cancer, and metastatic pancreatic duct adenocarcinoma.

In some embodiments of the present invention, the cancer to be treated has at least one mutation in a homologous recombination (HR) gene, i.e., it is an HR-deficient cancer. An HR-deficient cancer refers to a cancer having at least one cell with an abnormal level or activity of the HR gene. Such abnormal levels or activities interfere with normal HR gene function and can lead to the loss of HR-mediated DNA repair or reduced replication fork stability. In a preferred embodiment, the cancer to be treated is BRCA1-deficient and/or BRCA2-deficient. A BRCA1-deficient or BRCA2-deficient cancer refers to a cancer having one or more cells with abnormal BRCA1 levels or activity, or abnormal BRCA2 levels or activity. These abnormal levels or activities can interfere with the normal function of BRCA1 or BRCA2 and may lead to the loss of HR-mediated DNA repair or reduced stability of replication forks. Preferably, the proliferative disease is selected from BRCA-1 and/or BRCA-2-deficient tumors, and/or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, or pancreatic cancer.

Preferred examples of cancers that can be treated according to the present invention include ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, pancreatic cancer, stomach cancer, colorectal cancer, and lung cancer.

Preferred examples of treatable cancers according to the present invention include ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, and pancreatic cancer. Preferably, the cancer is a metastatic cancer, especially stage IV cancer.

Preferably, the cancers of various forms according to the invention have relapsed or progressed, preferably after first-line chemotherapy. Therefore, preferably, the combination according to the invention is used as a second- or third-line therapy, and more preferably as a second- or third-line therapy for treating HR-deficient cancers.

Ideally, the cancer to be treated is stage III (locally advanced) or stage IV (metastatic).

Preferably, the cancers to be treated according to various embodiments of the present invention have a potential deficiency in DNA damage repair (such as HR repair, e.g., HR deletion repair), i.e., HR-deficient cancers (HRD cancers), particularly HR-deficient ovarian cancer, HR-deficient fallopian tube cancer, HR-deficient primary peritoneal cancer, HR-deficient breast cancer, HR-deficient (castration-resistant) prostate cancer, or HR-deficient pancreatic cancer, such as pancreatic duct adenocarcinoma (mPDAC). In a particularly preferred embodiment, these cancers are advanced or metastatic, preferably metastatic. In one embodiment, cancer cells undergo mutations/deletions/insertions in one or more DNA repair genes listed in Figures 8 and/or 9, particularly ARID1A, ATM, ATRX, BAP1, BLM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, RAD51, RAD51B, and/or WRN. BRCA1/2 is preferred.

In one implementation, cancers or cancer patients are selected for treatment based on the presence of tumor markers. In a clinical setting, cancer/patient selection will include, but is not limited to, eligible tumor biomarkers, namely, noxious mutations including: ARID1A, ATM, ATRX, BAP1, BLM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, RAD51, RAD51B and/or WRN (preferably), BRCA1/2 being optimal, and/or other gene variants in the HR pathway as listed in Figures 8 and/or 9.

In a preferred embodiment, ACL1i is used in combination with several classes of cancer drugs (i.e., inhibitors of topoisomerase I, preferably irinotecan, more preferably in the form of its active metabolites SN-38, topoisomerase II, ATM, ATR, Wee1, BRD, and MEK), or in combination with mitomycin C paclitaxel, or with an antibody-drug conjugate of a tumor-specific antibody conjugated with free radiation or a TOP1 inhibitor, for the treatment or improvement of a patient’s proliferative disease (particularly cancer). Preferably, the cancer is HR-deficient carcinoma, particularly BRCA-1 and/or BRCA-2-deficient. The preferred ALC1i used are ALC1i-2, ALC1i-160, ALC1i-101, or ALC1i-123, or their pharmaceutically acceptable salts, isomers, solvents, chemically protected forms, or prodrugs. ALC1i-2 or ALC1i-101, or their pharmaceutically acceptable salts, isomers, solvents, chemically protected forms, or prodrugs, are preferred, with ALC1i-101 being the best. The best pharmaceutically acceptable salt is a sodium salt. Ideally, use the sodium salt of ALC1i-101. As needed, cancers excluding pancreatic cancer are excluded, especially when an ACL1i is used in combination with irinotecan or SN-38.

In a preferred embodiment, an ACL1i is an antibody-drug conjugate that binds to a tumor-specific antibody against a TOP1 inhibitor, preferably in combination with one of the cancer drugs listed above (such as trastuzumab deruxtecan, datopotamab deruxtecan (preferably), or sacituzumab deruxtecan). The combination of govitecan is used to treat or improve proliferative diseases, particularly cancers such as HR-deficient cancers, especially BRCA-1 and/or BRCA-2-deficient cancers. Preferred cancers include hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer, or pancreatic cancer. Advanced or metastatic cancers are preferred, with the latter being considered superior. The preferred ALC1i used are ALC1i-2, ALC1i-160, ALC1i-101, or ALC1i-123, with ALC1i-2 or ALC1i-101 being the most preferred, the latter being the best.

Preferably, the patients to be treated according to the various embodiments of the present invention are cancer patients, preferably suffering from cancers as defined above, such as breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanoma, more preferably ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, and pancreatic cancer, and, if necessary, having mutations/deletions/insertions in one or more HR genes (preferably BRCA1/2) as listed in Figures 8 and/or 9. In a particularly preferred embodiment, the cancer patient has HR-deficient cancer, particularly BRCA-1 and/or BRCA-2-deletion. As needed, excluding patients with pancreatic cancer, especially when ACL1i is used in combination with irinotecan or SN-38.

Preferably, the patients to be treated according to the various forms of the present invention are cancer patients, more preferably those suffering from cancers as defined above, such as breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, gastroesophageal cancer, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanosis. The patient has a tumor, preferably ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, or pancreatic cancer, preferably HR-deficient cancer, and is currently receiving or has received at least one of the aforementioned cancer treatments, preferably using a drug in combination with an ACL1i as defined above, and the patient typically shows no or only partial or unsatisfactory response after several treatment cycles. In a preferred embodiment, prior cancer treatment includes administration of an antibody-drug conjugate of at least one tumor-specific antibody that conjugates to a TOP1 inhibitor (such as trastuzumab deruxtecan, datopotamab deruxtecan (which is preferred), or sacituzumab govitecan).

In a preferred embodiment, ALC1i as defined above, in a pharmaceutical composition as defined above, and/or in a kit of parts as defined above, ACL1i can be combined with any of the following: adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, talazoparib, trastuzumab deruxtecan, datopomab deruxtecan. deruxtecan), and/or sacituzumab govitecan.

In a preferred embodiment, ACL1i, as defined above, in a pharmaceutical composition as defined above, and/or in a kit of parts as defined above, is administered orally, preferably in tablets or capsules. Experimental Section: Combination Therapy of ALC1 with Other Drugs for ALC1 Inhibitors

ALC1 is an ectopically regulated chromatin remodeling agent that relaxes chromatin and plays an important role in responding to DNA damage. It involves different repair pathways such as nucleotide excision repair or base excision repair and is known to regulate replication fork progression at the site of DNA damage (Ooka et al., 2018).

By inhibiting ALC1 using a specific small molecule (ALC1i) according to this invention, DNA damage accumulation is enhanced by making chromatin less accessible to DNA repair enzymes, leading to inefficient DNA repair. Disrupting ALC1's chromatin remodeling capacity through ALC1i enables highly selective treatment of several cancer types. Treatment of cancer cells with ALC1i results in increased _γH2AX protein levels, a marker of DNA damage (see Figure 6). Surprisingly, in our study, ALC1i treatment of cancer cells led to cell cycle arrest in the G2 phase (see Figure 5), similar to the effect of the PARP1/2 inhibitor olaparib, which also induces DNA damage and leads to increased G2 and M phases (Zhao et al., 2018, Wu et al., 2018). Topology isomerase 1 inhibitors

Topological isomerase 1 (TOP1) is involved in the relaxation of supercoiled DNA. It removes the helical constraints that hinder DNA replication and transcription (GILMOUR, 1986).

Instantaneous single-strand breakage in the double helix structure leads to DNA channel events or controlled rotation around DNA breakage (Wang, 1996).

During the topological isomerase reaction, TOP1 forms a covalently linked intermediate (TOP1-DNA-cleavage conjugate, TOP1cc) with the 5′ phosphate group of DNA. In this process, TOP1 is covalently captured on DNA, resulting in toxic DNA damage (Takahashi et al., 2010).

Loss of TOP1 function leads to impaired cell proliferation. Under normal conditions, it is crucial to maintain a balance between the utilization of TOP1 catalytic activity to preserve DNA topology and the accumulation of toxic DNA damage due to TOP1 capture (Li & Liu, 2016).

Topoisomerase 1 inhibitors interrupt DNA replication and induce DNA breaks, leading to reduced proliferation and cytotoxicity.

Irinotecan, also known as IUPAC (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxy-1H-piperano[3′,4′:6,7]-into[1,2-b]quinoline-9-yl-[1,4′-bipiperidine]-1′-carboxylic acid ester, is a TOP1 inhibitor (TOP1i) analogue of the naturally occurring alkaloid camptothecin. Also known as CPT-11, irinotecan is currently marketed in aqueous solution form such as Camptosar® (irinotecan hydrochloride injection). Irinotecan inhibits uncontrolled cell growth by inhibiting DNA unwinding and thus preventing DNA replication. The active metabolite of irinotecan is SN-38.

Topotecan (IUPAC: (19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20] tetoc-1(21),2,4(9),5,7,10,15(20)-hepten-14,18-dione) is TOP1i, which leads to the stability of TOP1-DNA covalent conjugates during the S phase. The mediated single-strand breakage cannot rejoin and develop into DNA double-strand breakage ( NCBI- Topotecan , nd-a) .

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody linked via a tetrapeptide-based cleavable linker to an effective topoisomerase I inhibitor. According to the invention, ADCs containing a topoisomerase I inhibitor are also considered to fall within the scope of topoisomerase I inhibitors used in combination with the ALC1i according to the invention. The combination of the ALC1i used according to the invention and datopotamab deruxtecan is preferred, particularly for the treatment of (e.g., triple-negative) breast cancer or non-small cell lung cancer. Synergistic effect of topoisomerase 1 inhibitors and ALC1i

Inhibition of TOP1 leads to DNA nicks and resealing during replication, which is associated with DNA relaxation. DNA strands break due to the collapse of replication forks (Holm, 1989).

Inhibition of ALC1 above TOP1 not only promotes replication fork disruption but also leads to an additional accumulation of DNA damage that cannot be repaired due to alterations in chromatin accessibility or recombination. It is hypothesized that, through this mechanism, co-administration of ALC1i with topotecan or other TOP1i will result in an additive effect on cancer cell proliferation. As demonstrated in this paper with other oncologists, ALC1i compounds are known to exhibit additive synergistic effects. In contrast, surprisingly, a synergistic inhibition of cancer cell proliferation was observed with the combination of the present invention.

Therefore, according to the present invention, ALC1 inhibitors synergistically influence the cellular response to DNA damage induced by TOP1i via a specific ALC1i. Thus, the inventors have determined that the combination of TOP1i and a specific ALC1i synergistically enhances the effects of both inhibitors. Since the TOP1i totopotecan shows a high MSA score when combined with the specific ALC1i used according to the present invention, this is expected to be the case with other TOP1i as well. Therefore, the combination of ALC1i and TOP1i used according to the present invention is preferred, particularly for the treatment of colorectal cancer. Topoisomerase 2 inhibitors

Topological isomerase 2 (TOP2) controls DNA entanglement and supercoiling. It allows one double helix to pass through another double helix, unwinding DNA by simultaneously cutting both strands of the DNA helix (Holm, 1989). This results in an increase/decrease of two units in the number of DNA loops, thereby promoting chromosome unwinding.

As an intermediate step in this process, transient double-strand breaks in DNA can occur, potentially leading to toxic genome fragments (McClendon & Osheroff, 2007).

TOP2 enzymes are involved in many DNA processes, including recombination, chromatin condensation/de-condensation of daughter chromosomes. TOP2-DNA cleavage conjugates are crucial for cellular function. Insufficient levels of these conjugates lead to mitotic failure, while excessive levels cause transient doublet breaks to become permanent doublet breaks, thus inhibiting the initiation of fundamental DNA processes that initiate various recombination and repair pathways (Fortune & Osheroff, 2000).

TOP2 inhibitors such as etoposide, doxorubicin, or teniposide increase the content of TOP2-DNA cleavage conjugates and can be used as first-line treatment for several solid tumors.

Teniposide (IUPAC: (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-phenylthio-2-yl-4,4a,6,7,8,8a-hexahydropiperano[3,2-d][1,3]dichloro-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofurano[6,5-f][1,3]benzodioxol-8-one) is a TOP2i with antitumor activity. It forms a conjugate with TOP2 and DNA, leading to DNA strand breakage; inhibition of DNA-protein crosslinking and DNA strand reconnection. It functions in the late S and early G phases of the cell cycle ( NCBI- Teniposide , nd-b ). Synergistic effect of topoisomerase 2 inhibitors with ALC1i.

Inhibition of TOP2 by TOP2 toxins leads to DNA double-strand breaks, thereby activating DNA recombination and repair processes, which require the DNA damage repair protein ALC1. Therefore, it can be hypothesized that additional inhibition of ALC1 by small molecule inhibitors will lead to the accumulation of DNA damage that cannot be repaired. Thus, the combination of ALC1i with teniposide, etoposide, or other TOP2i may lead to an increased cancer cell killing rate.

This assumption leads to a part of the present invention, which states that the ALC1 inhibitor of a specific ALC1i used in the present invention synergistically affects the cellular response induced by the TOP2i teniposide. Therefore, the inventors have determined that the combination of a TOP2 inhibitor and the ALC1 inhibitor of the present invention synergistically enhances the effects of both inhibitors. ATM inhibitor

The ataxia telangiectasia mutant (ATM) is a serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase-associated kinase (PIKK) family of protein kinases. ATM, along with its downstream target Chk2, is a major signaling pathway for DNA double-strand break (DSB) activation. In the DSB reaction, activated ATM collaborates with MRN conjugates, CtIP, and MRE11 to initiate femoral excision to produce single-stranded DNA (ssDNA) (You et al., 2009). This ssDNA forms the initiation receptor for homologous recombination repair (HRR) and activates a platform for the activation of the ATR-Chk1 pathway (Mimitou & Symington, 2009), a direct effector of multiple DNA damage and replication checkpoints. Consistent with its crucial role in maintaining genome integrity, genetic defects in ATM in humans and mice predispose them to lymphoma and radiation sensitivity (Shiloh & Kastan, 2001, Xu et al., 1996). Given that radiation and virtually all genotoxic anticancer agents have been observed to effectively activate the ATM-Chk2 signaling pathway, it is of interest whether this stimulation can pharmacologically manipulate ATM to enhance the efficacy of knowledge therapy.

AZ-32 (IUPAC: N -methyl-4-(6-phenylimidazo[1,2-a]pyridine-3-yl)benzamide) is an orally bioavailable ATM inhibitor that blocks the DNA damage response. It exhibits good blood-brain barrier penetration, in vitro radiosensitization of glioma cells, and improved survival in an in situ mouse model.

AZD-0156 (IUPAC: 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(tetrahydropyrano(oxan)-4-yl)imidazo[4,5-c]quinolin-2-one) is a first-in-class, orally bioavailable ATM inhibitor. It is a highly soluble, permeable compound with excellent proclinical pharmacokinetic properties. In a mouse xenograft model, AZD-0156 also showed efficacy when administered orally in combination with a DSB inducer. Further clinical evaluation is currently underway.

AZD-1390 (IUPAC: 7-fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-1-propyl-2-ylimidazo[4,5-c]quinoline-2-one) is an orally bioavailable ATM inhibitor. It effectively crosses the blood-brain barrier. In in vivo, syngeneic and patient-derived gliomas, as well as in the orthotopic lung-brain metastasis pattern, AZD-1390 sensitizes tumors to radiotherapy. Synergistic effect of ATM inhibitors with ALC1i .

Synthetic lethal mechanisms have been successfully applied in cancer treatment, such as PARP inhibitors for patients with BRCA1/BRCA2 mutations. Increasing evidence supports the view that deletions of many other HRR genes also sensitize tumor cells to PARP inhibitors (McCabe et al., 2006). In particular, human and mouse cells with ATM deletions are also sensitive to PARP inhibition (Löser et al., 2010, Williamson et al., 2010). Therefore, it can be hypothesized that ATM inhibitors enhance BRCAness in tumor cells through a similar mechanism and have a synergistic effect with ALCi.

ATMi causes DNA damage accumulation similar to ALC1i. Therefore, it can be hypothesized that the combination of ATMi and the ALC1i of this invention leads to a significant increase in unrepaired DNA and enhances cancer cell killing. ATR inhibitors

ATR (Adysmolar capillary dilation mutant (ATM) and Rad3-related protein kinase, a serine/threonine protein kinase upregulated in various cancer cell types) plays a crucial role in DNA repair, cell cycle progression, and cell survival. ATR is an important component of the DNA damage response (DDR) (Williamson et al., 2016). It induces homology recombination (HR)-dependent repair (Kim et al., 2016). ATR is responsible for signaling single-stranded DNA (ssDNA) (primarily due to replication stress (RS)) to S and G2/M checkpoints and for DNA repair; it is one of the key G2 checkpoint regulators (Bradbury et al., 2022). Furthermore, ATRs are essential regulators of immune checkpoint proteins (such as PD-L1) that respond to DNA damage. Inhibition of ATRs in tumor cells can increase the sensitivity of tumor cells to genotoxic agents and/or lead to cell death through apoptosis or cellular senescence (Barnieh et al., 2021).

Ceralasertib (AZD6738, CAS No. 1352226-88-0, CHEMBL4285417, AZD-6738, IUPAC name: imino-methyl-[1-[6-[( 3R )-3-methylmorpholin-4-yl]-2-( 1H -pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-sideoxy- ^λ6 -thione) is a morpholinopyrimidine-based inhibitor of ATR kinase with potential antitumor activity. After oral administration, ceralasertib selectively inhibits ATR activity by blocking downstream phosphorylation of serine/threonine protein kinase CHK1. This blockade of ATR-mediated signaling leads to inhibition of DNA damage checkpoint activation, disruption of DNA damage repair, and induction of tumor cell apoptosis. Furthermore, ceralasertib sensitizes tumor cells against chemotherapy and radiation therapy ( NCBI- ceralasertib, nd-c).

Elimusertib (CAS No. 1876467-74-1, elimusertib, BAY-1895344, BAY 1895344, BAY1895344 IUPAC: ( 3R )-3-methyl-4-[4-(2-methylpyrazol-3-yl)-8-( 1H -pyrazol-5-yl)-1,7-monidin-2-yl]morpholine) is an orally administered ATR-specific kinase inhibitor with potential antitumor activity. After oral administration, elimusertib selectively binds to and inhibits ATR activity, blocking ATR-mediated signaling. This inhibitor suppresses DNA damage checkpoint activation, disrupts DNA damage repair, and induces apoptosis in ATR-overexpressing tumor cells ( NCBI - Eliminatorib, nd-d). Synergistic effect of ATR inhibitors with ALC1i .

ATR-specific activation of large numbers of single-stranded DNA structures (ssDNA) (Barnieh et al., 2021b). ALC1 inhibition of ALC1 leads to impaired single-stranded DNA breakage repair, requiring activation of the ATR pathway to initiate this DNA repair. Given the dependence of ALC1 inhibitors on ATR activity, it can be hypothesized that ATR inhibitors and the specific ALC1 inhibitor used in this invention will exhibit synergistic anti-proliferative effects. Synergistic tests using the ALC1 inhibitor used in this invention, along with ceralasertib and elimusertib, confirm that ALC1 inhibition and ATR inhibition using the compounds of this invention have a synergistic effect. Wee1 inhibitor

WEE1, a G2 checkpoint kinase, plays a crucial role in cell cycle regulation and DNA damage recognition/repair. Its primary downstream target is the CDK1 B1 conjugate. Dysregulation of WEE1 in cancer cells weakens cell cycle regulation and allows for high proliferation rates. Therefore, overexpression of kinases like WEE1 in DDR is fundamental to maintaining gene stability (Ghelli Luserna di Rorà et al., 2020). Deactivation of p53 allows for complete cell cycle regulation by the G2/M checkpoint.

Inhibition of WEE1 leads to damage to the G2 DNA damage checkpoint. Following treatment with DNA-damaging agents, inhibition of WEE1 can prevent phosphorylation of cell cycle-dependent kinase 1 (CDK1, CDC2) and may lead to apoptosis. Cells lacking the cell cycle checkpoint G1, like most p53-deficient cancer cells, rely on the G2 checkpoint in the presence of DNA damage. Failure of the G2 checkpoint can sensitize p53-deficient tumors to antitumor agents and enhance their cytotoxicity.

Adavosertib (MK-1775, AZD 1775, IUPAC name: 1-[6-(2-hydroxypropyl-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-propyl-2-enylpyrazolo[3,4-d]pyrimidin-3-one) is a small molecule inhibitor of WEE1. It selectively targets tyrosine kinase to deactivate the CDC2/cycle protein B conjugate. It has been used to treat tumors, ovarian cancer, glioblastoma, and other tumors ( NCBI- adavosertib, nd-e). Synergistic effect of WEE1 inhibitors with ALC1i .

Cells treated with adavosertib exhibited a cell cycle arrest phenotype, leading to reduced proliferation. As shown in Figure 5, this effect was reflected in ALC1 inhibition, leading the authors to hypothesize that co-treatment with a WEE1 inhibitor and an ALC1 inhibitor would drastically reduce the number of cells escaping cell cycle arrest, resulting in a synergistic anti-proliferative effect. Co-treatment with a specific ALC1 inhibitor and the WEE1 inhibitor adavosertib in this invention confirmed this hypothesis. ( BRD inhibitor )

Bromodomains are evolutionarily conserved motifs that bind acetylated lysine from histone tails and recruit transcriptional mechanisms that promote the transcription of target genes. Bromodomain repressors prevent the interaction between the bromodomain and the acetyl group, thereby leading to the downregulation of certain genes (Pérez-Salvia & Esteller, 2016).

BAY-299 (C25H23N3O4, BAY-299, 2080306-23-4, BAY 299, BAY299, CHEMBL4086276, IUPAC: 6-(3-hydroxypropyl)-2-(1,3,6-trimethyl-2-sideoxybenzimidazol-5-yl)benzi[de]isoquinoline-1,3-dione) ( NCBI BAY-299, nd-f) is a dual inhibitor of bromodomain and PHD finger (BRPF) family member BRPF2, as well as TATA box-binding protein-related factors TAF1 and TAF1L (Bouché et al., 2017).

ABBV-744 (C28H30FN3O4, ABBV-744, ABBV744, ABBV 744, 2138861-99-9, IUPAC: N-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(1-hydroxy-1-methylethyl)phenyl]-6,7-dihydro-6-methyl-7-sideoxy-1H-pyrrolo[2,3-c]pyridine-2-methamide) is an inhibitor of the BDII domain of the BET family (Faivre et al., 2018). Synergistic effect of BRD inhibitors with ALC1i.

Disruption of the TAF1 bromodomain function impairs DNA end excision, replication protein A (RPA) and Rad51 loading, and HR repair, leading to genomic instability and hypersensitivity to DNA damage (Peng et al., 2021). The authors anticipated that the HR deficiency induced by the TAF1 inhibitor BAY-299 would synergize with the inhibition of other DNA repair pathways due to ALC1i action. Synergistic testing using a specific ALC1 inhibitor used in this invention and BAY-299 confirmed the synergistic effect between the specific ALC1 inhibitor and the bromodomain inhibitor.

BET family protein BRD4 not only acts as a major regulator in many genes involved in DNA damage responses or checkpoint activation, but also promotes DNA damage repair in a transcription-independent manner. In the latter case, BRD4 promotes and stabilizes the interaction with 53BP1, which then acts as the docking site for DNA repair conjugates (PMID: 24954901). The authors therefore anticipated a possible synergistic effect between BETi and DDR inhibitors (such as ALC1i). Synergistic tests with specific ALC1 inhibitors and specific BET BD2 inhibitors used in this invention confirmed the synergistic effect. Notably, BET BD2i exhibits lower toxicity compared to pan-BETi. PARP inhibitors

PARP (ADP-ribose) polymerases are a family of 17 proteins involved in various cellular processes, including stress responses, chromatin remodeling, DNA repair, and apoptosis. The best-described member of this family is PARP1, which plays a role in the detection and repair of single-stranded DNA breaks, alternative DNA repair pathways (including nucleotide excision repair, non-homologous end joining (canonical and substitutional), homologous recombination, and DNA mismatch repair). PARP inhibitors (PARPi) are a new class of anticancer drugs that compete with NAD ⁺ for PARP catalytic activity. PARPi has shown efficacy in treating HR-deficient tumors, particularly those with mutations in breast cancer-related genes 1 and 2 (BRCA1 and BRCA2) (Lai et al., 2020). Synergistic effects of PARP inhibitors with ALC1i are also discussed.

ALC1 is associated with PARP because it can be directly activated by PARP1 and other PARP family members during poly(ADP-ribose) synthesis. It can also affect the recruitment and release of PARP family members into damaged chromatin, and PARP1 function is significantly enhanced after gene interference with the ALC1 gene (Blessing et al., 2020; Juhász et al., 2020; Hewitt et al., 2021; Verma et al., 2021). ALC1 deficiency affects PARP1 capture, impairs the binding of NHEJ and HR proteins to DNA and inhibits these DNA repair mechanisms (Juhász et al., 2020), and affects PARP2 turnover (Blessing et al., 2020). As explained below (see Figure 2), the specific ALC1 inhibitor used in this invention exhibits a synergistic effect with PARP inhibition. Paclitaxel

Paclitaxel ( C47H51NO14, CAS No. 33069-62-4, Synonyms: P88XT4IS4D, Paclitaxel, Taxol, Taxol A, IUPAC : [( 1S , 2S ,3R, 4S ,7R, 9S , 10S , 12R , 15S )-4,12-diethoxy-15-[( 2R , 3S )-3-benzoylamino-2-hydroxy-3-phenylpropionic]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-sideoxy-6-oxatetracyclo[11.3.1.0 ^{3,10.0 4,7]} Heptadecanoyl-13-en-2-ylbenzoate is an antitumor agent that works by inhibiting mitosis. It currently plays a central role in the treatment of ovarian cancer, breast cancer, and lung cancer.

Paclitaxel treatment was associated with a low rate of elevated serum enzymes, but not with clinically significant cases of acute liver injury ( NCBI- paclitaxel, nd-h). Paclitaxel specifically and reversibly binds to the N-terminal 31 amino acid of the β-tubulin subunit in microtubules, promoting stable microtubule assembly (especially from β-tubulin heterodimers) and inhibiting its depolymerization, leading to cell cycle arrest in the G2/M phase, apoptosis, and inhibition of cell replication (Kampan et al., 2015). It promotes ROS production by enhancing the activity of plasma membrane-associated NADPH oxidase (NOX) (Alexandre et al., 2007). Synergistic effects of paclitaxel and ALC1i .

Paclitaxel induces the formation of reactive oxygen species, leading to significant DNA damage. Furthermore, paclitaxel inhibits CDK1 expression, reduces BRCA1 phosphorylation, induces the BRCAness phenotype, and inhibits the homologous recombination pathway (Yanaihara et al., 2023). Synergistic effects with the specific ALC1 inhibitor used in this invention were demonstrated in the co-dosing experiments shown below (see Figure 2). Mitochondrial C

Mitomycin C (C15H18N4O5, Mitomycin C, Mitomycin, CAS No. 50-07-7, Ametycine, Mutamycin, IUPAC: [( 4S , 6S , 7R , 8S )-11-amino-7-methoxy-12-methyl-10,13-dioxy-2,5-diazatetracyclo[7.4.0.0 ^{2,7.0 4,6} ]tetane-1(9),11-dien-8-yl]methylcarbamate) is a methylazopyrroloindoline antitumor antibiotic isolated from Streptomyces caespitosus and other Streptomyces species. Bioreduced mitomycin C generates oxygen free radicals, alkylates DNA, and induces interstrand DNA cross-linking, thereby inhibiting DNA synthesis. It exhibits preferential toxicity to hypoxic cells, and high concentrations of mitomycin C also inhibit RNA and protein synthesis ( NCBI- mitomycin C, nd-i). Synergistic effects of mitomycin C and ALC1i are also discussed.

Mitochondrial C-induced DNA damage of various types leads to inhibition of cell proliferation and massive cell death. Therefore, it can be hypothesized that the specific ALC1 inhibitor used in this invention inhibits ALC1, thus blocking the repair of this DNA damage and enhancing the antiproliferative effect of mitochondrial C. Surprisingly, synergistic effects were even confirmed during co-administration experiments with the specific ALC1 inhibitor used in this invention and mitochondrial C. Free radiation

Ionizing radiation is electromagnetic radiation or particle radiation (high-energy elementary particles) that can directly or indirectly produce ions in the passage of matter. The wavelength of ionizing electromagnetic radiation is equal to or less than the wavelength of short (far) ultraviolet radiation, including gamma rays and X-rays (NCBI – ionizing radiation, n.d.-k).

Ionizing radiation induces apoptosis, necrosis, and aging of cancer cells by causing DNA damage, affecting cancer cell organelles, and influencing tumor immune responses. It causes different types of DNA damage: SSB, DSB, DNA crosslinking, DNA-protein crosslinking, and indirect DNA damage caused by reactive oxygen species (ROS)/reactive nitrogen species (RNS) (JS Wang et al., 2018). Synergistic effects of ionizing radiation and ALC1i .

Ionizing radiation induces various types of DNA damage, leading to inhibition of cell proliferation and cell death. The authors hypothesized that inhibition of ALC1 with the ALC1i used in this invention would hinder the repair of this DNA damage, thereby enhancing the antiproliferative effect of ionizing radiation. This was confirmed during co-administration experiments with the specific ALC1 inhibitor used in this invention and ionizing radiation.

The typical dosage rate used according to this invention is 100–2400 cGy/min over 1 to 5 minutes. Antibody-drug conjugates (ADCs) are tumor-specific antibodies that conjugate with the TOP1 inhibitor trastuzumab deruxtecan (Enhertu).

Trastuzumab binds to the extracellular domain of the HER2 receptor and inhibits homodimerization and downstream HER2 signaling, leading to antibody-dependent cell - mediated cytotoxicity (Nami et al., 2018).

Trastuzumab deruxtecan (marketed under the brand name Enhertu) is an antibody-drug conjugate (ADC) consisting of the HER2-targeting antibody trastuzumab and the growth-inhibiting TOP1 inhibitor deruxtecan, linked via a tumor-selectively cleavable linker. This linker efficiently delivers the drug to the antibody, which is then selectively cleaved by an enzyme upregulated in tumor cells. (ENHERTU® (Fam-trastuzumab deruxtecan-nxki)).

Following drug release, TOP1i cause DNA damage and cell death (see the TOP1i section for details) (ENHERTU® (Fam-trastuzumab deruxtecan-nxki)). Enhertu is used to treat human epidermal growth factor 2 ( _HER2 )-positive breast cancer, HER2-mutant non-small cell lung cancer (NSCLC), and HER2-positive gastric or gastroesophageal adenocarcinoma (ENHERTU® (Fam-trastuzumab deruxtecan-nxki)). Sacituzumab govitecan.

Sacituzumab govitecan (marketed by Gilead Sciences under the brand name Trodelvy) is a Trop-2-targeting antibody-drug conjugate for the treatment of metastatic triple-negative breast cancer and metastatic urothelial carcinoma. Trodelvy binds to trophoblast cell surface antigen 2 (TROP2), which is expressed in HR+/HER2- breast cancer and triple-negative breast cancer and is associated with poor prognosis, creating TROP2 and an attractive therapeutic tumor-associated antigen.

Sacituzumab govitecan is a conjugate of a humanized anti-Trop-2 monoclonal antibody linked to SN-38, an active metabolite of irinotecan, a topoisomerase 1 inhibitor (TOP1i). Each antibody contains an average of 7.6 linked SN-38 molecules. The binding to the antibody allows for drug-specific targeting of cells expressing Trop-2. Because free SN-38 is membrane permeable, it can induce an antitumor effect (bystander effect) by being released into neighboring tumor cells before internalization of the antibody-drug conjugate through hydrolysis of the linker or after internalization via intracellular SN-38 release (Goldenberg et al., 2020).

Sacituzumab govitecan was approved for medical use in the United States in April 2020 and in the European Union in November 2021. It was designated a first-in-class drug by both the U.S. Food and Drug Administration ( FDA ) and the European Medicines Agency (EMA) (EMA, 2021). Datopotamab deruxtecan...

Datopotamab deruxtecan (Dato-DXd) is another Trop-2-targeting antibody-drug conjugate. Datopotamab deruxtecan (Dato-DXd) is a humanized anti-Trop2 immunoglobulin G1 monoclonal antibody covalently linked to deruxtecan (a derivative of the highly effective topoisomerase I inhibitor, exatecan) via a plasma-stabilized, tumor-selective tetrapeptide-based cleavable linker, resulting in reduced systemic exposure and off-target side effects. Dato-DXd is internalized in cells expressing Trop2, leading to the death of target tumor cells and bystander killing of neighboring cells in the tumor microenvironment (Okajima et al., 2021).

Based on the results of the TROPION-Breast01 Phase III trial, the United States accepted the Biologics License Application (BLA) for datopomab deruxtecan in April 2024 for the treatment of previously treated metastatic HR-positive, HER2-negative breast cancer patients (Adrian Kemp, 2024). Synergistic effect of ADCs and ALC1i .

The aforementioned ADCs facilitate the delivery of TOP1i to cancer cells and the release of drugs at specific sites within the cancer. In addition to exerting cytotoxic effects by binding to the respective surface antigens of conjugating antibodies, TOP1i also disrupts replication forks and causes DNA strand breakage.

As described above (explanation of TOP1i, the drug, and its synergistic effect with ALC1i), ALC1i above TOP1i can cause replication fork arrest and accumulate additional DNA damage in a more targeted environment. Therefore, it can be hypothesized that co-administration of ALC1i and TOP1i for targeted release is suitable for the treatment of HER2 _- positive and/or Trop1-positive cancers.

As demonstrated in this invention, ALC1 inhibition by a specific ALC1i synergistically affects cellular responses to DNA damage induced by trastuzumab and TOP1i (i.e., trastuzumab deruxtecan, datopotamab deruxtecan, and sacituzumab govitecan). Therefore, the inventors have determined that the effects of both drugs can be synergistically enhanced by using an ADC such as an anti-HER2 antibody in combination with TOP1i and a specific ALC1i. In various cell lines, the combination of trastuzumab deruxtecan, datopotamab deruxtecan, and sacituzumab govitecan with this specific ALC1i has shown high MSA scores, and it is expected that other antibody-drug conjugates of tumor-specific antibodies conjugated to TOP1 inhibitors will also exhibit this pattern. Therefore, it is preferable to use the ALC1i used according to the present invention and antibody-drug conjugates of tumor-specific antibodies conjugated to TOP1 inhibitors, particularly for the treatment of (e.g., Trop1 ⁺ or _HER2 ^{low /+} ) breast cancer, gastric cancer, or non-small cell lung cancer. MEK inhibitors

Trametinib (C26H23FIN5O4, GSK1120212, CAS No. 871700-17-3, IUPAC: N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trisyloxy-3,4,6,7-tetrahydropyridino[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide) targets and inhibits the MEK protein, which is part of the MAPK/ERK pathway. This pathway plays a crucial role in the growth and development of cancer cells. Trametinib is commonly used to treat cancers with specific mutations in the BRAF gene (BRAF V600E or V600K mutations) or mutations in the KRAS. Synergistic effect of MEK inhibitors and ALC1i

MEK inhibitors are known to induce extensive changes in the chromatin landscape of treated cells, including alterations in histioprotein acetylation patterns and gene expression levels. MEKi treatment also induces increased NF-κB activity, indicating increased DNA damage in response to treatment. The authors hypothesize that the ALC1i used in this invention inhibits ALC1, blocking the repair of this additional DNA damage, thereby enhancing the antiproliferative effect of MEK inhibitors. This was confirmed in in vivo co-administration studies of a specific ALC1 inhibitor used in this invention and trametinib.

The cell line used cell line The origin of cancer Cancer types HCC1937 breast Tubal cancer, ERneg HER ₂ neg SUM149PT breast Tubal cancer, ERneg HER ₂ neg MDA-MB-231 breast Adenocarcinoma, ERneg HER ₂ negative MDA-MB-436 breast Adenocarcinoma, ERneg HER ₂ negative DLD1 BRCA2-/- Colorectum Colorectal adenocarcinoma DLD1wt Colorectum Colorectal adenocarcinoma HCT116 Colorectum Colorectal adenocarcinoma SW620 Colorectum Colorectal adenocarcinoma HEPG2 liver Hepatocellular carcinoma BXPC3 pancreas Exocrine gland carcinoma PSN1 pancreas Exocrine gland carcinoma PSN1 resistance to talazoparib pancreas Exocrine gland carcinoma 22RV1 Prostate Prostate adenocarcinoma DU145 prostate Prostate adenocarcinoma PC-3 Prostate Prostate adenocarcinoma SKBR ₃ breast Adenocarcinoma, _HER2 pos HCC2429 lung Non-small cell lung cancer MiaPaCa2 pancreas Tube adenocarcinoma T47D breast vascular cancer ER pos HER ₂ neg

As a BRCA wild-type cell line, MDA-MB-231 cells were used. These cell lines were established from aneuploid female humans. These cells (MDA-MB-231 (ATCC® HTB-26™ Homo sapiens breast epithelium)) were extracted from the mammary gland (breast) at the metastasis site using pleural effusion. They can be obtained from many sources, including ATCC® HTB-26™.

SUM149PT cells were used as the BRCA-negative cell line. This cell line is a triple-negative breast cancer (TNBC) cell line derived from primary human invasive ductal carcinoma metastatic nodules in women aged 40 years. It contains a hemizygous BRCA1 mutation (p.Pro724Leufs*12) and is available from various sources, including bioIVT.

PSN1 cells were used. The human cell line was derived from pancreatic cancer tissue. It carried amplification of c-myc and activated c-Ki-ras, as well as deletion of one of the two p53 paired genes. The cell line can be obtained from many sources, including MERCK(94060601)).

Treating PSN1 cells with progressively increasing sub-toic doses of talazoparib for 3 months induced PSN1 talazoparib-resistant cells. These cells exhibited >10-fold resistance to talazoparib compared to parental PSN1 cells.

BxPC3 cells were used. These cells were extracted from pancreatic tissue of a 61-year-old woman with adenocarcinoma. The established cell line did not express CFTR (cystic fibrosis transmembrane regulatory protein), but did express mucin, pancreatic cancer-specific antigen, and CEA (carcinoembryonic antigen). These cells can be obtained from many sources, including MERCK (93120816).

22Rv1 cells were used. The cell line was derived from a xenograft that had been continuously propagated in mice following degeneration and relapse induced by castration of an androgen-dependent parental CWR22 xenograft. These cells were derived from prostate cancer and were epithelial. They expressed PSA (prostate-specific antigen) and had a detrimental mutation in BRCA2. The cell line can be obtained from many sources, including Accegen (ABC-TC0004).

DU145 cells were used. These cells were isolated from the brain of a 69-year-old man with prostate cancer, and the resulting cell line had an epithelial morphology. It was hypotriploid and contained mutations in BRCA1, BRCA2, RAD50, WRN, and TP53. The cell line could be obtained using ATCC HTB-81™.

DLD1wt cells were used. Cell lines were established from the colon of adult male patients with colorectal cancer. They were pseudodiploid (2n=46), expressed the p53 antigen, and had detrimental mutations in BRCA2, FANCA, and TP53. Cell lines were available from a variety of sources, including MERCK (90102540).

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

HCT116 cells were used. This cell line was derived from colonic tissue of adult men with colorectal cancer. It contains detrimental mutations in BRCA2, FANCA, and POLD1. This cell line can be obtained from many sources, including DSMZ (ACC 581)

PC-3 cells were used. These cells were derived from a 62-year-old male patient with grade IV prostate adenocarcinoma (specifically, bone metastasis). The cells were epithelial, nearly triploid, and contained a detrimental mutation in TP53. They were available from various sources, including MERCK (90112714).

SW620 cells were used. These cell lines were isolated from the lymph nodes of a 51-year-old man with Dukes' C colorectal adenocarcinoma and the cell lines were established. Cell lines can be obtained from many sources, including ATCC CCL-227 ^™ .

T47D cells were used. These cells were established from a 54-year-old human woman with invasive ductal carcinoma of the breast. The cells were extracted from the breast (mammary gland) using pleural effusion. They can be obtained from many sources, including ATCC HTB-133™.

HCC1937 cells were used. They were isolated from a 23-year-old woman with primary ductal carcinoma (specifically breast cancer). These cells were homozygous for the BRCA1 mutation, negative for p53 and HeR ₂ -neu, and epithelial in morphology. They were available from several sources, including Amsbio (catalog number AMS.EP-CL-0093).

MDA-MB-436 cells were used. These cells were derived from a 43-year-old woman with breast cancer, extracted from the metastatic breast tissue using pleural effusion. The cells exhibited pleomorphism with multinucleated components. They can be obtained from many sources, including Accegen (catalog number ABC-TC0655).

HEPG2 cells were used. The cell line was established from a 15-year-old male patient with hepatocellular carcinoma. These cells expressed several major plasma proteins, such as albumin, fibroinogen, and α2-macroglobulin, and had an epithelial-like morphology. They were available from ATCC HB-8065 ^™ .

SKBR3 (also known as SK-BR-3) is a human breast cancer cell line isolated in 1970 at the Memorial Sloan–Kettering Cancer Center for therapeutic research, particularly in the case of HER2 targeting. The SKBR3 cell line originated from pleural effusion due to adenocarcinoma in a 43-year-old Caucasian woman. The cell line overexpresses HER2 gene products, which are involved in several breast cancer proliferation pathways.

HCC2429 was derived from a 34-year-old non-smoking woman with metastatic non-small cell lung cancer, demonstrating a fusion of t(15;19)(q13.2;p13.1) and BRD4-NUTM1 ex11:ex2. This cell line was patented by Vanderbilt University Medical Center, Nashville, TN, USA.

MiaPaCa2 cells were also used. This cell line was derived from a 65-year-old male with undifferentiated pancreatic cancer. It exhibited neuroendocrine characteristics and was described as having mutations in KRAS, CDKN2A, and TP53. This cell line can be obtained from multiple sources, including ATCC (CRL-1420). Inhibitor response ( cell survival ) analysis was performed.

To validate the small molecule inhibitor, the pancreatic cell line PSN1 was used. Cells were seeded in 96-well plates (2000 cells/well) and titrated with an ALC1 inhibitor in the µM range. As a "no treatment" control, DMSO was added to the cells. Cells were cultured at 37°C and 5% _CO2 for 5 days, followed by fixation with 10% TCA for 1 hour and staining with sulfadiazine dye for 30 minutes. After washing the cells with 1% acetic acid, the stained cells were dissolved in 10 mM Tris (pH 10.5). Absorbance at 492 nm was measured using a Sunrise Tecan, and data were standardized to 100% viability (= DMSO control). The inhibitor-pair response curve was fitted using the curve fitting parameter "LL4" with Synergy Finder. The curves show the mean fit across three technical replicates. Synergistic effects with other drugs in cellular analysis .

To determine the ZIP synergistic rating, 2-D titrants of the two compounds were added to cells in the 96h-SRB-survival (above) assay format.

The score is calculated by adding the survival data readings from at least two duplicate SRB analyses to an open-source program called Synergy Finder.

"SynergyFinder (https://synergyfinder.fimm.fi) is a standalone web application for interactive analysis and visualization of drug combination screening data. Since its initial release in 2017, SynergyFinder has become a widely used web tool for discovering novel synergistic drug combinations in preclinical model systems (such as cell lines or cells derived from primary patients) and for better understanding the mechanisms of combination therapy efficacy or resistance" (Ianevski et al. 2020).

In the Zero Interaction Potency (ZIP) model, drug interactions are determined by comparing changes in the potency of dose-dependent curves between individual drugs and their combinations (https://synergyfinder.fimm.fi/synergy/synfin_docs/). This model is further described in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759128/.

SynergyFinder uses the cNMF algorithm to detect and replace anomalous measurements. Versions 2.0 and 3.0 are used to obtain the data shown in this article.

The summative synergistic score is the average of all dose combinations in the 2-D titration matrix. The Most Synergistic Area (MSA) is a 3×3 dose window showing the maximum synergistic effect in the dose-response matrix.

For an explanation of the collaboration scores calculated in this program, see Table 1: Table 1 : MSA Mark MSA rating explain MSA less than 9 - The interaction between the two drugs may not have a synergistic effect. MSA is between 9 and 10. + The interaction between the two drugs is likely to have a synergistic effect. MSA is between 10 and 20. ++ Synergistic effect between the two drugs MSA > 20 +++ The interaction between the two drugs exhibits a high synergistic effect.

The results of the present invention's combination of a specific ALC1 inhibitor (compound A) and several other classes of cancer drugs (compound B) on the treatment of different cancer cell lines are summarized in Figure 2. Combinations with an MSA (Maximum Synergistic Area) score below 9 indicate that the interaction may not have a synergistic effect and are marked with "-". MSA scores between 9 and 10 are marked with "+" and indicate that the interaction between compounds A and B may have a synergistic effect. MSA scores above 10 are marked with "++" and have a synergistic effect. MSA scores above 20 are marked with "+++" and are considered to have a high synergistic effect. As a comparison, Compound 1 and Compound 3 (chemical structures shown above) were tested and found to provide only additive effects (MSA score "-"), but no synergistic effects. In contrast, all test combinations according to the specific ALC1 inhibitor used in this invention showed synergistic anticancer effects (MSA scores "+", "++", or even "+++"). Cell cycle analysis

SUM149PT cells were seeded into 6-well plates and treated with ALC1i or DMSO for 48 h. Cells were harvested, washed with PBS, and then fixed/permeabilized with 75% ice-cold ethanol. After incubation at 4°C for >30 min, cells were stained with 1 μg/ml DAPI. Flow cytometry analysis was performed using FACS Fortessa (BD Bioscience). Flow cytometry analysis of cell cycle indicators (2n = G1 phase; 4n = G2/M phase) was performed using DNA content stained with the DNA intercalating agent DAPI. DMSO treatment was used to visualize cells in G1, S, and G2 phases. Treatment with an ALC1 inhibitor showed enrichment/blockage of G2 phase cells. γH2AX protein content was detected using Western blotting.

PSN1 cells were seeded into 6-well plates and treated with progressively increasing concentrations of ALC1i-101 or DMSO for 24 h. Cells were harvested and lysed using 1xSDS containing benzonase. After denaturation, samples were loaded onto gradient gels (Mini-PROTEAN TGX Stain-Free Precast Gels, 4-20%, BioRad 456-8095). Gel electrophoresis was performed, and proteins were transferred to nitrocellulose membranes using a TransBlot turbo (BioRad). The membrane was sealed for 1 hour using LiCor's blocking buffer, followed by staining with the following antibodies: 1°AB: anti-gH2AX (Abcam, AB11174), α-tubulin (Sigma, T9026); 2°AB (Licor): IRDye 800CW goat anti-rabbit 925-32211, IRDye 680RD donkey anti-mouse 925-68072.

Images of the membrane were captured using LiCor. Protein quality was determined by band analysis using (FIJI, image J), and the γH2AX protein bands were standardized to their corresponding α-tubulin bands. Finally, different treatment groups were standardized to a DMSO control group to show the percentage changes in protein quality. MiaPaCa2 cell-derived xenografts (CDX) were used.

To test the in vivo combination of ALC1i with MEKi, 5 x 10⁵ MiaPaCa2 cells (a pancreatic cancer cell line with the KRAS G12C mutation) were injected into the flanks of NMRI nude mice in 50% Matrigel and 50% PBS. Randomized monotherapy and combination therapy were initiated when the mean tumor size reached 250 mm³. Treatment was administered daily as an oral suspension. ALC1i-101 was reconstituted at 250 mg/kg in SyrSpend MEKi, and trametinib was reconstituted at 0.5 mg/kg in 10% Kolliphor and 10% PEG400. References

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The contents of the drawings contained in this specification are described below. In this regard, reference is also made to the detailed description of the invention above and/or below.

Figure 1: Structure and molecular name of the selected ALC1 inhibitors. These selected ALC1 inhibitors (or their isomers, pharmaceutically acceptable salts, solvent compounds, chemically protected forms, and precursors) are preferably used in accordance with the present invention.

Figure 2: Synergistic score and MSA of cancer cells treated with ALC1i in combination with other drugs.

The table summarizes the 2-D 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 area) 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 greater than 10 are marked with "++" and indicate synergistic effects. MSA scores greater than 20 are marked with "+++" and are considered to have high synergistic effects.

Figure 3: Example of 96-hour SRB analysis: pancreatic cancer cell lines treated with ALC1i or ATMi.

PSN1 cells were seeded in 96-well plates and titrated with either ALC1i-101 or ATMi (ATM inhibitor AZD-1390). Cells were cultured at 37°C and 5% _CO2 for 4 days, fixed with 10% TCA, and stained with sulfonated rhodamine to analyze cell viability. Data were standardized to a DMSO control group, indicating 100% viability. Inhibitor-pair response curves were fitted using the curve fitting parameter "LL4" with Synergy Finder. The curves show the mean fit of three technical replicates.

Figure 4: Example of 2-D titration: co-treatment cell proliferation analysis of pancreatic cancer cells.

Cancer cells were seeded in 96-well plates and treated with ALC1i for 2-D titration of the designated drug. Cells were cultured at 37°C and 5% CO2 for 4 days, fixed with 10% TCA, and stained with sulfonated rhodamine to analyze cell viability. Synergy scores were calculated using Synergy Finder. Combination therapy with ALC1i-101 and ATMi showed high synergy area scores of 10 or higher. An MSA score greater than 10 was an indicator of strong synergy.

Figure 5: Cell cycle analysis of cancer cells treated with ALC1i.

SUM-149-PT cells were seeded in 6-well plates and treated with ALC1i or DMSO for 48 hours. 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. ALC1i treatment showed enrichment/arrest in the G2 phase.

Figure 6: Increased γH2AX protein content under ALC1i treatment.

PSN1 cells were treated with ALC1i or DMSO for 24 hours. Western ink dot assay was performed using antibodies against phosphorylated H2AX (γH2AX) and α-tubulin. The protein band images are shown in the top figure, and the bottom figure shows the γH2AX protein content of the α-tubulin-loaded control group and the DMSO-treated sample.

Figure 7: _EC50 values (µM) of 96-hour SRB analysis and 11-day colony formation analysis of HR-toughened (HRP) and HR-deficient (HRD) cells treated with ALCi.

Different cancer cell lines with different mutations in the homologous recombination repair pathway (HR) were seeded into 96-well plates and treated with different ALCi titrations. Cells were cultured at 37°C and 5% CO2 for 4 days (96 h) or 11 days (colony formation), fixed with 10% TCA, and stained with sulforhodamine to analyze cell viability. Data were standardized to a DMSO control group, indicating 100% viability. Inhibitor-pair response curves with variable slopes (four parameters) were modeled using GraphPad Prism.

Figure 8: List of HR genes.

The list of genes involved in the DNA damage response (DDR) cited in Wood RD, Mitchell M, & Lindahl T Mutation Research (2005), Science (2001), the second edition of the reference book DNA Repair and Mutagenesis (2006), and Nature Reviews Cancer (2011, revised by R. Wood and M. Lowery on Wednesday, June 10, 2020) (Human DNA Repair Genes, n.d.).

Figure 9: List of genes associated with homologous recombination repair pathways (HR).

Summary of genes from Toh & Ngeow, 2021; Kim et al., 2021; Yamamoto & Hirasawa, 2021 and the HRD-signature genes from Peng et al, 2014.

Figure 10: Synergistic effect of ALC1i-101 and trametinib in MiaPaCa2 CDX experiment.

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TW202535405A_113140867_SEQL.xml

Claims (17)

An ectopic inhibitor of a chromodomain-helicase-DNA-binding protein 1-like (ALC1) protein, wherein the inhibitor specifically binds to an ectopic binding pocket formed by amino acids spanning amino acid residues 101 to 219 of SEQ ID NO:1, and is used in combination with the following for the treatment or improvement of proliferative diseases in patients and/or to enhance the efficacy of treatment for proliferative diseases: a) inhibitors of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK; b) mitomycin C or paclitaxel; c) free radiation; or d) an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor. An ectopic inhibitor of ALC1 used according to claim 1, wherein the ectopic binding pocket comprises or consists of the following: 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 or consisting of the following: SEQ ID NO:1 includes Y153, C156, L157, A160, L163, V173, E175, R178, L186, H187, L190, F193, L200, and E212. The ALC1 inhibitor (ALC1i) used according to claim 1 or 2, wherein the ALC1 inhibitor (ALC1i) is based on formula (I). (I) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein (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 annulated carbocyclic or heterocyclic Z, then A6 is C; (iii) A7 is selected from N or CH, or when A7 participates in annulated carbocyclic or heterocyclic Z, then A7 is C; (iv) L2 is selected from the group consisting of: -CH2 _- R4, –CF2– R4, _{-CH2- CH2} - _R4 , -CH2- _CH2 - _CH2 -R4, -O-R4, -NH-R4, -N=R4; (v) L3 is selected from the group consisting of: _CH2 -R9, –CF2–R9, _{-CH2- CH2} -R9, _-CH2- CF2-R9, -CH2 _{- CH2} - _CH2 -R9, -O-R9, -NH-R9, -N=R9; or (vi) L2 and L3 together with the A8 they are connected to 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 absent; (viii) Z is a 5-, 6-, or 7-membered carbon ring or heterocyclic ring, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and may form a ring with the central nucleus or be covalently linked (ix). R4 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -CF3, Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH; (x) R9 is a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered carbocyclic or heterocyclic ring, which may be substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, -CF3, Et, -OMe, and -SMe; (xi) R _R6 is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which, as desired, is substituted by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO₂ , Me, -CF₃, Et, -OMe, and -SMe; (xii) or _R6 is H; or (xiii) when A7 participates in the annulated carbocyclic or heterocyclic ring Z, then A5 and A6 are independently selected from -N or -CH and A8 is selected from -N, -CH, -CH₂ _- N, _-CH₂ -CH, or -NH-CH; or according to formula (II). (II) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein (i) X is N or S; (ii) A is C or N; ( _iii ) _R1 is –CO- _OR6 , -CO- _R7 , or -CO- _NR6RA , preferably _R1 is –CO- _OR6 ; (iv) _R2 is _-R7 , _-NHR8 , _-OR7 , _-COR7 , Br, _-C3-8 -cycloalkyl (preferably cyclopropyl), or _–C4-8 -cycloenyl (preferably cyclohexenyl); or (v) _R1 and R ₂ together form a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the following groups: -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, _-OR₇ , _-R₇ , or –( _CH₂ ) _m -L, where m is 0, 1, or 2, and L is a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the following groups: -OH, _-NO₂ -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, _-hydroxyC1-3 -alkyl and =O; (vii) _R4 is H or _-C1-3 -alkyl, 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 5, 6 or 7-membered carbocyclic or heterocyclic, adamantyl, _C1-4 -alkyl, or -N( _CH3 ) ₂ , which may be substituted as desired, preferably substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -CO- _OR6 , -Br, -Cl, -F, -I, -R _9. -OR ₉ , =O, and [-O-CH ₂ -CH ₂ ] _q -NH-biotin, wherein q is 1, 2, 3, or 4, or two adjacent substituents form a 5, 6, or 7-membered carbon ring or heterocyclic ring; or (ix) R ₄ and R ₅ together form a 5, 6, or 7-membered carbon ring, which is substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, -NO ₂ , -CN, -Br, -Cl, -F, -I, -OR ₉ , -R ₉ , =CH- _RA , and –CH _{2 -RA} , preferably R ₄ and R ₅ together form a C _5-7 -cycloalkyl; (x) R ₆ is H, -C _1-6 -alkyl, -C _2-6 -alkenyl, -C _2-6 -Alynyl, which may be substituted as desired, preferably _R6 is H; (xi) _R7 is _-C1-3 -alkyl, _-C2-3 -alkenyl, _-C2-3 -alkynyl, which may be substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -Br, -Cl, -F, -I, _-CH3 , _-OCH3 , or _-SCH3 ; (xii) _R8 is H or _C1-6 -alkyl, preferably H; (xiii) _R9 is _-C1-6 -alkyl, _{-C2-6-alkenyl, -C2-6-alkynyl, -C1-6 - alkyl} -aryl, or _C1-6 -alkyl-heteroaryl (preferably isothiazolium, thiazolium, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-thiadiazole, pyridine, or pyrazole), wherein, as desired, they are substituted by one, two, or three substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-NO₂ , -CN, -CONH₂, -CONH-C₁ _{-3 -} alkyl (preferably –CONH-CH₃), -NH-CO- _{C₁ -3} -alkyl (preferably -NH-CO- _CH₃ ), -C₁ _-6 -alkyl (preferably _-CH₃ , ethyl, propyl, tert-butyl, or pentyl), -C₁- ₃ -halogen (preferably -CF₃ ₎ . -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 , -OC1-4 - alkyl ( preferably -OCH3} ), _-OC1-3 -alkyl- _OC1-3 -alkyl (preferably –O- _CH2 -O- _CH3 ), _-SCH3 , or when _R9 is _-C1-6 In the case of -alkyl-aryl, the two adjacent substituents on the aryl moiety can form a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which is substituted as needed; (xiv) _RA is H, a carbocyclic or heterocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the following group: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-R9 , -O- _R7 , -O-( _CH2 ) _OR9 , _{-SO2NH2 ,} and =O, where o is 0 or 1. An ALC1 inhibitor (ALC1i) according to formula (II) (II) and its isomers, salts, solvents, chemically protected forms, and precursors, wherein (i) X is N or S; (ii) A is C or N; ( _iii ) _R1 is –CO- _OR6 , -CO- _R7 , or -CO- _NR6RA , preferably _R1 is –CO- _OR6 ; (iv) _R2 is _-R7 , _-NHR8 , _-OR7 , _-COR7 , Br, _-C3-8 -cycloalkyl (preferably cyclopropyl), or _–C4-8 -cycloenyl (preferably cyclohexenyl); or (v) _R1 and R ₂ together form a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, ₂ , or 3 substituents independently selected from the following groups: -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, _-OR₇ , _-R₇ , or –( _CH₂ ) _m -L, where m is 0, 1, or 2, and L is a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the following groups: -OH, _-NO₂ -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, _-hydroxyC1-3 -alkyl and =O; (vii) _R4 is H or _-C1-3 -alkyl, 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 5, 6 or 7-membered carbocyclic or heterocyclic, adamantyl, _C1-4 -alkyl, or -N( _CH3 ) ₂ , which may be substituted as desired, preferably substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -CO- _OR6 , -Br, -Cl, -F, -I, -R _9. -OR ₉ , =O, and [-O-CH ₂ -CH ₂ ] _q -NH-biotin, wherein q is 1, 2, 3 or 4, or two adjacent substituents form a 5, 6 or 7-membered carbon ring or heterocyclic ring; or (ix) R ₄ and R ₅ together form a 5, 6 or 7-membered carbon ring, which is substituted as needed, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -OH, -NO ₂ , -CN, -Br, -Cl, -F, -I, -OR ₉ , -R ₉ , =CH- _RA , and –CH _{2 -RA} , preferably R ₄ and R ₅ together form a C _5-7 -cycloalkyl; (x) R ₆ is H, -C _1-6 -alkyl, -C _2-6 -alkenyl, -C _2-6 -Alynyl, which may be substituted as desired, preferably _R6 is H; (xi) _R7 is _-C1-3 -alkyl, _-C2-3 -alkenyl, _-C2-3 -alkynyl, which may be substituted as desired, preferably substituted by 1, 2 or 3 substituents independently selected from the group consisting of: -Br, -Cl, -F, -I, _-CH3 , _-OCH3 , or _-SCH3 ; (xii) _R8 is H or _C1-6 -alkyl, preferably H; (xiii) _R9 is _-C1-6 -alkyl, _{-C2-6-alkenyl, -C2-6-alkynyl, -C1-6 - alkyl} -aryl, or _C1-6 -alkyl-heteroaryl (preferably isothiazolium, thiazolium, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-thiadiazole, pyridine, or pyrazole), wherein, as desired, they are substituted by one, two, or three substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-NO₂ , -CN, -CONH₂, -CONH-C₁ _{-3 -} alkyl (preferably –CONH-CH₃), -NH-CO- _{C₁ -3} -alkyl (preferably -NH-CO- _CH₃ ), -C₁ _-6 -alkyl (preferably _-CH₃ , ethyl, propyl, tert-butyl, or pentyl), -C₁- ₃ -halogen (preferably -CF₃ ₎ . -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 , -OC1-4 - alkyl ( preferably -OCH3} ), _-OC1-3 -alkyl- _OC1-3 -alkyl (preferably –O- _CH2 -O- _CH3 ), _-SCH3 , or when _R9 is _-C1-6 In the case of -alkyl-aryl, the two adjacent substituents on the aryl moiety can form a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which is substituted as needed; (xiv) _RA is H, a carbocyclic or heterocyclic ring, which is substituted as needed, preferably by 1, 2, or 3 substituents independently selected from the following group: -OH, _-NO₂ , -CN, -Br, -Cl, _-F , _-I , _-R₉ , -O-R₇, -O-( _CH₂ ) _OR₉ , _-SO₂NH₂ =O, where o is 0 or 1, which is 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. The ALC1i used 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 the annulated carbocyclic or heterocyclic ring Z and the other is N; A8 is N or CH, or A5 is N; one of A6 and A7 is C and participates in the annulated 5-, 6- or 7-membered carbocyclic or heterocyclic ring, preferably 5- or 6-membered aryl or heteroaryl Z and the other is N; A8 is N; L2 is _CH2 - _CH2 -R4 and L3 is _CH2 - _CH2 -R9 or _CH2 - _CF2 -R9 Alternatively, L2 and L3 together with the A8 to which they are attached form a 5- or 6-membered heterocyclic ring, preferably piperidinyl or pyrrolidinyl substituted with R4 and R9; L4 is absent; Z is any 6-membered carbon ring or heterocyclic ring, preferably forming a 6-membered aryl or heteroaryl ring with the central nucleus, wherein Z is substituted as desired by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, Me, _-CF3 , Et, -OMe, -SMe, and _NO2 ; R4 is COOH or tetrazolyl; R9 R1 is any 4-, 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, Me, _-CF3 , Et, -OMe, and -SMe; and _R6 is any 5- or 6-membered carbocyclic or heterocyclic ring, substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -I, -OH, _-NO2 , Me, _-CF3 , Et, -OMe, and -SMe, or _R6 is H, or ALC1i has the structure of formula (II), wherein: X is N or S; A is C or N; _R1 is –CO- _OR6 , -CO-R _7. or -CO-NR _6RA , preferably _R1 is –CO-OR ₆ ; _R2 is -R ₇ , -NHR ₈ , -OR ₇ , -COR ₇ , Br, -C _{3-8 -} cycloalkyl (preferably cyclopropyl), or –C _4-8 -cycloalkenyl (preferably cyclohexenyl); or _R1 and _R2 together form a 5, 6, or 7-membered carbon ring or heterocyclic ring, which is substituted as needed, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, -NO ₂ , -CN, -Br, -Cl, -F, -I, -OC _1-3 -alkyl, =O, and [-O-CH ₂ -CH ₂ ]-NH-CH(OH)-O-tBu; R _R3 is H, =O, -OH, _-OR7 , _-R7 , or –( _CH2 ) _m -L, where m is 0, 1, or 2, and L is a 5, 6, or 7-membered carbon ring or heterocyclic ring, which may be substituted as desired, preferably substituted by 1, 2, or 3 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, -O- _C1-3 -alkyl, _-hydroxyC1-3 -alkyl, and =O; _R4 is H or _-C1-3 -alkyl, preferably H; _R5 is -( _CH2 ) _m -L or -( _CH2 ) _m- (CH=CH)-L, where m is 0, 1, or 2, preferably 0. Or 1, and L are 5, 6, or 7-membered carbocyclic or heterocyclic, adamantine, _C1-4 -alkyl, or -N( _CH3 ) ₂ , which are substituted as desired, preferably substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: -OH, _-NO2 , -CN, -CO- _OR6 , -Br, -Cl, -F, -I, _-R9 , _-OR9 , =O, and [-O- _CH2 - _CH2 ] _q -NH-biotin, wherein q is 1, 2, 3, or 4, or two adjacent substituents form a 5, 6, or 7-membered carbocyclic or heterocyclic ring; or _R4 and R _{R4 and R5} together form a 5, 6, or 7-membered carbon ring, which may be substituted as desired, preferably by 1, 2, or 3 substituents independently selected from the following group: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-OR9 , _-R9 , =CH- _RA , and _–CH2 - _RA . Preferably, _R4 and _R5 together form a _C5-7 -cycloalkyl group; _R6 is H, _-C1-6 -alkyl, _-C2-6 -alkenyl, or _-C2-6 -ynyl, which may be substituted as desired, preferably _R6 is H; _R7 is _-C1-3 -alkyl, _-C2-3 -alkenyl, or _-C2-3- alkyl. -Alynyl group, which is substituted as desired, preferably substituted by one, two or three substituents independently selected from the group consisting of: -Br, -Cl, -F, -I, _-CH3 , _-OCH3 , or _-SCH3 ; _R8 is H or _C1-6 -alkyl, preferably H; _R9 is _{-C1-6 -} alkyl, -C2-6-alkenyl, _-C2-6 -alkynyl, _-C1-6 -alkyl-aryl, or _C1-6 -alkyl-heteroaryl (preferably isothiazolium, thiazolium, tetrazolium, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-thiadiazole, pyridine, or pyrazole), wherein, as desired, they are substituted by one, two, or three substituents selected from the group consisting of: -Br, -Cl, -F, -I, _-NO₂ , -CN, -CONH₂, -CONH-C₁ _{-3 -} alkyl (preferably –CONH-CH₃), -NH-CO- _{C₁ -3} -alkyl (preferably -NH-CO- _CH₃ ), -C₁ _-6 -alkyl (preferably _-CH₃ , ethyl, propyl, tert-butyl, or pentyl), -C₁- ₃ -halogen (preferably -CF₃ ₎ . -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 , -OC1-4 - alkyl ( preferably -OCH3} ), _-OC1-3 -alkyl- _OC1-3 -alkyl (preferably –O- _CH2 -O- _CH3 ), _-SCH3 , or when _R9 is _-C1-6 When -alkyl-aryl, the two adjacent substituents on the aryl moiety can form a 5, 6, or 7-membered carbocyclic or heterocyclic ring, which may be substituted as needed; _RA is H, a carbocyclic or heterocyclic ring, which may be substituted as needed, preferably by 1, 2, or 3 substituents independently selected from the following group: -OH, _-NO2 , -CN, -Br, -Cl, -F, -I, _-R9 , -O- _R7 , -O-( _CH2 ) _OR9 , _{-SO2NH2 ,} and =O, where o is 0 or 1. The ALC1i used 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 the annulated carbocyclic or heterocyclic Z; L3 is _CH2 - _CF2 -R9 or each of L2 and L3 is _CH2 - _CH2 ; or L2 and L3 together with the A8 to which they are linked form a piperidine ring or pyrrolidine ring substituted with R4 and R9; L4 is absent; Z is a phenyl or cyclohexyl group forming a ring with the central nucleus, wherein Z is substituted as desired by one, two, or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, -F, -OH, Me, _-CF3 , -OMe, and _-NO2 , R4 R9 is COOH or tetrazolium; R6 is phenyl, cyclobutyl, cyclopentyl or adamantyl, substituted as desired by one, two or three (preferably one) substituents selected from the group consisting of: -Br, -Cl, _-CF3 , Me, _-CH2 - _CF3 , and -OMe; R6 is any 6-membered carbon ring or heterocyclic ring (preferably phenyl or cyclohexyl; more preferably phenyl), substituted as desired by one, two or three (preferably one) substituents selected from the group consisting of: Br, -Cl, -F, Me, _-CF3 , -OMe, and _-NO2 . The ALC1i used according to any one of requests 1 to 6, wherein the ALC1i is selected from the following groups: ;and And its isomers, pharmaceutically acceptable salts, solvents, chemically protected forms, and precursors. The ALC1i used according to any one of claims 1 to 7, wherein the ALC1i and an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK, BRD, or PARP, or mitomycin C, paclitaxel, or an antibody drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor, such as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan, are administered simultaneously or subsequently. The ALC1i used according to any one of claims 1 to 8, wherein the proliferative disease is selected from HR-deficient carcinoma, 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. A pharmaceutical composition comprising an ALC1i as defined in any one of claims 1 to 7 and a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, and/or BRD, MEK; b) mitomycin C or paclitaxel; or c) an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor. If the pharmaceutical composition of claim 10 is used to treat or improve proliferative diseases, preferably HR-deficient carcinomas, more preferably BRCA-1 and/or BRCA-2-deficient tumors, and/or 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. A kit of parts comprising (i) an ALC1i as defined in any of claims 1 to 7, and instructions for use in combination with the following: a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK, and/or BRD; b) mitomycin C or paclitaxel; or c) free radiation; or d) an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor; or (ii) an inhibitor of a) topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK, and/or BRD; or b) mitomycin C. C. Paclitaxel, or an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor, and instructions for use in combination with an ALC1i as defined in any of claims 1 to 5, and (iii) an ALC1i as defined in any of claims 1 to 5, individually packaged, and a) an inhibitor of topoisomerase I, topoisomerase II, ATM, ATR, Wee1, MEK, and/or BRD, or b) mitomycin C or paclitaxel, or c) an antibody-drug conjugate of a tumor-specific antibody conjugated to a TOP1 inhibitor, as needed, with instructions for use for the treatment or improvement of proliferative diseases. The kit of parts according to claim 12 is used for the treatment or improvement of proliferative diseases, preferably HR-deficient carcinomas, more preferably BRCA-1 and/or BRCA-2-deficient tumors, and/or 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. The ALC1i used 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 in combination with any one of the following: adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, mitomycin C. Teniposide, Topotecan, AZD-5305, Niraparib, Olaparib, Rucaparib, Veliparib, Talazoparib, Trastuzumab deruxtecan, Datopotamab deruxtecan, and/or Sacituzumab govitecan. A pharmaceutical composition comprising ALC1i-101 or a salt thereof and trastuzumab deruxtecan for the treatment or improvement of proliferative diseases, preferably HR-deficient carcinomas, more preferably BRCA-1 and/or BRCA-2-deficient carcinomas, and/or the proliferative disease being selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer, or pancreatic cancer. A pharmaceutical composition comprising ALC1i-101 or a salt thereof and trastuzumab deruxtecan, used to treat advanced or metastatic cancers with homologous recombination deletion (HRD) mutations. The ALC1i used according to any one of claims 1 to 9, the pharmaceutical composition according to claims 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 deruxtecan and has shown or not shown at least a partial response, preferably after several treatment cycles.