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WO2025088175A1 - Inhibiteurs d'alc1 destinés à être utilisés dans le traitement du cancer par potentialisation des effets de plusieurs classes de médicaments anticancéreux approuvés - Google Patents

Inhibiteurs d'alc1 destinés à être utilisés dans le traitement du cancer par potentialisation des effets de plusieurs classes de médicaments anticancéreux approuvés Download PDF

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WO2025088175A1
WO2025088175A1 PCT/EP2024/080317 EP2024080317W WO2025088175A1 WO 2025088175 A1 WO2025088175 A1 WO 2025088175A1 EP 2024080317 W EP2024080317 W EP 2024080317W WO 2025088175 A1 WO2025088175 A1 WO 2025088175A1
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alkyl
group
optionally substituted
phenyl
ome
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William M. MENZER
Katharina SAHIRI
Adrian SCHOMBURG
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Eisbach Bio GmbH
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Eisbach Bio GmbH
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • ALC1 INHIBITORS FOR USE IN TREATING CANCER BY POTENTIATING THE EFFECTS OF SEVERAL CLASSES OF APPROVED CANCER DRUGS The present invention relates to the use of small molecule compounds that allosterically inhibit ALC1 (CHD1L), in particular the use of two classes of allosteric inhibitors of ALC1 (CHD1L), of Formula (I) and Formula (II), that show a potentiating, preferably synergistic effect in the treatment of proliferative disease when combined with several classes of cancer drugs, namely inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or when combined with mitomycin C, paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor.
  • 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)).
  • PARP inhibitor Poly(ADP-ribose)-Polymerase inhibitor (PARPi)
  • PARPi Poly(ADP-ribose)-Polymerase inhibitor
  • chemotherapeutic agents are not targeted therapies, the biggest problems of conventional chemotherapeutic agents are the side effects caused by cytotoxicity on one hand and the development of drug resistance on the other. The latter is the main factor that eventually causes the treatment to fail despite an initial successful response to the chemotherapeutic agents. Therefore, in order to overcome the limitations of such chemotherapeutic agents, it is necessary to develop new targeted therapeutic agents that specifically interfere with cancer cell proliferation.
  • the present invention is based on the surprising finding that specific ALC1 inhibitors, namely those wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1, in particular those of Formula (I) and of Formula (II), possess synergistic, anti-proliferative activity when being combined with several classes of known cancer drugs, namely inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, MEK, or when being combined with specific established cancer drugs, namely mitomycin C or paclitaxel, or when being combined with ionizing radiation, or when being combined with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor.
  • specific ALC1 inhibitors namely those wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1, in particular those of Formula (I) and of Formula (I
  • ALC1 inhibitors in combination with other cancer drugs may lead to more than the expected additive efficacy is as follows.
  • Activation of the DNA damage pathway leads to the recruitment of many proteins to damaged chromatin, notably also specific chromatin remodeling enzymes, including the macrodomain-containing nucleosome remodeler ALC1 (CHD1L) (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017).
  • CHD1L macrodomain-containing nucleosome remodeler ALC1
  • Macrodomains generally bind ADP-ribose, oligo-ADP-ribose and poly-ADP-ribose (PAR) (Karras et al., 2005), thus proteins containing macrodomains respond and recruit to PARP activation sites on the genome, including during DNA damage and with relevance for cancer.
  • PARP poly-ADP-ribose
  • ALC1 is a validated oncogene and is often genetically amplified together with PARP1 in BRCA1/2-deficient ovarian and breast cancer samples. Few ALC1i are described in the art e.g. by Abbott et al.
  • ALC1 inhibitors wherein the inhibitors specifically bind to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1, in particular inhibitors with structures according to Formula (I) and Formula (II), and which inhibit the ATPase function and/or nucleosome remodeling function of ALC1, show synergistic effects in combination with and potentiate the effects of a) a number of compounds from several classes of cancer drugs, namely • inhibitors of Topoisomerase I (e.g. topotecan) • inhibitors of Topoisomerase II (e.g.
  • teniposide • inhibitors of ATM (e.g. AZ-32, AZD-1056, or AZD-1390) • inhibitors of ATR (e.g. ceralasertib, elimusertib) • inhibitors of WEE1 (e.g. adavosertib) • inhibitors of BRD (e.g. BAY-299 or ABBV-744), • inhibitors of MEK (e.g. trametinib) b) specific established cancer drugs, namely mitomycin C or paclitaxel, c) ionizing radiation, and d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g.
  • ATM e.g. AZ-32, AZD-1056, or AZD-1390
  • ATR e.g. ceralasertib, elimusertib
  • WEE1 e.g. adavosertib
  • trastuzumab deruxtecan e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan.
  • specific ALC1 inhibitors e.g. AZD-5305, niraparib, olaparib, pamiparib, rucaparib, talazoparib, and veliparib
  • PARP inhibitors e.g. AZD-5305, niraparib, olaparib, pamiparib, rucaparib, talazoparib, and veliparib
  • this combination of specific ALC1 inhibitors and PARP inhibitors has been found to be particularly suitable for use in treating pancreatic cancer or fallopian tube cancer.
  • ALC1 inhibition by the specific ALC1 inhibitors inhibits efficient DNA repair by rendering chromatin less accessible to DNA repair enzymes. This leads to enhanced cancer cell killing and/or reduce off-target effects of the chemotherapeutic agent or the cancer drugs even if used at lower doses and thus lessen cellular toxicity in non-cancer cells.
  • ALC1 inhibitors used according to the invention in particular of Formula (I) and Formula (II), may thus also mediate sensitization to compounds a), b), and d) as listed above.
  • the present inventors further expect that manipulation of ALC1 activity via the present ALC1 inhibitors used according to the invention could induce strong anti-proliferative effects and in addition be sufficient to bypass an acquired resistance to compounds a),b), and d) listed above, as well as to PARP1 and PARP2 inhibition.
  • ALC1 inhibitors of the invention in particular of Formula (I) and Formula (II), respectively, and compounds a), b), and d
  • PARP1 and/or PARP2 inhibitor treatment can be used for therapies in oncology, including in a relapse condition and when there is progression in advanced clinical progression stages.
  • the present invention provides a novel combination regimen to treat or ameliorate proliferative disease and preferably tumor diseases, in particualar characterized by loss of sensitivity to the above-
  • the present inventors determined that by using a combination of ALC1 inhibitors used according to the invention, in particular characterized by Formula (I) and Formula (II), and adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, or talazoparib, as well as trastuzumab deruxtecan, the effect of adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxe
  • ALC1 inhibitors used according to the invention in particular characterized by Formula (I) and Formula (II), in combination with adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD- 5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, or talazoparib, as well as trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan provides inter alia (i) an efficient therapy of cancers that are amenable to adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trame
  • the present invention is directed at an allosteric inhibitor of Chromodomain- helicase-DNA-binding protein 1-like (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1, preferably an inhibitor of ALC1 (ALC1i) according to Formula (I) or pharmaceutically acceptable salts, isomers, solvates, chemically protected forms, and prodrugs thereof, wherein A5 and A8 are each independently selected from N or CH; A6 is selected from N or CH, or when A6 takes part in the annulated carbo- or heterocycle Z, then A6 is C; A7 is selected from N or CH, or when A7 takes part in the annulated carbo- or heterocycle Z, then A7 is C; L2 is selected from the group consisting of -CH 2 -R4, –CF 2 – R4, -CH 2 -CH 2 - R4, -CH 2
  • trastuzumab deruxtecan for use in enhancing efficacy of a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK b) mitomycin C, or paclitaxel, c) ionizing radiation, or d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g.
  • the inhibitor of ALC1 (ALC1i) according to formula (II) is for use in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient in combination with an inhibitor of PARP, or for use in enhancing efficacy of an inhibitor of PARP in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient.
  • the present invention is directed at a pharmaceutical composition
  • a pharmaceutical composition comprising an ALC1i as defined herein and a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD and/or MEK, b) mitomycin C, paclitaxel, or c) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan).
  • a pharmaceutical composition comprising an ALC1i as defined herein and a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD and/or MEK, b) mitomycin C, paclitaxel, or c) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g. trastuzumab deruxtecan, datopotamab deruxtec
  • the present invention is directed to a kit of parts, comprising an ALC1i as described herein with instructions to combine it with a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, b) mitomycin C, or paclitaxel, c) ionizing radiation; or d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g.
  • trastuzumab deruxtecan e.g. trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan
  • a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, b) mitomycin C, or paclitaxel, or c) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor e.g.
  • trastuzumab deruxtecan datopotamab deruxtecan, or sacituzumab govitecan
  • FIG. 1 Structures and molecule names of selected ALC1 inhibitors. These selected ALC1 inhibitors (or isomers, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs thereof) are preferably used in accordance with the present invention.
  • Figure 2 Synergy Scores and MSA of cancer cells treated with a combination of ALC1i vs.
  • results of the 2-D titrations of different combinations of an ALC1i (compound A) with another drug (compound B) in different cancer cell lines are summarized in this table.
  • Drug combinations with an MSA (most synergistic area) score below 9 indicate interactions that are likely not synergistic and are labeled with a “-”.
  • An MSA score between 9-10 is labeled with “+” and indicates that the interaction of compound A and B is likely to be synergistic.
  • MSA scores above 10 are marked “++” are synergistic.
  • MSA scores greater than 20 are labeled as “+++” and considered highly synergistic.
  • Figure 3 Example for 96-hour SRB assay: pancreatic cancer cell line treated with ALC1i or ATMi.
  • PSN1 cells were seeded into 96-well plates and treated with titrations of ALC1i-101 or an ATMi (ATM inhibitor AZD-1390).
  • the cells were cultured at 37°C, CO 2 5% for 4 days, fixed with 10%TCA and stained with sulforhodamine staining to analyze cell survival.
  • the data was normalized to DMSO controls indicating 100 % survival.
  • Inhibitor vs. response curves were fitted with the Synergy Finder using the curve fitting parameter “LL4”. The curves show an average fit of 3 technical replicates.
  • Figure 4 Example for 2-D titration: co-treatment cell proliferation assay of pancreatic cancer cells.
  • Cancer cells were seeded into 96-well plates and treated with a 2-D titration of an ALC1i vs. the indicated drug.
  • the cells were cultured at 37°C, CO 2 5% for 4 days, fixed with 10%TCA and stained with sulforhodamine staining to analyze cell survival.
  • the synergy score is calculated using the Synergy Finder.
  • Treatment with ALC1i-101 in combination with ATMi show highly synergistic area scores of above 10 respectively. MSA scores over 10 are an indication of strong synergy.
  • Figure 5 cell cycle analysis of ALC1i treated cancer cells. SUM-149-PT cells were seeded into 6-well plates and treated with ALC1i or DMSO for 48h.
  • Figure 7 EC50 values ( ⁇ M) of 96 hour SRB assay and 11 days colony formation assay of HR proficient (HRP) and HR deficient (HRD) cells treated with ALCi.
  • HR homologous recombination repair pathways
  • FIG. 8 List of HR genes. List of genes involved in DNA Damage Response (DDR) (Human DNA Repair Genes, n.d.) cited in Wood RD, Mitchell M, & Lindahl T Mutation Research, 2005, in Science, 2001, in the reference book DNA Repair and Mutagenesis, 2nd edition, 2006, and in Nature Reviews Cancer, 2011 (modified by R. Wood and M. Lowery on Wednesday 10th June 2020).
  • DDR DNA Damage Response
  • Figure 9 List of genes related to the homologous recombination repair pathway (HR).
  • CHD1L Chrodomain-helicase-DNA-binding protein 1-like
  • ALC1 The amino acid sequence of human ALC1 is as specified in SEQ ID NO: 1 as known in the art, e.g. as specified in WO2022/117782 A1.
  • the 897 amino acid residues long protein consists of an N-terminal Snf2-like DNA dependent ATPase domain spanning amino acid residues 40 to 513, which contains the conserved helicase motifs critical for catalysis (Flaus et al., 2006). This domain is composed of two RecA like lobes ranging from amino acid residues 48 to 261 and 351 to 513, respectively.
  • the allosteric binding pocket is spatially separated from that part of ALC1 involved in binding ATP.
  • the ATPase domain is followed by a linker region ranging from amino acid residues 514 to 703, which contains a putative coiled-coil region (amino acid residues 638 to 675), and a C-terminal macrodomain (amino acid residues 704 to 897).
  • the macrodomain has been shown to directly interact with the ATPase domain, thereby inhibiting its catalytic function (Lehmann et al., 2017; Singh et al., 2017). This interaction is released upon poly(ADP-ribose) binding to the macrodomain, leading to an activation of the chromatin remodelling enzyme.
  • alkyl refers to a saturated straight or branched hydrocarbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, e.g.
  • heteroalkyl refers to a saturated straight or branched hydrocarbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e.1, 2, 3, 4, 5, 6, 7, 8, or 9, e.g.
  • heteroatoms are selected from O, S, and N, e.g.
  • heteroalkyl refers to O-CH 3 , -OC 2 H 5 , -CH 2 -O-CH 3 , - CH 2 -O-C 2 H 5 , -CH 2 -O-C 3 H 7 , -CH 2 -O-C 4 H 9 , -CH 2 -O-C 5 H 11 , C 2 H 4 -O-CH 3 , -C 2 H 4 -O-C 2 H 5 , -C 2 H 4 -O- C 3 H 7 , -C 2 H 4 -O-C 4 H 9 etc.
  • Heteroalkyl groups are optionally substituted.
  • haloalkyl refers to a saturated straight or branched hydrocarbon chain in which one or more hydrogen atoms are replaced by halogen atoms, e.g. by fluorine, chlorine, bromine or iodine.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • haloalkyl refers to -CH 2 F, -CHF 2 , -CF 3 , -C 2 H 4 F, -C 2 H 3 F 2 , C 2 H 2 F 3 , -C 2 HF 4 , -C 2 F 5 , -C 3 H 6 F, -C 3 H 5 F 2 , -C 3 H 4 F 3 , -C 3 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 , - C2HCl4, C2Cl5, -C3H6Cl, -C3H5Cl2, C3H4Cl3, -C3H3Cl4, -C3H2Cl5, -C3HCl6, and -C3Cl7
  • Haloalkyl groups are optionally substituted.
  • the term “5, 6, or 7 membered carbocycle” is used in the context of the present invention to refer to “cycloalkyl", “cycloalkenyl” or “aryl” with 5, 6, or 7 carbon atoms forming a ring.
  • the term “cycloalkyl” includes cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups are optionally substituted.
  • cycloalkenyl includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups are optionally substituted.
  • aryl refers to a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • the aryl group comprises 6 to 10 carbon atoms, i.e. a C 6-10 aryl group.
  • an aryl group is a phenyl group, which is most preferred, or a naphthyl group.
  • Aryl is optionally substituted.
  • 5, 6, or 7 membered heterocycle is used in the context of the present invention to refer to monocyclic "5, 6, or 7 membered heterocycloalkyl” or monocyclic “5, 6, or 7 membered heteroaryl” with 5, 6, or 7 atoms forming a ring.
  • the term “5, 6, or 7 membered heterocycloalkyl” refers to a saturated monocycle, wherein at least one of the carbon atoms are replaced by 1, or 2 (for the five membered ring) or 1, 2, or 3 (for the six membered ring) or 1, 2, 3, or 4 (for the seven membered ring) of the same or different heteroatoms, preferably selected from O, N and S.
  • heterocycloalkyl examples include 1-(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, or 2- piperazinyl.
  • Heterocycloalkyl groups are optionally substituted.
  • heteroaryl refers to a 5, 6 or 7-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, or 3 (for the five membered ring) or 1, 2, 3, or 4 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S.
  • heteroaryls furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl.
  • Heteroaryl groups are optionally substituted.
  • aralkyl corresponds to an arylalkyl residue, i.e. an alkyl that is substituted with an aryl group as defined above. If two or more radicals can be selected independently from each other, then the term “independently” means that the radicals may be the same or may be different.
  • R' and R'' are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl or together form a heteroaryl, or heterocycloalkyl;
  • “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia (United States Pharmacopeia-33/National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention.
  • Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of a compound described herein or a derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • 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.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of Formula (I) or Formula (II), and especially a compound shown in Fig.1.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard H. et al. (1989) J. Med. Chem.32(12): 2503- 2507). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard H. “Design of Prodrugs”, Elsevier Science Ltd. (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 0039051 A2 discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • a “patient” means any mammal or bird that may benefit from a treatment with the compounds described herein.
  • a “patient” is selected from the group consisting of laboratory animals, domestic animals, or primates including chimpanzees and human beings. It is particularly preferred that the “patient” is a human being.
  • treat means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
  • prevent means preventing that a disorder occurs in a subject for a certain amount of time.
  • a compound described herein is administered to a subject with the aim of preventing a disease or disorder, said disease or disorder is prevented from occurring at least on the day of administration and preferably also on one or more days (e.g. on 1 to 30 days; or on 2 to 28 days; or on 3 to 21 days; or on 4 to 14 days; or on 5 to 10 days) following the day of administration.
  • a “pharmaceutical composition” according to the invention may be present in the form of a composition, wherein the different active ingredients and diluents and/or carriers are admixed with each other, or may take the form of a combined preparation, where the active ingredients are present in partially or totally distinct form.
  • An example for such a combination or combined preparation is a kit-of-parts.
  • An “effective amount” is an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration. The effective amount in each individual case may be determined empirically by a skilled artisan according to established methods in the art.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • a saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • the compounds of the invention can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • SEQ ID NO 1 MERAGATSRGGQAPGFLLRLHTEGRAEAARVQEQDLRQWGLTGIHLRSYQLEGVNWLAQR FHCQNGCILGDEMGLGKTCQTIALFIYLAGRLNDEGPFLILCPLSVLSNWKEEMQRFAPG LSCVTYAGDKEERACLQQDLKQESRFHVLLTTYEICLKDASFLKSFPWSVLVVDEAHRLK NQSSLLHKTLSEFSVVFSLLLTGTPIQNSLQELYSLLSFVEPDLFSKEEVGDFIQRYQDI EKESESASELHKLLQPFLLRRVKAEVATELPKKTEVVIYHGMSALQKKYYKAILMKDLDA FENETAKKVKLQNILSQLRKCVDHPYLFDGVEPEPFEVGDHLTEASGKLHLLDKLLAFLY SGGHRVLLFSQMTQMLDILQDYMDYRGYSYERVDGSVRGEERHLAI
  • the present inventors have identified that said allosteric inhibitors of ALC1 (CHD1L), in particular those of Formula (I) and Formula (II), show a potentiating, preferably synergistic effect in the treatment of proliferative disease when combined with several classes of cancer drugs, namely inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, with mitomycin C, paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor.
  • ALC1 inhibitors as a known class of cancer drugs could be combined with several other classes of known cancer drugs, e.g. inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, or MEK, with mitomycin C, or paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor.
  • tests with known ALC1i showed not over-additive efficacies against cancer cell lines.
  • the present invention is based on the surprising finding that said specific allosteric ALC1 inhibitors, preferably those of Formula (I) and of Formula (II), possess synergistic anti-proliferative activity when combined with inhibitors of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, with mitomycin C, or paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor.
  • these combinations are expected to be suitable in the treatment of proliferative diseases.
  • the ALC1 inhibitors preferably those characterized by Formula (I) and Formula (II), the latter being known from the art (WO 2022/117782 A1), which are used in accordance with the present invention, appear to be involved in allosteric regulation of the nucleosome sliding activity of ALC1. These compounds specifically bind to an allosteric pocket and are capable of inhibiting activity of ALC1. Compounds that bind to the ATPase site of ALC1 and block the ATPase activity have to compete with ATP for binding to the ATPase site.
  • the allosteric inhibitors of ALC1 used according to the invention do not have this limitation since they do not have to prevent ATP from binding but inhibit ALC1’s activity through a different mechanism.
  • the present inventors have identified ALC1 inhibitors that are capable of specifically binding to an allosteric pocket of ALC1. The question remained and has been not answered by the art yet, whether these specific ALC1 inhibitors would provide synergistic efficacy with other classes of cancer drugs.
  • the present invention is directed at an allosteric inhibitor of Chromodomain- helicase-DNA-binding protein 1-like (ALC1), wherein the inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1 for use in treating or ameliorating a proliferative disease in a patient in combination with and/or for use in enhancing the efficacy in treating a proliferative disease of a) an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or b) mitomycin C, paclitaxel, c) ionizing radiation, or d) an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor (e.g.
  • AAC1 inhibitor Chromodomain- helicase-DNA-binding protein 1-like
  • trastuzumab deruxtecan a trastuzumab deruxtecan, datopotamab deruxtecan, or sacituzumab govitecan.
  • the term “specifically binds” as used in this context indicates a K D of the compound to full length human ALC1 with an amino acid sequence according to SEQ ID NO: 1 of 200 ⁇ M or lower, preferably of 100 ⁇ M, more preferably of 50 ⁇ M, more preferably of 10 ⁇ M or lower, more preferably of 5 ⁇ M or lower, even more preferably of 1 ⁇ M and even more preferably of 500 nM or lower.
  • SEQ ID NO: 1 a K D of the compound to full length human ALC1 with an amino acid sequence according to SEQ ID NO: 1 of 200 ⁇ M or lower, preferably of 100 ⁇ M, more preferably of 50 ⁇ M, more preferably of 10 ⁇ M or lower, more preferably of 5 ⁇ M or lower, even more preferably of 1 ⁇ M and even more preferably
  • the K D of a compound of the invention is measured by immobilizing full length human ALC1 on the surface of a chip and the compound is subsequently applied to the immobilized protein. Preferably such measurement is carried out at 37°C.
  • the allosteric inhibitor of ALC1 used according to the invention exhibits an IC 50 value in a FRET based nucleosome remodeling assay of 500 ⁇ M or less, preferably 250 ⁇ M or less, more preferably 100 ⁇ M or less, more preferably 50 ⁇ M or less, more preferably 10 ⁇ M or less, more preferably 5 ⁇ M or less, or even more preferably 1 ⁇ M or less.
  • the K D and the IC 50 as described herein are determined as disclosed in WO 2022/117782 A1. Not every amino acid within the amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1 is forming the surface of the allosteric pocket of ALC1 available for binding to the compounds used according to the invention. This is due to the fact that some amino acids are buried in the pocket and are poorly accessible and others are not even part of the pocket but are located within or on the outside surface of ALC1.
  • the allosteric binding pocket to which the inhibitors of ALC1 used according to the present invention specifically bind comprises or consists of amino acids L101, Y153, C156, L157, A160, L163, K164, V173, D174, E175, A176, H177, R178, L179, S183, L186, H187, T189, L190, F193, L200, L201, T202, N208, S209, E212, L213, L216, and F219 of SEQ ID NO: 1, more preferably the binding pocket comprises or consists of Y153, C156, L157, A160, L163, V173, E175.
  • WO2022/117782 A1 depicts how the skilled person can visualize the suitability of a given compound to fit into the allosteric binding pocket, and thus provides further guidance on the selection of compounds that fulfill the steric, hydrophobicity, and hydrophilicity as well as charge requirements in the pocket.
  • a minimal set of structural coordinates of the amino acids of ALC1 involved in binding to the compounds of the invention is provided in Fig.
  • WO2022/117782 A1 it can be determined whether the inhibitor specifically binds to the allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO: 1. Based on their orientation within the pocket the different amino acids that are accessible at the surface of the pocket can form different non-covalent bonds, in particular hydrogen bonds, ionic interactions, van der Waals interactions and hydrophobic interactions.
  • the inhibitor used according to the invention forms non-covalent bond(s) with one or more amino acids of the allosteric binding pocket, preferably with one or more of the backbone of amino acids L157, A160, K164, V173, D174, H177, R178, L179, L186, N208, and/or E212 of ALC1 and/or the sidechains of L101, Y153, C156, L157, A160, L163, E175, R178, L179, L186, H187, L190, F193, T202, N208, E212, or L213 of ALC1, more preferably with the backbone of D174, H177, and R178 of ALC1, and the sidechain of Y153, E175, R178, H187, T202, N208 and/or E212 of ALC1.
  • the inhibitor of ALC1 used according to the invention non-covalently binds to: (i) the aromatic ring of the sidechain of amino acid Y153 of ALC1 ring face-to-face or edge-to-face pi-pi interaction with aromatic carbo- or heterocyclic substituents or forming cation-pi, polar-pi, or halogen- pi interactions with polar, charged, or carbo-halogen substituents; (ii) the terminal oxygen of the sidechain of amino acid Y153 of ALC1 with a hydrogen bond donating group; (iii) the carbonyl oxygen of the backbone of H177 with carbo halogens or hydrogen bond donating groups; (iv) the carbonyl oxygen of the backbone of D174 with carbo halogens or hydrogen bond donating groups; (v) the sidechain of E175 with a hydrogen bond donating or accepting group; (vi) the sidechain of R178 with a hydrogen bond donating or accepting group; (vii) the backbone carbon
  • the inhibitor of ALC1 (ALC1i) used according to the invention is an inhibitor of ALC1 (ALC1i) according to Formula (II) wherein (i) R 5 comprises an aromatic ring that pi-stacks with the aromatic ring of Y153; and/or (ii) N is a hydrogen bond accepting group for the terminal OH of Y153; and/or (iii) R 1 comprises a group that is a hydrogen bond donating group to the backbone carbonyl oxygen of H177; and/or (iv) R 3 comprises a carbohalogen or hydrogen bond donating group that binds to the carbonyl oxygen of the backbone of D174; and/or (v) R 1 and R 2 together form an aromatic or heteroaromatic monocyle comprising a hydrogen bond donating or accepting group especially at or adjacent to the R 1 position which can act as a hydrogen bond doating or accepting group to the side chain of E175 and/or R178; and/or (vi) R 1 and R 2 together form
  • the ALC1i according to Formula (I) preferably shows inhibition >50% at concentrations at or below 250 ⁇ M, preferably has an IC 50 of ⁇ 250 ⁇ M, and more preferably of ⁇ 25 ⁇ M.
  • the IC 50 is preferably measured in a FRET based nucleosome remodeling assay as described in WO 2022/117782 A1.
  • the ALC1i according to Formula (I) preferably has an EC 50 of ⁇ 250 ⁇ M, preferably of ⁇ 50 ⁇ M; and more preferably of ⁇ 10 ⁇ M.
  • the EC 50 is preferably measured in cell proliferation assay with an SRB based readout as described in WO 2022/117782 A1. If not specifically indicated otherwise, the residues with normal, i.e. not subscript, integers, relate to compounds of formula (I), those residues with subscript integers relate to compounds of formula (II).
  • A5 and A6 are N;
  • A7 takes part in the annulated carbo- or heterocycle, preferably carbocycle Z, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • A8 is -CH 2 -N, -CH 2 -CH, or -NH-CH, preferably -NH-CH.
  • A5, A7 and A8 are N and A6 takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, - OMe, -SMe, and -NO 2 .
  • A5, A7 and A8 are N and A6 takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 .
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4.
  • L2 is selected from the group consisting of -CH 2-R4, –CF2– R4, -CH2-CH2-R4, -CH2-CH2-CH2-R4, - NH-R4; and R4 is 6-membered aryl or 5-, 6- or 7-membered heteroaryl, preferably 5- or 6 -membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -CF 3 , Me, Et, -OMe, and -SMe, or R4 is hydrogen, methyl, or COOH.
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9. In an embodiment it is preferred that: L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, -CH 2 -CF 2 -R9; and R9 is a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, - CF 3 , Et, -OMe, and -SMe.
  • L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and R9.
  • L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and R9;
  • R4 is hydrogen, methyl, or COOH;
  • R9 is a 4-, 5-, 6-, 7-membered carbo- or heterocycle, preferably phenyl or 5- or 6-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF 3 , Et, -OMe, and -SMe.
  • L4 is absent.
  • A5, A7 and A8 are N; and L4 is absent.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L4 is absent.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L4 is absent.
  • A5, A7 and A8 are N; and L4 is absent R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L4 is absent R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe,
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L4 is absent R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N; and L4 is absent R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; and R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; and R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • R4 is hydrogen, methyl, COOH or tetrazolyl.
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4; and R4 is hydrogen, methyl, COOH or tetrazolyl.
  • R9 is any 4-, 5-, 6- 7-, 8-, 9-, or 10-membered carbo- or heterocycle, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, - CF 3 , Me, Et, -OMe, and -SMe.
  • R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e.
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, -CH 2 -CF 2 -R9; and R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 - , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe or R6 is H.
  • L4 is absent; and R6 is a 5-, or 6-membered carbo- or heterocycle, preferably 6-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • Z is a 6 membered aryl, or a 5-, 6-membered heteroaryl, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, - I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 .
  • A5 is N; one of A6 and A7 is CH and the other one is N; or one of A6 and A7 is C and takes part in the annulated carbo- or heterocycle Z and the other one is N;
  • A8 is N or CH;
  • L2, L3, L4 are independently from each other selected from the group consisting of CH 2 , –CF 2 –, CH 2 - CH 2 , CH 2 -CH 2 -CH 2 , O, N, and NH, or are absent, or L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle substituted by R4 and R9;
  • Z is any 5-, 6- or 7-membered carbo- or heterocycle and can be annulated to the central core or connected via a covalent bond and optionally substituted with one, two, or three (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF
  • A5 is N; one of A6 and A7 is C and takes part in the annulated carbo- or heterocycle Z and the other one is N;
  • A8 is N;
  • L2 is CH 2 -CH 2 and L3 is CH 2 -CH 2 or CH 2 -CF 2 ; or L2 and L3 together with the A8 to which they are connected form a 5- or 6-membered heterocycle (preferably piperidine or a pyrrolidine) substituted by R4 and R9;
  • L4 is absent;
  • Z is a 6-membered carbo- or heterocycle annulated to the central core, wherein Z is optionally substituted with one, two, or three (preferably one) substituents selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and NO 2 ;
  • R4 is COOH or CH 2 N 4 ;
  • R9 is a 4-, 5-, 6-,
  • each one of A5, A7 and A8 is N;
  • A6 is C and takes part in the annulated carbo- or heterocycle Z, preferably 5-, 6- or 7-membered carbo- or heterocycle, optionally substituted with one, two, or three (preferably one) substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe;
  • L2 is CH 2 -CH 2 -R4;
  • L3 is CH 2 -CH 2 -R4 or -CH 2 -CF 2 -R9; or L2 and L3 together with the A8 to which they are connected form a piperidine ring or a pyrrolidine ring, substituted by R4 and R9;
  • L4 is absent;
  • Z is phenyl or cyclohexy
  • A5, A7 and A8 are N;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; and L4 is absent.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; and L4 is absent.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L4 is absent.
  • A5, A7 and A8 are N;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • L4 is absent;
  • R6 is a phenyl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, - CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and
  • R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and
  • R6 is a 6 membered aryl or 5-, 6- or 7-membered heteroaryl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of
  • A5, A7 and A8 are N;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • L4 is absent;
  • R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and
  • R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and
  • R6 is phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is -CH 2 -R4, -CH 2 -CH 2 - R4, -CH 2 -CH 2 -CH 2 -R4;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; L4 is absent; and
  • R6 is a phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F,
  • A5, A7 and A8 are N; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 - , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • C 5 -, C 6 - or C 7 -cycloalkyl C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N; L4 is absent; R9 is C 5 to C 7 -cycloalkyl, i.e. C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 - , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9 L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 - , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • C 4 - i.e. C 5 -, C 6 - or C 7 -cycloalkyl
  • C 6 to C 10 -bicycloalkyl i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl
  • C 6 to C 10 -spiroalkyl i.e.
  • A5, A7 and A8 are N;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, i.e. C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO 2 ;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 - , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e.
  • C 6 -, C 7 -, C 8 - , C9- or C10-bicycloalkyl C6 to C10-spiroalkyl, i.e. C6-, C7-, C8-, C9- or C10-spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF 3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9;
  • L4 is absent;
  • R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • C 4 - i.e. C 5 -, C 6 - or C 7 -cycloalkyl
  • C 6 to C 10 -bicycloalkyl i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl
  • C 6 to C 10 -spiroalkyl i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R9 is C 5 to C 7 -cycloalkyl C 4 to C 7 -cycloalky
  • C 4 - i.e. C 5 -, C 6 - or C 7 -cycloalkyl
  • C 6 to C 10 - bicycloalkyl i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl
  • C 6 to C 10 -spiroalkyl i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9; L4 is absent; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • C 4 - i.e. C 5 -, C 6 - or C 7 -cycloalkyl
  • C 6 to C 10 -bicycloalkyl i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl
  • C 6 to C 10 -spiroalkyl i.e.
  • A5, A7 and A8 are N; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9 L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, i.e. C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e.
  • C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl C 6 to C 10 -spiroalkyl, i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -spiroalkyl, phenyl, 5 or 6 membered heteroaryl, adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, Me, -CF 3 , Et, -OMe, and -SMe; more preferably cyclopentyl, cyclohexyl, phenyl, bromo-phenyl, bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, or adamantyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N;
  • L3 is selected from the group consisting of -CH2-R9, -CH2-CH2- R9, and -CH2-CF2-R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO2; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, C 5 -, C 6 - or C 7 -cycloalkyl, C 6 to C 10 -bicycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C 4 to C 7 -cycloalkyl, i.e.
  • C 4 - i.e. C 5 -, C 6 - or C 7 -cycloalkyl
  • C 6 to C 10 -bicycloalkyl i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl
  • C 6 to C 10 -spiroalkyl i.e.
  • A5, A7 and A8 are N; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH; R9 is C 4 to C 7 -cycloalkyl, i.e. C 4 -, i.e.
  • C 5 -, C 6 - or C 7 -cycloalkyl C 6 to C 10 -bicycloalkyl, i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R
  • C 4 - i.e. C 5 -, C 6 - or C 7 -cycloalkyl
  • C 6 to C 10 -bicycloalkyl i.e. C 6 -, C 7 -, C 8 -, C 9 - or C 10 -bicycloalkyl
  • C 6 to C 10 -spiroalkyl i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH
  • A5, A7 and A8 are N;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF3, Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is
  • C4-, C5-, C6- or C7-cycloalkyl C6 to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH
  • A5, A7 and A8 are N;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent;
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; and R4 is hydrogen, methyl, COOH or tetrazolyl, preferably
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ; and L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4; L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent; R4 is hydrogen, methyl, COOH or tetrazolyl, preferably CO
  • C4-, C5-, C6- or C7-cycloalkyl C6 to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • R6 is phenyl ortho substituted with a substituent selected from the group consisting of -Br, -Cl, -F, -I, - OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably Br.
  • L4 is absent; and R6 is phenyl ortho substituted with a substituent selected from the group consisting of -Br, -Cl, -F, -I, - OH, -NO 2 , Me, -CF 3 , Et, -OMe, and -SMe, preferably -Br, -Cl, -F, -I, more preferably Br.
  • A5, A7 and A8 are N;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO2;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent;
  • R4
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably CO
  • C4-, C5-, C6- or C7-cycloalkyl C6 to C10-bicycloalkyl, i.e. C6-, C7-, C8- , C 9 - or C 10 -bicycloalkyl, C 6 to C 10 -spiroalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbo- or heterocycle Z, in particular a 5, 6, or 7 membered carbo- or heterocycle Z, preferably carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, which optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9; L4 is absent;
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably CO
  • A5, A7 and A8 are N;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably COOH;
  • R9 is C 4 to C 7 -cycloalkyl, i.e.
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl, preferably CO
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl, which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl,
  • A5, A7 and A8 are N and A6 is C and takes part in the annulated carbocycle Z, in particular a 5, 6, or 7 membered carbocycle Z, preferably phenyl. which is optionally substituted with one, two, or three, preferably one substituent(s) selected from the group consisting of -Br, -Cl, -F, -I, -OH, Me, -CF 3 , Et, -OMe, -SMe, and -NO 2 ;
  • L2 is selected from the group consisting of -CH 2 -R4, -CH 2 -CH 2 - R4, and -CH 2 -CH 2 -CH 2 -R4;
  • L3 is selected from the group consisting of -CH 2 -R9, -CH 2 -CH 2 - R9, and -CH 2 -CF 2 -R9;
  • L4 is absent;
  • R4 is hydrogen, methyl, COOH or tetrazolyl,
  • the inhibitors of ALC1 (ALC1i) according to formula (I) of the first and further aspects of the invention have the specific structures as indicated in Fig.1.
  • the inhibitor of ALC1 (ALC1i) used according to the invention is an inhibitor of ALC1 (ALC1i) according to Formula (II): and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: X is N or S; A is C or N; R 1 is –CO-OR6, -CO-R7, or -CO-NR6RA, preferably R1 is –CO-OR6; R 2 is -R 7 , -NHR 8 , -O-R 7 , -C-O-R 7 , Br, -C 3-8 -cycloalkyl (preferably cyclopropyl), or –C 4-8 -cycloalkenyl (preferably cyclohexenyl); or R 1
  • the ALC1i according to Formula (II) preferably shows inhibition >50% at concentrations at or below 250 ⁇ M, preferably has an IC 50 of ⁇ 250 ⁇ M, and more preferably of ⁇ 25 ⁇ M.
  • the IC 50 is preferably measured in a FRET based nucleosome remodeling assay as described in WO 2022/117782 A1.
  • the ALC1i according to Formula (II) preferably has an EC 50 of ⁇ 250 ⁇ M, preferably of ⁇ 50 ⁇ M; and more preferably of ⁇ 10 ⁇ M.
  • the EC 50 is preferably measured in a cell proliferation assay with an SRB based readout as described in WO 2022/117782 A1.
  • X is N, this includes the option of X being N-H, and /or when A is N, R 4 may be absent.
  • R 6 is H;
  • R 7 is -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -alkyl, -C 2-3 -alkenyl, i.e.
  • R 8 is H or C 1-6 -alkyl, preferably H, R 9 is -C 1-6 -alkyl, i.e.
  • X is N.
  • A is C.
  • R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 -optionally substituted, preferably R 6 is H; In a preferred embodiment of the invention, R 1 is –CO-OH.
  • X is N and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 - optionally substituted, preferably R 6 is H.
  • A is C and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 - optionally substituted, preferably R 6 is H.
  • X is N, A is C and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e. C2-, C3-optionally substituted, preferably R6 is H.
  • X is N, A is C and R 1 is –CO-OH or -CO-NH 2.
  • R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • X is N and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • A is C and R2 is -NHR8, wherein R8 is H or C1-6-alkyl, preferably H.
  • R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, - C 1-3 -alkyl, i.e.
  • R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • R 1 is –CO-OH and R 2 is -NHR 8 , wherein R 8 is H or C 1- 6 -alkyl, preferably H.
  • X is N and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 - optionally substituted, preferably R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • A is C and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 - optionally substituted, preferably R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • X is N
  • A is C and R 1 is –CO-OR 6 , or -CO-NR 6 R A
  • R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 -optionally substituted, preferably R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • X is N
  • A is C
  • R 1 is –CO-OH or -CO-NH 2
  • R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • X is N
  • A is C
  • X is N
  • A is C
  • R 1 and R 2 together form an uracil or 3-deazauracil.
  • X is N, R 1 and R 2 together form an uracil or 3- deazauracil.
  • A is C, and R1 and R2 together form an uracil or 3- deazauracil.
  • X is N, A is C and R 1 and R 2 together form an uracil or 3-deazauracil.
  • A is C
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is C
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is C
  • R 1 is –CO-OH or -CO-NH 2
  • X is N
  • R 2 is -NHR 8
  • A is C
  • X is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is C
  • R 1 and R 2 together form an uracil or 3- deazauracil
  • A is C
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C1-3-alkyl, i.e. C1-, C2-, C3-, -alkyl, -C2-3-alkenyl, i.e. C2-, C3-alkenyl, -C2-3-alkynyl, i.e. C2-, C3- optionally substituted, preferably R 6 is H and R 3 is -C 1-3 -alkyl, i.e.
  • R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -alkyl, or –(CH 2 ) m -L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and - hydroxyC 1-3 -alkyl.
  • R 1 is –CO-OH
  • R 2 is -NHR 8
  • R 8 is H or C 1-6 - alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e.
  • R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e.
  • X is N
  • A is C
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is C
  • R 1 is –CO-OH or -CO-NH 2
  • R 2 is - NHR 8
  • R 8 is H or C 1-6 -alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e.
  • X is N
  • X is N
  • A is C
  • R 1 and R 2 together form an uracil or 3-deazauracil and R 3 is -C 1-3 -alkyl, i.e.
  • X is N
  • R 1 and R 2 together form an uracil or 3- deazauracil and R 3 is -C 1-3 -alkyl, i.e.
  • A is C
  • R 1 and R 2 together form an uracil or 3- deazauracil and R 3 is -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -alkyl, or –(CH 2 ) m -L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and - hydroxyC 1-3 -alkyl and R 3 is -C 1-3 -alkyl, i.e.
  • X is N
  • A is C
  • R 1 and R 2 together form an uracil or 3- deazauracil
  • R 3 is -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -alkyl, or –(CH 2 ) m -L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and - hydroxyC 1-3 -alkyl.
  • X is N, R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e.
  • A is C, R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e.
  • X is N
  • A is C
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is C
  • R1 is –CO-OH or -CO-NH2
  • X is N
  • A is C
  • R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, - C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e.
  • R 1 is –CO-OH
  • X is N
  • R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e.
  • A is C, R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e.
  • X is N
  • A is C
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is C
  • R 1 is –CO-OH or -CO-NH 2
  • R 2 is - NHR 8
  • X is N
  • X is N
  • A is C
  • X is N
  • A is N and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 - optionally substituted, preferably R 6 is H.
  • X is N, A is N and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 -optionally substituted, preferably R 6 is H.
  • X is N, A is N and R 1 is –CO-OH or -CO-NH 2.
  • A is N and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • A is N and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e.
  • R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • X is N
  • A is N and R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • X is N
  • A is N and R 1 is –CO-OH or -CO-NH 2 and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H.
  • A is N
  • X is N
  • A is N
  • R 1 and R 2 together form an uracil or 3- deazauracil.
  • X is N
  • A is N and R 1 and R 2 together form an uracil or 3-deazauracil.
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6 R
  • R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OH or -CO-NH 2
  • A is N
  • R 2 is -NHR 8
  • m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and - hydroxyC 1-3 -alkyl.
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OH or -CO-NH 2
  • R 2 is - NHR 8
  • m is 0 and L is phenyl or a 5, 6 or 7 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and -hydroxyC 1-3 -alkyl.
  • A is N
  • X is N
  • A is N
  • X is N
  • A is N
  • R 1 and R 2 together form an uracil or 3- deazauracil
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 - optionally substituted, preferably R 6 is H and R 3 is -C 1-3 -alkyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 -optionally substituted, preferably R 6 is H and R 3 is -C 1-3 -alkyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OH or -CO-NH 2
  • R 3 is -C 1-3 - alkyl, i.e. C 1 -, C 2 -, C 3 -alkyl, or –(CH 2 ) m -L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and -hydroxyC 1-3 -alkyl.
  • A is N
  • R 2 is -NHR 8
  • R 8 is H or C 1-6 -alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -alkyl, or –(CH 2 ) m -L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and - hydroxyC 1-3 -alkyl.
  • R 1 is –CO-OR 6 , or -CO-NR 6 R A preferably R 6 is H, - C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • R 6 is H
  • R 2 is -NHR 8
  • R 8 is H or C 1-6 -alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e.
  • R 1 is –CO-OH
  • R 2 is -NHR 8
  • R 8 is H or C 1-6 - alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e.
  • X is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e.
  • R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e.
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -alkenyl, -C 2-3 -alkynyl, i.e. C 2 -, C 3 - optionally substituted, preferably R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H and R3 is -C1-3-alkyl, i.e.
  • C1-, C2-, C3-alkyl, or –(CH2)m-L wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and -hydroxyC 1-3 -alkyl.
  • X is N
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • R 6 is H and R 2 is -NHR 8 , wherein R 8 is H or C 1-6 -alkyl, preferably H and R3 is -C1-3-alkyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OH or -CO-NH 2
  • R 2 is - NHR 8
  • R 8 is H or C 1-6 -alkyl, preferably H and R 3 is -C 1-3 -alkyl, i.e.
  • A is N
  • X is N
  • A is N
  • A is N
  • R 1 and R 2 together form an uracil or 3- deazauracil and R 3 is -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -alkyl, or –(CH 2 ) m -L, wherein m is 0 and L is phenyl or a 5 membered heteroaryl, preferably phenyl, optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -NO 2 , -CN, -Br, -Cl, -F, -I, -O-C 1-3 -alkyl, and - hydroxyC1-3-alkyl and R3 is -C1-3-alkyl, i.e.
  • X is N
  • A is N
  • R 1 and R 2 together form an uracil or 3- deazauracil
  • R 3 is -C 1-3 -alkyl, i.e.
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • X is N
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6
  • R A preferably R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e. C 2 -, C 3 -, -alkenyl, -C 2-3 -alkynyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OH or -CO-NH 2
  • A is N
  • A is N
  • R 1 is –CO-OR 6 , or -CO-NR 6 R
  • R 6 is H, -C 1-3 -alkyl, i.e. C 1 -, C 2 -, C 3 -, -alkyl, -C 2-3 -alkenyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OR 6
  • -CO-NR 6 R A preferably R 6 is H, -C 1-3 -alkyl, i.e.
  • X is N
  • A is N
  • R 1 is –CO-OH or -CO-NH 2
  • R 2 is - NHR 8
  • A is N
  • X is N
  • A is N
  • A is N
  • X is N
  • R A is a substituted carbocycle with 1 or 2 substituents independently selected from the group consisting of -Br, -Cl, -F, -O-(CH 2 ) o -R 9 , or -SCH 3 , wherein o is 0 or 1.
  • R 9 is -C 1-4 -alkyl, i.e.
  • C 1 -, C 2 -, C 3 -, or C 4 -alkyl -C 2-4 - alkenyl, i.e. C 2 -, C 3 -, or C 4 -alkenyl, or -C 1-6 -alkyl-aryl, i.e. C 1 -, C 2 -, C 3 -, C 4 -, C 5 - or C 6 -alkyl-aryl, optionally substituted with 1 or 2 substituents selected from the group consisting of -Cl, -CH 3 , -OCH 3 , or -SCH 3 .
  • C 1 -, C 2 -, C 3 -, or C 4 -alkyl -C 2-4 - alkenyl, i.e. C 2 -, C 3 -, or C 4 -alkenyl, or -C 1-6 -alkyl-aryl, i.e. C 1 -, C 2 -, C 3 -, C 4 -, C 5 - or C 6 -alkyl-aryl, optionally substituted with 1 or 2 substituents selected from the group consisting of -Cl, -CH 3 , -OCH 3 , or -SCH 3.
  • R A is a substituted carbocycle with 1 or 2 substituents independently selected from the group consisting of -Br, -Cl, -F, -O-(CH 2 ) o -R 9 , or -SCH 3 , wherein o is 0 or 1.
  • the ALC1i of the invention have the specific structures as indicated in Fig. 1.
  • the ALC1i are used in combination with an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or with mitomycin C, paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor.
  • the enzyme topoisomerase I (TOPI) is involved in relaxation of supercoiled DNA. It removes helical constrains that otherwise hinder DNA replication and transcription. Suitable inhibitors of Topoisomerase I are known in the art and are commercially available.
  • Examples for use in accordance with the invention are irinotecan, SN-38, topotecan, camptothecin (NSC-100880) or derivatives thereof, such as hydroxy camptothecine, 7-ethylcamptothecin, or 9-aminocamptothecin, rubitecan, Genz-644282 (CAS No.529488- 28-6), belotecan (CKD-602) hydrochloride, or beta-lapachone.
  • Irinotecan, SN-38, or topotecan are preferred, irinotecan is most preferred (preferably in the form of its active metabolite SN-38).
  • Topoisomerase II (TOPII) manages DNA tangles and supercoils.
  • Topoisomerase II Suitable inhibitors of Topoisomerase II are known in the art and are commercially available. Examples of inhibitors of Topoisomerase II for use in accordance with the invention are teniposide, etoposide, anthracyclines like aclarubicin, epirubicin, idarubicin, doxorubicin, daunorubicin, pirarubicin (NSC-333054), zorubicin, aclarubicin or caminomycin, amonafide, mitoxantrone (NSC-301739), pixantrone maleate, dexrazoxane, ellipticine hydrochloride, phenoxodiol (haginin E), etoposide (VP-16), voreloxin (SNS-595) hydrochloride, and amsacrine.
  • anthracyclines like aclarubicin, epirubicin, idarubicin, dox
  • Ataxia telangiectasia mutant is a serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinase.
  • PIKK phosphatidylinositol 3-kinase-related kinase
  • Suitable inhibitors of ATM are known in the art and are commercially available. Examples of inhibitors of ATM for use in accordance with the invention are AZ-32 (CAS No.
  • ATR Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase
  • ATM ATM
  • Rad3-related protein kinase ATR is a serine/threonine protein kinase. Suitable inhibitors of ATR are known in the art and are commercially available.
  • inhibitors of ATR for use in accordance with the invention are ceralasertib (AZD6738) (CAS No. 1352226-88-0), elimusertib, VX-803 (M4344) (CAS No.1613191-99-3), AZ20 (CAS No.1233339-22-4), ETP-46464 (CAS No. 1345675-02-6), Berzosertib (VE-822) (CAS No. 1232416-25-9), Dactolisib (BEZ235) (CAS No. 915019-65-7), VE-821 (CAS No. 1232410-49-9), Schisandrin B (Sch B) (CAS No.
  • HAMNO NSC-111847)
  • Torin 2 CAS No. 1223001-51-1
  • CGK 733 CAS No.905973-89-9
  • RP-3500 CAS No.2417489-10-0
  • SKLB-197 Ceralasertib and elimusertib are preferred.
  • the WEE1 G2 Checkpoint kinase has a crucial role in cell cycle regulation and DNA damage recognition / repair. Suitable inhibitors of WEE1 are known in the art and are commercially available.
  • inhibitors of WEE1for use in accordance with the invention are adavosertib (CAS No.955365- 80-7), Zn-C3 (CAS No. 2376146-48-2), PD0166285 (CAS No. 185039-89-8), or Debio 0123 (CAS No. 2243882-74-6).
  • Adavosertib is preferred.
  • Bromodomains are a family of evolutionarily conserved motifs that bind the acetylated lysines in histone tails and recruit transcriptional machinery promoting target gene transcription.
  • Inhibitors of bromodomains (BET inhibitors) are known in the art and are commercially available.
  • inhibitors of BRD for use in accordance with the invention are BAY-299 (CAS No.2080306-23-4), ABBV- 774 (CAS No. 2138861-99-9), (+)-JQ1 (CAS No. 1268524-70-4), I-BET762 (CAS No. 1260907-17-2), OTX015 (CAS No. 202590-98-5), I-BET151 (CAS No. 1300031-49-5), CPI-203 (CAS No. 1446144-04- 2), PFI-1 (CAS No. 1403764-72-6), MS436 (CAS. No.1395084-25-9), CPI-0610 (CAS No. 1380087-89- 7), see e.g. M.
  • RVX2135 (CAS No.1253733- 17-3), FT-1101 (CAS No. 1776060-36-6), BAY1238097 (CAS. No. 1564268-08-1), INCB054329 (CAS. No. 1628607-64-6), BMS-986158 (CAS. No. 1800340-40-2), ABBV-075 (CAS. No.1445993-26-9), GS- 5829 (CAS. No. 1637771-14-2), and PLX51107 (CAS No. 1627929-55-8). BAY-299 and ABBV-774 are preferred.
  • MEK is an integral part of the MAP kinase signal transduction pathway.
  • MEK acts as a dual- specificity kinase, phosphorylating both serine/threonine and tyrosine residues. It specifically activates the extracellular signal-regulated kinase (ERK) through phosphorylation, which then goes on to regulate various targets in the cell, influencing processes such as growth, proliferation, differentiation, and survival.
  • Examples of inhibitors of MEK for use in accordance with the invention are trametinib (CAS No.871700- 17-3), cobimetinib (CAS No. 934660-93-2), binimetinib (CAS No. 606143-89-9), selumetinib (CAS No.
  • the present invention is directed to the ALC1i according to Formula (II) as described above for use in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient in combination with an inhibitor of PARP, or for use in enhancing efficacy of an inhibitor of PARP in treating or ameliorating pancreatic cancer or fallopian tube cancer in a patient.
  • the preferred embodiments described herein for the first aspect are also preferred for the second aspect, in particular the definitions of the ALC1i according to Formula (II) and of the PARP inhibitors.
  • the ALC1i according to formula (II) potentiates the cancer-cell killing efficacy of the PARPi, (ii) a reduced amount of PARPi is administered, and/or (iii) PARPi resistance is bypassed. That is, the present invention also relates to the ALC1i according to Formula (II) for use in treating or ameliorating pancreatic cancer, which is preferred, or fallopian tube cancer in a patient in combination with an inhibitor of PARP.
  • inhibitors of PARP PARPi
  • PARPi inhibitors of PARP
  • PARP nuclear Poly-ADP-ribose polymerase
  • DDR DNA damage response
  • PARP-1 and -2 add poly-ADP-ribose (PAR) chains to chromatin components and to factors belonging to the DDR
  • PARP-3 targets chromatin components via mono- ADP-ribosylation.
  • PARPs get recruited to DNA lesions by recognizing specifically altered, DNA-damage induced structures, which activates their PARylation activity, which in turn regulates their activity and the activity of other DDR and chromatin proteins, facilitating the DDR (Ray Chaudhuri and Nussenzweig, 2017).
  • PARP inhibitors PARPi
  • HR homologous- recombination
  • C 1-6 -alkyl alkynyl (e.g. C 2-6 -alkynyl), arylalkyl (e.g. aryl-C 1-6 -alkyl), cycloalkyl (e.g. C 3- 8-cycloalkyl), cycloalkylalkyl (e.g. C3-8-cycloalkyl-C1-6-alkyl), haloalkyl (e.g. C1-6-haloalkyl), hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene), oxo, heterocycloalkyl (e.g.
  • C 2-8 -hetero cycloalkyl C 2-8 -hetero cycloalkyl
  • heterocycloalkylalkyl e.g. C 2-8 -heterocycloalkyl-C 1-6 -alkyl
  • alkylcarbonyl e.g. C 1-6 -alkyl-carbonyl
  • arylcarbonyl e.g. C 1-6 -alkyl-carbonyl
  • heteroarylcarbonyl alkylsulfonyl (e.g. C 1-6 -alkyl-sulfonyl), arylsulfonyl, heteroarylsulfonyl, (R A R B )alkylene (e.g.
  • R A R B -C 1-6 -alkylene
  • NR A R B carbonyl
  • NR A R B carbonylalkylene
  • NR A R B carbonyl-C 1-6 -alkylene
  • NR A R B sulfonyl
  • R A R B sulfonylalkylene
  • each IV R 6 is selected from OH, NO 2 , CN, Br, Cl, F, I, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 2-8 - heterocycloalkyl; C 2-6 -alkenyl, alkoxy (e.g. C 1-6 -alkoxy), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6 - alkyl), alkoxycarbonyl (e.g. C 1-6 -alkoxy-carbonyl), alkoxycarbonylalkyl (e.g.
  • C 1-6 -alkoxy- carbonyl-C 1-6 -alkyl C 2-6- alkynyl, aryl, arylalkyl (e.g. aryl-C 1-6 -alkyl), C 3-8 -cycloalkylalkyl (e.g. C 3-8 -cycloalkyl-C 1-6 -alkyl, haloalkoxy (e.g. C 1-6 -haloalkoxy), haloalkyl (e.g. C 1-6 - haloalkyl), hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene), oxo, heteroaryl, heteroarylalkoxy (e.g.
  • heteroaryl- C 1-6 -alkoxy heteroaryloxy, heteroarylthio, heteroarylalkylthio (e.g. heteroaryl-C 1-6 -alkylthio), heterocycloalkoxy (e.g. C 2-8 -heterocycloalkoxy), C 2-8 - heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (R A R B )C 1-6 -alkylene, (NR A R B )carbonyl, (R A R B )carbonylalkylene (e.g.
  • R A R B carbonyl-C 1-6 -alkylene), (NR A R B )sulfonyl, and (NR A R B )sulfonylalkylene (e.g. (NR A R B )sulfonyl-C 1-6 -alkylene);
  • I V R 1 , IV R 2 , and IV R 3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl (e.g. C 2-6 -alkenyl), alkoxy (e.g. C 1-6 -alkoxy), alkoxycarbonyl (e.g. C 1-6 -alkoxy- carbonyl), alkyl (e.g.
  • C 1-6 -alkyl C 1-6 -alkyl
  • cycloalkyl e.g. C 3-8 -cycloalkyl
  • alkynyl e.g. C 2-6 -alkynyl
  • cyano haloalkoxy (e.g. C 1-6 -haloalkoxy), haloalkyl (e.g. C 1-6 -haloalkyl), hydroxyl, hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene), nitro, NR A R B , NR A R B alkylene (e.g.
  • I V A and IV B are each independently selected from hydrogen, Br, Cl, F, I, OH, C 1-6 -alkyl, C 3-8- cycloalkyl, alkoxy (e.g. C 1-6 -alkoxy), alkoxyalkyl (e.g.
  • C 1-6 -alkoxy-C 1-6 -alkyl wherein C 1-6- alkyl, C 3-8- cycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO 2 , CN, Br, Cl, F, I, C 1-6- alkyl, and C 3-8 -cycloalkyl, wherein I V B is not OH; RA, and RB are independently selected from the group consisting of hydrogen, alkyl (e.g. C1-6-alkyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), and alkylcarbonyl (e.g.
  • C 1-6 -alkyl-carbonyl C 1-6 -alkyl-carbonyl
  • R A and R B taken together with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from the group consisting of -O-, -NH, -N(C 1-6 -alkyl)-, -NCO(C 1 - 6 -alkyl)-, -N(aryl)-, -N(aryl-C 1 - 6 -alkyl-), -N(substituted-aryl-C 1-6 -alkyl-)-, - N(heteroaryl)-, -N(heteroaryl-C 1 -C 6 -alkyl-)-, -N(substituted-heteroaryl-C 1-6 alkyl-)-, and -S- or S(O)q-, wherein q is 1 or 2 and
  • C 1- 6 -alkyl cycloalkyl (e.g. C 3-8 -cycloalkyl), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6 -alkyl), haloalkyl (e.g. C 1-6 -haloalkyl), hydroxyalkylene (e.g. hydroxy-C 1-6 -alkylene), and (NR A R B )alkylene (e.g.
  • NR A R B C 1-6 -alkylene that inhibits PARP1 and PARP2 is selected from the group consisting of a compound of (a) formula (V) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: VR 1 is hydrogen or fluorine; and VR 2 is hydrogen or fluorine; and (b) formula (VI) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: V I R 1 , VI R 2 , and VI R 3 are independently selected from the group consisting of hydrogen, alkenyl (e.g. C 1-6 -alkenyl), alkoxy (e.g.
  • C 1-6 -alkoxy alkoxycarbonyl (e.g. C 1-6 -alkoxycarbonyl), alkyl (e.g. C 1-6 -alkyl), alkynyl (e.g. C 1-6 -alkynyl), cyano, haloalkoxy (e.g. C 1-6 - haloalkoxy), haloalkyl (e.g. C 1-6 -haloalkyl), halogen, hydroxy, hydroxyalkyl (e.g.
  • V I A is a nonaromatic 4, 5, 6, 7, or 8-membered ring that contains 1 or 2 nitrogen atoms and, optionally, one sulfur or oxygen atom, wherein the nonaromatic ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl (e.g. C 1-6 -alkenyl), alkoxy (e.g. C 1-6 -alkoxy), alkoxyalkyl (e.g. C 1-6 -alkoxy-C 1-6 -alkyl), alkoxycarbonyl (e.g.
  • alkenyl e.g. C 1-6 -alkenyl
  • alkoxy e.g. C 1-6 -alkoxy
  • alkoxyalkyl e.g. C 1-6 -alkoxy-C 1-6 -alkyl
  • alkoxycarbonyl e.g.
  • C 1-6 -alkoxycarbonyl alkoxycarbonylalkyl (e.g. C 1-6 - alkoxycarbonyl- C 1-6 -alkyl), alkyl (e.g. C 1-6 -alkyl), alkynyl (e.g. C 1-6 -alkynyl), aryl, arylalkyl (e.g. aryl- C 1-6 -alkyl), cycloalkyl (e.g. C 3-8 -cycloalkyl), cycloalkylalkyl (e.g. C 3- 8 -cycloalkyl-C 1-6 -alkyl), cyano, haloalkoxy (e.g.
  • C 1-6 -haloalkoxy haloalkyl (e.g. C 1-6 - haloalkyl), halogen, heterocycle, heterocyclealkyl (e.g. heterocycle-C 1-6 -alkyl), heteroaryl, heteroarylalkyl (e.g. heteroaryl-C 1-6 -alkyl), hydroxy, hydroxyalkyl (e.g. C 1-6 - hydroxyalkyl), nitro, NR C R D , (NR C R D )alkyl (e.g. (NR C R D )-C 1-6 -alkyl), (NR C R D )carbonyl, (NR C R D )carbonylalkyl (e.g.
  • R A , R B , R C , and R D are independently selected from the group consisting of hydrogen, alkyl (e.g. C 1-6 -alkyl), and alkycarbonyl (e.g C 1-6 -alkylcarbonyl).
  • R 1 is: H; halogen; cyano; an optionally substituted alkyl (e.g.
  • the PARPi is selected from the group consisting of AZD-5305, olaparib, talazoparib, niraparib, pamiparib, rucaparib, and veliparib, in particular the group consisting of olaparib, talazoparib, niraparib, pamiparib, rucaparib, and veliparib.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the ALC1i as specified for the first aspect of the invention and an inhibitor of Topoisomerase I, Topoisomerase II, ATM, ATR, Wee1, BRD, and/or MEK, or mitomycin C, or paclitaxel, or an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor preferably for use in treating and/or amelioration of a proliferative disease, preferably cancer.
  • the ALC1i used is a compound of formula (I) or a compound of formula (II), more preferably a compound having a structure as shown in Figure 1, or isomers, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs thereof.
  • the preferred pharmaceutically acceptable salt is the sodium salt.
  • the ALC1i as defined above, the pharmaceutical composition as defined above, and/or the kit of parts as defined above is for use in treating or ameliorating a proliferative disease, preferably cancer, more preferably the proliferative disease selected from a BRCA-1 and/or BRCA-2-deficient tumor, and/or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, or pancreatic cancer.
  • BRCA1 and BRCA2 proteins are involved in both promoting homologous recombination (HR)- mediated DNA repair and controlling the stability of stalled replication forks.
  • ALC1i for use according to the invention is particularly suitable if used alone or in combination with PARPi.
  • the proliferative disease is selected from a cancer.
  • cancer which preferably is a tumor (also called neoplasm), in particular a solid tumor, refers to cells having the capacity for autonomous growth. Examples of such cells include cells having an abnormal state or condition characterized by rapidly proliferating cell growth.
  • the term is meant to include cancerous growths, e.g., tumors; oncogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • malignancies of the various organ systems such as respiratory, cardiovascular, renal, reproductive, hematological, neurological, hepatic, gastrointestinal, and endocrine systems; as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, and cancer of the small intestine.
  • Cancer that is “naturally arising” includes any cancer that is not experimentally induced by implantation of cancer cells into a subject, and includes, for example, spontaneously arising cancer, cancer caused by exposure of a patient to a carcinogen(s), cancer resulting from insertion of a transgenic oncogene or knockout of a tumor suppressor gene, and cancer caused by infections, e.g., viral infections.
  • a carcinogen e.g., a tumor suppressor gene
  • infections e.g., viral infections.
  • the term “carcinoma” is art recognized and refers to malignancies of epithelial or endocrine tissues. The term also includes carcinosarcomas, which include malignant tumors composed of carcinomatous and sarcomatous tissues.
  • hematopoietic neoplastic disorders includes diseases involving hyperplastic/neoplastic cells of hematopoietic origin.
  • a hematopoietic neoplastic disorder can arise from myeloid, lymphoid or erythroid lineages, or precursor cells thereof.
  • the cancer is breast cancer, ovarian cancer, prostate cancer, pancreatic carcinomas, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), gastric cancer, gastroesophageal cancer, non-small cell lung cancer, bladder cancer, endometrial cancer, brain cancer, in particular astrocytoma cancer or glioma cancer, cervix cancer, kidney cancer (in particular RCC), thyroid cancer, fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanoma.
  • the cancer is basal-like cancer, basal-like breast cancer, triple negative breast cancer, high grade cancer, or high grade serous ovarian cancer cell.
  • the cancer is breast cancer, prostate cancer, pancreatic carcinomas, fallopian tube cancer, colorectal cancer, hepatocellular carcinoma, or bone cancer (preferably osteosarcoma).
  • the cancer is selected form the group consisting of ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, castration resistant prostate cancer, and pancreatic ductal adenocarcinoma, in particular metastatic ovarian cancer, metastatic fallopian tube cancer, metastatic primary peritoneal cancer, metastatic breast cancer, metastatic castration resistant prostate cancer, and metastatic pancreatic ductal adenocarcinoma.
  • the cancer to be treated has at least one mutation in a homologous recombination (HR) gene, i.e. is a HR deficient cancer.
  • HR homologous recombination
  • a cancer that is HR deficient refers to a cancer that has one or more cells having abnormal levels or activities of at least one HR gene. These abnormal levels or activities interfere with the normal HR gene function and can cause a defect in HR- mediated DNA repair or decrease the stability of replication forks.
  • the cancer to be treated is BRCA1 deficient and/or BRCA2 deficient.
  • a cancer that is BRCA1 deficient or BRCA2 deficient refers to a cancer that has one or more cells having abnormal BRCA1 levels or activities, or abnormal BRCA2 levels or activities. These abnormal levels or activities interfere with the normal function of BRCA1 or BRCA2 and can cause a defect in HR-mediated DNA repair or decrease the stability of replication forks.
  • the proliferative disease is selected from a BRCA-1 and/or BRCA-2-deficient tumor, and/or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, non-small cell lung cancer, or pancreatic cancer.
  • cancers treatable according the various aspects of the invention are ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, colorectal cancer, and pulmonary cancer.
  • cancers treatable according to the various aspects of the invention are ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, and pancreatic cancer.
  • the cancer is metastatic cancer, in particular a stage IV cancer.
  • the cancer to be treated in accordance with the various aspects of the invention has relapsed or progressed, preferably after a first line chemotherapy.
  • the combinations according to the present invention are for use as second line or third line therapy, more preferably for second line or third line therapy for the treatment of a HR deficient cancer.
  • the cancer to be treated is at stage III (locally advanced) or IV (metastatic).
  • the cancer to be treated in accordance with the various aspects of the invention has underlying defects in DNA damage repair, like HR repair, i.e. is a HR deficient cancer (HRD cancer), in particular a HR deficient ovarian cancer, HR deficient fallopian tube cancer, HR deficient primary peritoneal cancer, HR deficient breast cancer, HR deficient (castration resistant) prostate cancer, or HR deficient pancreatic cancer, such as pancreatic ductal adenocarcinoma (mPDAC).
  • HRD cancer HR deficient cancer
  • HR deficient ovarian cancer HR deficient fallopian tube cancer
  • HR deficient primary peritoneal cancer HR deficient breast cancer
  • HR deficient (castration resistant) prostate cancer or HR deficient pancreatic cancer, such as pancreatic ductal adenocarcinoma (mPDAC).
  • HR deficient cancer such as pancreatic ductal adenocarcinoma (mPDAC).
  • these cancers are advanced or metastatic, most preferred metastatic.
  • cancer/patient selection would include but is not limited to eligible tumor biomarkers, i.e., deleterious mutations including ARID1A, ATM, ATRX, BAP1, BLM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, RAD51, RAD51B and/or WRN, which are preferred, BRCA1/2 being most preferred, and/or other gene variants in the HR pathway as listed in Figures 8 and/or 9.
  • eligible tumor biomarkers i.e., deleterious mutations including ARID1A, ATM, ATRX, BAP1, BLM, BRCA1, BRCA2, BARD1, BRIP1, CHEK1, CHEK2, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, RAD51,
  • the ACL1i is used in combination with several classes of cancer drugs, namely inhibitors of Topoisomerase I, preferably irinotecan, preferably in the form of its active metabolite SN-38, Topoisomerase II, ATM, ATR, Wee1, BRD, and MEK, or combined with mitomycin C paclitaxel, with ionizing radiation, or with an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, in treating or ameliorating a proliferative disease in a patient, in particular cancer.
  • the cancer is HR deficient cancer, in particular BRCA-1 and/or BRCA-2-deficient.
  • the preferred ALC1i used are ALCi-2, ALCi-160, ALCi-101, or ALCi-123, or pharmaceutically acceptable salt, isomers, solvate, chemically protected form, or prodrugs thereof, particularily preferred ALCi-2 or ALCi-101, or pharmaceutically acceptable salt, isomers, solvate, chemically protected form, or prodrugs thereof, ALCi-101being most preferred.
  • the most preferable pharmaceutically acceptable salt is the sodium salt.
  • the sodium salt of ALCi-101 is used.
  • the cancer does not include pancreatic cancer, in particular when the ACL1i is used in combination with irinotecan or SN-38.
  • the ACL1i is used in combination with several classes of cancer drugs as listed above, preferably an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, such as trastuzumab deruxtecan, datopotamab deruxtecan (which is preferred), or sacituzumab govitecan, in treating or ameliorating a proliferative disease in a patient, in particular cancer, such as HR deficient cancer, in particular BRCA-1 and/or BRCA-2-deficient.
  • the preferred cancer is hepatocellular carcinoma, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, prostate cancer, colorectal cancer, or pancreatic cancer.
  • the cancer is advanced or metastatic, the latter being preferred.
  • the preferred ALC1i used are ALCi-2, ALCi-160, ALCi- 101, or ALCi-123, particularly preferred ALCi-2 or ALCi-101, the latter being most preferred.
  • the patient to be treated in accordance with the various aspects of the invention is a cancer patient, preferably having the cancer as defined above, e.g.
  • breast cancer ovarian cancer, prostate cancer, pancreatic carcinomas, gastric, gastroesophageal, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, uterine cancer, bone cancer (preferably osteosarcoma), fallopian tube cancer, peritoneal cancer, acute myeloid leukemia, or uveal melanoma, more preferably ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, and pancreatic cancer, and optionally having mutations/deletions/insertions in one or more of the HR genes as listed in Figures 8 and/or 9, preferably BRCA1/2.
  • the cancer patient has a HR deficient cancer, in particular BRCA-1 and/or BRCA-2-deficient.
  • patients having pancreatic cancer are not included, in particular when the ACL1i is used in combination with irinotecan or SN-38.
  • the patient to be treated in accordance with the various aspects of the invention is a cancer patient, preferably having the cancer as defined above, e.g.
  • the previous cancer therapy included administration of at least one antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor, such as trastuzumab deruxtecan, datopotamab deruxtecan (which is preferred), or sacituzumab govitecan.
  • a TOP1 inhibitor such as trastuzumab deruxtecan, datopotamab deruxtecan (which is preferred), or sacituzumab govitecan.
  • the ALC1i as defined above, in the pharmaceutical composition as defined above, and/or in the kit of parts as defined above, the ACL1i is combined with any one of adavosertib, AZ-32, AZD-1056, AZD-1390, BAY-299, ABBV-744, trametinib, ceralasertib, elimusertib, paclitaxel, Mitomycin C, teniposide, topotecan, AZD-5305, niraparib, olaparib, rucaparib, veliparib, pamiparib, talazoparib,trastuzumab deruxtecan, datopotamab deruxtecan, and/or sacituzumab govitecan.
  • the ALC1i as defined above, in the pharmaceutical composition as defined above, and/or in the kit of parts as defined above, the ACL1i is administered orally, preferably
  • ALC1 is an allosterically regulated chromatin remodeler that relaxes chromatin and plays an important role in response to DNA damage. It is implicated in different repair pathways like nucleotide excision repair or base excision repair and is known to regulate replication fork progression at DNA damage sites (Ooka et al., 2018). Inhibition of ALC1 via specific small molecules (ALC1i) used according to the invention leads to inefficient DNA repair by rendering chromatin less accessible to DNA repair enzymes potentiating the accumulation of DNA damage. Disruption of the chromatin remodeling forces of ALC1 through ALC1i enables a highly selective therapy of several cancer-types.
  • Treatment of cancer cells with ALC1i leads to increase of ⁇ H2AX protein levels, a marker for DNA damage (see Figure 6).
  • treatment of cancer cells with ALC1i lead to cell cycle arrest in the G2 phase (see Figure 5), resembling the effect of an inhibitor for PARP1/2, olaparib, which also induces DNA damage and leads to an increased G2, M-phase (Zhao et al., 2018, Wu et al., 2018).
  • Topoisomerase 1 inhibitors The enzyme topoisomerase 1 (TOP1) is involved in relaxation of supercoiled DNA. It removes helical constrains that otherwise hinder DNA replication and transcription (GILMOUR, 1986).
  • Topotecan (IUPAC: (19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13- diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione) is a TOP1i that leads to stabilization of the TOP1-DNA covalent complex during S-Phase. Mediated single strand breaks cannot be re-ligated and develop to DNA double strand breaks (NCBI – Topotecan, n.d.-a).
  • Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker.
  • ADCs comprising a topoisomerase I inhibitor are also considered to be coverd by the topoisomerase I inhibitors used in combination with the ALC1i in accordance with the invention.
  • a combination of an ALC1i used according to the present invention and datopotamab deruxtecan is used, in particular for treating (e.g. triple negative) breast cancer or non-small-cell lung cancer.
  • ALC1 inhibition via specific ALC1i synergistically impacts the cellular response to the DNA damage induced by TOP1i.
  • the present inventors determined that by using a combination of a TOP1i and a specific ALC1i, the effects of both inhibitors can be synergistically enhanced.
  • TOP1i topotecan shows high MSA scores in combination with said specific ALC1i used according to the invention, thus, it can be expected that this will also be the case for other TOP1i.
  • a combination of an ALC1i used according to the present invention and a TOP1i is used, in particular for treating colorectal cancer.
  • Topoisomerase 2 manages DNA tangles and supercoils. It can pass one double helix through another, untangling DNA by cutting both strands of the DNA helix simultaneously (Holm, 1989). This leads to an increase / decrease of the linking number of DNA loops by two units, promoting chromosome disentanglement. As an intermediate of this process, transient DNA double strand breaks are generated, possibly leading to toxic genome fragmentation (McClendon & Osheroff, 2007). TOP2 enzymes are involved in numerous DNA processes including recombination, separation of daughter chromosomes and chromatin condensation / de-condensation.
  • Teniposide (IUPAC: (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2- yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)- 5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one) is a TOP2i with antineoplasmtic activity.
  • ATM inhibitors Ataxia telangiectasia mutant is a serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinase.
  • ATM together with its downstream target Chk2, is the major signaling pathway activated by DNA double strand breaks (DSBs).
  • DSBs DNA double strand breaks
  • activated ATM in cooperation with the MRN complex, CtIP and MRE11, initiates strand resection to generate tracts of single stranded DNA (ssDNA) (You et al., 2009).
  • AZ-32 (IUPAC: N-methyl-4-(6-phenylimidazo[1,2-a]pyrazin-3-yl)benzamide) is an orally bioavailable ATM inhibitor that blocks the DNA damage response. It has good blood-brain barrier penetration, radio-sensitizes glioma cells in vitro and improves survival in orthotopic mouse models.
  • AZD-0156 (IUPAC: 8-[6-[3-(dimethylamino)propoxy]pyridin-3-yl]-3-methyl-1-(oxan-4- yl)imidazo[4,5-c]quinolin-2-one) is a first in class orally bioavailable ATM inhibitor. It is a permeable, highly soluble compound with excellent preclinical pharmacokinetic properties.
  • AZD-0156 also shows efficacy in the mouse xenograft model when combined with DSB inducing agents. It is currently undergoing further clinical assessment.
  • AZD-1390 (IUPAC: 7-fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-1-propan-2- ylimidazo[4,5-c]quinolin-2-one) is an orally bioavailable ATM inhibitor. It can efficiently cross the blood- brain barrier. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD-1390 sensitized tumors to radiotherapy.
  • ATR inhibitors ATR Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase
  • ATR is an important component of the DNA damage response (DDR) (Williamson et al., 2016). It induces homologous recombination (HR)-dependent repair (Kim et al., 2016).
  • ATR is responsible for signaling single stranded DNA (ssDNA), principally due to replication stress (RS), to the S and G2/M checkpoints and DNA repair, one of key G2 checkpoint regulators (Bradbury et al., 2022). Also, ATR is essential regulator of immune checkpoint proteins such as PD-L1 in response to DNA damage. ATR inhibition in tumor cells may either increase the sensitivity of tumor cells to genotoxic agents and/or cell death by apoptosis or cellular senescence (Barnieh et al., 2021). Ceralasertib (AZD6738, CAS No.
  • ceralasertib sensitizes tumor cells to chemo- and radiotherapy (NCBI - Ceralasertib, n.d.-c). Elimusertib (CAS No.
  • ATR-overexpressing tumor cells NCBI - Elimusertib, n.d.-d.
  • Synergy of ATR inhibitors with ALC1i ATR is specifically activated in response to extensive single stranded DNA structures (ssDNA) (Barnieh et al., 2021b).
  • ssDNA extensive single stranded DNA structures
  • ALC1 inhibition of ALC1 leads to a dysfunctional single strand DNA break repair, requiring the ATR pathway to be activated in order to initiate this DNA repair.
  • ALC1 inhibitors Due to the dependence on ATR activity in the context of an ALC1 inhibitor, it can be hypothesized that ATR inhibitors and the specific ALC1 inhibitors used in the invention would exhibit synergistic anti-proliferative effect. Synergy testing with ALC1 inhibitors used in the invention and ceralasertib and elimusertib confirmed that ALC1 inhibition using the compounds of the invention is synergistic with ATR inhibition.
  • Wee1 inhibitors The WEE1 G2 Checkpoint kinase has a crucial role in cell cycle regulation and DNA damage recognition / repair. The main downstream target of WEE1 is the cyclin dependent kinase 1(CDK1) B1 complex.
  • WEE1 is deregulated in cancer cells weakening the cell cycle regulation and allowing the high proliferation rate. Therefore, overexpression of kinases like WEE1 in DDR is fundamental for the maintenance of genetic stability (Ghelli Luserna di Rorà et al., 2020). In case of an inactive p53, the cell cycle is entirely regulated by G2/M checkpoint. Inhibition of WEE1 leads to impairment of the G2-DNA damage checkpoint. Upon treatment with DNA damaging agents, inhibition of WEE1 prevents phosphorylation of the cyclin-dependent kinase 1 (CDK1, CDC2) and potentially leads to apoptosis.
  • CDK1, CDC2 cyclin-dependent kinase 1
  • Adavosertib (MK-1775, AZD 1775, IUPAC name: 1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6- [4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one) is a small molecule inhibitor of WEE1. It selectively targets the tyrosine kinase to inactivate the CDC2/cyclin B complex. It has been used for the treatment of neoplasms, ovarian cancer, glioblastoma and other tumors (NCBI - Adavosertib n.d.-e).
  • Bromodomains are a family of evolutionarily conserved motifs that bind the acetylated lysines in histone tails and recruit transcriptional machinery promoting target gene transcription. Bromodomain inhibitors prevent interaction between the bromodomain and the acetyl group, causing 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-oxobenzimidazol-5-yl)benzo[de]isoquinoline-1,3- dione)
  • NCBI BAY-299, n.d.-f is a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated 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- oxo-1H-Pyrrolo[2,3-c]pyridine-2-carboxamide) is an inhibitor of the BDII domain of the BET family (Faivre et al., 2018).
  • the BET family protein BRD4 not only functions as a master regulator of many genes which play a part in DNA damage response or are involved in checkpoint activation, but also contributes to DNA damage repair in a transcriptionally independent manner. In the latter case, BRD4 facilitates and stabilizes the interaction of 53BP1 that in turn serves as docking sites for the DNA repair complex (PMID: 24954901).
  • the authors thus anticipated that a possible synergistic effect of BETi and DDR inhibitors like ALC1i. Synergy testing with the specific ALC1 inhibitor used in the invention and BET BD2 specific inhibitor confirmed the synergistic effects. It is worth mentioning the low toxicity of BET BD2i compared to pan- BETi.
  • PARP Poly (ADP-ribose) polymerases are a family of 17 proteins involved in several cellular processes, including the stress response, chromatin remodeling, DNA repair and apoptosis. The best described family member is PARP1, which plays role in the detection and repair of single-strand DNA breaks, in alternative DNA repair pathways, including nucleotide excision repair, non-homologous end joining (both classical and alternative), in homologous recombination and in DNA mismatch repair.
  • PARP inhibitors (PARPi) are a novel class of anti-cancer drugs which compete with NAD + for the PARP catalytically active site.
  • PARPi have shown to be effective in the treatment of HR deficient tumors, especially in tumors with mutations in Breast Cancer Associated 1 and 2 (BRCA1 and BRCA2) genes (Lai et al., 2020).
  • ALC1 is associated with PARPs due to its ability to be directly activated upon poly-(ADP-ribose) synthesis by PARP1 and other PARP family members, its ability to influence the recruitment and release of PARP family members to damaged chromatin, and the robust potentiation of PARPi function seen upon genetic interference with the ALC1 gene (Blessing et al., 2020; Juhász et al., 2020; Hewitt et al., 2021; Verma et al., 2021).
  • the ALC1 deficiency impacts PARP1 trapping, which impairs binding of NHEJ and HR proteins to DNA and suppresses these DNA repair mechanisms (Juhász et al., 2020) and influences PARP2 turnover (Blessing et al., 2020).
  • the specific ALC1 inhibitors used in the invention exhibit synergistic effects with PARP inhibition.
  • Paclitaxel Paclitaxel C47H51NO14, CAS No.
  • Paclitaxel binds specifically in a reversible manner to the N-terminal 31 amino acids of the beta-tubulin subunit in the microtubules, promotes the assembly of stable microtubules especially from ⁇ -tubulin heterodimers and inhibits their depolymerisation, which results in cell cycle arrest in the G2/M-phase, apoptosis and inhibition of cell replication (Kampan et al., 2015).
  • Mitomycin 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-dioxo-2,5- diazatetracyclo[7.4.0.0 2,7 .0 4,6 ]trideca-1(9),11-dien-8-yl]methyl carbamate) is a methylazirinopyrroloindoledione antineoplastic antibiotic isolated from the bacterium Streptomyces caespitosus and other Streptomyces bacterial species.
  • Bioreduced mitomycin C generates oxygen radicals, alkylates DNA, and produces interstrand DNA cross-links, thereby inhibiting DNA synthesis. Preferentially toxic to hypoxic cells, mitomycin C also inhibits RNA and protein synthesis at high concentrations (NCBI - Mitomycin C, n.d.-i). Synergy of Mitomycin C with ALC1i
  • the numerous types of DNA damage induced by Mitomycin C result in inhibition of cellular proliferation and massive cell death. It may thus be hypothesized that inhibition of ALC1 using the specific ALC1i used in the invention would hamper the repair of this DNA damage, resulting in the potentiation of the anti-proliferative effect of Mitomycin C.
  • Ionizing radiation is an electromagnetic radiation or particle radiation (high energy elementary particles) capable of directly or indirectly producing ions in its passage through matter.
  • the wavelengths of ionizing electromagnetic radiation are equal to or smaller than those of short (far) ultraviolet radiation and include gamma and X-rays (NCBI – ionizing radiation, n.d.-k). Ionizing radiation induces apoptosis, necrosis, and senescence of cancer cells by causing DNA damage, affects cancer cell organelles, tumor immune response.
  • Typical dose rates to be used in accordance with the invention are 100–2400 cGy/min for 1 to 5 min.
  • ADC Antibody drug conjugates
  • Trastuzumab Deruxtecan Enhertu
  • Trastuzumab binds to the extracellular domain of the HER2—receptor and prevents homodimerization, HER2-downstream signalling and leads to antibody-dependent cell-mediated cytotoxicity (Nami et al., 2018).
  • Trastuzumab deruxtecan (sold under the brand name Enhertu) is an antibody drug conjugate (ADC) consisting of the HER2-directed antibody trastuzumab and the cytostatic TOP1i deruxtecan, connected via a tumor-selective cleavable linker. This linker attaches the drug-payload to the antibody and is selectively cleaved by enzymse upregulated in tumor cells.
  • ADC antibody drug conjugate
  • Enhertu is used to treat human epidermal growth factor 2 (HER2) positive breast cancers, non-small cell lung cancer (NSCLC) with a HER2 mutation and gastric or gastroesophageal junction adenocarcinoma that are HER2-positive (ENHERTU® (Fam- trastuzumab Deruxtecan-nxki)).
  • Sacituzumab govitecan Sacituzumab govitecan, sold under the brand name Trodelvy by Gilead Sciences, is a Trop-2- directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple- negative breast cancer and metastatic urothelial cancer.
  • Trodelvy binds to Trophoblast cell-surface antigen 2 (TROP2), expressed and associated with poor prognosis in HR+/HER2- breast cancer and triple-negative breast cancers, making TROP2 and attractive tumor-associated antigen for treatments.
  • Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with topoisomerase 1 inhibitor (TOP1i) SN-38, the active metabolite of irinotecan. Each antibody having on average 7.6 molecules of SN-38 attached. Linkage to an antibody allows the drug to specifically target cells expressing Trop-2.
  • SN-38 Because free SN-38 is membrane-permeable, it may elicit antitumor effects in adjacent tumor cells (bystander effect) before internalization of the antibody–drug conjugate through hydrolysis of the linker or by intracellular SN-38 release after internalization (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. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) consider it to be a first-in-class medication (European Medicines Agency (EMA), 2021).
  • FDA Federal and Drug Administration
  • EMA European Medicines Agency
  • Datopotamab deruxtecan is another Trop2-directed antibody and topoisomerase inhibitor drug conjugate.
  • Datopotamab deruxtecan (Dato-DXd) is a humanized anti-Trop2 immunoglobulin G1 monoclonal antibody covalently linked to deruxtecan, a highly potent topoisomerase I inhibitor (TOP1i), a derivative of exatecan, via a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker, resulting in reduced systemic exposure and off-target adverse effects.
  • TOP1i highly potent topoisomerase I inhibitor
  • Dato-DXd into Trop2-expressing cells leads to death of target tumor cells and bystander killing of neighboring cells in the tumor microenvironment (Okajima et al., 2021).
  • Datopotamab deruxtecan Biologics License Application was accepted in the US for patients with previously treated metastatic HR-positive, HER2-negative breast cancer in April 2024, based on results from the TROPION-Breast01 Phase III trial (Adrian Kemp, 2024).
  • Synergy of ADCs with ALC1i The above-mentioned ADCs facilitate the transport of the TOP1i into cancer cells and releases the drug at cancer-specific sites.
  • the TOP1i disrupts the replication fork and leads to DNA strand breaks.
  • ALC1i on top of the TOP1i may contribute to replication fork stalling and accumulation of additional DNA damage in an even more targeted context. It could thus be hypothesized that ALC1i co-dosed with the targeted release of TOP1i would be suitable in treating HER2-positive and/or Trop1-positive cancer.
  • the present inventors determined that by using a combination of an ADC like anti-HER2 antibody with a TOP1i and a specific ALC1i, the effects of both drugs can be synergistically enhanced.
  • trastuzumab deruxtecan As trastuzumab deruxtecan, datopotamab deruxtecan and sacituzumab govitecan show high MSA scores in combination with said specific ALC1i in multiple different cell lines, it can be expected that this will also be the case for other antibody drug conjugates with a tumor specific antibody conjugated to a TOP1 inhibitor.
  • a combination of an ALC1i used according to the present invention and an antibody drug conjugate with a tumor specific antibody conjugated to a TOP1 inhibitor is used, in particular for treating (e.g. Trop1 + or HER2 low/+ ) breast cancer, gastric cancer or non-small cell lung cancer.
  • MEK inhibitors Trametinib (C26H23FIN5O4, GSK1120212, CAS No.
  • IUPAC N-(3- ⁇ 3- Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[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 critical role in the growth and development of cancer cells. Trametinib is often used in the treatment of cancers which have a specific mutation in the BRAF gene (BRAF V600E or V600K mutations) or mutations in KRAS.
  • MDA-MB-231 Cell Lines used as a BRCA wild-type cell line, MDA-MB-231 cells were used. The cells were established from an aneuploid female human. The cells were extracted from the mammary gland (breast) in the metastatic site as a pleural effusion. (MDA-MB-231 (ATCC® HTB-26TM Homo sapiens epithelial mammary gland) It is available from numerous sources including ATCC® HTB-26TM. As a BRCA negative cell line, SUM149PT cells were used. The cell line is a triple negative breast cancer (TNBC) cell line, derived from primary human invasive ductual carcinoma metastatic nodule from a 40-year-old female.
  • TNBC triple negative breast cancer
  • PSN1 cells were used.
  • the human cell line was derived from pancreatic adenocarcinoma tissue. It harbors an amplification of c-myc and activated c-Ki-ras and a loss of one of the two p53 alleles.
  • the cell line is available from numerous sources including MERCK (94060601).
  • PSN1 talazoparib resistant cells were generated by treating PSN1 cells with incresing sub-toic doses of talazoparib for 3 months. These cells show > 10 fold resistance to talazoparib over the parental PSN1 cells.
  • BxPC3 cells were used.
  • the cells were extracted from the pancreas tissue of a 61-year-old female with adenocarcinoma.
  • the established cell line does not express CFTR (cystic fibrosis transmembrane conductance regulator), but it expresses mucin, the pancreas cancer specific antigen, and CEA (carcinoembryonic antigen).
  • the cells are available from numerous sources including MERCK (93120816). 22Rv1 cells were used.
  • the cell line is derived from a xenograft that was serially propagated in mice after castration-induced regression and relapse of the parental CWR22 xenograft that was androgen- dependent.
  • the cells originate from prostate carcinoma and are epithelial.
  • the cell line is available at numerous sources including MERCK (90102540).
  • DLD1 BRCA2-/- cells were used. This cell line originated from the DLD1-wt and is a BRCA2 knockout cell line. It is available at several sources including Creative Biogene (CSC-RT0028). HCT116 cells were used. This cell line originates from colon tissue from an adult male with colorectal carcinoma. It has damaging mutations in BRCA2, FANCA and POLD1. This cell line is available at numerous sources including the DSMZ (ACC 581). PC-3 cells were used.
  • the cell line originates from a 62-year-old male patient with a grade IV prostatic adenocarcinoma, specifically from a bone metastasis.
  • the cells are epithelial, near triploid and have a damaging mutation in TP53. They are available at numerous sources including MERCK (90112714).
  • SW620 cells were used. The cells were isolated from the lymph node of a 51-year-old male with Dukes’ C colorectal adenocarcinoma and a cell line was established. The cell line is available at numerous sources including ATCC CCL-227 TM T47D cells were used. The cell line was established from a 54-year-old female human with an infiltrating ductal carcinoma of the breast.
  • the cells were extracted from the mammary gland (breast) as a pleural effusion. They are available at numerous sources including ATCC HTB-133 TM HCC1937 cells were used. They were isolated from a 23-year-old female with a primary ductal carcinoma, specifically from a mammary gland. The cell line has a homozygous BRCA1 mutation and is negative for expression of p53 and Her2-neu, the morphology is epithelial. The cells are available at several sources including Amsbio (Cat. No. AMS.EP-CL-0093). MDA-MB-436 cells were used.
  • the cell line is derived from a 43-year-old female with breast adenocarcinoma, it was extracted from the mammary gland in the metastatic site as a pleural effusion.
  • the cells are pleomorphic with multinucleated component cells. They are available at numerous sources including Accegen (Cat. No. ABC-TC0655).
  • HEPG2 cells were used.
  • the cell line was established from a 15-year-old male patient with a hepatocellular carcinoma.
  • the cells express several major plasma proteins like albumin, fibrinogen, and alpha 2-macroglobulin, the morphology is epithelial-like.
  • SKBR3 also known as SK-BR-3
  • ATCC HB-8065 TM SKBR3 is a human breast cancer cell line isolated by the Memorial Sloan–Kettering Cancer Center in 1970 that is used in therapeutic research, especially in context of HER2 targeting.
  • SKBR3 cells were derived from a pleural effusion due to an adenocarcinoma originating in a 43- year-old Caucasian female.
  • the cell line over-expresses the HER2 gene product, which has been implicated in several breast cancer proliferation pathways.
  • HCC2429 was established from a 34-year old non-smoking woman with metastatic non-small cell lung carcinoma, demonstrating a t(15;19)(q13.2;p13.1) with a BRD4-NUTM1 ex11:ex2 fusion.
  • the cell line is patented by Vanderbilt University Medical Center, Arlington, TN, USA.
  • MiaPaCa2 cells were also utilized. This cell line was derived from a 65-year-old while male with undifferentiated pancreatic carcinoma. Exhibits neuroendocrine features and described to carry mutations in KRAS, CDKN2A and TP53. This cell line is available at multiple sources, including ATCC (CRL-1420). Inhibitor vs.
  • pancreatic cell line PSN1 was used for validation of the small molecule inhibitors.
  • Cells were seeded in 96-well plates (2000 cells/well) and treated with titrations of ALC1 inhibitors in the ⁇ M range.
  • DMSO was added to the cells.
  • the cells were cultured at 37°C, CO 2 5 % for 5 days until they were fixed with 10% TCA for 1h and stained with sulforhodamine dye for 30 minutes. After washing the cells with 1% Acetic Acid, 10 mM Tris (pH 10.5) solution was used to solubilize the stained cells.
  • SynergyFinder https://synergyfinder.fimm.fi is a stand-alone web-application for interactive analysis and visualization of drug combination screening data. Since its first release in 2017, SynergyFinder has become a widely used web-tool both for the discovery of novel synergistic drug combinations in pre- clinical model systems (e.g. cell lines or primary patient-derived cells), and for better understanding of mechanisms of combination treatment efficacy or resistance” (Ianevski et al.2020).
  • Zero interaction potency the drug interaction relationship is determined by comparison of the change in potency of the dose-dependent curves between individual drugs and their combination (https://synergyfinder.fimm.fi/synergy/synfin_docs/). The model is further described in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759128/. SynergyFinder uses a cNMF algorithm to detect and replace outlier measurements. The Version used to obtain the data as shown herein are Version 2.0 and 3.0. The summary synergy score is averaged over all dose combinations from the 2-D titration matrix.
  • the most synergistic area shows the most synergistic 3-by-3 dose-window in the dose-response matrix.
  • Table 1 The results for the combinations of the invention of the specific ALC1 inhibitors used according to the invention (compound A) and several examples of other classes of cancer drugs (compound B) on the treatment of different cancer cell lines are summarized in Figure 2.
  • Drug combinations with an MSA (most synergistic area) score below 9 indicate interactions that are likely not synergistic and are labeled with a “-”.
  • An MSA score between 9-10 is labeled with “+” and indicates that the interaction of compound A and B is likely to be synergistic.
  • MSA scores above 10 are marked “++” are synergistic.
  • MSA scores greater than 20 are labeled as “+++” and considered highly synergistic.
  • “Compound 1” and “Compound 3” were tested and were found to provide only additive (MSA score “-”), but no synergistic effect.
  • all tested combinations of the specific ALC1 inhibitors used according to the invention show a synergistic anti cancer effect (MSA scores “+”, “++” or even “+++”).
  • Cell cycle analysis SUM149PT cells were seeded into 6-well plates and treated with ALC1i or DMSO for 48h. Cells were harvested, washed in PBS before fixation/permeabilization with 75% ice-cold ethanol.
  • the membrane was blocked for 1h with intercept blocking buffer from LiCor and then stained with the following antibodies: 1°AB: Anti-gH2AX (Abcam, AB11174), alpha-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 taken using the LiCor. Protein amount was determined via band analysis using (FIJI, image J) and the ⁇ H2AX protein bands were normalized to the corresponding a-tubulin bands. Finally, the different treatment groups were normalized to the DMSO control to show the percent-change in protein amounts.
  • 1°AB Anti-gH2AX (Abcam, AB11174), alpha-tubulin (sigma, T9026) 2°AB (Licor): IRDye 800CW Goat anti-Rabbit 925-32211, IRDye 680RD Donkey anti-
  • Topoisomerase II as a target for anticancer drugs: When enzymes stop being nice. Progress in Nucleic Acid Research and Molecular Biology, 221–253. https://doi.org/10.1016/s0079-6603(00)64006-0 Ghelli Luserna di Rorà, A., Cerchione, C., Martinelli, G., & Simonetti, G. (2020). A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. Journal of Hematology &Amp; Oncology, 13(1). https://doi.org/10.1186/s13045-020-00959-2 GILMOUR, D. (1986). Topoisomerase I interacts with transcribed regions in Drosophila cells.
  • Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) (Oncotarget (2015) 6 (22496-22512) DOI: 10.18632/oncotarget.4318). Oncotarget, 11(10), 942.
  • PROTACs PROteolysis TArgeting Chimeras
  • SynergyFinder 3.0 an interactive analysis and consensus interpretation of multi-drug synergies across multiple samples.
  • NAR. gkac382 https://doi.org/10.1093/nar/gkac382 Kemp, A. (2024).
  • Targeted PARP Inhibition Combined with FGFR1 Blockade is Synthetically Lethal to Malignant Cells in Patients with Pancreatic Cancer. Cells, 9(4), 911. https://doi.org/10.3390/cells9040911 Lehmann, L.C., Hewitt, G., Aibara, S., Leitner, A., Marklund, E., Maslen, S.L., Maturi, V., Chen, Y., van der Spoel, D., Skehel, J.M., et al. (2017).
  • Datopotamab deruxtecan a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells.
  • Molecular Cancer Therapeutics 20(12), 2329– 2340. https://doi.org/10.1158/1535-7163.MCT-21-0206 Ooka, M., Abe, T., Cho, K., Koike, K., Takeda, S., & Hirota, K. (2018).
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Abstract

La présente invention concerne l'utilisation de composés à petites molécules qui inhibent de manière allostérique ALC1 (CHD1L), en particulier deux classes d'inhibiteurs allostériques d'ALC1 (CHD1L), de formule (I) et de formule (II), qui présentent un effet potentialisateur, de préférence additif, dans le traitement d'une maladie proliférative lorsqu'elles sont combinées à plusieurs classes de médicaments anticancéreux, à savoir des inhibiteurs de topoisomérase I, topoisomérase II, ATM, ATR, Wee1, BRD et MEK, ou lorsqu'elles sont combinées avec de la mitomycine C, du paclitaxel, avec un rayonnement ionisant, ou avec un conjugué anticorps-médicament avec un anticorps spécifique de la tumeur conjugué à un inhibiteur de TOP1. En outre, la présente invention concerne lesdits inhibiteurs d'ALC1 de formule (II) qui présentent un effet synergique dans le traitement du cancer du pancréas ou du cancer de la trompe de Fallope lorsqu'ils sont combinés avec un inhibiteur de PARP (Poly (ADP-ribose)-Polymérase (PARPi)). Étant synergiques avec la fonction desdits médicaments anticancéreux, lesdits inhibiteurs d'ALC1, en particulier ceux de formule (I) et de formule (II), potentialisent les propriétés d'élimination des cellules cancéreuses des médicaments anticancéreux susmentionnés, permettant en particulier des approches thérapeutiques dans lesquelles l'un des inhibiteurs susmentionnés est déjà utilisé dans le cadre de la norme de soins.
PCT/EP2024/080317 2023-10-25 2024-10-25 Inhibiteurs d'alc1 destinés à être utilisés dans le traitement du cancer par potentialisation des effets de plusieurs classes de médicaments anticancéreux approuvés Pending WO2025088175A1 (fr)

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