4-OXO-1,4-dihydropyridazine derivatives as ARYL hydrocarbon receptor agonists for the treatment of cancer

Abstract

The present invention relates to novel aryl hydrocarbon receptor agonists of formula (I) and the use thereof for the treatment of cancer.

Description

[0001] 4-OXO- 1 ,4-DIHYDROPYRIDAZINE DERIVATIVES AS ARYL HYDROCARBON RECEPTOR AGONISTS FOR THE TREATMENT OF CANCER

[0002] According to the International Agency for Research on Cancer, cancer is recognized as the leading cause of death worldwide in 2020, estimating around 10 million cases of cancer-related deaths, and 19.3 million patients newly diagnosed with cancer (Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians 2021 , 71 (3), 209-249. https: / / doi.org / 10.3322 / caac.21660). The most frequent cancer type in female patients is breast cancer counting for 11.7% of all newly diagnosed female cancers. Breast cancers are classified into different tumor types, either based on its location or based on the type of receptor proteins expressed by the cancer cells. These classifications strongly influence the treatment regimen and its prognoses. Based on the expression of several surface receptors, tumors can be classified either into hormone receptors-positive (HR+), HER2 / neu-positive (HER+) or triple negative (TNBC) breast cancers (Jayasekara, H.; Maclnnis, R. J.; Chamberlain, J. A.; Dite, G. S.; Leoce, N. M.; Dowty, J. G.; Bickerstaffe, A.; Win, A. K.; Milne, R. L.; Giles, G. G.; Terry, M. B.; Eccles, D. M.; Southey, M. C.; Hopper, J. L. Mortality after Breast Cancer as a Function of Time since Diagnosis by Estrogen Receptor Status and Age at Diagnosis. International journal of cancer 2019, 145 (12), 3207-3217. https: / / doi.org / 10.1002 / ijc.32214). The most aggressive type of breast cancers are the so-called triple-negative breast cancers (TNBC). Such tumors are lacking both HR and HER2 / neu receptors, making it very challenging to specifically target these cancer cells, resulting in the lowest 4-year survival rates (77%) compared to the other breast cancer types (Wu, Q.; Siddharth, S.; Sharma, D. Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs. Cancers 2021 , 13 (15), 3697. https: / / doi.org / 10.3390 / cancers13153697). Therefore, nowadays several new strategies are being extensively studied to unveil new treatment options for the TNBC type, for instance, poly(ADP-ribose) polymerase inhibitors, such as olaparib, or programmed death-ligand 1 (PD-L1 ) blockers like atezolizumab. However, the therapeutic performance of those options is still not satisfying, that is why there is still a great need and research interest in novel and better therapy options for TNBCs (Lyons, T. G. Targeted Therapies for Triple-Negative Breast Cancer. Current Treatment Options in Oncology 2019, 20 (11 ), 82. https: / / doi.org / 10.1007 / s11864-019- 0682-x; Heimes, A.-S.; Schmidt, M. Atezolizumab for the Treatment of Triple-Negative Breast Cancer. Expert Opinion on Investigational Drugs 2019, 28 (1 ), 1-5. https: / / doi.Org / 10.1080 / 13543784.2019.1552255).

[0003] One of the novel emerging therapy options for targeting several types of cancer, including specifically TNBC, is the use of aryl hydrocarbon receptor (AHR) modulators. These are a family of compounds that impact the activity of the AHR protein which plays an essential role in the response against environmental pollutants through activation of transcription of several genes involved in elimination of toxic agents, including halogenated aromatic hydrocarbons, polyaromatic compounds, flavonoids, indoles and dioxin like compounds, or (anticancer) drugs, etc. (Safe, S.; Lee, S.-O.; Jin, U.-H. Role of the Aryl Hydrocarbon Receptor in Carcinogenesis and Potential as a Drug Target. Toxicological Sciences 2013, 135 (1 ), 1-16. https: / / doi.org / 10.1093 / toxsci / kft128). However, the pathway was found also to modulate the activity of synthetic compounds by modification. This modulation could either promote activation of procarcinogens as in the case of benzo[a]pyrene and 2- amino-1 -methyl-6-phenylimidazo[4,5-b]pyridine or prodrugs, for example, eupatorine and diindolylmethane (Androutsopoulos, V. P.; Tsatsakis, A. M.; Spandidos, D. A. Cytochrome P450 CYP1 A1 : Wider Roles in Cancer Progression and Prevention. BMC Cancer 2009, 9 (1 ), 187. https: / / doi.org / 10.1186 / 1471 -2407-9-187; Androutsopoulos, V.; Arroo, R. R.; Hall, J. F.; Surichan, S.; Potter, G. A. Antiproliferative and Cytostatic Effects of the Natural Product Eupatorin on MDA-MB-468 Human Breast Cancer Cells Due to CYP1 -Mediated Metabolism. Breast Cancer Research: BCR 2008, 10 (3), R39. https: / / doi.Org / 10.1186 / bcr2090).

[0004] It has been the object of the present invention to provide novel aryl hydrocarbon receptor agonists for the treatment of cancer.

[0005] The present invention provides compounds of formula (I):

[0006] wherein

[0007] X is 0 or NR4;

[0008] R4is hydrogen, OH, NH2, CN, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted;

[0009] A is a methyl group and E is hydrogen; or

[0010] A and E together are a group of formula -CH=CH-, -CH2-CH2-, -CH2-, -C(CH3)=CH- , - CH=C(CH3)-, -N=CH- -NH-CH2-, -O-CH2-, -C(CH2R3)=CH- -CH=C(CH2R3)-, - C(OR3)=CH-, or -CH =C(OR3)-; or

[0011] A and E together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group; or

[0012] A and R4together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group and E is hydrogen;

[0013] R3is an alkyl group, an alkenyl group, or an optionally substituted aryl group; R1ais OH, a C1-4 alkyloxy group, or a group of formula -N(R6)R5;

[0014] R5is hydrogen, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted; and

[0015] R6is hydrogen or a methyl group; or

[0016] R5and R6together are part of an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group; m is 0, 1 or 2; each R2is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O- C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R2together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S; or a salt thereof.

[0017] The present invention further provides a pharmaceutical composition comprising a compound of formula (I):

[0018] wherein

[0019] X is 0 or NR4;

[0020] R4is hydrogen, OH, NH2, CN, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted;

[0021] A is a methyl group and E is hydrogen; or

[0022] A and E together are a group of formula -CH=CH-, -CH2-CH2-, -CH2-, -C(CH3)=CH- , - CH=C(CH3)-, -N=CH- -NH-CH2-, -O-CH2-, -C(CH2R3)=CH- -CH=C(CH2R3)-, - C(OR3)=CH-, or -CH =C(OR3)-; or

[0023] A and E together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group; or

[0024] A and R4together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group and E is hydrogen;

[0025] R3is an alkyl group, an alkenyl group, or an optionally substituted aryl group; R1ais OH, a C1-4 alkyloxy group, or a group of formula -N(R6)R5;

[0026] R5is hydrogen, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted; and

[0027] R6is hydrogen or a methyl group; or

[0028] R5and R6together are part of an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group; m is 0, 1 or 2; each R2is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O- C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R2together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S; or a salt thereof.

[0029] The present invention moreover provides a compound of formula (I):

[0030] wherein

[0031] X is 0 or NR4;

[0032] R4is hydrogen, OH, NH2, CN, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted;

[0033] A is a methyl group and E is hydrogen; or

[0034] A and E together are a group of formula -CH=CH-, -CH2-CH2-, -CH2-, -C(CH3)=CH- , - CH=C(CH3)-, -N=CH- -NH-CH2-, -O-CH2-, -C(CH2R3)=CH- -CH=C(CH2R3)-, - C(OR3)=CH-, or -CH =C(OR3)-; or

[0035] A and E together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group; or

[0036] A and R4together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group and E is hydrogen;

[0037] R3is an alkyl group, an alkenyl group, or an optionally substituted aryl group; R1ais OH, a C1-4 alkyloxy group, or a group of formula -N(R6)R5;

[0038] R5is hydrogen, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted; and

[0039] R6is hydrogen or a methyl group; or

[0040] R5and R6together are part of an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group; m is 0, 1 or 2; each R2is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O- C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R2together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S; or a salt thereof, for use as a medicament.

[0041] Preferably, each R2is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO- O-C(CH3)3, or a group of formula -O-CH2-C6H5; or two groups R2together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S.

[0042] Further preferably, R1ais the following group: wherein n is 0, 1 or 2; and each R1is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O- C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R1together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S.

[0043] Preferably, each R1is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO- O-C(CH3)3, or a group of formula -O-CH2-C6H5; or two groups R1together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S.

[0044] Further preferably, A and E together are a group of formula -CH=CH-, -CH2-CH2-, - C(CH3)=CH-, or -CH=C(CH3)-.

[0045] Moreover preferably, A and E together are a group of formula -CH=CH-. Further preferably, A is a methyl group and E is hydrogen.

[0046] Moreover preferably, X is 0.

[0047] Further preferably, X is NR4.

[0048] Moreover preferably, R4is an optionally substituted phenyl group.

[0049] Further preferred are compounds having the following formula (II): wherein R1, R2, n and m are as defined above or below, or a salt thereof.

[0050] Further preferably, n is 0 or 1 .

[0051] Moreover preferably, each R1(if present) is independently selected from a hydroxy group, a halogen atom (especially F, Cl or Br), a methyl group, a methoxy group, or a group of formula -O-CH2-C6H5.

[0052] Further preferably, R2is independently selected from a hydroxy group, a bromine atom, a chlorine atom, a -COOCH3 group, a CH3 group, a -O-CH3 group, or a group of formula -O-CH2-C6H5; or two groups R2together may be a group of formula -O-CH2-CH2-O-, or -O-CH2-O-. Moreover preferably, R2is independently a methoxy group, or a group of formula -0- CH2-C6H5; or two groups R2together may be a group of formula -O-CH2-CH2-O-, or - O-CH2-O-.

[0053] Especially preferred are the following compounds, or a salt thereof:

[0054] According to a further preferred embodiment, the compound of formula (I) has the following formula (la):

[0055] According to a further preferred embodiment, the compound of formula (I) has the following formula (lb):

[0056] Preferably, R1ais selected from the following groups:

[0057] -OCH3; -OH; NH2; -N(CH3)2; and NHC1-4 alkyl; wherein n is 0, 1 or 2; and each R1is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O- C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R1together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S. Further preferably, R1ais selected from the following groups: wherein n is 0, 1 or 2; and each R1is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O- C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R1together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S.

[0058] Preferably, each R1is independently selected from a hydroxy group, a halogen atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO- O-C(CH3)3, a group of formula -O-CH2-C6H5; or two groups R1together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S.

[0059] Moreover preferably, the compound of formula (I) has the following formula (II):

[0060] Further preferably, each R1is independently selected from a hydroxy group, a halogen atom, a -CH3 group, a -O-CH3 group, a -COOCH3 group, a -OCOCH3 group, or a group of formula -O-CH2-C6H5; or two groups R1together may be a group of formula -O-CH2- CH2-O-.

[0061] Moreover preferably, n is 0 or 1 and R1is selected from a hydroxy group, a -CH3 group, a fluorine atom, a chlorine atom, or a bromine atom.

[0062] Further preferably, each R2is independently selected from a hydroxy group, a fluorine atom, a chlorine atom, a -NH2 group, a -COOCH3 group, a -OCOCH3 group, a CH3 group, a -O-CH3 group, a -O-CF3 group, a group of formula -NH-CO-O-C(CH3)3, or a group of formula -O-CH2-C6H5; or two groups R2together may be a group of formula - O-CH2-CH2-O-, -O-CH2-O-, or -CH2-CH2-CH2-CH2-.

[0063] Moreover preferably, m is 0, 1 or 2, and R2is a hydroxy group; or two groups R2together may be a group of formula -O-CH2-CH2-O-.

[0064] Especially preferred are compounds of formula (la) or (lb), wherein R1ais selected from the following groups: wherein n is 0 or 1 ;

[0065] R1is selected from a hydroxy group, a -CH3 group, a fluorine atom, a chlorine atom, or a bromine atom; m is 0, 1 or 2; and

[0066] R2is a hydroxy group, a methoxy group, a group of formula -O-CH2-C6H5, or a - OCOCH3 group (especially a hydroxy group); or two groups R2together may be a group of formula -O-CH2-CH2-O-.

[0067] Preferably, X is 0.

[0068] Further preferably, A is a methyl group and E is hydrogen.

[0069] Moreover preferably, A and E together are a group of formula -CH=CH-.

[0070] Further preferably, R1ais a group of formula -N(R6)R5.

[0071] Moreover preferably, R6is hydrogen.

[0072] Further preferably, R5is an optionally substituted phenyl group, an optionally substituted pyridyl group or a cyclohexyl group.

[0073] Moreover preferably, the compound of formula (I) of the present invention is selected from the following compounds, or a salt thereof:

[0074] SelectAHRyl F;

[0075] Further preferably, the protecting group PG is a suitable protecting group as e.g. detailed in the book: Greene's Protective Groups in Organic Synthesis; Author(s): Peter G. M. Wuts, Theodora W. Greene; First published: 10 April 2006; Print ISBN:9780471697541 (Online ISBN:9780470053485 |DOI:10.1002 / 0470053488. Preferred protecting groups are carboxylic acid esters; especially acetate, propionate, succinate, and malate. Further preferred protecting groups are CH3, CH2C6H5, Allyl (- CH2CH=CH2), Benzoyl (-COCeHs), Acyl (-COCH3, -COalkyl), pivaloyl (-COC(CH3)3), Silyl PG (-Si(alkyl)3, -Si(C6H5)2-C(CH3)3), MOM (-CH2OCH3), THP (c-CH-O-(CH2)4), and -C(CH3)3.

[0076] According to a further preferred embodiment, the following compounds are excluded from the present invention:

[0077]

[0078] The most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt thereof.

[0079] It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., any embodiment for R1amay be combined with any embodiment of R2).

[0080] In the compounds of formula (I), A and E together may be part of an optionally substituted aryl group, or an optionally substituted heteroaryl group. As an example, if A and E are part of an unsubstituted phenyl group, the corresponding compound of formula (I) will have the following structure:

[0081] The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 15 carbon atoms, especially from 1 to 10 (e.g., 1 , 2, 3 or 4) carbon atoms, for example a methyl (Me, CH3), ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.

[0082] The expression C1-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms. The expression C1-4 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl (Me), CF3, CD3, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl group.

[0083] The expressions alkenyl and alkynyl refer to at least partially unsaturated, straightchain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, especially from 2 to 10 (e.g. 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s), and alkynyl groups have one or two (especially preferably one) triple bond(s).

[0084] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a 2,2,2-trichloroethyl, difluoromethyl, fluoromethyl or a trifluoromethyl group.

[0085] The expression C1-4 haloalkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms, wherein one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

[0086] The expression C1-4 alkyloxy group refers to a group of formula -O-C1-4 alkyl; the expression C1-4 haloalkyloxy refers to a group of formula -O-C1-4 haloalkyl.

[0087] The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group as defined above in which one or more (preferably 1 to 8; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by a SO or a SO2 group. A heteroalkyl group as defined herein contains at least one carbon atom. The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy. Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

[0088] Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Especially preferably, a heteroalkyl group contains from 1 to 6 (e.g. 1 , 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). The term C1-6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from 0, S and / or N (especially 0 and / or N). The term C1-4 heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1 , 2 or 3 heteroatoms selected from 0, S and / or N (especially 0 and / or N).

[0089] Further preferably, the expression heteroalkyl refers to an alkyl group as defined above (straight-chain or branched) in which one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, sulfur or nitrogen atom or a CO group; this group preferably contains from 1 to 6 (e.g. 1 , 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen); this group may preferably be substituted by one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) fluorine, chlorine, bromine or iodine atoms or OH, =0, SH, =S, NH2, =NH, N3, CN or NO2 groups.

[0090] Examples of heteroalkyl groups are groups of formulae: Ra-0-Ya-, Ra-S-Ya- Ra-S0-Ya-, Ra-S02-Ya-, Ra-N(Rb)-S02-Ya- Ra-S02-N(Rb)-Ya-, Ra-N(Rb)-Ya- Ra-C0-Ya-, Ra-C(=NRd)-Ya-, Ra-0-C0-Ya-, Ra-C0-0-Ya-, Ra-C0-N(Rb)-Ya- Ra-N(Rb)-CO-Ya-, Ra-N(Rb)-C(=NRd)-Ya- Ra-O-CO-N(Rb)-Ya- Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya- Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya- Ra-O-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-O-Ya- Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya- Ra-S-CO-O-Ya- Ra-O-CO-S-Ya- Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya- Ra-S-CS-N(Rb)-Ya- Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya- Ra-O-CS-S-Ya-, wherein Rabeing a hydrogen atom, a Ci-Ce alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rbbeing a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rcbeing a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rdbeing a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group and Yabeing a bond, a

[0091] Ci-Ce alkylene, a C2-C6 alkenylene or a C2-C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom. Further, one or more hydrogen atoms of the above groups may be replaced by fluorine or chlorine atoms.

[0092] Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, -OCD3, -OCF3, ethoxy, n-propyloxy, isopropyloxy, butoxy, te / Y-butyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, -SC Me, -NHAc, -CONH2, methoxyethyl, 1 - methoxyethyl, 1 -ethoxyethyl, 2-m ethoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, / V-ethyl-ZV-methylcarbamoyl or A / -m ethylcarbamoyl. Further examples of heteroalkyl groups are nitrile (-CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

[0093] The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.

[0094] The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1 , 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heterocycloalkyl group as defined herein contains at least one carbon atom. A heterocycloalkyl group has preferably 1 or 2 ring(s) containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, 0, N and S). The expression heterocycloalkyl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g. -N(CH2CH2)2O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.

[0095] The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms.

[0096] The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1 , 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heteroalkylcycloalkyl group as defined herein contains at least one carbon atom. A heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.

[0097] The expression aryl refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. The expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

[0098] The expression heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, comprising one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably 0, S or N). A heteroaryl group as defined herein contains at least one carbon atom. The expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH2 or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2- imidazolyl), phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4-hydroxypyridyl (4-pyridonyl), 3,4-hydroxypyridyl (3,4- pyridonyl), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolinyl groups. The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1 H-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing from 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0099] The expression heteroaralkyl refers to groups containing both aryl and / or heteroaryl groups and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, 0 and S) and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1 , 2 or 3 heteroatoms selected from 0, S and N and / or one or two cycloalkyl groups each containing 5 or 6 ring carbon atoms and / or one or two heterocycloalkyl groups, each containing 5 or 6 ring atoms comprising 1 , 2, 3 or 4 oxygen, sulfur or nitrogen atoms.

[0100] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl- heterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl- alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkyl- cycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group. As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups.

[0101] The term halogen refers to F, Cl, Br or I.

[0102] The term "optionally substituted" refers to a group which is unsubstituted or substituted by one or more (especially by one, two or three; preferably by one or two; especially preferably by one) substituents. If a group comprises more than one substituent, these substituents are independently selected, i.e. , they may be the same or different.

[0103] Examples for substituents are fluorine, chlorine, bromine and iodine and OH, SH, NH2, =0, -SO3H, -SO2NH2, -COOH, -COOMe, -COOEt, CH2OH, -COMe (Ac), -NHSO2Me, -SO2NMe2, -CH2NH2, -NHAc, -S02Me, -CONH2, -CN, -NHCONH2, -NHC(NH)NH2, - NOHCH3, -N3 and -NO2 groups. Further examples of substituents are C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 heteroalkyl, C3-C18 cycloalkyl, C1-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C1-C19 heteroalkylcycloalkyl, Ce-Cis aryl, C1-C17 heteroaryl, C7-C20 aralkyl and C1-C19 heteroaralkyl groups; especially Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-C10 cycloalkyl, C1-C9 heterocycloalkyl, C4-C12 alkylcycloalkyl, C1-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl and C1-C11 heteroaralkyl groups, further preferably Ci-Ce alkyl and Ci-Ce heteroalkyl groups.

[0104] Preferred substituents are halogen atoms (e.g. F, Cl, Br) and groups of formula -OH, =0, -O-C1-6 alkyl (e.g. -OMe, -OCD3, -OCF3, -OEt, -O-nPr, -O-iPr, -O-nBu, -O-iBu and -O-tBu), -NH2, -NHC1-6 alkyl, -N(CI-6alkyl)2, -COOH, -COOMe, -COOEt, -CH2OH, - CH2NH2, -CH2CH2-O-CH3, -COMe, -NHS02Me, -PO(CH3)2, -SO2NMe2, -SO3H, - SO2NH2, -CONH2, -CH2NH2, -CN, -C1-6 alkyl (e.g. -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu and -CF3), -SH, -S-CO-C1-6 alkyl, -S-C1-6 alkyl, -NHAc, -NO2, -C^CH, -CH=C(CH3)2, - CH=CHCH2OCH2CH3, -NHCONH2, -SO2NMe2, -S02Me, phenyl, -O-CH2-C6H5, C1-6 heteroalkyl, C3-7 cycloalkyl (e.g., cyclopropyl), and heterocycloalkyl groups containing from 3 to 6 ring atoms selected from 0, N and C.

[0105] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated.

[0106] The rings of any cycloalkyl aryl group, heterocycloalkyl aryl group, cycloalkyl heteroaryl group and heterocycloalkyl heteroaryl group may be bonded to each other via a single or double bond or these rings may be annulated.

[0107] It should be appreciated that certain compounds of formula (I) may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis / trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-lngold-Prelog or R / S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of formula (I) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.

[0108] According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and / or increases the formation of desired active metabolites. Accordingly, the present invention also encompasses the partially and fully deuterated compounds of formula (I). The term hydrogen also encompasses deuterium.

[0109] The therapeutic use of compounds according to formula (I), their salts (especially their pharmacologically acceptable salts), solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

[0110] The present invention further provides pharmaceutical compositions comprising one or more compounds described herein or a salt (especially a pharmaceutically acceptable salt), solvate or hydrate thereof, optionally in combination with one or more carrier substances and / or one or more adjuvants.

[0111] The present invention further provides a compound or a pharmaceutical composition as described herein for use in the treatment of one or more diseases described below (especially cancer).

[0112] The present invention moreover provides a compound or a pharmaceutical composition as described herein for the preparation of a medicament, especially for the treatment of one or more diseases described below (especially cancer).

[0113] According to a further preferred embodiment, the present invention provides a method for the treatment of one or more diseases described below (especially cancer) in a subject which comprises administering to the subject an effective amount of a compound of formula (I), or a salt thereof.

[0114] According to a moreover preferred embodiment, the present invention provides a method for the treatment of one or more diseases described below (especially cancer) in a subject which comprises administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula (I), or a salt thereof.

[0115] The subject may be a human or an animal; especially a human. The compounds of the present invention are useful in the treatment of inflammation- related diseases; especially inflammatory diseases, cancer, and / or neurodegenerative diseases

[0116] The compounds of the present invention are especially useful in the treatment of cancer; especially liver cancer and breast cancer such as triple-negative breast cancer (TNBC), HER2-positive breast cancer and / or hormone receptor (HR)-positive breast cancer.

[0117] The compounds of the present invention are further useful in the treatment of a disease by modulating AHR activity.

[0118] The compounds of the present invention are moreover useful in the treatment of a disease (especially cancer) by agonistic AHR activation.

[0119] The compounds of the present invention are further useful in the treatment of a disease (especially cancer) wherein AHR is overexpressed.

[0120] The compounds of the present invention are further useful in the treatment of a disease (especially cancer) which is induced or worsened by an AHR antagonist.

[0121] The compounds of the present invention are further useful in the treatment of a disease (especially cancer) by modulating the activity of cytochrome p450 enzymes (especially CYP1A1 ).

[0122] The compounds of the present invention are further useful in the treatment of a disease (especially cancer) by inhibition of the activity of protein kinases; especially tyrosine kinases. Preferably, the cancer is breast cancer (especially triple-negative breast cancer, HER2-positive breast cancer or hormone receptor (HR)-positive breast cancer; most preferably triple-negative breast cancer) or liver cancer.

[0123] The present invention moreover provides the use of the compounds described herein in affecting the aryl hydrocarbon (AH) receptor; especially for use in affecting the AH receptor agonistically.

[0124] The present invention further provides a method for affecting the aryl hydrocarbon (AH) receptor (especially for affecting the AH receptor agonistically) which comprises administering to a subject in need thereof (e.g., a subject suffering from cancer) an effective amount of a compound of formula (I), or a salt thereof.

[0125] The present invention also relates to pro-drugs which are composed of a compound of formula (I) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-arylalkyl- oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy.

[0126] Preferably, the present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of formula (I).

[0127] Examples of pharmacologically acceptable salts of sufficiently basic compounds are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the compounds described herein.

[0128] The compounds described herein may be solvated, especially hydrated. The hydratization / hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water-free compounds. The solvates and / or hydrates may e.g. be present in solid or liquid form.

[0129] In general, the compounds and pharmaceutical compositions described herein will be administered by using the known and acceptable modes known in the art.

[0130] For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, and polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.

[0131] In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 1 mg to about 10,000 mg, preferably from about 5 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

[0132] Preferably, the compounds disclosed herein are biologically acting as agonists of the aryl-hydrocarbon receptor (AHR) triggering the activation and nuclear internalization of the AHR complex that is subsequently acting as transcription factor of CYP450 enzymes, especially also CYP1A1 , amongst others. In consequence, the compounds disclosed herein are preferably themselves oxidized by the upregulated CYP450 enzymes, especially by CYP1A1 , yielding in oxidized compound derivatives that gain inhibitory efficacy against several protein kinases, especially against members of the tyrosine kinases family.

[0133] This mode of action represents an auto-activated gate keeper mechanism responsible for selective prodrug activation and, hence, selectivity against diseased cells, especially breast cancer cells, in particular triple-negative breast cancer (TNBC) and HER2 / neu-positive breast cancer, and hepatic carcinoma, amongst others.

[0134] This extraordinary mode of action hijacks exactly that molecular recognition and pathway, i.e. AHR pathway, that is used by (resistant) cancer cells to detoxify xenobiotics (like anticancer agents) and turns it selectively (selectivity indices up to >1 ,500) against these cancer cells by triggering an intracellular suicide mechanism, i.e. inhibition of multiple protein kinases, the latter being another feature likely to prevent fast development of cancer cell resistance against the compounds disclosed herein.

[0135] Compounds having some structural similarity have been already described (e.g., in WO 2017 / 202816 A1 ; and Liu J. et al., Arch. Pharm. Chem. Life Sci. 2019, 352: 1800338 (doi.org / 10.1002 / ardp.201800338), however, the described compounds were published to act as AHR antagonists, the opposite of the compounds disclosed herein. Furthermore, in the aforementioned cases, evidence is missing that those compounds could have cancer-selective activity, i.e. being active against cancer cells but with high selectivity index more or less inactive against healthy, non-cancer cells.

[0136] EXAMPLES

[0137] I. Synthesis of compounds of formula (I)

[0138] Syntheses of dihydropyridazinone 3 (compound 1) and its mono-Zdihydroxy derivatives 4 are illustrated in Scheme 1 and Scheme 2. (Gama, F. H. S., Souza, R. O. M. A. de & Garden, S. J. An efficient green protocol for the preparation of acetoacetamides and application of the methodology to a one-pot synthesis of Biginelli dihydropyrimidines. Expansion of dihydropyrimidine topological chemical space. RSC Advances 5, 70915- 70928 (2015)).

[0139] Synthesis of dihydropyridazinones 3 and 4 started with refluxing 2,2,6-trimethyl-4H- 1 ,3-dioxin-4-one with respective aniline derivatives in aqueous solution to yield corresponding A / -aryl-3-oxobutanamides 1 , which were subsequently treated with preformed diazonium salts (formed from the respective anilines and NaNO2 in HCI) in the presence of sodium acetate to afford hydrazines 2. Refluxing the hydrazine intermediates 2 with / V, / V-dimethylformamide dimethylacetal (DMF-DMA) afforded the cyclized dihydropyridazinone 3 (Scheme 1 ). R = C6H5; 4-C6H4F; 4-C6H4CI; 4-C6H4Br;

[0140] 4-C6H4l; 4-C6H4CH3; 2-pyridinyl; 3-pyridinyl;

[0141] 2-C6H4-OCH2C6H5; 3-C6H4-OCH2C6H5;

[0142] 4-C6H4-OCH2C6H5

[0143] R2= H; 2,3-C6H4-(O(CH2)2O-); 2-OCH2C6H; 3-OCH2C6H5; 4-OCH2C6H5; 2,3-(OCH2C6H5)2; 2,4-(OCH2C6H5)2; 2,5-(OCH2C6H5)2; 2,6-(OCH2C6H5)2; 3,4-(OCH2C6H5)2

[0144] Dihydropyridazinones 3

[0145] Scheme 1 . Synthesis of dihydropyridazinones 3

[0146] The mono-, di-O-protected dihydropyridazinones were further subjected to hydrogenolysis or BB to yield the corresponding, desired mono-, dihydroxy derived dihydropyridazinones 4 (Scheme 2).

[0147] O-protected a) H2Pd / C; b) BBr3Mono-, dihydroxy derived

[0148] Dihydropyridazinones 3 dihydropyridazinones 4

[0149] R1= H; 2-OCH2C6H5; 3-OCH2C6H5; R1= H; 2-OH; 3-OH; 4-OH;

[0150] 4-OCH2C6H5; 2-OCH3; 3-OCH3; 4-OCH3; R2= H, 2-OH; 3-OH; 4-OH;

[0151] R2= H, 2-OCH2C6H5; 3-OCH2C6H5; 4-OCH2C6H5; 2,3-(OH)2; 2,4-(OH)2; 2,5-(OH)2:

[0152] 2-OCH3; 3-OCH3; 4-OCH3; 2,3-(OCH2C6H5)2; 2,6-(OH)2; 3,4-(OH)2

[0153] 2,4-(OCH2C6H5)2; 2,5-(OCH2C6H5)2;

[0154] 2.6-(OCH2C6H5)2; 3,4-(OCH2C6H5)2;

[0155] 2,3-(OCH3)2; 2,4-(OCH3)2; 2,5-(OCH3)2;

[0156] 2.6-(OCH3)2; 3,4-(OCH3)2

[0157] Scheme 2. Synthesis of mono-, dihydroxy derived dihydropyridazinones 4 from 0- benzyl or 0-Me derived dihydropyridazinones

[0158] General Procedure I for synthesis of N-aryl-3-oxo-butanamide

[0159] A / -Aryl-3- oxobutanamide 1

[0160] The amine (1 equivalent) was dissolved or suspended in water (2 ml / mmol of amine) and heated to reflux. 2,2,6-trimethyl-4H-1 ,3-dioxin-4-one (2 equivalent) was added at this point and refluxed further until the reaction was complete. The reaction progress was monitored using TLC. The mixture was cooled to room temperature and 2M HCI (1 ml / 2.5 mmol of amine) solution was added. The mixture was extracted with ethyl acetate three times. The combined organic phases were washed with brine, dried over Na2SO4 and filtered. The crude product was subjected to a medium pressure flush column chromatography affording the desired A / -aryl-3-oxobutanamide. 3-Oxo-N-phenylbutanamide (Kabi, A. K. et al. HFIP-mediated strategy towards [3-oxo amides and subsequent Friedel-Craft type cyclization to 2-quinolinones using recyclable catalyst. Tetrahedron Letters 61 , 152535 (2020))

[0161] 1H NMR (400 MHz, Chloroform-d) 5 = 9.08 (s, 1 H), 7.54 (d, J=7.6, 2H), 7.33 (t, J=7.9, 2H), 7.12 (t, J=7.4, 1 H), 3.59 (s, 2H), 2.33 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 205.4, 163.2, 137.4, 129.0, 124.6, 120.1 , 49.5, 31.3 ppm.

[0162] N-(4-Fluorophenyl)-3-oxobutanamide

[0163] 1H NMR (400 MHz, Chloroform-d) 5 = 9.14 (s, 1 H), 7.51 (dd, J = 8.9, 4.9 Hz, 2H), 7.07 - 6.96 (m, 2H), 3.59 (s, 2H), 2.33 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 205.5, 163.3, 159.5 (JC-F = 243 Hz), 133.5, 122.0, 121.9, 115.7, 115.5, 49.2, 31.4 ppm.

[0164] 3-Oxo-N-(p-tolyl)butanamide

[0165] 1H NMR (400 MHz, Chloroform-d) 5 = 8.98 (s, 1 H), 7.42 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 3.58 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 205.3, 163.2, 134.9, 134.2, 129.5, 120.2, 49.6, 31.3, 20.9 ppm.

[0166] N-(3-(Benzyloxy)phenyl)-3-oxobutanamide

[0167] 1H NMR (400 MHz, Chloroform-d) 5 = 9.11 (s, 1 H), 7.46 - 7.34 (m, 5H), 7.34 - 7.28 (m, 1 H), 7.21 (t, J=8.1 , 1 H), 7.04 (dd, J=7.9, 1.9, 1 H), 6.74 (dd, J=8.1 , 2.5, 1 H), 5.04 (s, 2H), 3.56 (s, 2H), 2.30 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 205.2, 163.4, 159.3, 138.6, 136.8, 129.7, 128.5, 127.9, 127.5, 112.5, 111.2, 106.8, 70.0, 49.7, 31 .2. HRMS: m / z calc, for Ci7Hi8NO3+[M+H]+: 284.1281 ; found: 284.1280.

[0168] N-(2-(Benzyloxy)phenyl)-3-oxobutanamide

[0169] 1H NMR (400 MHz, Chloroform-d) 5 = 9.29 (s, 1 H), 8.35 (dd, J=7.9, 1.7, 1 H), 7.50 (d, J=7.2, 2H), 7.44 - 7.38 (m, 2H), 7.37 - 7.31 (m, 1 H), 7.08 - 6.91 (m, 3H), 5.17 (s, 2H), 3.57 (s, 2H), 2.30 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 204.0, 163.3, 147.5, 136.4, 128.6, 128.1 , 127.4, 124.1 , 121.3 (x2), 120.4, 111.8, 70.8, 50.8, 31.1 ppm. HRMS: m / z calc, for C17H16NO3- [M-Hp: 282.1136; found: 282.1138.

[0170] General Procedure for synthesis of hydrazines 2

[0171] / V-Aryl-3- oxobutanamide 1

[0172] Hydrazines 2

[0173] Amine (5.64 mmol, 1 .0 equ.) was suspended in water (4.4 mL) and cone. HCI. (2.2 mL) was added to it and the mixture was cooled to 0°C. In a separate flask, NaNC (506 mg, 7.34 mmol, 1.3 equ.) was dissolved in water (4.8 mL), then added to the amine salt in small quantities, so that the temperature inside the reaction vessel would not exceed 5°C. Meanwhile, a respective ZV-aryl-3-oxobutanamide (5.64 mmol, 1.0 equ.) was dissolved in a mixture of ethanol / water (19.2 mL, v / v: 8 / 1.6), and sodium acetate (509 mg, 6.21 mmol, 1.1 equ.) was added to it. The diazonium mixture was added to this in portions without increasing the temperature above 5°C and the mixture was stirred at 0°C for 2 hours. The mixture was filtered over sintered glass, the precipitate was washed with cold water and dried under vacuum. When the obtained precipitate was a mixture of the product hydrazine the starting material oxoamide, the mixture was used without further purification (no characterization was made).

[0174] 3-Oxo-N-phenyl-2-(2-phenylhydrazineylidene)butanamide 2A (Bandyopadhyay, P. et al. Synthesis and bio-evaluation of aryl hydrazono esters for oviposition responses in Aedes albopictus. Bioorganic & Medicinal Chemistry Letters 21 , 794-797 (2011 ))

[0175] 1H NMR (400 MHz, Chloroform-d) 5 = 14.75 (s, 1 H), 11.46 (s, 1 H), 7.63 (dd, J=8.3, 1.4, 2H), 7.46 - 7.33 (m, 6H), 7.23 - 7.12 (m, 2H), 2.60 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 199.5, 163.1 , 141.7, 137.1 , 129.6, 129.0, 126.1 , 125.4, 124.8, 120.9, 115.9, 26.1 ppm.

[0176] N-( 2-(Benzyloxy)phenyl)-3-oxo-2-(2-phenylhydrazineylidene)butanamide

[0177] The product was obtained, after the filtration and the solvent removal, as a mixture of the product and the starting N-(2-(Benzyloxy)phenyl)-3-oxobutanamide in a ratio of 4:1 (calculated from a NMR spectrum) and applied for the next step without further purification.1H NMR (400 MHz, Chloroform-d) 5 = 14.72 (s, 1 H), 11.86 (s, 1 H), 8.38 (dd, J=7.8, 1.7, 1 H), 7.58 - 6.95 (m, 13H), 5.25 (s, 2H), 2.57 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 198.9, 162.9, 148.4, 141.8, 136.6, 129.6, 128.5, 127.9, 127.6, 127.1 , 126.6, 125.1 , 124.5, 121.1 , 121.1 , 115.8, 112.2, 70.6, 26.1 ppm. HRMS: m / z calc, for C23H22N3O3+[M+H]+: 388.1656; found: 388.1641. N-( 3-(Benzyloxy)phenyl)-3-oxo-2-(2-phenylhydrazineylidene)butanamide

[0178] The product was obtained, after the filtration and the solvent removal, as a mixture of the product and the starting N-(3-(Benzyloxy)phenyl)-3-oxobutanamide in a ratio of 1 :1 (calculated from a NMR spectrum) and applied for the next step without further purification.). HRMS: m / z calc, for C23H22N3O3+[M+H]+: 388.1656; found: 388.1666.

[0179] 1H NMR (500 MHz, Chloroform-d) 5 = 15.09 (s, 1 H), 11 .45 (s, 1 H), 7.71 (t, J=8.5, 3H), 7.60 (d, J=7.5, 2H), 7.43 (t, J=7.6, 2H), 7.40 - 7.32 (m, 3H), 7.18 - 7.08 (m, 2H), 7.08 - 6.99 (m, 2H), 5.27 (s, 2H), 2.60 (s, 3H) ppm.13C NMR (126 MHz, Chloroform-d) 5 = 199.5, 162.8, 147.6, 137.6, 136.4, 131.6, 128.9, 128.6, 128.0 (x2), 126.9, 125.4, 124.4, 121.8, 120.6, 114.7, 112.9, 70.5, 26.1 ppm. HRMS: m / z calc, for C23H22N3O3+[M+H]+: 388.1656; found: 388.1666. 1H N MR (500 MHz, Chloroform-d) 5 = 14.69 (s, 1 H), 11.44 (s, 1 H), 7.62 (d, J=8.0, 2H), 7.48 - 7.43 (m, 2H), 7.42 - 7.34 (m, 5H), 7.30 (t, J=8.1 , 1 H), 7.16 (t, J=7.5, 1 H), 7.07 (t, J=2.5, 1 H), 6.95 (d, J=8.0, 1 H), 6.81 (dd, J=8.2, 2.5, 1 H), 5.12 (s, 2H), 2.56 (s, 3H) ppm.13C NMR (126 MHz, Chloroform-d) 5 = 199.5, 163.0, 160.0, 143.0, 137.1 , 136.6, 130.5, 129.0, 128.7, 128.1 , 127.4, 126.1 , 124.8, 121.0, 112.0, 109.0, 102.3, 70.2, 26.2 ppm. HRMS: m / z calc, for C23H22N3O3+[M+H]+: 388.1656; found: 388.1664.

[0180] General Procedure III for cyclization to dihydripyridazinones 3

[0181] Hydrazines 2 Dihydropyridazinones 3

[0182] The hydrazine (1.0 equ.) was dissolved in DMF-DMA (approximately 20.0 equ.) and the reaction mixture was refluxed until a no trace of the hydrazine was detected by TLC. The mixture was cooled down to a room temperature and water was added (20 mL). The mixture was successively extracted with EtOAc (3 x 15 mL) and chloroform (3 x 15 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and the solvent was removed under vacuum. The crude product was purified using a flush column chromatography.

[0183] 4-Oxo-N, 1 -diphenyl-1 ,4-dihydropyridazine-3-carboxamide (1, SelectAHRyl A) 1H N MR (500 MHz, Chloroform-d) 5 = 12.30 (s, 1 H), 8.39 (d, J=7.7, 1 H), 7.81 (d, J=7.3, 2H), 7.70 (dd, J=7.7, 1 .8, 2H), 7.56 (t, J=7.9, 2H), 7.52 - 7.43 (m, 1 H), 7.38 (t, J=7.8, 2H), 7.15 (t, J=7.5, 1 H), 6.96 (d, J=7.8, 1 H) ppm.13C NMR (126 MHz, Chloroforme d = 171.0, 158.8, 145.7, 143.2, 139.9, 138.1 , 130.0, 129.2, 129.0, 124.7, 121.9, 121.5, 120.6 ppm.

[0184] N-( 4-fluorophenyl)-4-oxo- 1 -phenyl- 1, 4-dihydropyridazine-3-carboxamide (11)

[0185] 1H NMR (400 MHz, Chloroform-d): 6 = 12.33 (brs, 1 H), 8.40 (d, 1 H, J = 7.7 Hz), 7.78 (dd, 2H, J = 9.1 , 4.8 Hz), 7.70 - 7.68 (m, 2H), 7.55 (t, 2H, J = 7.6 Hz), 7.51 - 7.46 (m, 1 H), 7.06 (t, 2H, J = 8.7 Hz), 6.96 (d, 1 H, J = 7.7 Hz) ppm.13C NMR (101 MHz, Chloroform-d): 6 = 170.9, 159.5 (d, JC-F = 243.8 Hz), 158.8, 145.6, 143.8, 143.2, 140.0, 130.0, 129.3, 122.2 (d, JC-F = 7.9 Hz), 121.9, 121.5, 115.7 (d, JC-F = 22.4 Hz) ppm.

[0186] N-( 4-chlorophenyl)-4-oxo- 1 -phenyl- 1, 4-dihydropyridazine-3-carboxamide (12)

[0187] 1H NMR (400 MHz, Chloroform-d): 6 = 12.38 (brs, 1 H), 8.40 (d, 1 H, J = 7.7 Hz), 7.76 (d, 1 H, J = 8.8 Hz), 7.69 - 7.67 (m, 2H), 7.57 - 7.52 (m, 2H), 7.50 - 7.46 (m, 1 H), 7.33 (d, 2H, J = 8.8 Hz), 6.96 (d, 1 H, J = 7.7 Hz) ppm.13C NMR (100 MHz, Chloroform-d): 5 = 170.9, 158.9, 145.4, 143.2, 140.0, 136.7, 130.0, 129.3, 129.0, 122.6, 122.0, 121.8, 121 .5 ppm. N-(4-Bromophenyl)-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxamide (13)

[0188] 1H NMR (400 MHz, Chloroform-d): 6 = 12.57 (brs, 1 H), 8.42 - 8.38 (m, 3H), 7.76 - 7.68 (m, 3H), 7.55 (t, 2H, J = 7.6 Hz), 7.49 - 7.46 (m, 1 H), 7.10 - 7.06 (m, 1 H), 6.99 (d, 1 H, J = 7.7 Hz) ppm.13C NMR (100 MHz, Chloroform-d): 5 = 170.7, 159.3, 151.5, 148.4, 145.3, 143.2, 139.8, 138.2, 130.0, 129.2, 122.4, 121.5, 120.2, 115.3 ppm.

[0189] 1H NMR (400 MHz, Chloroform-d): 5 = 12.49 (brs, 1 H), 8.89 (d, 1 H, J = 2.6 Hz), 8.42 (d, 1 H, J = 7.7 Hz), 8.40 (dd, 1 H, J = 4.8, 1 .5 Hz), 8.36 (ddd, 1 H, J = 8.4, 2.6, 1 .5 Hz), 7.71 - 7.68 (m, 2H), 7.58 - 7.54 (m, 2H), 7.52 - 7.48 (m, 1 H), 7.32 (dd, 1 H, J = 8.3, 4.7 Hz), 7.00 (d, 1 H, J = 7.7 Hz) ppm.13C NMR (100 MHz, Chloroform-d): 5 = 170.9,

[0190] 159.4, 145.7, 145.2, 143.2, 142.2, 140.2, 134.9, 130.1 , 129.4, 127.6, 123.7, 122.2, 121 .6 ppm.

[0191] 1-(2,3-dihydrobenzo[b][1 ,4]dioxin-5-yl)-4-oxo-N-phenyl-1,4-dihydropyridazine-3-

[0192] 1H NMR (400 MHz, Chloroform-d) 5 = 12.36 (s, 1 H), 8.19 (d, J = 7.7 Hz, 1 H), 7.84 - 7.76 (m, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.20 - 7.09 (m, 2H), 7.05 - 6.98 (m, 1 H), 7.02 - 6.93 (m, 1 H), 6.86 (d, J = 7.7 Hz, 1 H), 4.36 - 4.27 (m, 4H) ppm.13C NMR (101 MHz, Chloroform-c ) 5 = 170.8, 159.0, 146.1 , 144.5, 143.7, 138.2, 137.1 , 132.3, 129.0, 124.5,

[0193] 121.4, 120.6, 120.4, 118.8, 118.8, 64.8, 64.1 ppm.

[0194] N-( 2-(Benzyloxy)phenyl)-4-oxo- 1 -phen y 1-1, 4-dihydropyridazine-3-carboxamide (23)

[0195] 1H NMR (500 MHz, Chloroform-d) 5 = 12.60 (s, 1 H), 8.68 (d, J=7.9, 1 H), 8.34 (d, J=7.7, 1 H), 7.69 (d, J=7.9, 2H), 7.58 (d, J=7.7, 2H), 7.53 (t, J=7.7, 2H), 7.45 (t, J=7.4, 1 H), 7.39 (t, J=7.5, 2H), 7.31 (t, J=7.5, 1 H), 7.10 - 6.94 (m, 3H), 6.92 (d, J=7.7, 1 H), 5.29 (s, 2H) ppm.13C NMR (126 MHz, Chloroform-d) 5 = 170.7, 158.9, 148.1 , 146.0, 143.3,

[0196] 139.5, 136.7, 129.9, 129.0, 128.5, 128.5, 127.8, 127.1 , 124.4, 121.9, 121.4 (x2), 121.3, 112.1 , 70.6 ppm. HRMS: m / z calc, for C24H18N3O3- [M-Hp: 396.1354; found: 396.1349.

[0197] .1H N MR (500 MHz, Chloroform-d) 5 = 12.33 (s, 1 H), 8.38 (d, J=7.7, 1 H), 7.76 (s, 1 H), 7.70 (d, J=7.9, 2H), 7.55 (t, J=7.7, 2H), 7.51 - 7.43 (m, 3H), 7.39 (t, J=7.5, 2H), 7.32 (t, J=7.4, 1 H), 7.28 - 7.24 (m, 2H), 6.96 (d, J=7.7, 1 H), 6.82 - 6.76 (m, 1 H), 5.10 (s, 2H) ppm.13C NMR (126 MHz, Chloroform-d) 5 = 170.9, 159.3, 158.9, 145.6, 143.2, 139.9, 139.2, 137.0, 130.0, 129.6, 129.2, 128.5, 127.9, 127.5, 122.0, 121.5, 113.1 , 112.0, 106.7, 70.0 ppm. HRMS: m / z calcd for C24H2oN303+[M+H]+: 398.1499; found 398.1488.

[0198] 1-(2-(Benzyloxy)phenyl)-4-oxo-N-phenyl-1,4-dihydropyridazine-3-carboxamide (24)

[0199] .1H NMR (500 MHz, Chloroform-d) 5 = 12.38 (s, 1 H), 8.21 (d, J=7.6, 1 H), 7.81 (d, J=8.0, 2H), 7.59 (dd, J=7.8, 1.6, 1 H), 7.42 (td, J=8.0, 1.6, 1 H), 7.39 - 7.27 (m, 7H), 7.17 - 7.08 (m, 3H), 6.80 (d, J=7.6, 1 H), 5.12 (s, 2H) ppm.13C NMR (101 MHz, Chloroform-cf) 5 = 170.8, 159.0, 151.1 , 146.1 , 144.0, 138.2, 135.4, 133.0, 131.1 , 129.0, 128.8, 128.4, 127.2, 127.0, 124.5, 122.0, 120.6, 120.2, 114.2, 71.4 ppm. HRMS: m / z calc, for C24H20N3O3- [M-H]-: 396.1354; found: 396.1359. 1-(3-(Benzyloxy)phenyl)-4-oxo-N-phenyl-1,4-dihydropyridazine-3-carboxamide (22)

[0200] 1H NMR (500 MHz, Chloroform-d) 5 = 12.30 (s, 1 H), 8.35 (d, J=7.6, 1 H), 7.84 - 7.75 (m, 2H), 7.45 - 7.34 (m, 9H), 7.23 (dd, J=8.0, 2.2, 1 H), 7.15 (t, J=7.4, 1 H), 7.06 (dd, J=8.3, 2.4, 1 H), 6.93 (d, J=7.7, 1 H), 5.14 (s, 2H) ppm.13C NMR (101 MHz, Chloroformed) 5 = 171.0, 159.9, 158.8, 145.6, 144.3, 139.9, 138.0, 136.0, 130.8, 129.0, 128.7, 128.3, 127.6, 124.7, 121.9, 120.6, 115.7, 113.6, 108.6, 70.5 ppm. HRMS: m / z calc. for C24H18N3O3- [M-H]-: 396.1354; found: 396.1357.

[0201] 1H NMR (400 MHz, Chloroform-d) 5 = 12.39 (s, 1 H), 8.22 (d, J = 7.6 Hz, 1 H), 7.84 - 7.77 (m, 2H), 7.36 (dt, J = 9.6, 7.6 Hz, 2H), 7.25 - 7.15 (m, 2H), 7.18 - 7.10 (m, 1 H), 7.05 (q, J = 4.9, 4.5 Hz, 1 H), 6.89 (d, J = 7.7 Hz, 1 H), 3.95 (s, 3H), 3.82 (s, 2H) ppm.13C NMR (101 MHz, Chloroform-cf) 5 = 170.9, 159.0, 153.5, 145.9, 143.8, 142.3, 138.1 , 137.5, 129.0, 124.7, 124.6, 120.6, 117.8 (x2), 113.6, 61.9, 56.3 ppm. 1-( 2-methoxyphenyl)-N-(3-methoxyphenyl)-4-oxo- 1, 4-dihydropyridazine-3-

[0202] 1H NMR (400 MHz, Chloroform-d) 5 = 12.41 (s, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 7.63 (g, J = 1.5, 1.1 Hz, 1 H), 7.57 (dd, J = 7.9, 1.7 Hz, 1 H), 7.45 (ddd, J = 9.1 , 7.5, 1.7 Hz, 1 H), 7.27 - 7.20 (m, 2H), 7.10 (td, J = 7.7, 1.2 Hz, 1 H), 7.05 (dd, J = 8.4, 1.2 Hz, 1 H), 6.85 (d, J = 7.6 Hz, 1 H), 6.75 - 6.65 (m, 1 H), 3.87 (s, 3H), 3.82 (s, 3H) ppm.13C NMR (101 MHz, Chloroform-d) 5 = 170.8, 160.0, 159.1 , 151.9, 145.9, 144.0, 139.3, 132.4, 131.1 , 129.5, 126.9, 121.4, 120.3, 112.8, 112.3, 111.0, 105.7, 56.1 , 55.2 ppm.

[0203] General Procedure IV for cleavage of benzyl groups to phenol derived dihydropyridazinones 4

[0204] Dihydropyridazinones 3 Mono-, dihydroxy derived dihydropyridazinones 4

[0205] The benzyl protected dihydropyridazinone (1 egu.) was dissolved in a mixture of MeOH / THF and Pd / C (10% weight of the benzyl protected dihydropyridazinone) was placed. The mixture was placed under a hydrogen atmosphere and stirred at room temperature until the reaction was complete. THF was removed under vacuum, the catalyst was filtered off through a pad of celite and the filtrate was concentrated under vacuum. The crude product was purified via a flush column chromatography to afford the mono-7dihydroxy substituted dihydropyridazinones 4.

[0206] N-(2-Hydroxyphenyl)-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxamide

[0207] (Select AH Ryl F)

[0208] .1H NMR (400 MHz, DMSO-d6) 6 = 12.35 (s, 1 H), 10.40 (s, 1 H), 9.02 (d, J=7.7, 1 H), 8.42 - 8.35 (m, 1 H), 7.83 (dd, J=7.7, 1.7, 2H), 7.68 - 7.59 (m, 2H), 7.57 - 7.49 (m, 1 H), 6.99 - 6.89 (m, 3H), 6.79 (ddd, J=8.6, 6.0, 2.7, 1 H) ppm.13C NMR (101 MHz, DMSO-cfe) 5 = 170.2, 158.4, 147.3, 145.2, 143.1 , 141.6, 129.7, 128.7, 126.8, 124.3, 121.5, 121.1 , 120.4, 118.7, 114.8 ppm. HRMS: m / z calc, for Ci7Hi4N3O3+[M+H]+: 308.1030; found: 308.1041.

[0209] N-( 3-Hydroxyphenyl)-4-oxo- 1 -phenyl- 1, 4-dihydropyridazine-3-carboxamide ( 3, SelectAHRyl E) yield.1H NMR (500 MHz, Chloroform-d) 5 = 12.44 (s, 1 H), 8.40 (d, J=7.7, 1 H), 7.95 (s, 1 H), 7.79 (d, J=7.9, 2H), 7.58 (t, J=7.9, 2H), 7.53 - 7.47 (m, 1 H), 7.24 - 7.20 (m, 1 H), 7.06 - 7.02 (m, 1 H), 6.98 (d, J=7.7, 1 H), 6.70 - 6.63 (m, 2H) ppm.13C NMR (126 MHz, DMSO-de) 6 = 169.4, 159.5, 157.8, 147.8, 142.9, 141.7, 139.2, 129.7, 129.7, 128.6, 121.4, 120.4, 111.4, 110.4, 106.7 ppm. HRMS: m / z calc, for CI7HI4N3O3+[M+H]+: 308.1030; found: 398.1028. 1-(2-Hydroxyphenyl)-4-oxo-N-phenyl-1,4-dihydropyridazine-3-carboxamide (37,

[0210] 1H NMR (400 MHz, DMSO-d6) 6 = 11.98 (s, 1 H), 10.65 (s, 1 H), 8.63 (d, J=7.8, 1 H), 7.73 - 7.66 (m, 2H), 7.49 (dd, J=8.0, 1 .7, 1 H), 7.38 (tt, J=7.9, 2.0, 3H), 7.18 - 7.07 (m, 2H), 7.00 (td, J=7.7, 1.3, 1 H), 6.85 (d, J=7.7, 1 H) ppm.13C NMR (101 MHz, DMSO-d6) 5 = 169.3, 159.6, 150.6, 147.5, 145.4, 138.2, 131.1 , 130.8, 129.0, 126.6, 124.2, 119.7, 119.6, 119.4, 117.0 ppm. HRMS: m / z calc, for C17H12N3O3- [M-Hp: 306.0884; found: 306.0887.

[0211] 1-( 3-Hydroxyphenyl)-4-oxo-N-phenyl- 1, 4-dihydropyridazine-3-carboxamide (18,

[0212] (1H NMR (400 MHz, DMS0-d6) 5 = 11.85 (s, 1 H), 10.10 (s, 1 H), 8.96 (d, J=7.8, 1 H), 7.72 (d, J=7.8, 2H), 7.39 (t, J=8.1 , 3H), 7.24 - 7.18 (m, 2H), 7.15 (t, J=7.4, 1 H), 6.93 - 6.85 (m, 2H) ppm.13C NMR (101 MHz, DMS0-d6) 6 = 169.4, 159.6, 158.4, 147.5, 143.9, 141.5, 138.2, 130.5, 129.1 , 124.2, 120.4, 119.7, 115.6, 11 1.4, 108.4 ppm. HRMS: m / z calc, for C17H12N3O3- [M-Hp: 306.0884; found: 306.0876. N-(4-Hydroxyphenyl)-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxamide (Select AH Ryl D)

[0213] (..1H NMR (500 MHz, DMSO-d6) 5 = 11.64 (s, 1 H), 9.37 (s, 1 H), 9.00 (d, J=7.8, 1 H), 7.80 (d, J=7.4, 2H), 7.62 (t, J=8.0, 2H), 7.55 - 7.48 (m, 3H), 6.90 (d, J=7.8, 1 H), 6.77 (d, J=8.9, 2H) ppm.13C NMR (126 MHz, DMSO-d6) 6 = 169.5, 158.9, 154.0, 147.7, 142.9, 141.6, 129.9, 129.7, 128.6, 121.4, 121.3, 120.3, 115.4 ppm.

[0214] General Procedure V for cleavage of O-methyl to mono-, dihydroxy dihydropyridazinones 4

[0215] Dihydropyridazinones 3 Mono-, dihydroxy derived dihydropyridazinones 4

[0216] R1= H, OCH3, (OCH3)2R1= H,OH, (OH)2

[0217] R2= H, OCH3(OCH3)2R2= H, OH, (OH)2

[0218] Methoxy pyridazinone (1 equ.) was placed and dry DCM (5 m 1 / 0.1 mL) was added followed by BB (4 equ). The reaction was stirred until the reaction was finished. Water was added, followed by EtOAc. The mixture was extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under a vacuum.

[0219] 1H N MR (400 MHz, DMSO-de) 6 = 12.01 (s, 1 H), 9.62 (s, 2H), 8.60 (d, J = 7.7 Hz, 1 H), 7.74 - 7.67 (m, 2H), 7.43 - 7.34 (m, 2H), 7.19 - 7.10 (m, 1 H), 7.00 - 6.91 (m, 2H), 6.89 - 6.78 (m, 2H) ppm.13C NMR (101 MHz, DMSO-de) 5 = 169.3, 159.6, 147.3, 146.7, 145.4, 139.6, 138.2, 131.9, 129.0, 124.1 , 119.7, 119.4, 118.9, 116.5, 116.1 ppm.

[0220] 1-(2-hydroxyphenyl)-N-(3-hydroxyphenyl)-4-oxo-1,4-dihydropyridazine-3-

[0221] 1H NMR (400 MHz, DMSO-de) 5 = 11 .89 (s, 1 H), 10.60 (s, 1 H), 9.51 (s, 1 H), 8.62 (d, J = 7.7 Hz, 1 H), 7.48 (d, J = 7.9 Hz, 1 H), 7.42 - 7.31 (m, 1 H), 7.29 (s, 1 H), 7.21 - 7.07 (m, 2H), 7.00 (t, J = 6.7 Hz, 2H), 6.84 (d, J = 7.7 Hz, 1 H), 6.53 (d, J = 8.0 Hz, 1 H) ppm.13C NMR (101 MHz, DMSO-cfe) 5 = 169.3, 159.4, 157.8, 150.6, 147.5, 145.3, 139.2, 131.1, 130.8, 129.7, 126.7, 119.5, 119.4, 117.0, 111.3, 110.4, 106.7 ppm.

[0222] II. Biological evaluation of in vitro anti-proliferative / cytotoxic effects towards human cancer and healthy cells

[0223] In vitro cell viability assays evaluating the compounds cytotoxic / cytostatic activity and selectivity against human cancer and healthy cells The compounds were tested against several human cell lines including breast cancer cell lines (MCF-7, T-47D, MDA-MB-468, BT-474, MDA-MB-231 , HCC1937 and SK- BR-3), colon cancer cell lines (HCT116, HT-29 and Caco-2), prostate cancer cell line (PC3), hepatocarcinoma (HepG2), cervical cancer cell line (HeLa), Ewing’s sarcoma (SK-N-MC, SK-ES-1 , CADO-ES-1 and MHH-ES-1), lung adenocarcinoma (HCC827), leukemia cell lines (HEL, Kasumi-1 , THP-1, K562 and MV4-11 ), human embryonic kidney cell line (HEK293) and non-malignant (fibrocystic) breast cell lines (184B5, MCF10A). All human cell lines used were obtained from DSMZ (Braunschweig, Germany) and ATCC (Manassas, VA, USA).

[0224] DMEM high glucose (4.5 g / L), McCoy’s 5a Medium Modified, MEM with Earle's Salts, RPMI1640, L-glutamine (2 mM), penicillin (107Units / L) / streptomycin (10 g / L), 0.05% trypsin-EDTA, Phosphate Buffered Saline (PBS) and fetal calf serum (FCS) were purchased from Capricorn Scientific GmbH (Ebsdorfergrund, Germany), while Endopan 3 medium kit was from PAN-Biotech (Aidenbach, Germany). Digitonin was supplied by Riedel De Haen (Seelze, Germany) and dimethyl sulfoxide (DMSO) from Duchefa Biochemie (Haarlem, The Netherlands). Crystal violet (CV) and resazurin were bought from Sigma-Aldrich (St. Louis, MO, USA). Paraformaldehyde (PFA) and acetic acid were supplied by Carl Roth (Karlsruhe, Germany).

[0225] Cell culture and other lab plastics have been purchased from TPP (Trasadingen, Switzerland), Greiner Bio-One (Frickenhausen, Germany), Sarstedt (Numbrecht, Germany) and Coming (Coming, NY, USA). MDA-MB-468 and SK-BR-3 cells were grown in DMEM supplemented with 4.5 g / L of glucose and 10% (v / v) heat-inactivated FCS, SK-N-MC was cultivated using MEM with Earle's Salts supplemented with 10% (v / v) heat-inactivated FCS and 1 % (v / v) penicillin / streptomycin. 184B5 and MCF10A were grown in Endopan 3 medium kit as indicated by the manufacturer’s guidelines. The HCT116 cell line was cultivated in McCoy’s 5a Medium Modified supplemented with 10% (v / v) heat-inactivated FCS. All other cell lines were grown in RPMI 1640 supplemented with 1% (v / v) glutamine, 1 % (v / v) penicillin / streptomycin and 10% (v / v) heat-inactivated FCS. The cell lines were cultivated in a humidified atmosphere at 37 °C and 5% CO2 (standard growth conditions). For 2D cultures, cells were seeded in 96-well or 384-well plates using different cell densities, depending on the growth properties of the distinct cell lines. For leukemia suspension cell lines, 2x104cells / 100 pL were seeded in each 96-well. For the other, adherent cell lines, 6X 103 / 100 pL were seeded in each 96-well.1(10.3390 / pharmaceuticsl 3040460) For higher throughput, especially MDA-MB-468, SK-BR-3 and 184B5 cells were tested in 384-well format seeding 4x103cells / 60 pL / 384-well. The cells were incubated for 24 h under standard growth conditions. Afterwards, 100 pL (96-well) or 20 pL (384-well) of 2x desired concentration were added to each well to reach the desired 1 x test concentration, and cells were treated for 72 h under standard growth conditions. After incubation, cell viability was determined using CV in case of adherent cells in 96-well and resazurin assay for suspension cells in 96-well and all assays in 384-well. Moreover, the mentioned protocol was also followed to determine the cytotoxicity of the hydroxyl derivatives of selectAHRyl A (1).

[0226] The effect of selectAHRyl A (1) against MDA-MB-468 3D spheroids was studied as well. For that purpose, MDA-MB-468 cells were seeded in a density of 5x103cells / 80 pL / well in spheroids medium (DMEM supplemented with 4.5 g / L of glucose, 10% v / v heat-inactivated FCS and 3% v / v matrigel) using ultra-low adhesion 96-well plates. Afterwards, plates were centrifuged for 10 min and grown under standard growth conditions. After spheroids growth for 48 h, 80 pL of 2x desired concentrations were added to each well to reach the desired 1 x test concentration, and cells were treated for 72 or 120 h under standard growth conditions. Finally, the cells’ viability was determined by using resazurin assay.2(10.1 177 / 1087057106292763)

[0227] Besides the read-out of the MDA-MB-468 spheroids assays, the resazurin assay was also used for all leukemia suspension cell lines. In case of leukemia cell lines 50 pL and in case of MDA-MB-468 spheroids 40 pL of 5x resazurin working solution were added to each well to reach a final concentration of 50 pM. The cells were incubated for 2 h, and fluorescence yielding from the conversion of resazurin to resorufin by viable cells (exc / em = 545 / 595 nM) was measured by using a SpectraMax iD5 plate reader (Molecular Devices, San Jose, CA, USA).3(10.3390 / ijms222312718)

[0228] For all other adherent cell lines, the viability determination was performed by using CV assay. For that purpose, incubation medium was discarded and cells were washed once with PBS. Afterwards, the cells were fixed using 50 pL / well of 4% PFA (w / v) in PBS for 15 min. Then the solution was discarded and the plates were dried at RT for 15 min followed by staining with 50 pL / well of CV working solution (0.1 % CV w / v in PBS) for 15 min. The staining solution was discarded, plates were washed with ddbhO and dried overnight at RT. Finally, 50 pL / well of 33% (v / v) acetic acid were used to solubilize the stain, and the absorbance of the plates was measured at wavelengths of 570 nm (CV) and 670 nm (background) by using the SpectraMax iD5 plate reader4(10.3390 / molecules27144363)

[0229] Finally, the cell viability was calculated and normalized, whereby the read-outs of untreated cells were considered to represent 100% viability and those of cells treated with 125 pM of the cytotoxic saponin digitonin as 0% viability.

[0230] SelectAHRyl A (1) showed cytotoxicity of very varying degrees against a broader panel of human cell lines (Fig. 1 ). The compound was found to be most active against the triple-negative breast cancer (TNBC) cell line MDA-MB-468 with an absolute ICso value of 0.22 pM. Moreover, the compound caused a substantial cytotoxic effect against the cancer cell lines MCF-7, SK-BR-3 (both breast, hormone receptors-positive and TNBC, respectively) and HepG2 (liver) as well. Interestingly, the compound showed a significantly lower effect against all the other human cell lines, noteworthy, also including all tested non-cancerous cell lines 184B5, MCF10A (both breast, ICso = 287.1 pM and > 375 pM, respectively) and HEK293 (embryonic kidney, ICso > 375 pM). Additionally, the compound also caused a cytotoxic and / or anti-proliferative effect in MDA-MB-468 3D spheroids after 72 h and 120 h of treatment with relative ICso values of 1.02 and 0.83 pM, respectively (Fig. 2). Fig. 3 summarizes the impact of several selected hydroxy derivatives of selectAHRyl A (1) on the viability of MDA-MB-468 cells. Tab. 1 summarizes the IC50 values of selectAHRyl derivatives as determined based on 384-well format screenings with MDA-MB-468, SK-BR-3 and 184B5 cells.

[0231] Fig. 1 : Dose-response curves of the viability of selected human cell lines treated with selectAHRyl A (1) for 72 h. The data are presented as means ± SEM. MDA-MB-468 and SK-BR-3: triple-negative breast cancer (TNBC); MCF-7: hormone receptors- positive breast cancer; HepG2: liver cancer; HEK293: human embryonic kidney (non- cancerous); 184B5 and MCF10A: human breast (non-cancerous).

[0232] Fig. 2 : Dose-response curves of the viability of 3D spheroids of MDA-MB-468 cells (TNBC) after 72 and 120 h treatment with selectAHRyl A (1). The data are presented as means ± SEM.

[0233] Fig. 3: Dose-response curves of the viability of MDA-MB-468 cells (TNBC) after 72 h treatment with selected hydroxy derivatives of selectAHRyl A (1). The data are presented as means ± SEM.

[0234] Tab. 1 : Structures of selectAHRyl derivatives and their ICso values as determined based on 384-well format screenings with MDA-MB-468, SK-BR-3 and 184B5 cells after 72 h treatment.

[0235] Activation of the Aryl Hydrocarbon Receptor (AHR) pathway including upregulation of CYP1 A 1 and CYP1B1 enzymes plays an essential role for the anti-proliferative activity and selectivity of select AH Ryl A (1) Global transcriptom ics analyses and data enrichment suggested an involvement of the Aryl Hydrocarbon Receptor (AHR) pathway mediating the selectAHRyls’ cytotoxic / cytostatic effect. Hence, RT-qPCR analyses were performed to confirm the upregulation of the genes regulated by the AHR pathway upon treatment with selectAHRyl A (1).

[0236] MDA-MB-468, SK-BR-3 and 184B5 cell lines were treated with selectAHRyl A (1 ) using ICso (or 100 pM in case of 184B5 where an IC50 > 200 pM was detected) for different time intervals (2, 6, 24 and 48 h) and a negative control of untreated cells representing 0 h treatment was included. The RNA was isolated by using the quick-RNA miniprep kit (Zymo Research, Freiburg i. Br. , Germany), the integrity and the concentration of the isolated RNA were determined by using agarose gel (0.5% w / v; Carl Roth (Karlsruhe, Germany) electrophoresis and the SpectraDrop™ of a SpectraMax iD5 (Molecular Devices, San Jose, CA, USA), respectively. 0.5 pg of isolated RNA were used to synthesize the first cDNA strand by using RevertAid RT Reverse Transcription Kit and oligo dT primers (Thermo Fisher Scientific, Waltham, MA, USA). Afterwards, qPCR analyses were performed. For that purpose, NCBI’s Primer-Blast was used to design target-specific qPCR primers (Table S5) that were synthesized by and purchased from Eurofins Genomics (Ebersberg, Germany). GreenMaster mix (Jena Bioscience, Jena, Germany) was used to conduct the qPCR analyses that were carried out by using a CFX96™ Real-Time PCR Detection System (BioRad, Hercules, CA, USA). The qPCR data were analyzed by using the AACt methodology with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as referencing housekeeping gene. RNA isolation, cDNA synthesis and qPCR were performed as indicated by the manufacturers’ guidelines.5(10.1371 / journal. pone.0041345)

[0237] Four selected genes were studied, namely CYP1A 1, CYP1B1, AHRR and AHR. As shown in Fig. 4, selectAHRyl A (1) induced significant induction of CYP1A1 and CYP1B1 expression in both triple-negative MDA-MB-468 and SK-BR-3 breast cancer cells, what was, contrarily, not observed in non-cancerous 184B5 cells. Remarkably, a strong induction of AHRR expression after 6 h treatment was prominent in SK-BR-3 but not seen in MDA-MB-468 and 184B5. Furthermore, it was noted that selectAHRyl A (1) induced a significant increase in AHR expression in MDA-MB-468 and SK-BR-3, whereas it led to slight reduction of AHR expression in 184B5. These data highlighted the importance of the AHR and CYP1A1 expression level and activity for the cytotoxicity of selectAHRyl A (1).

[0238] Fig. 4: Effect of selectAHRyl A (1) on the mRNA expression levels of selected AHR pathway-associated genes in MDA-MB-468 (TNBC), SK-BR-3 (TNBC) and 184B5 (healthy breast). The cells were treated for 0, 2, 6, 24 and 48 h with the cell line specific ICsos of selectAHRyl A (1) in case of MDA-MB-468 and SK-BR-3, and with 100 pM in case of 184B5.

[0239] SelectAHRyl A (1) induces the translocation of AHR protein from cytosol into the nucleus, confirming functional agonistic AHR activation by the compound

[0240] In order to prove the hypothesis that selectAHRyl A (1) might directly interfere the AHR pathway, most likely by acting as an AHR agonist, the flux of AHR protein upon treatment was investigated by using immunofluorescence microscopic imaging, since agonistic AHR activation should cause the delocalization of AHR protein from the cytosol into the cell’s nucleus.

[0241] MDA-MB-468 cells were seeded in 8-well cell culture chamber slides with a density of 5x104cells / well and allowed to adhere for 24 h under standard growth conditions. Afterwards, cells were treated with selectAHRyl A (1) applying its IC50 for 30 or 60 min. Untreated cells were included to represent the no treatment condition (0 h). Upon completion of the treatment period, the cells were washed once with PBS and fixed by addition of 4% (w / v) PFA in PBS solution and incubation for 10 min at RT, followed by washing intensively with ice-cold PBS. Next, cell permeabilization was achieved by applying PBS containing 0.1 % (v / v) triton X-100 for 10 min, followed by intensive washing using ice-cold PBS. Then, the cells were treated for blocking with 1 % (w / v) BSA and 22.52 mg / mL glycine in PBST (PBS + 0.1 % v / v Tween 20) for 30 min at RT. Afterwards, the blocking solution was discarded, and the cells were incubated overnight with diluted AHR antibody (1 :200) in 1 % (w / v) BSA in PBST at 4°C. Subsequently, the cells were washed intensively with ice-cold PBS, followed by the incubation with the secondary antibody (1 :1000) in 1 % (w / v) BSA in PBST for 1 h at RT in the dark.6 7(10.7150 / ijbs.75084, 10.1111 / imm.12046)lntensive washing was repeated, and cells were mounted by applying Prolong® Diamond Antifade Mountant for 24 h at RT.8(10.1007 / 978-1 -4939-7701 -7_6) Finally, cells were imaged by using a LSM900 confocal laser scanning microscope (Zeiss, Oberkochen, Germany) using the Alexa flour 488 and DAPI channels. Fiji software was used for data analyses. The DAPI channel was used to determine the location of the nuclei, whereas the mean Alexa fluor 488 fluorescence intensity in the cytosol and nuclei represented the expression and localization of the AHR protein. The sum of AHR protein in the nuclei and the cytosol was considered as 100%, and the distribution of AHR between nuclei and cytosol was calculated as a percentage.9(10.1038 / s41388-021 -02161 -1 )

[0242] Indeed, compared to untreated cells, upon selectAHRyl A (1) treatment a differential distribution of AHR protein between the cells’ nuclei and cytosols was detected. Before treatment, the distribution of AHR in both cell compartments was detected (nuclei: 59% and cytosols: 41 %). However, a 30 min treatment with the compound led to an increase by 11 % in AHR protein accumulation in the nuclei , accompanied with a reduced AHR quantity in the cytosol (nuclei: 70% and cytosols: 30%) as illustrated in Fig. 5. Accordingly, the observed induction of the translocation of the AHR protein from the cytosol into the nucleus gives evidence for an agonistic activation of the AHR protein by selectAHRyl A (1).

[0243] Fig. 5 : Translocation of AHR protein in MDA-MB-468 cells caused by treatment with selectAHRyl A (1), indicating functional agonistic AHR activation by the compound.

[0244] Antagonists of AHR and CYP1A1 counteract the cytotoxic activity of selectAHRyl A (1), confirming a vital role of the AHR pathway in the compounds’ mode-of-action

[0245] To confirm the importance of the AHR pathway for the activity of selectAHRyl A (1), cells were treated with selectAHRyl A (1) in combination with several AHR pathwayaffecting compounds. Co-treatment assays were performed, amongst others, with MDA-MB-468 TNBC cells. CH-223191 (AHR inhibitor) and bergamottin (CYP1A1 inhibitor) (both purchased from Hycultec, Beutelsbach, Germany), applied each with a fixed concentration of 12.5 pM, were combined with a serial dilution of selectAHRyl A (1) (0.02-375 pM) for treating the cells for 72 h. Finally, the cells’ viability was determined by conducting CV assays as described above.

[0246] As illustrated in Fig. 6, the AHR antagonist CH-223191 led to a 10-fold reduction of selectAHRyl A (1) activity, indicated by a corresponding ICso shift. Interestingly, in MDA-MB-468 cells, the inhibition of CYP1A1 with bergamottin reduced the cytotoxic effect of selectAHRyl A (1) by nearly 200-folds. A comparable impact of AHR and CYP1A1 inhibition on the compound’s activity, however to a lower extent, was also detected in SK-BR-3 cell. Noteworthy, in case of the non-cancerous 184B5 cell line, bergamottin was detected without effect on selectAHRyl A‘s (1) activity. The results showed that the AHR and its downstream pathway, especially CYP1 A1 , are crucial for anti-proliferative effect of selectAHRyl A (1), and act, hence, as kind of gatekeeper mechanism of action for selectAHRyl A (1) and the claimed compound family.

[0247] Fig. 6: Dose-response curves of the viability of MDA-MB-468 cells (TNBC) after 72 h treatment with selectAHRyl A (1) alone in comparison with co-treatments of selectAHRyl A (1) with either the AHR inhibitor CH-223191 or the CYP1A1 inhibitor bergamottin (both applied with a fixed concentration of 12.5 pM). The data are presented as means ± SEM.

[0248] Protein kinase assays reveal an inhibition of several protein kinases, in particular of the tyrosine kinase family, by selectAHRyl B (37) as proposed cytotoxic principle of that compound family

[0249] To elucidate the mode of cell death induction by selectAHRyl B (37), the compound was tested at 50 nM against a panel of protein kinases (PK) using a radiometric protein kinase assay (33PanQinaseTMActivity Assay; www.reactionbiology.com / assay- protocol-panqinase / ) conducted by Reaction Biology (Malvern, PA, USA).10(10.1016 / j.ddtec.2015.10.007) In brief, the PK reaction cocktails were incubated at 30°C for 60 minutes. The reaction was stopped with 50 pl of 2 % (v / v) H3PO4, plates were aspirated and washed two times with 200 pl 0.9 % (w / v) NaCI. Incorporation of33Pi (counting of “cpm”) was determined with a microplate scintillation counter (Microbeta, Wallac, Australia). For each kinase, the median value of the cpm was defined as "low control" (n=3). This value reflects unspecific binding of radioactivity to the plate in the absence of a protein kinase but in the presence of the substrate. Additionally, for each kinase the median value of the cpm in the absence of any inhibitor was taken as the "high control" (n=3). The difference between high and low control of each enzyme was taken as 100 % activity. As part of the data evaluation the low control of each kinase was subtracted from the high control value as well as from their corresponding "compound values". The residual activity (in %) for each compound well was calculated by using the following formula: 100 X [(signal of compound - low control) I (high control - low control).

[0250] Tab. 2: Effect of selectAHRyl B (37) (50 nM, 60 min incubation) on the catalytic activity of protein kinases. TK: tyrosine kinase family; AGC: cAMP-dependent, cGMP- dependent and protein kinase C family; TKL: tyrosine kinase-like family; CMGC: cyclin- dependent kinases, mitogen-activated protein kinases, glycogen synthase kinases, and CDK-like kinases family; CAMK: calcium / calmodulin-dependent protein kinases family; STE: sterile protein kinase family; CK1 : casein kinase 1 family; atypical and other kinases.

[0251] III. Biological evaluation of in vivo MTD and anti-tumor efficacy towards a MDA- MB-468 mouse xenograft

[0252] In vivo studies, using NMRI nu / nu mice and intraperitoneal (i.p.) application route, were conducted in order to investigate the compound’s maximum tolerated dose (MTD), safety and efficacy.

[0253] To determine the MTD, the compound was applied twice a day for 7 days. Five independent groups, each consisting of 2 mice, were included. Each group was treated with one of the following doses: 0, 25, 50, 100 or 150 mg / kg. The vehicle used for compound application was 5% DMSO, 20% PEG and 75% cyclodextrin solution (30% (2-hydroxypropyl)-|3-cyclodextrin + 0.5% hydroxypropyl methylcellulose in PBS). After the treatment phase, the animals were kept for one week under inspection (follow-up phase) to confirm the absence of any side effects. No detectable adverse effects were observed during the treatment and the follow-up period when applying the maximum concentration of 150 mg / kg / dose (300 mg / kg / day) (data not shown).

[0254] After confirming the safety margin of the compound, the dose of 100 mg / kg was selected to be tested in an efficacy study with two groups (control vs. treated) each comprising 10 NMRI nu / nu xenograft mice. 106human MDA-MB-468 triple-negative breast cancer (TNBC) cells / animal were inoculated subcutaneously (s.c.) into the left flank of 6 - 8 weeks old anesthetized female NMRI nu / nu mice. Mice were maintained under sterile and controlled conditions (22°C, 50% relative humidity, 12 h light-dark cycle, autoclaved food and bedding, acidified drinking water). Tumor growth and body weights, besides visual inspection of the general appearance and behaviour of the animals, were daily measured in two dimensions with a caliper. Tumor volumes were determined by the formula: TV = (width2x length) x 0.5. The treatment was started as soon as the tumor volumes reached a mean of 0.09 cm3, ten days after tumor cells inoculation. The animals were treated twice daily applying 0 and 100 mg / kg / dose to the control and treatment group, respectively, for 39 days using i.p. route. SelectAHRyl A (1) remarkably inhibited the tumor growth. At the last day of treatment the tumor / control (T / C) ratio was 75%. Tumor growth curves are illustrated in Fig. 7. As shown in Fig. 8, the body weights of the mice were not at all affected by the treatment throughout the whole period of treatment and follow-up. At the end of the study, the mice were anesthetized and sacrified in accordance with the ethical guidelines, the tumors were exciced, fixed and embedded in FFPE. Subsequently, the tumor tissues of both treatment groups were histopathologically inspected, highlighting that those tumors that were treated with selectAHRyl A (1) finally consisted mainly of fibrotic, no longer proliferating tissue, with only a very small proportion of still viable tumor cells. In comparison, tumors of the control group consisted for the most part of viable tumor cells that were still capable to proliferate (see Fig. 9). Fig. 7: Tumor growth in female NMRI nu / nu MDA-MB-468 (human TNBC) xenograft mice. The animals were treated twice daily applying 0 and 100 mg / kg / dose of selectAHRyl A (1) in vehicle to the control and treatment group, respectively. Tumor dimensions were measured by using a caliper, and tumor volumes were determined with the formula: TV = (width2x length) x 0.5.

[0255] Fig. 8: Body weights of female NMRI nu / nu MDA-MB-468 (human TNBC) xenograft mice throughout the efficacy study. The animals were treated twice daily applying 0 and 100 mg / kg / dose of selectAHRyl A (1) in vehicle to the control and treatment group, respectively. The mice body weights are given as mean per study group ± SD.

[0256] Fig. 9 : Tumor histopathology. White arrows indicate viable tumor cells / tissue (also appearing darker than fibrotic or necrotic tissue), black arrows indicating fibrotic tissue and black triangles indicating necrotic areals.

[0257] References:

[0258] 1. Mladenovic, M. et al. pH-Responsive Release of Ruthenium Metallotherapeutics from Mesoporous Silica-Based Nanocamers. Pharmaceutics 13, 460 (2021 ).

[0259] 2. Ivascu, A. & Kubbies, M. Rapid generation of single-tumor spheroids for high- throughput cell function and toxicity analysis. J. Biomol. Screen. 11 , 922-932 (2006).

[0260] 3. Lam, Y. T. H. et al. Rare Glutamic Acid Methyl Ester Peptaibols from Sepedonium ampullosporum Damon KSH 534 Exhibit Promising Antifungal and Anticancer Activity. Int. J. Mol. Sci. 22, 12718 (2021 ).

[0261] 4. Ware, I. et al. Bioactive Phenolic Compounds from Peperomia obtusifolia. Molecules 27, 4363 (2022).

[0262] 5. Lichtenfels, R. et al. Comparative Expression Profiling of Distinct T Cell Subsets Undergoing Oxidative Stress. PloS One 7, e41345 (2012).

[0263] 6. Cichocka, M. et al. The Novel Role of hnRNP UL1 in Human Cell Nucleoli. Int. J. Biol. Sci. 18, 4809-4823 (2022).

[0264] 7. Quintana, F. J. The aryl hydrocarbon receptor: a molecular pathway for the environmental control of the immune response. Immunology 138, 183-189 (2013). Jacobs, K. A. & Gavard, J. 3D Endothelial Cell Migration. Methods Mol. Biol.

[0265] Clifton NJ 1749, 51-58 (2018). Meinhardt, A.-L. et al. The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner. Oncogene 41, 1376-1382 (2022).. Wang, Y. & Ma, H. Protein kinase profiling assays: a technology review. Drug Discov. Today Technol. 18, 1-8 (2015).

Claims

CLAIMS1. Pharmaceutical composition comprising a compound of formula (I):whereinX is 0 or NR4;R4is hydrogen, OH, NH2, CN, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted;A is a methyl group and E is hydrogen; orA and E together are a group of formula -CH=CH-, -CH2-CH2-, -CH2-, - C(CH3)=CH- , -CH=C(CH3)-, -N=CH- -NH-CH2-, -O-CH2-, -C(CH2R3)=CH-, - CH=C(CH2R3)-, -C(OR3)=CH-, or -CH =C(OR3)-; orA and E together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group; orA and R4together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group and E is hydrogen;R3is an alkyl group, an alkenyl group, or an optionally substituted aryl group;R1ais OH, a C1-4 alkyloxy group, or a group of formula -N(R6)R5;R5is hydrogen, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted; andR6is hydrogen or a methyl group; orR5and R6together are part of an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group; m is 0, 1 or 2; each R2is independently selected from a hydroxy group, a halogen atom, a - NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O-C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R2together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S; or a salt thereof.

2. A compound of formula (I):whereinX is 0 or NR4;R4is hydrogen, OH, NH2, CN, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted;A is a methyl group and E is hydrogen; orA and E together are a group of formula -CH=CH-, -CH2-CH2-, -CH2-, - C(CH3)=CH- , -CH=C(CH3)-, -N=CH- -NH-CH2-, -O-CH2-, -C(CH2R3)=CH-, - CH=C(CH2R3)-, -C(OR3)=CH-, or -CH =C(OR3)-; orA and E together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group; orA and R4together are part of an optionally substituted aryl group, or an optionally substituted heteroaryl group and E is hydrogen;R3is an alkyl group, an alkenyl group, or an optionally substituted aryl group;R1ais OH, a C1-4 alkyloxy group, or a group of formula -N(R6)R5;R5is hydrogen, or an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroaralkyl group; all of which groups may optionally be substituted; andR6is hydrogen or a methyl group; orR5and R6together are part of an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group; m is 0, 1 or 2; each R2is independently selected from a hydroxy group, a halogen atom, a - NH2 group, a -COOCH3 group, a -OCOCH3 group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O-C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -O-PG, wherein PG is a protecting group; or two groups R2together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S; or a salt thereof, for use as a medicament.

3. Pharmaceutical composition according to claim 1 or compound for use according to claim 2, wherein R1ais the following group:wherein n is 0, 1 or 2; and each R1is independently selected from a hydroxy group, a halogen atom, a - NH2 group, a -COOCH3group, a -OCOCH3group, a C1-4 alkyl group, a C1-4 alkyloxy group, a C1-4 haloalkyl group, a C1-4 haloalkyloxy group, a group of formula -NH-CO-O-C(CH3)3, a group of formula -O-CH2-C6H5, or a group of formula -0-PG, wherein PG is a protecting group; or two groups R1together may be part of a cycloalkyl group comprising 5 or 6 ring atoms, or of a heterocycloalkyl group comprising 5 or 6 ring atoms and at least one heteroatom which is independently selected from 0, N and S.

4. Pharmaceutical composition according to claim 1 or 3 or compound for use according to claim 2 or 3, wherein A and E together are a group of formula - CH=CH-, -CH2-CH2-, -C(CH3)=CH- or -CH=C(CH3)-.

5. Pharmaceutical composition according to claim 1 or 3 or compound for use according to claim 2 or 3, wherein A and E together are a group of formula - CH=CH-.

6. Pharmaceutical composition according to claim 1 or 3 or compound for use according to claim 2 or 3, wherein A is a methyl group and E is hydrogen.

7. Pharmaceutical composition according to any one of claims 1 or 3 to 6 or compound for use according to any one of claims 2 to 6, wherein X is 0.

8. Pharmaceutical composition according to any one of claims 1 or 3 to 6 or compound for use according to any one of claims 2 to 6, wherein X is NR4.

9. Pharmaceutical composition or compound for use according to claim 7, wherein R4is an optionally substituted phenyl group.

10. Pharmaceutical composition or compound for use according to claim 3 having the following formula (II):11 . Pharmaceutical composition or compound for use according to any one of the preceding claims 3 to 10, wherein n is 0 or 1.

12. Pharmaceutical composition or compound for use according to any one of the preceding claims 3 to 11 , wherein each R1is independently selected from a hydroxy group, a halogen atom (especially F, Cl or Br), a methyl group, a methoxy group, or a group of formula -O-CH2-C6H5.

13. Pharmaceutical composition according to any one of claims 1 or 3 to 12 or compound for use according to any one of claims 2 to 12, wherein each R2is independently selected from a hydroxy group, a bromine atom, a chlorine atom, a -COOCH3 group, a CH3 group, a -O-CH3 group, or a group of formula -O-CH2- CeHs; or two groups R2together may be a group of formula -O-CH2-CH2-O-, or -O-CH2-O-.

14. Pharmaceutical composition according to any one of claims 1 or 3 to 12 or compound for use according to any one of claims 2 to 12, wherein each R2is independently a methoxy group, or a group of formula -O-CH2-C6H5; or two groups R2together may be a group of formula -O-CH2-CH2-O-, or -O-CH2-O-.

15. Pharmaceutical composition comprising one of the following compounds, or a salt thereof:

16. A compound which is selected from the following compounds, or a salt thereof:

17. Pharmaceutical composition according to any one of claims 1 or 3 to 15 further containing one or more carrier substances and / or one or more adjuvants.

18. Compound for use according to any one of claims 2 to 14 or 16, or pharmaceutical composition according to any one of claims 1 or 3 to 15 or 17 for use in the treatment of inflammation-related diseases; especially inflammatory diseases, cancer, and / or neurodegenerative diseases.

19. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of cancer.

20. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of breast cancer.

21. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of triple-negative breast cancer (TNBC), HER2-positive breast cancer and / or hormone receptor (HR)-positive breast cancer.

22. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of liver cancer.

23. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of a disease (especially cancer) by modulating AHR activity.

24. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of a disease (especially cancer) by agonistic AHR activation.

25. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of a disease (especially cancer) wherein AHR is overexpressed.

26. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of a disease (especially cancer) which is induced by an AHR antagonist.

27. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of a disease (especially cancer) by modulating the activity of cytochrome p450 enzymes (especially CYP1A1 ).

28. Compound for use according to any one of claims 2 to 14, or 16, or pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17 for use in the treatment of a disease (especially cancer) by inhibition of the activity of protein kinases; especially tyrosine kinases.

29. Use of a compound according to any one of claims 2 to 14, or 16 for the preparation of a medicament for the treatment of one or more of the diseases of any one of claims 18 to 28.

30. A method for the treatment of one or more of the diseases of any one of claims 18 to 28 in a subject which comprises administering to the subject an effective amount of a compound according to any one of claims 2 to 14, or 16, or of a pharmaceutical composition according to any one of claims 1 , or 3 to 15, or 17.31 . A compound which is selected from the following compounds, or a salt thereof:

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