N-heteroaryl derivatives and uses thereof for treating cancer

Abstract

The present invention relates to N-heteroaryl derivatives of formula (F), and the isomers, stereoisomers and pharmaceutical acceptable salts thereof. The invention further relates to pharmaceutical compositions comprising such derivatives and their use for treating a cancer.

Description

[0001] 7V-HETEROARYL DERIVATIVES AND USES THEREOF FOR TREATING CANCER

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the field of medicine, in particular to V-heteroaryl derivatives, and uses thereof in the treatment of cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] Cancer is the second leading cause of death worldwide. Indeed, nearly 1 in 6 deaths is due to cancer. The prevalence of cancer is also extremely high as more than 15 million new cases are diagnosed each year, and the number of new cases is expected to rise by about 70% over the next 2 decades.

[0006] In particular, cancers of the central nervous system (CNS) are a major cause of suffering and death. Among them, glioblastomas (GB) account for 50% of all malignant tumors of the CNS. Despite aggressive multimodal treatment, the median survival after diagnosis is only 15 months, and almost all GB relapse. In children and adolescents, the most common malignant brain tumors are medulloblastomas (MB). Their current treatment results in long-term survival in 60-75% of young patients, but at the cost of serious side-effects that considerably impair children's quality of life over the long term. There is therefore an urgent need to propose new therapeutic options for these intracranial cancers, to control their progression while limiting the deleterious secondary effects.

[0007] Cancer, and particularly CNS malignancies, thus remains a global challenge that requires innovative compounds and new strategies to achieve improved outcomes and enhanced quality of life for patients.

[0008] For the past 10 years, quinoxaline derivatives as anticancer agents have been investigated and two of them, XK469 and CQS were developed in clinical trials. However, these molecules have shown a relative therapeutic efficacy while exhibiting severe side effects. Further quinoxaline derivatives were developed by Montana et al. (Molecules, 2014, 19, 14987-14998), Hajri et al. (European Journal of Medicinal Chemistry, 2016, 124, 959-966), Montero et al. (Pharmaceuticals 2022, 15, 781), and Ahan et al. (Bull. Korean Chem. Soc., 2023, 1-7) and have shown interesting anti-proliferative activities on different cell lines including neuroblastoma and glioblastoma cells. More specifically, the ICso of a quinoxaline substituted by an oxyranyl-5 -nitrofuranyl (also referenced herein as M44-F2 or MARC) on SK-N-SH and IMR-32 neuroblastoma cell lines were 3.9 and 5 pM, respectively.

[0009] Based on these previous results, quinoxaline derivatives are considered as attractive candidates for further investigation in the pursuit of anticancer agents. Therefore, there remains a need to identify and develop new drugs and new compounds to be used in improved treatment of cancers. The present invention seeks to meet these and other needs.

[0010] SUMMARY OF THE INVENTION

[0011] In this context, the inventors synthesized and provided novel compounds of formula (I). More particularly, they demonstrated a therapeutic interest, particularly for the treatment of cancer, especially those associated with the CNS. More specifically, the inventors have shown that compounds of the invention exhibit an impressive cytotoxicity against medulloblastoma and glioblastoma cell lines, with noteworthy selectivity towards cancer cells.

[0012] The present invention therefore relates to a compound of formula (F) wherein: A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen, and B represents with the proviso that when B represents O , A is a 5-10 heteroaryl substituted by at least one halogen, and with the proviso that said compound is not 2-chloro-3-[3-(5-nitrofuran-2-yl)oxiran-2- yl] quinoxaline, and the isomers, stereoisomers and pharmaceutical acceptable salts thereof. Particularly, A is a 5-10 heteroaryl selected in a group consisting of quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,8-naphtyridinyl, pyridinyl, and pyrazinyl, said 5-10 heteroaryl is optionally substituted by at least one halogen. Preferably, the at least one halogen is chorine, fluorine, bromine, iodine, more preferably chlorine or fluorine.

[0013] In an embodiment, the present invention relates to a compound of formula (I), wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom and is substituted by at least one halogen, with the proviso that said compound is not 2-chloro-3-[3-(5-nitrofuran-2- yl)oxiran-2-yl]quinoxaline.

[0014] In a preferred embodiment, the compound of formula (I) has a formula selected in a group consisting of:

[0015] wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine, or wherein Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine. In a more preferred embodiment, the compound of formula (I) has the following formula (la): wherein Ri and R2 represent independently a hydrogen, a chlorine, or a fluorine with the proviso at least one chosen among Ri and R2 is a chlorine or a fluorine. In an embodiment, the present invention relates to a compound of formula (II): wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen. In an embodiment, the present invention relates to a compound of formula (III): wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

[0016] In an embodiment, the present invention relates to a compound of formula (IV): wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

[0017] In a further embodiment, a compound of formula (F) has the the following formula (Ik): wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine with the proviso at least one chosen among Ri and R2 is a halogen, preferably chlorine or a fluorine; or the following formulae (Ilk), (Illk), and (IVk): wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

[0018] A preferred compound of the invention is a compound selected in a group consisting of:

[0019] - 6,7-dichloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0020] - 7-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0021] - 6-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0022] - 8-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0023] - 6,7-difluoro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0024] - 2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0025] - 8-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0026] - 6,7-dichloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0027] - 2-chloro-3-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0028] - 6,7-difluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0029] - 2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0030] - 4-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0031] - l-(2-(5-nitrofuran-2-yl)vinyl)isoquinoline;

[0032] - 7-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline;

[0033] - 6-fluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0034] - 6-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline;

[0035] - 4-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0036] - 2-((5-nitrofuran-2-yl)ethynyl)quinoxaline; and

[0037] - 6,7-difluoro-2-((5-nitrofuran-2-yl)ethynyl)quinoxaline.

[0038] Another object of the invention is a compound according to the invention as defined herein for use as a drug or a medicament. Another object is a pharmaceutical or veterinary composition comprising a compound as defined herein, and a pharmaceutically acceptable excipient.

[0039] A particular object of the invention is a pharmaceutical composition for use for treating a cancer. Preferably, the cancer is selected in a group consisting of: myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, central nervous system cancer, peripheral nervous system cancer, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma. More preferably, the cancer is a central nervous system cancer or a peripheral nervous system cancer, and particularly, medulloblastoma, neuroblastoma, and glioblastoma, preferably glioblastoma and medulloblastoma.

[0040] In a particular embodiment, the pharmaceutical composition for use according to the invention is administered in combination with another antitumoral drug (chemotherapy, targeted therapy, immunotherapy, hormonotherapy) and / or radiotherapy.

[0041] In a further particular embodiment, the pharmaceutical composition for use as defined herein is such that the compound of the invention is administered at a dose ranging from 0.001 mg / kg body weight to 100 mg / kg body weight.

[0042] LEGEND OF FIGURES

[0043] Figure 1: Inhibition of MB, GB cell survival by compounds 7-10 (PEP67, PEP70, PEP71, and PEP74) of the invention. Cell survival analysis in two human MB and two human GB cell lines by Alamar Blue assay after 72 h of treatment with increase concentrations of drugs.

[0044] Figure 2: Inhibition of medulloblastoma 3D micromasses growth (formed by HD-MB03 cells) Figure 3: Inhibition of medulloblastoma 3D micromasses migration (formed by ONS-76 cells) Figure 4: Inhibition of glioblastoma 3D micromasses growth (formed by U87-MG cells) Figure 5: Inhibition of glioblastoma 3D micromasses migration (formed by U251-MG cells) Figure 6: Inhibition of medulloblastoma 3D micromasses (formed by ONS76 cells) grafted in cerebellum slices by compound 7 (PEP67) over time.

[0045] Figure 7: Inhibition of glioblastoma 3D micromasses (formed by U251 cells) grafted in brain slices by compound 7 (PEP67) over time.

[0046] DETAILED DESCRIPTION OF THE INVENTION

[0047] According to the present invention, the terms below have the following meanings: The term “halogen” corresponds to a fluorine, a chlorine, a bromine, or an iodine atom. In a preferred embodiment, the halogen is a chlorine.

[0048] The term “aryl” corresponds to a mono- or bi- or tri- or tetra-cyclic aromatic hydrocarbons having from 6 to 24 carbon atoms. For instance, the term “aryl” includes phenyl, naphtalenyl, anthracenyl, or pyrenyl. In a preferred embodiment, the aryl is a phenyl.

[0049] The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 5 and 24 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom. Examples of such mono- and poly-cyclic heteroaryl group may be: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. In a particular embodiment, the heteroaryl comprises between 5 and 10 atoms and at least one nitrogen. Preferably, the 5-10 heteroaryl is quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,8-naphtyridinyl, pyridinyl, and pyrazinyl.

[0050] The expression “substituted by at least one radical” means that the group or radical is substituted by one or several radicals of the list. The expression “optionally substituted” means that the group or radical is not substituted (i.e., unsubstituted) or substituted by one or several radicals of the list.

[0051] The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers, and anomers. In a particular embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers.

[0052] As used herein, the term “pharmaceutically acceptable salt” includes inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. The “pharmaceutically salts” also include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt.

[0053] As used herein, the terms “treatment”, “treat” or “treating” refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease, in particular a cancer. In certain embodiments, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other embodiments, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease. In particular, such terms refer to decreased development of tumors, decreased tumor burden, tumor regression, and / or prevention or delay of metastasis occurrence and cancer relapse.

[0054] As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to a mammal, even more preferably to a human, including adult, child, newborn and human at the prenatal stage. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.

[0055] The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule. As used herein, the terms "active principle", "active ingredient", "active pharmaceutical ingredient", “medicine”, and “drug” are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect.

[0056] As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a cancer, or to cure or to attenuate the effects of a cancer.

[0057] As used herein, the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of a cancer. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the cancer. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the cancer to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.

[0058] As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.

[0059] As used herein, the term “immunotherapy”, “immunotherapeutic agent” or “immunotherapy treatment” refers to a cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells. It includes immunization of the patient with tumor antigens (e.g., by administering a cancer vaccine), in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or administration of molecules stimulating the immune system such as cytokines, or administration of therapeutic antibodies as drugs, in which case the patient's immune system is recruited by the therapeutic antibodies to destroy tumor cells. In particular, antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors. The terms “kit”, “product” or "combined preparation", as used herein, defines especially a "kit of parts" in the sense that the combination partners (a) and (b), as defined in the present application can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit of parts can then be administered simultaneously or chronologically staggered, that is at different time points for any part of the kit of parts. The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied. The combination partners (a) and (b) can be administered by the same route or by different routes.

[0060] As used herein, the term “simultaneous” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered simultaneously, i.e., at the same time.

[0061] As used herein, the term “sequential” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered sequentially, i.e., one after the other. Preferably, when the administration is sequential, all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute.

[0062] As used herein, the term “separate” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered at distinct time of the day. Preferably, when the administration is separate, the active ingredients are administered with an interval of about 1 hour to about 24 hours, preferably with an interval of about 1 hour and 15 hours, more preferably with an interval of about 1 hour and 8 hours, even more preferably with an interval of about 1 hour and 4 hours.

[0063] The present invention provides new compounds of the following formula (I), including pharmaceutical acceptable salts, isomers and stereoisomers thereof, of therapeutic interest.

[0064] According to the invention, a compound has the following formula (F): wherein: A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen, and B represents with the proviso that when B represents is a 5-10 heteroaryl substituted by at least one halogen, and with the proviso that said compound is not 2-chl oro-3 - [3 -(5 -nitrofuran-2-yl)oxiran-2- yl]quinoxaline.

[0065] A further object of the invention is a compound of formula (F): wherein: A is a 5-10 heteroaryl comprising at least one nitrogen atom substituted by at least one halogen, and B represents with the proviso that said compound is not 2-chloro-3-[3-(5-nitrofuran-2-yl)oxiran-2- yl]quinoxaline.

[0066] The compound 2-chloro-3-[3-(5-nitrofuran-2-yl)oxiran-2-yl]quinoxaline disclosed by Montero et al. (Pharmaceuticals 2022, 15, 781), also referenced herein “PEP38F1”, has the following formula: and is outside the scope of the present invention. Particularly, it includes any stereoisomers, preferably compounds I la and 11b of Montero et al. having the following formulae respectively. PEP38F1, and compounds I la and 1 lb of Montero et al. are therefore outside the scope of the present invention.

[0067] In an embodiment, B represents O

[0068] According to an embodiment of the invention, a compound has the following formula (I): wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom substituted by at least one halogen, with the proviso that said compound is not 2-chloro-3-[3-(5-nitrofuran-2-yl)oxiran-2- yl]quinoxaline.

[0069] In an embodiment, a compound of formula (I) is such that A is a 5-10 heteroaryl comprising at least one nitrogen atom substituted by at least one halogen.

[0070] In a particular embodiment, the halogen is chorine, fluorine, bromine, or iodine. In a preferred embodiment, the halogen is chlorine or fluorine. In a further particular embodiment, A is a 5-10 heteroaryl selected in a group consisting of quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,8-naphtyridinyl, pyridinyl, and pyrazinyl, said 5-10 heteroaryl is substituted by at least one halogen as defined herein. More particularly, a compound of formula (I) according to the invention has a formula selected in a group consisting of: wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine, or wherein Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine. In this embodiment, if R3 is absent, at least one group among Ri and R2 is a halogen, preferably a chlorine or a fluorine. If R3 is present, at least one group among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0071] In a preferred embodiment, a compound of formula (I) has a quinoxalinyl core. According to this preferred embodiment, the compound of formula (I) has the following formula (la) or (lb): wherein Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine.

[0072] In a more preferred embodiment, a compound of formula (I) has the formula (la): wherein Ri and R2 represent independently a hydrogen, a chlorine, or a fluorine, with the proviso that at least one chosen among Ri and R2 is a chlorine or a fluorine.

[0073] A preferred compound of formula (I) or (la) is a compound selected in a group consisting of:

[0074] - 6,7-dichloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0075] - 7-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0076] - 6-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0077] - 8-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline; and

[0078] - 6,7-difluoro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline.

[0079] In an embodiment, a compound of formula (I) has a quinazolinyl core. According to this preferred embodiment, the compound of formula (I) has the following formula (Ic) or (Id): wherein RI,R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine.

[0080] In an embodiment, a compound of formula (I) has a quinolinyl core. According to this preferred embodiment, the compound of formula (I) has the following formula (le), (If), or (Ig): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0081] In an embodiment, a compound of formula (I) has an isoquinolinyl core. According to this preferred embodiment, the compound of formula (I) has the following formula (Ih) or (li): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine. In an embodiment, a compound of formula (I) has a 1,8-naphtyridinyl core. According to this preferred embodiment, the compound of formula (I) has the following formula (Ij): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0082] In an embodiment, a compound of formula (I) has a pyridinyl, a pyrazinyl, or pyrimidinyl core. According to this preferred embodiment, the compound of formula (I) has the following formula (Ik): wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri and R2 is a halogen, preferably chlorine or a fluorine. In a particular embodiment, Xi is N and X2 is C. In a further particular embodiment, Xi is C and X2 is N.

[0083] In a further embodiment B represents -CH=CH-.

[0084] According to an embodiment of the invention, a compound has the following formula (II): wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

[0085] In an embodiment, a compound of formula (II) is such that A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen. In a particular embodiment, the halogen is chorine, fluorine, bromine, or iodine. In a preferred embodiment, the halogen is chlorine or fluorine. In a further particular embodiment, A is a 5-10 heteroaryl selected in a group consisting of quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,8- naphtyridinyl, pyridinyl, and pyrazinyl, said 5-10 heteroaryl is optionally substituted by at least one halogen as defined herein.

[0086] More particularly, a compound of formula (II) according to the invention has a formula selected in a group consisting of:

[0087] wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. In a particular embodiment, at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine. In a further particular embodiment, at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine. In this embodiment, if R3 is absent, at least one group among Ri and R2 is a halogen, preferably a chlorine or a fluorine. If R3 is present, at least one group among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0088] In a preferred embodiment, a compound of formula (II) has a quinoxalinyl core. According to this preferred embodiment, the compound of formula (II) has the following formula (Ila) or (lib): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

[0089] In a more preferred embodiment, a compound of formula (II) has the following formula (Ila) wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. Preferably, Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0090] A preferred compound of formula (II), (Ila), or (lib) is a compound selected in a group consisting of:

[0091] - 2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0092] - 8-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0093] - 6,7-dichloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0094] - 2-chloro-3-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline; and

[0095] - 6,7-difluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline.

[0096] In a preferred embodiment, a compound of formula (II) has a quinolinyl core. According to this preferred embodiment, the compound of formula (II) has the following formula (lie), (Ilf) or (Ilg’): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

[0097] In a more preferred embodiment, a compound of formula (II) has the following formula (lie) or (Ilg’): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. Preferably, Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0098] A preferred compound of formula (II), (lie), (Ilf) or (Ilg’) is a compound selected in a group consisting of:

[0099] - 2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0100] - 4-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0101] - 7-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline;

[0102] - 6-fluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0103] - 6-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline; and

[0104] - 4-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline.

[0105] In a preferred embodiment, a compound of formula (II) has an isoquinolinyl core. According to this preferred embodiment, the compound of formula (II) has the following formula (Ila) or

[0106] (lib): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

[0107] In a more preferred embodiment, a compound of formula (II) has the following formula (Ilh’) : 1 wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. Preferably, Ri, R2, and R3 represent a hydrogen.

[0108] A preferred compound of formula (II), (Ilh’) or (Hi) is l-(2-(5-nitrofuran-2- yl)vinyl)isoquinoline.

[0109] In an embodiment, a compound of formula (II) has a pyridinyl or pyrazinyl core. According to this preferred embodiment, the compound of formula (II) has the following formula (Ilk): wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. In a particular embodiment, at least one chosen among Ri and R2 is a halogen, preferably chlorine or fluorine. In a particular embodiment, Xi is N and X2 is C. In a further particular embodiment, Xi is C and X2 is N.

[0110] In a further embodiment, B represents

[0111] According to an embodiment of the invention, a compound has the following formula (III): wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

[0112] In an embodiment, a compound of formula (III) is such that A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen. In a particular embodiment, the halogen is chorine, fluorine, bromine, or iodine. In a preferred embodiment, the halogen is chlorine or fluorine. In a further particular embodiment, A is a 5-10 heteroaryl selected in a group consisting of quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,8- naphtyridinyl, pyridinyl, and pyrazinyl, said 5-10 heteroaryl is optionally substituted by at least one halogen as defined herein.

[0113] More particularly, a compound of formula (III) according to the invention has a formula selected in a group consisting of: wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. In a particular embodiment, at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine. In a further particular, at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine. In this embodiment, if R3 is absent, at least one group among Ri and R2 is a halogen, preferably a chlorine or a fluorine. If R3 is present, at least one group among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0114] In an embodiment, a compound of formula (III) has a pyridinyl or pyrazinyl core. According to this preferred embodiment, the compound of formula (III) has the following formula (Illk): wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. In a particular embodiment, at least one chosen among Ri and R2 is a halogen, preferably chlorine or fluorine. In a particular embodiment, Xi is N and X2 is C. In a further particular embodiment, Xi is C and X2 is N.

[0115] In a further embodiment B represents -C = C-.

[0116] According to an embodiment of the invention, a compound has the following formula (IV): wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

[0117] In an embodiment, a compound of formula (IV) is such that A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen. In a particular embodiment, the halogen is chorine, fluorine, bromine, or iodine. In a preferred embodiment, the halogen is chlorine or fluorine. In a further particular embodiment, A is a 5-10 heteroaryl selected in a group consisting of quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,8- naphtyridinyl, pyridinyl, and pyrazinyl, said 5-10 heteroaryl is optionally substituted by at least one halogen as defined herein.

[0118] More particularly, a compound of formula (IV) according to the invention has a formula selected in a group consisting of: wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. In a particular embodiment, at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine. In a further particular embodiment, at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine. In this embodiment, if R3 is absent, at least one group among Ri and R2 is a halogen, preferably a chlorine or a fluorine. If R3 is present, at least one group among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine. In a further particular embodiment Ri, R2, and R3 represent a hydrogen.

[0119] In a preferred embodiment, a compound of formula (IV) has a quinoxalinyl core. According to this preferred embodiment, the compound of formula (IV) has the following formula (IVa) or

[0120] (IVb): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

[0121] In a more preferred embodiment, a compound of formula (IV) has the following formula (IVa): wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. Preferably, Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine.

[0122] A preferred compound of formula (IV), (IVa), or (IVb) is a compound selected in a group consisting of:

[0123] - 2-((5-nitrofuran-2-yl)ethynyl)quinoxaline; and

[0124] - 6,7-difluoro-2-((5-nitrofuran-2-yl)ethynyl)quinoxaline.

[0125] In an embodiment, a compound of formula (IV) has a pyridinyl or pyrazinyl core. According to this preferred embodiment, the compound of formula (IV) has the following formula (IVk): wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine. In a particular embodiment, at least one chosen among Ri and R2 is a halogen, preferably chlorine or fluorine. In a particular embodiment, Xi is N and X2 is C. In a further particular embodiment, Xi is C and X2 is N.

[0126] In a preferred embodiment of the invention, a compound of formula (F) is selected in a group consisting of:

[0127] - 6,7-dichloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0128] - 7-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0129] - 6-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0130] - 8-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0131] - 6,7-difluoro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;

[0132] - 2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0133] - 8-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0134] - 6,7-dichloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0135] - 2-chloro-3-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;

[0136] - 6,7-difluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline; - 2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0137] - 4-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0138] - l-(2-(5-nitrofuran-2-yl)vinyl)isoquinoline;

[0139] - 7-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline;

[0140] - 6-fluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0141] - 6-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline;

[0142] - 4-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;

[0143] - 2-((5-nitrofuran-2-yl)ethynyl)quinoxaline; and

[0144] - 6,7-difluoro-2-((5-nitrofuran-2-yl)ethynyl)quinoxaline.

[0145] As illustrated by examples, the inventors have demonstrated the therapeutic interest of the compounds of the invention.

[0146] Accordingly, the present invention relates to a pharmaceutical or veterinary composition comprising a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (ink), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) according to the invention or any particular compound as disclosed herein. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient.

[0147] The present invention relates to the use of a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) according to the invention or any particular compound as disclosed herein as a drug or a medicine. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) according to the invention or any particular compound as disclosed herein, is administered to said subject in need thereof. The invention also relates to the use of a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) according to the invention or any particular compound as disclosed herein, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising a compound of (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) according to the invention or any particular compound as disclosed herein for use as a drug.

[0148] The present invention also concerns:

[0149] - a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound for preventing and / or treating or for use for preventing and / or treating a cancer; and / or

[0150] - a pharmaceutical composition comprising a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, and an antitumor drug, in particular for the prevention and / or the treatment of cancer or for use in the prevention and / or the treatment of cancer; and / or

[0151] - a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for preventing and / or treating a cancer or for use for preventing and / or treating a cancer in combination with an antitumor drug such as chemotherapy, immunotherapy, and / or hormonotherapy, and / or with radiotherapy, optionally before, simultaneously and / or after surgery (e.g., tumor resection); and / or - a kit comprising (a) a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein; and (b) an antitumor drug as a combined preparation for simultaneous, separate or sequential use, for preventing and / or treating cancer or for use for preventing and / or treating a cancer; and / or

[0152] - the use of a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (ink), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the prevention and / or the treatment of a cancer; and / or

[0153] - the use of a pharmaceutical composition comprising a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, and an additional antitumor drug, for the manufacture of a medicament, a medicine or a drug for the prevention and / or the treatment of a cancer; and / or

[0154] - the use of a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the prevention and / or the treatment of a cancer in combination with a treatment with an antitumor drug such as chemotherapy, immunotherapy, and / or hormonotherapy, and / or with radiotherapy, optionally before, simultaneously and / or after surgery (e.g., tumor resection); and / or

[0155] - a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Illf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound;

[0156] - a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (inf), (Illg), (Illh), (Illi), (ink), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, and an additional antitumor drug, optionally with radiotherapy;

[0157] - a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ik), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg’), (Ilh), (Ilh’), (Hi), (Ilk), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (Ulf), (Illg), (Illh), (Illi), (Illk), (IV), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVg’), (IVh), (IVh’), (IVi), or (IVk) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound; the method further comprises chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy, optionally before, simultaneously and / or after surgery (e.g., tumor resection).

[0158] The term “cancer”, as used herein, refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. The cancer may affect solid or hematopoietic tissues. Examples of cancer include, but are not limited to, solid tumors and hematological cancers, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, lung cancer, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, bile duct cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, melanoma, skin cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, oesophagal cancer, colon cancer, head and neck cancer, brain cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia, mastocytosis and any symptom associated with mastocytosis.

[0159] In a particular aspect, the cancer is selected in a group consisting of: myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, central nervous system cancer, peripheral nervous system cancer, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma. In a preferred aspect, the cancer is a central nervous system cancer or a peripheral nervous system cancer. In a more preferred aspect, the cancer is a central nervous system cancer or a peripheral nervous system cancer, which is medulloblastoma, neuroblastoma, and glioblastoma, preferably glioblastoma and medulloblastoma.

[0160] The administration route can be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumor or parenteral (including subcutaneous, intramuscular, intravenous and / or intradermal). Preferably, the administration route is parental, oral or topical. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition, kit, product or combined preparation is preferably administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.

[0161] The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets or capsules that contain solid vehicles in a way known in the art. Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.

[0162] Pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.

[0163] Preferably, the treatment with the compound according to the invention or the pharmaceutical composition according to the invention starts no longer than a month, preferably no longer than a week, after the diagnosis of the disease. In a particular embodiment, the treatment starts the day of the diagnosis.

[0164] The compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses. Preferably, the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day.

[0165] The duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably comprised between 1 day and 50 weeks, more preferably between 1 day and 30 weeks, still more preferably between 1 day and 15 weeks, even more preferably between 1 day and 10 weeks. In a particular embodiment, the duration of the treatment is of about 1 week. Alternatively, the treatment may last as long as the disease persists. The amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient. In a particular embodiment, is administered at a dose ranging from 0.001 mg / kg body weight to lOO mg / kg body weight, preferably from 0.001 mg / kg body weight to 30 mg / kg body weight. In a particular embodiment, the pharmaceutical composition of the invention is administered in combination with another antitumoral drug (chemotherapy, targeted therapy, immunotherapy, hormonotherapy) and / or radiotherapy.

[0166] The additional antitumor drug can be selected in the non-exhaustive list of antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti -metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor and an anti-EGFR agent and / or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key biological functions.

[0167] Antimitotic agents include, but are not limited to, paclitaxel, docetaxel and analogs such as larotaxel (also called XRP9881; Sanofi -Aventis), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol-Meyer-Squibb), BMS-275183 (Bristol-Meyer- Squibb), ortataxel (also called IDN 5109, BAY 59-8862 or SB-T-101131; Bristol-Meyer- Squibb), RPR 109881 A (Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT- 287 (TAPESTRY), PG-paclitaxel (also called CT-2103, PPX, paclitaxel poliglumex, paclitaxel polyglutamate or Xyotax™), ABRAXANE® (also called Nab-paclitaxel; ABRAXIS BIOSCIENCE), tesetaxel (also called DJ-927), IDN 5390 (INDENA), taxoprexin (also called docosahexanoic acid-paclitaxel; PROTARGA), DHA-paclitaxel (also called Taxoprexin®), cabazitaxel (also called JEVTANA®, Sanofi), and MAC-321 (WYETH). Preferably, antimitotic agents are docetaxel, paclitaxel, and is more preferably docetaxel.

[0168] Inhibitors of topoisomerases I and / or II include, but are not limited to etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicin, anthracyclines such as doxorubicin, epirubicin, daunorubicin, idarubicin and mitoxantrone. Inhibitors of topoisomerase I and II include, but are not limited to intoplicin.

[0169] The additional antitumor agent can be alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes. Non-exhaustive examples thereof include uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, cisplatin, carboplatin, fotemustine, oxaliplatin, thiotepa, streptozocin, dacarbazine, and temozolomide. In a particular embodiment, the DNA alkylating agent is preferably cisplatin, carboplatin, temozolomide, fotemustine or dacarbazine.

[0170] Anti-metabolic agents block the enzymes responsible for nucleic acid synthesis or become incorporated into DNA, which produces an incorrect genetic code and leads to apoptosis. Non- exhaustive examples thereof include, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, and more particularly methotrexate, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, 5 -fluorouracil, gemcitabine and capecitabine. In a particular embodiment, such an agent is gemcitabine.

[0171] The additional anti-tumor agent can also be a targeted agent, in particular a kinase inhibitor. The kinase may be selected from the group consisting of intracellular tyrosine or serine / threonine kinases, receptors tyrosine or serine / threonine kinase. The kinase could be selected among EGFR family, ALK, B-Raf, MEK, and mTOR. For instance, the agents may have ability to inhibit angiogenesis based on the inhibitory activities on VEGFR and PDGFR kinases. In particular, the targeted agent can be selected among the multiple kinase inhibitor drugs which are already approved: Gleevec®, which inhibits Bcr-Abl and c-Kit, and Iressa® and Tarceva®, which both inhibit EGFR, sorafenib (Nexavar®, BAY 43-9006) which inhibits Raf, dasatinib (BMS-354825) and nilotinib (AMN-107, Tasigna®) which also inhibits Bcr-Abl, lapatinib which also inhibits EGFR, temsirolimus (Torisel®, CCI-779) which targets the mTOR pathway, sunitinib (Student®, SU11248) which inhibits several targets including VEGFR as well as specific antibodies inactivating kinase receptors: Herceptin® and Avastin®. The anti- EGFR agent can be selected among gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS 1421373-98-9), poziotinib, WZ4002, preferably is erlotinib or cetuximab. The ALK inhibitor can be selected among crizotinib, entrectinib, ceritinib, alectinib, brigatinib, lorlatinib, TSR-011, CEP-37440, and ensartinib. The B-Raf inhibitor can be selected among vemurafenib, dabrafenib, regorafenib, and PLX4720. The MEK inhibitor can be selected among cobimetinib, trametinib, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733. The antitumor agent can be IDO1 inhibitors such as epacadostat.

[0172] The term “therapy”, as used herein, refers to any type of treatment of cancer (i.e., antitumor therapy), including an adjuvant therapy and a neoadjuvant therapy. Therapy comprises radiotherapy and therapies, preferably systemic therapies such as hormone therapy, chemotherapy, immunotherapy and targeted therapy.

[0173] The term “adjuvant therapy”, as used herein, refers to any type of treatment of cancer given as additional treatment, usually after surgical resection of the primary tumor, in a patient affected with a cancer that is at risk of metastasizing and / or likely to recur. The aim of such an adjuvant treatment is to improve the prognosis. Adjuvant therapies comprise radiotherapy and therapy, preferably systemic therapy, such as hormone therapy, chemotherapy, immunotherapy and targeted therapy.

[0174] The term “hormone therapy” or “hormonal therapy” or “hormonotherapy” refers to a cancer treatment having for purpose to block, add or remove hormones. For instance, in breast cancer, the female hormones estrogen and progesterone can promote the growth of some breast cancer cells. So, in these patients, hormone therapy is given to block estrogen and a non-exhaustive list commonly used drugs includes: tamoxifen, toremifene, anastrozole, exemestane, letrozole, goserelin, leuprolide, megestrol acetate, and fluoxymesterone. As used herein, the term “chemotherapeutic treatment” or “chemotherapy” refers to a cancer therapeutic treatment using chemical or biological substances, in particular using one or several antineoplastic agents.

[0175] The term “radiotherapeutic treatment” or “radiotherapy” is a term commonly used in the art to refer to multiple types of radiation therapy including internal and external radiation therapies or radioimmunotherapy, and the use of various types of radiations including X-rays, gamma rays, alpha particles, beta particles, photons, electrons, neutrons, radioisotopes, and other forms of ionizing radiations.

[0176] The term “therapeutical antibody” refers to any antibody having an anti-tumoral effect. Preferably, the therapeutical antibody is a monoclonal antibody. Therapeutic antibodies are generally specific for surface antigens, e.g., membrane antigens. Most preferred therapeutic antibodies are specific for tumor antigens (e.g., molecules specifically expressed by tumor cells), such as CD20, CD52, ErbB2 (or HER2 / Neu), CD33, CD22, CD25, MUC-1, CEA, KDR, aVb3, and the like. The therapeutical antibody includes, but is not limited to, antibodies such as trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), alemtuzumab, gemtuzamab, cetuximab, pertuzumab, epratuzumab, basiliximab, daclizumab, labetuzumab, sevirumab, tuvurimab, palivizumab, infliximab, omalizumab, efalizumab, natalizumab, clenoliximab, and bevacizumab.

[0177] In a particular aspect, the antitumor agent can be an immunomodulator. The immunomodulator can be a cancer vaccine, molecules stimulating the immune system such as cytokines, therapeutic antibodies, preferably monoclonal antibodies, in particular antibodies directed against antigens specifically presented or overexpressed at the membrane of tumor cells or directed against cell receptors which blockade prevent tumor growth, adoptive T-cell therapy, immune checkpoint inhibitor treatment, and any combination thereof.

[0178] For instance, the immunomodulator can be:

[0179] - an immune checkpoint inhibitor (ICI), preferably an inhibitor of of PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand), PD-L2, CTLA-4 (cytotoxic T lymphocyte associated protein 4), TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), LAG-3 (Lymphocyte-activation gene 3), NKG2D, NKG2L, KIR, VISTA, BTLA (B- and T-lymphocyte attenuator), or TIGIT (T cell immunoreceptor with Ig and ITIM domains), , especially an antibody directed against an anti-CTLA-4 such as ipilimumab, an antibody directed against PD-1 such as nivolumab, pembrolizumab, orBGB-A317, an antibody directed against PDL1 such as atezolizumab, avelumab, or durvalumab, an antibody directed against LAG-3 such as BMS-986016, an antibody directed against TIM-3, an antibody directed against TIGIT, an antibody directed against BLTA, or a combination thereof; or

[0180] - an activator of a costimulatory molecule, in particular an agonist of 0X40, CD2, CD27, CDS, ICAM-1, LFA-1 (CDl la / CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD 160, B7-H3 or CD83 ligand; In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB- A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

[0181] Several anti -PD-1 antibodies are already clinically approved and others are still in clinical developments. For instance, the anti-PDl antibody can be selected from the group consisting of Pembrolizumab (also known as Keytruda®, MK-3475), Nivolumab (Opdivo®, MDX-1106, BMS-936558, ONO-4538), Pidilizumab (CT-011), Cemiplimab (Libtayo®), Camrelizumab, AUNP12, AMP-224, AGEN-2034, BGB-A317 (Tisleizumab), PDR001 (spartalizumab), MK- 3477, SCH-900475, PF-06801591, JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103 (HX-008), MEDL0680 (also known as AMP-514) MEDI0608, JS001 (see Si-Yang Liu et al., J. Hematol. Oncol.10: 136 (2017)), BI-754091, CBT- 501, INCSHR1210 (also known as SHR-1210), TSR-042 (also known as ANB011), GLS-010 (also known as WBP3055), AM-0001 (Anno), STI-1110 (see WO 2014 / 194302), AGEN2034 (see WO 2017 / 040790), MGA012 (see WO 2017 / 19846), or IBI308 (see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540), monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, described in WO 2006 / 121168. Bifunctional or bispecific molecules targeting PD-1 are also known such as RG7769 (Roche), XmAb20717 (Xencor), MEDI5752 (AstraZeneca), FS118 (F-star), SL-279252 (Takeda) and XmAb23104 (Xencor).

[0182] Antibodies directed against CTLA-4 and bifunctional or bispecific molecules targeting CTLA- 4 are also known such as ipilimumab, tremelimumab, MK-1308, AGEN-1884, XmAb20717 (Xencor), MEDI5752 (AstraZeneca). Antibodies directed against TIGIT are also known in the art, such as BMS-986207 or AB 154, BMS-986207 CPA.9.086, CHA.9.547.18, CPA.9.018, CPA.9.027, CPA.9.049, CPA.9.057, CPA.9.059, CPA.9.083, CPA.9.089, CPA.9.093, CPA.9.101, CPA.9.103, CHA.9.536.1, CHAN.536.3, CHA.9.536.4, CHA.9.536.5, CHA.9.536.6, CHA.9.536.7, CHA.9.536.8,

[0183] CHAN.560.1, CHAN.560.3, CHA.9.560.4, CHA.9.560.5, CHA.9.560.6, CHA.9.560.7,

[0184] CHAN.560.8, CHA.9.546.1, CHA.9.547.1, CHA.9.547.2, CHA.9.547.3, CHA.9.547.4,

[0185] CHAN.547.6, CHA.9.547.7, CHA.9.547.8, CHA.9.547.9, CHA.9.547.13, CHA.9.541.1,

[0186] CHAN.541.3, CHAN.541.4, CHA.9.541.5, CHA.9.541.6, CHA.9.541.7, and CHA.9.541.8 as disclosed in WO 19232484. Anti-TIGIT antibodies are also disclosed in WO 16028656, W016106302, WO16191643, W017030823, W017037707, WO17053748, WO17152088, WO18033798, WO18102536, WO18102746, W018160704, W018200430, WO18204363, W019023504, WO19062832, WO19129221, WO19129261, WO19137548, WO19152574, WO19154415, WO19168382 and WO19215728.

[0187] The LAG-3 inhibitor can be selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro). Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008 / 132601, WO 2010 / 019570, WO 2014 / 140180, WO 2015 / 116539, WO 2015 / 200119, WO 2016 / 028672, US 9,244,059, US 9,505,839, which are incorporated herein by reference in their entirety.

[0188] The TIM-3 inhibitor can be MGB453 (Novartis) or TSR-022 (Tesaro). Further known anti- TIM-3 antibodies include those described, e.g., in WO 2016 / 1 1 1947, WO 2016 / 071448, WO 2016 / 144803, US 8,552,156, US 8,841,418, and US 9,163,087, which are incorporated herein by reference in their entirety.

[0189] Preferably, the immunotherapy is selected from the group consisting of ipilimumab, nivolumab, BGB-A317, pembrolizumab, atezolizumab, avelumab, or durvalumab, BMS-986016, and epacadostat, or any combination thereof.

[0190] Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting. EXAMPLES

[0191] Example A: Chemistry

[0192] General information

[0193] Melting points were determined on a Buchi melting point apparatus (BUCHI Corporation, New Castle, United States).

[0194] High-resolution mass spectrometry analyses were carried out at the Spectropole, Faculte des Sciences de Saint-Jerome (Marseille, France) with a mass spectrometer SYNAPT G2 HDMS Waters (Milford, MA, United States) equipped with an electrospray ionisation source (electrospray tension: 2.8 kV; orifice tension: 20 V; nebulisation gas flow (nitrogen): 100 L / h). Samples were dissolved in 300 pL of dichloromethane, diluted at 1 / 102 in methanol solution at 0.1 mM sodium chloride, and introduced into the ionisation source at 10 pL / min. High- resolution mass spectra were obtained with a time-of-flight (TOF) analyser. Exact mass measurements were repeated in triplicate with external calibration.

[0195] NMR spectra were recorded on a Bruker Avance NEO 400 MHz NanoBay spectrometer at the Faculte de Pharmacie of Marseille. ('H-NMR: reference CDCh = 7.26 ppm, reference DMSO- d6 = 2.50 ppm and13C-NMR: reference CDCh = 76.9 ppm, reference DMSO-d6 = 39.52 ppm). TLC was performed on 5 cm * 10 cm aluminium plates coated with silica gel 60F-254 (Merck) in an appropriate eluent. Visualization was performed with ultraviolet light (234 nm).

[0196] Reagents were purchased and used without further purifications from Sigma-Aldrich or Fluorochem.

[0197] Ultra-High Performance Liquid Chromatography (UHPLC) analyses were performed using an Agilent 1290 Series apparatus (binary pump G4220A, autosampler G1330B, column oven G1316C, photodiode array detector G4212A) at the Faculte de Pharmacie of Marseille. The system was piloted by OpenLAB CDS ChemStation Edition C.01.07 computer software. The chromatographic separation was achieved using a Zorbax Eclipse Plus C18 column 50 * 2.1 mm, 1.8 m Agilent (Santa Clara, CA, United States) protected by a Zorbax Eclipse Plus C18 (5 x 2.1 mm, 1.8 m) guard column. Water acidified with 0.1% of formic acid (v / v) as Solvent A, and acetonitrile acidified with 0.1% of formic acid (v / v) as Solvent B was used for the gradient elution at 0.5 mL.min'1. The gradient program was: 5% B (from 0 to 2.0 min), 5% to 100% B (from 2.0 min to 10.0 min), 100% B (from 10.0 min to 13.0 min with post time of 2.0 min). UV detection wave- length set at 254 nm and injection volume of 1.0 pL. LC-MS analyses were performed at the Faculty of Pharmacy in Marseille using a Thermo Scientific Accela High Speed LC System® coupled with a Thermo MSQ Plus® quadrupole mass spectrometer. The RP-HPLC column used was a Thermo Hypersil Gold® 50 x 2.1 mm (Cl 3), with 1.9 pm particle size. The parameters were as follows: execution time (min): 10.00; injection volume: 5.00 pL; channel: UV VIS l; wavelengths: 220 nm, 260 nm, 280 nm, and 300 nm .

[0198] General scheme for the synthesis of compounds 7-10, and 13

[0199] Scheme 1:

[0200] 1h at -25°C

[0201] 2h at rt.

[0202] General synthesis procedure for compounds 1, 2a, 2b, and 3.

[0203] To appropriate chloro substituted diaminobenzene (1 eq.) in ethanol was added pyruvic aldehyde (2 eq.). The reaction mixture was stirred overnight at room temperature. Then, the mixture was extracted in dichloromethane (3 x 40 mL) and washed with H2O (3 x 40 mL) before being dried with sodium sulfate.

[0204] Compound 1 was purified by flash chromatography puriFlash®. Diastereoisomers 2a and 2b were not separated at this point but the mixture of both was purified by flash chromatography puriFlash®. Diastereoisomers 3a and 3b were purified by flash chromatography puriFlash®.

[0205] 6,7-dichloro-2-methylquinoxaline 1 Yield = 60%, orange solid. 7-chloro-2-methylquinoxaline 2a and 6-chloro-2-methylquinoxaline 2b Yield = 75%, orange solid of racemic mixture.

[0206] 8-chloro-2-methylquinoxaline 3a

[0207] Yield = 80%, orange solid.

[0208] 5-chloro-2-methylquinoxaline 3b

[0209] Yield < 5%, orange liquid.

[0210] General synthesis procedure and characterisation of compounds 4, 5a, 5b, and 6.

[0211] To appropriate chloro substituted methylquinoxaline (1 eq.) in carbon tetrachloride was added A-bromosuccimide (2 eq.) and benzoyl peroxide (0.01 eq.). The reaction mixture was stirred for 8h at 80°C. Then, the mixture was extracted in di chloromethane (3 x 40 mL) and washed with H2O (3 x 40 mL) before being dried with sodium sulfate.

[0212] Compound 4 was purified by flash chromatography puriFlash®. Diastereoisomers 5a and 5b were purified by flash chromatography puriFlash®. Compound 6 was purified by flash chromatography puriFlash®.

[0213] 6,7-dichloro-2-(dibromomethyl)quinoxaline 4

[0214] Yield = 38%, white solid, mp = 184.1 °C

[0215] 'H-NMR (400 MHz, CDCh): 5 9.36 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 6.71 (s, 1H).

[0216] 13C-NMR (101 MHz, CDCh): 5 153.79, 145.59, 140.71, 138.22, 136.06, 135.91, 130.06, 129.84, 37.95.

[0217] HRMS-ESI m / z calcd for C9H4Br2C12N2 [M+Ag]+: 478.7128; Found: 478.7127.

[0218] 7-chloro-2-(dibromomethyl)quinoxaline 5a

[0219] Yield = 10%, white solid, mp = 146.8°C

[0220] 'H-NMR (400 MHz, CDC13): 5 9.37 (s, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.76 (q, J = 3.7 Hz, 1H), 6.74 (s, 1H).

[0221] 13C-NMR (101 MHz, CDCh): 5 153.02, 145.47, 142.28, 137.99, 137.20, 132.09, 130.68, 128.22, 38.27.

[0222] HRMS-ESI m / z calcd for C9H5Br2ClN2 [M+Ag]+: 444.7520; Found: 444.7519.

[0223] 6-chloro-2-(dibromomethyl)quinoxaline 5b Yield = 15%, white solid, mp = 120.8°C

[0224] 'H-NMR (400 MHz, CDCh): 5 9.36 (s, 1H), 8.08 (q, J = 5.7 Hz, 2H), 7.76 (q, J = 3.8 Hz, 1H),

[0225] 6.73 (s, 1H).

[0226] 13C-NMR (101 MHz, CDCh): 5 153.72, 144.64, 140.60, 139.84, 137.00, 132.19, 130.40, 128.41, 38.22.

[0227] HRMS-ESI m / z calcd for C9H5Br2ClN2 [M+Ag]+: 444.7520; Found: 444.7522.

[0228] 8-chloro-2-(dibromomethyl)quinoxaline 6

[0229] Yield = 53%, white solid mp = 154.1 °C

[0230] 'H-NMR (400 MHz, CDCh): 5 9.47 (s, 1H), 8.08 (q, J = 3.2 Hz, 1H), 7.92 (q, J = 3.0 Hz, 1H),

[0231] 7.74 (q, J = 5.3 Hz, 1H), 6.84 (s, 1H).

[0232] 13C-NMR (101 MHz, CDC13): 5 153.38, 145.70, 142.95, 136.16, 133.52, 131.04, 130.80, 128.30, 38.32.

[0233] HRMS-ESI m / z calcd for C9H5Br2ClN2 [M+H]+: 336.8559; Found: 336.8568.

[0234] General synthesis procedure and characterisation of compounds 7, 8, 9, 10, and 13 from TDAE reaction

[0235] To appropriate chloro substituted dibromomethylquinoxaline (1 eq.), 5-nitro-2-furaldehyde (2 eq.) and tetrakisdimethylaminoethylene (0.01 eq) were added in THF (20 mL) in a two-necked flask under inert gas. The reaction mixture was stirred for 1 h at 25 °C. Then, the mixture was extracted in ethyl acetate (3 x 40 mL) and washed with H2O (3 x 40 mL) before being dried with sodium sulfate. Each compound was then purified by flash chromatography puriFlash®.

[0236] 6,7-dichloro-2-(3-(5-nitrofuran-2-yl)oxiran-2- yl)quinoxaline (PEP67) 7

[0237] Yield = 10%, white solid, mp = 200.0°C

[0238] 'H-NMR (400 MHz, CDCh): 5 8.88 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.34 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 4.72 (d, J = 1.8 Hz, 1H), 4.42 (d, J = 1.8 Hz, 1H).

[0239] 13C-NMR (101 MHz, CDCh): 5 151.89, 150.37, 143.37, 141.47, 140.57, 135.84, 135.54, 130.10, 129.81, 112.78, 112.21, 59.13, 54.04. HRMS-ESI m / z calcd for C14H7CI2N3O4 [M+H]+: 351.9886; Found: 351.9886.

[0240] 7-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline (PEP70) 8

[0241] Yield = 15%, orange solid, mp = 199.6°C

[0242] 'H-NMR (400 MHz, CDCh): 5 8.88 (s, 1H), 8.09 (t, J = 4.5 Hz, 2H), 7.76 (q, J = 3.8 Hz, 1H), 7.34 (d, J = 3.7 Hz, 1H), 6.78 (d, J = 3.7 Hz, 1H), 4.73 (d, J = 1.8 Hz, 1H), 4.42 (d, J = 1.8 Hz, 1H).

[0243] 13C-NMR (101 MHz, CDC13): 5 152.07, 150.15, 142.49, 142.17, 141.35, 136.92, 131.77, 130.71, 128.13, 112.69, 112.22, 59.22, 54.03.

[0244] HRMS-ESI m / z calcd for CwHsCINsO4[M+Na]+: 340.0096; Found: 340.0098.

[0245] 6-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline (PEP71) 9

[0246] Yield = 13%, red solid, mp = 179.5°C

[0247] ‘H-NMR (400 MHz, CDCh): 5 8.90 (s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.77 (q, J = 3.8 Hz, 1H), 7.34 (d, J = 3.7 Hz, 1H), 6.78 (d, J = 3.7 Hz, 1H), 4.73 (d, J = 1.8 Hz, 1H), 4.43 (d, J = 1.8 Hz, 1H).

[0248] 13C-NMR (101 MHz, CDCh): 5 152.10, 149.35, 143.28, 143.05, 140.43, 136.66, 132.05, 130.47, 128.39, 112.66, 112.22, 59.23, 54.00.

[0249] HRMS-ESI m / z calcd for CwHsCINsCh [M+Na]+: 340.0096; Found: 340.0098.

[0250] 8-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline (PEP74) 10

[0251] Yield = 20%, white solid, mp = 198.1°C

[0252] 'H-NMR (400 MHz, CDC13): 5 8.85 (s, 1H), 8.02 (q, J = 3.2 Hz, 1H), 7.86 (q, J = 2.9 Hz, 1H), 7.68 (q, J = 5.4 Hz, 1H), 7.27 (d, J = 3.7 Hz, 1H), 6.71 (d, J = 3.7 Hz, 1H), 4.78 (d, J = 1.8 Hz, 1H), 4.37 (d, J = 1.8 Hz, 1H).

[0253] 13C-NMR (101 MHz, CDC13): 5 152.08, 149.88, 143.71, 142.69, 138.71, 133.13, 130.85, 130.33, 128.60, 112.64, 112.23, 59.56, 54.24.

[0254] HRMS-ESI m / z calcd for CwHsCINsC [M+Na]+: 318.0276; Found: 318.0277.

[0255] 6,7-difluoro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline (PEP77) 13

[0256] Yield =19 % Yellow solid, mp =183 °C

[0257] ‘H NMR (400 MHz, CDC13) 5 8.88 (s, 1H), 7.87 (ddd, J= 20.8, 10.2, 8.1 Hz, 2H), 7.34 (d, J= 3.1 Hz, 1H), 6.78 (d, J = 3.1 Hz, 1H), 4.72 (d, J= 1.9 Hz, 1H), 4.42 (d, J= 1.8 Hz, 1H)13C NMR (101 MHZ, CDCI3) 5 154.53 (d, J= 14.3 Hz), 154.32 (d, J= 20.1 Hz), 151.91 (d, J= 19.3 Hz), 151.68 (d, J = 21.9 Hz), 149.67, 149.64, 142.78, 142.75, 140.39 (d, J = 10.8 Hz), 139.52 (d, J= 10.9 Hz), 115.34 (dd, J= 17.2, 1.7 Hz), 115.03 (dd, J = 17.3, 1.9 Hz). 59.23, 54.15

[0258] HRMS (ESI-TOF) m / z : [M+H]+calculated C14H7F2N3O, 342.0297, found 342.0293

[0259] In a dry vial, the methyl-substituted azaheterocycle (quinoxaline, quinoline, isoquinoline, or quinazoline) (1 eq.), the corresponding aldehyde (1.5 eq.), and TFA (10 mol%) are dissolved in dry toluene under a nitrogen (N2) atmosphere. Iron(II) acetate (10 mol%) is then added. The reaction mixture is stirred at 120°C for 12 hours. After cooling to room temperature, the mixture is filtered. The obtained filtrate is purified by silica gel chromatography using a dichloromethane / EYO mixture (95:5) as eluent.

[0260] 2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline (PEP78) 14

[0261] Yield = 63% Yellow solid, mp = 225°C

[0262] ‘HNMR (400 MHz, CDCh) 5 8.96 (s, 1H), 8.08 (t, J = 8.9 Hz, 2H), 7.77 (dd, J = 15.7, 8.9 Hz, 3H), 7.61 (d, J = 15.7 Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 6.75 (d, J = 3.7 Hz, 1H)13C NMR (101 MHZ, CDCh) 5 154.91, 148.98, 145.63, 142.99, 142.73, 131.20, 130.73, 129.93, 129.88, 129.77, 121.30, 114.10, 113.94

[0263] HRMS (ESI-TOF) m / z : [M+H]+calculated C14H9N3O3, 268.0717, found, 268.0717

[0264] 8-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline (PEP79) 15

[0265] Yield = 57% Yellow solid, mp = 216°C

[0266] 'H NMR (400 MHz, CDCh) 5 9.00 (s, 1H), 8.02 (m, 3H), 7.85 (d, J = 15.8 Hz, 1H), 7.65 (d, J = 15.8 Hz, 1H ), 7.40 (d, J = 3.8 Hz, 1H), 6.80 (d, J = 3.8 Hz, 1H)

[0267] 13C NMR (101 MHZ, CDCh) 5 154.28, 148.88, 145.71, 143.13, 139.35, 133.36, 130.67, 129.82, 128.87, 128.41, 121.93, 113.98, 113.63

[0268] HRMS (ESI-TOF) m / z : [M+H]+calculated C14H8CIN3O3, 302.0327, found, 302.0330

[0269] 6,7-dichloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline (PEP80) 16 Yield = 51% Yellow solid, mp = 242°C

[0270] ‘HNMR (400 MHz, CDCh) 5 8.93 (s, 1H), 8.20 (s, 2H), 7.76 (d, J = 15.8 Hz, 1H), 7.57 (d, J =

[0271] 15.8 Hz, 1H), 7.40 (d, J = 3.8 Hz, 1H), 6.79 (d, J = 3.8 Hz, 1H)

[0272] 13C NMR (101 MHz, CDCh) 5 153.87, 149.29, 146.03, 141.14, 140.71, 135.32, 134.66, 129.76 (2C), 128.31, 121.66, 113.93, 113.38

[0273] HRMS (ESI-TOF) m / z : [M+H]+calculated C14H7CI2N3O3, 335.9937, found, 335.9933

[0274] 2-chloro-3-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline (PEP81) 17

[0275] Yield = 40% Yellow solid, mp =233 °C

[0276] ‘H NMR (400 MHz, CDCh) 5 8.11 (m, 1H), 8.04 (m, 1H), 7.95 (d, J = 15.6 Hz, 1H), 7.88 (d, J = 15.6 Hz, 1H), 7.83 (m, 2H), 7.40 (d, J = 3.8 Hz, 1H), 6.81 (d, J = 3.8 Hz, 1H)13C NMR (101 MHz, CDCh) 5 154.22, 146.72, 146.63, 141.50, 141.00, 131.05, 130.60, 128.97, 128.12, 125.98, 122.84, 113.99, 113.40

[0277] HRMS (ESI-TOF) m / z : [M+H]+calculated C14H8CIN3O3, 302.0327, found, 302.0326

[0278] 6,7-difluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline (PEP82) 18

[0279] Yield =45 % Yellow solid, mp = 207°C

[0280] ‘H NMR (400 MHz, CDCh) 5 8.92 (s, 1H), 7.82 (ddd, J= 13.8, 10.3, 8.2 Hz, 2H), 7.75 (d, J= 15.9 Hz, 1H), 7.58 (d, J= 15.9 Hz, 1H), 7.40 (d, J= 3.8 Hz, 1H), 6.77 (d, J= 3.8 Hz, 1H)13C NMR (101 MHz, CDCh) 5 154.34, 154.29, 148.88 (d, J= 3.1 Hz), 146.26 (d, J= 3.1 Hz), 145.48, 145.45, 140.15 (d, J= 10.8 Hz), 139.73 (d, J= 10.4 Hz), 128.76, 121.50, 115.21 (dd, J = 13.0, 1.6 Hz), 115.04 (dd, J= 13.0, 1.9 Hz), 113.99, 113.71

[0281] HRMS (ESI-TOF) m / z [M+H]+calculated C14H7F2N3O3, 304.0528, found, 304.0526

[0282] 2-(2-(5-nitrofuran-2-yl)vinyl)quinoline (PEP83) 19

[0283] Yield = 75% Yellow solid, mp =183 °C

[0284] 'H NMR (400 MHz, CDC13) 5 8.18 (dd, J = 8.5, 1.0 Hz, 1H), 8.08 (dd, J = 8.5, 1.0 Hz, 1H), 7.81 (dd, J = 8.4, 1.1 Hz, 1H), 7.74 (m, 1H), 7.62 (d, J = 7.4 Hz, 2H), 7.59 (m, 2H), 7.39 (d, J = 3.8 Hz, 1H), 6.70 (d, J = 3.8 Hz, 1H).

[0285] 13C NMR (101 MHz, CDCI3) 5 155.37, 153.69, 148.47, 136.96, 133.63, 130.27, 129.65, 128.00, 127.74, 127.09, 120.99, 119.32, 113.97, 112.62.

[0286] HRMS (ESI-TOF) m / z : [M+H]+calculated C15H10N2O3, 267.0764, found, 267.0764

[0287] 4-(2-(5-nitrofuran-2-yl)vinyl)quinoline (PEP84) 20

[0288] Yield = 56% Yellow solid, mp =153°C

[0289] 'H NMR (400 MHz, CDC13) 5 8.94 (d, J = 4.6 Hz, 1H), 8.28 (m, 2H), 8.11 (d, J = 16.1 Hz, 1H), 7.78 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.66 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.57 (dd, J = 4.6, 0.8 Hz, 1H), 7.41 (d, J = 3.8 Hz, 1H), 7.14 (d, J = 16.1 Hz, 1H), 6.70 (d, J = 3.8 Hz, 1H)

[0290] 13C NMR (101 MHz, CDC13) 5 154.31, 149.84, 148.58, 140.62, 130.06, 129.67, 128.06, 127.09, 125.81, 123.09, 119.80, 116.87, 113.51, 112.37

[0291] HRMS (ESI-TOF) m / z : [M+H]+calculated C15H10N2O3, 267.0764, found 267.0764 l-(2-(5-nitrofuran-2-yl)vinyl)isoquinoline (PEP85) 21 Yield = 77% Yellow solid, mp =199°C

[0292] ‘HNMR (400 MHz, CDCh) 5 8.57 (m, J = 5.6 Hz, 1H), 8.40 (dd, J = 7.5, 1.1 Hz, 1H), 8.26 (d, J = 15.4 Hz, 1H), 7.89 (m, 1H), 7.82 (d, J = 15.4 Hz, 1H), 7.76 (m, 2H), 7.64 (dd, J = 7.5, 1.1 Hz, 1H), 7.40 (d, J = 3.8 Hz, 1H), 6.68 (d, J = 3.8 Hz, 1H)

[0293] 13C NMR (101 MHZ, CDCh) 5 155.21, 152.17, 142.39, 136.60, 130.11, 127.68, 127.39, 127.22, 126.93, 123.97, 121.18, 120.13, 113.77, 113.07

[0294] HRMS (ESI-TOF) m / z : [M+H]+calculated C15H10N2O3, 267.0764, found 267.0764

[0295] 7-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline (PEP 86) 22

[0296] Yield = 41% Yellow solid,

[0297] 'H NMR (400 MHz, DMSO-d6) 5 8.45 (d, J = 8.5 Hz, 1H), 8.02 (m, 2H), 7.95 (d, J = 8.5 Hz, 1H), 7.80 (m, 2H), 7.68 (m, 2H), 7.24 (d, J = 3.8 Hz, 1H)

[0298] 13C NMR (101 MHz, DMSO-d6) 5 154.56, 154.46, 151.03, 147.50, 136.67, 134.28, 132.16, 129.47, 127.01, 126.95, 125.63, 120.89, 120.11, 114.92, 114.05

[0299] HRMS (ESI-TOF) m / z : [M+H]+calculated C15H9CIN2O3, 301.0374, found 301.0374.

[0300] 6-fluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline (PEP87) 23

[0301] Yield = 42% Yellow solid, mp =192°C

[0302] 'H NMR (400 MHz, DMSO-d6) 5 8.43 (d, J = 8.6 Hz, 1H), 8.08 (dd, J = 9.3, 5.4 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.85 (m, 3H), 7.72 (td, J = 9.3, 5.4, 3.9 Hz, 1H), 7.58 (d, J = 16.2 Hz, 1H), 7.23 (d, J = 3.9 Hz, 1H)

[0303] 13C NMR (101 MHz, DMSO-d6), 158.93, 155.15, 153.50, 151.64, 144.61, 137.08, 132.60, 131.65, 128.40, 121.78, 120.68, 120.39, 115.59, 114.59, 111.34.

[0304] HRMS (ESI-TOF) m / z : [M+H]+calculated C15H9FN2O, 285.0670, found 285.0668.

[0305] 6-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline (PEP 88) 24

[0306] Yield = 16% Yellow solid, mp =211 °C

[0307] 'H NMR (400 MHz, DMSO-d6) 5 8.45 (d, J = 8.5 Hz, 1H), 8.02 (m, 2H), 7.95 (d, J = 8.5 Hz, 1H), 7.80 (m, 2H), 7.68 (m, 2H), 7.24 (d, J = 3.8 Hz, 1H)

[0308] 13C NMR (101 MHz, DMSO-d6) 5 154.56, 154.46, 151.03, 147.50, 136.67, 134.28, 132.16, 129.47, 127.01, 126.95, 125.63, 120.89, 120.11, 114.92, 114.05

[0309] HRMS (ESI-TOF) m / z : [M+H]+calculated C15H9CIN2O3, 301.0374, found 301.0373

[0310] 4-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline (PEP89) 25

[0311] Yield = 32% Yellow solid, mp =213°C

[0312] XH NMR (400 MHz, DMSO-d6) 5 8.23 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.93 (m, 2H), 7.81 (d, J = 3.9 Hz, 1H), 7.76 (m, 1H), 7.57 (d, J = 16.2 Hz, 1H), 7.24 (d, J = 3.9 Hz, 1H)

[0313] 13C NMR (101 MHz, DMSO-d6) 5 154.71, 154.17, 151.49, 148.32, 141.84, 131.79, 131.34, 129.51, 128.37, 124.94, 123.62, 120.94, 120.86, 115.30, 114.71

[0314] HRMS (ESI-TOF) m / z : [M+H]+ calculated C15H9CIN2O3, 301.0374, found 301.0372

[0315]

[0316] Compounds 26-27 were prepared in two steps starting from their ethylenic analogue.

[0317] In the first step, 600 mg (1 eq.) of the corresponding 2-(5-nitrofuran-2-yl)ethenylquinoxaline derivative was dissolved in 10 mL of acetic acid in a 100 mL flask equipped with a condenser. A solution of 0.23 mL of bromine in 10 mL of acetic acid was then added dropwise. The reaction was stirred at room temperature for 4 hours, after which the reaction mixture was poured into water. The resulting precipitate was collected by filtration, washed with water, and dried. In the second step, 500 mg (1 eq.) of the precipitate obtained was dissolved in 10 mL of acetonitrile in a 100 mL flask. A solution of 300 mg of NaOH in 10 mL of water was then added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted three times with dichloromethane, and the combined organic layers were washed three times with water, dried over MgSCL, and concentrated under reduced pressure. The product was purified by silica gel chromatography using a dichloromethane / diethyl ether mixture.

[0318] 2-((5-nitrofuran-2-yl)ethynyl)quinoxaline (PEP90) 26

[0319] Yield = 22% Yellow solid, mp =203 °C 'H NMR (400 MHz, CDCh) 5 9.01 (s, 1H), 8.16 (m, 2H), 7.84 (m, 2H), 7.37 (d, J = 3.8 Hz, 1H), 7.01 (d, J = 3.8 Hz, 1H)

[0320] 13C NMR (101 MHz, CDCh) 5 146.80, 142.35, 141.62, 137.78, 137.47, 131.69, 131.36, 129.58, 119.92, 112.33, 93.80, 80.24

[0321] HRMS (ESI-TOF) m / z : [M+H]+calculated C14H7N3O3, 266.0560, found 266.0569

[0322] 6,7-difluoro-2-((5-nitrofuran-2-yl)ethynyl)quinoxaline (PEP91) 27

[0323] Yield =25 % Yellow solid, mp =204°C

[0324] XH NMR (400 MHz, CDCh) 8.99 (s, 1H), 7.87 (ddd, J= 12.1, 10.1, 8.1 Hz, 2H), 7.38 (d, J = 3.8 Hz, 1H), 7.03 (d, J= 3.8 Hz, 1H).

[0325] 13C NMR (101 MHz, CDCh) 5 154.81 (d, J = 2.8 Hz), 154.65 (d, J= 3.0 Hz), 152.23 (d, J = 1.5 Hz), 152.07 (d, .7= 2.0 Hz), 139.88 (d, J= 10.9 Hz), 139.20 (d, J= 11.0 Hz), 137.74, 137.71, 137.5, 120.18, 115.43 (dd, J= 17.6, 1.8 Hz), 115.20 (dd, J= 17.6, 1.5 Hz), 112.28, 93.20, 80.95 HRMS (ESI-TOF) m / z : [M+H]+calculated C14H5F2N3O3, 324.0191, found, 324.0193

[0326] Example B: Biology

[0327] I. Material and Methods

[0328] Cell culture

[0329] Human HDMB-03 cells (RRID: CVCL S506), were kindly provided by the Institute for Research on Cancer and Aging (Nice, France). Human ONS- 76 (RRID: CVCL 1624) cell line was kindly provided by the Wolfson Childhood Cancer Research Center (New Castle, UK). RPE-1 cells (ref. CRL- 4000), U87-MG (ref. HTB-14) and U251-MG cells were purchased from the American Type Culture Collection, Rockville, MD, USA. All the cells were maintained at 37°C in a humidified atmosphere and 5% CO2. HDMB-03 cells were cultured in RPMI 1640 medium (Gibco, ref. 21875034) supplemented with 10% fetal bovine serum (FBS), 1% Non-Essential Amino Acids (Gibco, ref. 11140035) and of 1% of 50 U / mL penicillin and 50 g / mL streptomycin (PS). ONS-76 cells were grown in RPMI 1640 medium supplemented with 10% FBS and 1% PS. U87-MG and U251- MG were cultured as monolayers in Dubelcco’s modified Eagle’s medium (DMEM, Life technologies, Saint Aubin, France) supplemented with 10% FBS, and 1% PS. RPE-1 cells were grown in DMEM F-12 medium supplemented with 10% FBS and 1% PS. A mtDsRed plasmid has been transfected in each cell line using Lipofectamine 2000 (Invitrogen, ref. 11668019) following the manufacturer’s protocol. Stable transfectants were obtained after geneticin selection (0.8 mg / mL, Gibco, ref. 10131035) and two cycles of fluorescence-activated cell sorting (FACS). Cell cultures between 3 and 17 passages from defrosting were used for all bioassays.

[0330] Compounds

[0331] Stock solutions of compounds of the invention at 50, 25 and 10 mM were prepared in dimethylsulfoxide (DMSO; Sigma-Aldrich, Saint-Quentin-Fallavier, France) according to the solubility of the compounds. The purity of all compounds was determined over 95% before testing, by integration on1H-NMR spectra, and confirmed by UHPLC as previously described methodology. Stock solutions were aliquoted and stored at 20°C. For culture and experiments in living cells, the drugs were freshly diluted at an appropriate concentration in a culture medium.

[0332] Alamar Blue cellular viability assay

[0333] Exponentially growing cells (15,625 cells / cm2for RPE-1, 6,250 cells / cm2for ONS-76, 28,125 cells / cm2for HDMB-03, and 9,375 cells / cm2for U87-MG and U251-MG respectively) were detached with 20% trypsin Fisher GibcoTM (Waltham, MA, USA) and seeded by 100 L / well of a 96-well plate (Falcon® 96-well Clear Flat Bottom TC-treated Culture Microplate) for 24h for all cell lines. After this incubation period, 100 pL of appropriate concentrations of freshly diluted compounds, or fresh culture medium for control wells and blanks, were added. Each of the concentration points of the dilution range was iterated at least 3 times (triplicates). The maximum tested concentration of each drug was calculated to avoid more than l%o DSMO at the highest concentration, which could have an impact on cell viability. After 72h of drug treatment, 20 pL of Alamar blue were added in each well, and cells were incubated at 37°C for 5h. Finally, cell fluorescence was measured with a PHERAstar Omega BMG LABTECH plate reader. At least three in-dependent experiments (in triplicate) were performed, and data were expressed as mean ± SD. Spheroids

[0334] DsRed-expressing cells were plated in round bottom 96-well microplates (1,200 cells / well for HDMB-03, 2,000 cells / well for ONS-76, 1,000 cells / well for U87-MG, and 1,500 cells / well for U251-MG) in appropriate culture medium containing 10% FBS and 20% methyl cellulose (Sigma-Aldrich, ref. M7027) for 72h. Spheroids were then treated with appropriate concentrations of freshly diluted drugs, or fresh culture medium for control wells and blanks. Spheroid growth was quantified over time for 14 days by acquisition of DsRed fluorescence signal using the PHERAstar FS multi-plate reader (ex 580 nm / em 620 nm - “well scanning” mode 10 x 10). Images were captured with the JuLITM Stage live imaging system (Nano- Entek). Spheroid cell viability was measured at the end of the 14 days by the alamar blue assay after overnight incubation of 20 pL Alamar blue at 37°C.

[0335] Organotypic models

[0336] Experimental procedure for organotypic models followed previous work from our laboratory. Slices were exposed to a con- centration of 1 or 5 pM of PEP67 two times a week. Tumour growth and invasion within the slices were analysed over time, using the JuLITM Stage imaging system (lex 580 nm / lem 620 nm - image acquisition with a 4X objective and automated stitching 5 x 6 images) and the PHERAstar® FS multi-plate reader (lex 580 nm / lem 620 nm - fluorescence signal acquisition with a 15 x 15 matrix scanning mode).

[0337] II. Results

[0338] The compounds of the invention exhibit selective and potent activity against MB and GB cells.

[0339] The Alamar Blue cellular viability assay was used to evaluate the cytotoxicity of compound of the invention on MB and GB cells. The results yielded valuable insights into the compounds efficacy and selectivity as potential anticancer agents. Notably, the compounds exhibited varying degrees of dose-dependent cytotoxicity after 72h of treatment against MB and GBM cells, with ICso values - i.e., concentrations that reduce cell survival by 50% - providing an indicator of their potency (Figure 1). The highest dose tested for all compounds was 25 pM except for PEP67 and PEP70 which highest dose was reduced to 10 pM and 15 pM, respectively, due to solubility issues. Among the MB cells, the compounds of the invention displayed lower IC50 values than XK469 and CQS (Table 1). The highest dose tested for these compounds did not allow us to determine their respective IC50 on these MB cells. PEP67 demonstrated the highest degree of cytotoxicity, with IC50 values close to 1 pM.

[0340] Table 1: IC50 (pM) values and selectivity index (SI) of tested drugs after 72h of treatment of human MB cells (HD-MB03, ONS-76) and normal epithelial cells (RPE-1), determined by 4- parameters logistic regression. Values are the average of at least three independent experiments ± SD.

[0341] HD-MB03 SI ONS-76 SI RPE-1

[0342] M44-F2 4.84 ± 1.13 2.74 6.06 ± 0.62 2.18 13.24 ± 4.21

[0343] PEP38F1 2.76 ± 1.14 5.90 3.81 ± 0.79 4.27 16.27 ± 1.79

[0344] PEP70 2.92 ± 0.44 > 5 2.26 ± 1.07 > 6 > 15

[0345] PEP71 4.53 ± 1.55 3.13 3.63 ± 1.45 3.91 14.20 ± 0.49

[0346] PEP74 4.45 ± 1.41 3.94 4.54 ± 1.63 3.86 17.54 ± 2.73

[0347] PEP67 1.00 ± 0.27 > 10 1.23 ± 1.06 > 8 > 10

[0348] XK-469 > 25 > 25 NA

[0349] CQS > 25 > 25 NA

[0350] In GB cells, the compounds of the invention displayed cytotoxicity patterns analogous to those observed in medulloblastoma, with competitive IC50 values (Table 2). Notably, PEP67 again exhibited one of the highest cytotoxicity with IC50 below the micromolar range, highlighting its potential as promising candidate for further development.

[0351] Table 2: IC50 (pM) values and selectivity index (SI) of tested drugs after 72h of treatment of human GB cells (U87-MG, U251-MG) and normal astrocytes (C8-D1A), determined by 4- parameters logistic regression. Values are the average of at least three independent experiments ± SD.

[0352] The compounds of the invention have antiproliferative and antimigratory properties in GBM and MB tumor spheroids. The investigation of the anticancer potential of the quinoxaline derivatives was extended to three-dimensional (3D) spheroid models, aiming to mimic the complex architecture of tumor masses more accurately. Spheroids consisting of DsRed-expressing MB and GB cells were exposed to the compounds of the invention once at the beginning of the experiment, and tumor progression was monitored for 14 days. Fluorescence signal acquisition revealed that each of the tested molecules exerted a concentration-dependent inhibitory effect on spheroid growth over time.

[0353] PEP67 emerged as the most active compound across all 3D models, consistently demonstrating a substantial reduction in spheroid growth. Moreover, treatment with PEP67 significantly prevented cancer cell migration in invasive models (ie., ONS-76 and U251-MG), underscoring its ability to impede tumor progression in this physiologically relevant context. The efficacy of PEP67 in inhibiting the progression of both invasive models and tumor growth suggests its potential as a potent anticancer agent.

[0354] To further assess the cytotoxicity of these compounds within the 3D spheroid models, an Alamar Blue assay was conducted at completion of the experiment (14 days) and ICso values were determined. Once again, PEP67 exhibited the highest cytotoxicity against all four cell lines, with ICso values of 4.91 ± 3.09 pM in HD-MB03, 0.35 ± 0.03 pM in ONS-76, 1.06 ± 0.4 in U251-MG, and 1.99 ± 1.54 pM in U87-MG. In contrast, the unchlorinated quinoxaline M44- F2 showed lower cytotoxicity, highlighting the benefits of the halogen in the activity for the epoxide series. Though, cytotoxicity of PEP38F1 was lost in GB cells (ICso > 25 pM) and reduced in ONS- 76 MB cells, showing us that the position of the chlorine atom has also its role to play in biological activity of the quinoxalines in epoxide series. These comprehensive findings collectively highlight the potential of PEP67 as an anticancer agent in both spheroid growth and migration inhibition, and cytotoxicity. The results also underscore the significance of conducting assessments in physiologically relevant 3D models, providing a bridge between traditional cell-based assays and more complex in vivo systems.

[0355] To further evaluate the anticancer potential of PEP67 in a complex and physiologically relevant context, we used organotypic brain and cerebellum slices. Spheroids, representing DsRed- expressing MB and GB cells, were grafted onto these tissue slices to model tumor growth.

[0356] Slices were maintained with drug-free medium, and 5 pM PEP67 containing medium for control and treated conditions, respectively. Drug exposure of grafted slices confirmed the potential of PEP67 as an anticancer candidate by reducing tumor growth and invasion across brain and cerebellum tissues.

Claims

CLAIMS1. A compound of formula (F):wherein: A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen, and B represents, -CH=CH-, or -C=C-,with the proviso that when B represents O , A is a 5-10 heteroaryl substituted by at least one halogen, and with the proviso that said compound is not 2-chloro-3-[3-(5-nitrofuran-2-yl)oxiran-2- yl] quinoxaline, and the isomers, stereoisomers and pharmaceutical acceptable salts thereof.

2. The compound according to claim 1, wherein A is a 5-10 heteroaryl selected in a group consisting of quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,8-naphtyridinyl, pyridinyl, and pyrazinyl, said 5-10 heteroaryl is optionally substituted by at least one halogen.

3. The compound according to claim 1 or 2, wherein the halogen is chorine, fluorine, bromine, iodine, preferably chlorine or fluorine.

4. The compound according to any one of claims 1 to 3, wherein said compound has the following formula (I):wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom substituted by at least one halogen, with the proviso that said compound is not 2-chloro-3-[3-(5-nitrofuran-2-yl)oxiran-2- yl]quinoxaline.

5. The compound according to any one of claim 1 to 4, wherein said compound has a formula selected in a group consisting of:wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine with the proviso that at least one chosen among Ri, R2, and R3 is a halogen, preferably a chlorine or a fluorine, or wherein Ri and R2 represent independently a hydrogenor a halogen, preferably a chlorine or a fluorine, with the proviso that at least one chosen among Ri and R2 is a halogen, preferably a chlorine or a fluorine.

6. The compound according to any one of claims 1 to 5, wherein said compound has the following formula:wherein Ri and R2 represent independently a hydrogen, a chlorine, or a fluorine, with the proviso that at least one chosen among Ri and R2 is a chlorine or a fluorine.

7. The compound according to any one of claims 1 to 3, wherein said compound has the following formula (II):wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

8. The compound according to any one of claims 1 to 3, and 7, wherein said compound has a formula selected in a group consisting of:wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

9. The compound according to any one of claims 1 to 3, 7, and 8, wherein said compound has the following formula:wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

10. The compound according to any one of claims 1 to 3, wherein said compound has the following formula (III):wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

11. The compound according to any one of claims 1 to 3, and 10, wherein said compound has a formula selected in a group consisting of:, wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

12. The compound according to any one of claims 1 to 3, wherein said compound has the following formula (IV):wherein A is a 5-10 heteroaryl comprising at least one nitrogen atom optionally substituted by at least one halogen.

13. The compound according to any one of claims 1 to 3, and 12, wherein said compound has a formula selected in a group consisting of:wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

14. The compound according to any one of claims 1 to 3, 12, and 13, wherein said compound has the following formula (IVa):wherein Ri, R2, and R3 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

15. The compound according to any one of claim 1 to 3, wherein said compound has the following formula (Ik):wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine with the proviso at least one chosen among Ri and R2 is a halogen, preferably chlorine or a fluorine; or the following formulae (Ilk), (Illk), and (IVk):wherein Xi and X2 represent independently C or N, and Ri and R2 represent independently a hydrogen or a halogen, preferably a chlorine or a fluorine.

16. The compound according to claim 1, wherein said compound is selected in a group consisting of:- 6,7-dichloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;- 7-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;- 6-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;- 8-chloro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;- 6,7-difluoro-2-(3-(5-nitrofuran-2-yl)oxiran-2-yl)quinoxaline;- 2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;- 8-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;- 6,7-dichloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;- 2-chloro-3-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;- 6,7-difluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoxaline;- 2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;- 4-(2-(5-nitrofuran-2-yl)vinyl)quinoline;- l-(2-(5-nitrofuran-2-yl)vinyl)isoquinoline;- 7-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline;- 6-fluoro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;- 6-chloro-2-(2-(5-nitrofuran-2-yl) vinyl)quinoline;- 4-chloro-2-(2-(5-nitrofuran-2-yl)vinyl)quinoline;- 2-((5-nitrofuran-2-yl)ethynyl)quinoxaline; and- 6,7-difluoro-2-((5-nitrofuran-2-yl)ethynyl)quinoxaline.

17. The compound according to any one of claims 1 to 16, for use as a medicine.

18. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 16, and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 18, for use for treating a cancer.

20. The pharmaceutical composition for use according to claim 19, wherein the cancer is selected in a group consisting of: myelofibrosis, acute lymphoblastic leukemia, acutemyeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, central nervous system cancer, peripheral nervous system cancer, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma.

21. The pharmaceutical composition for use according to claim 19 or 20, wherein the cancer is a central nervous system cancer or a peripheral nervous system cancer, preferably medulloblastoma, neuroblastoma, and glioblastoma, more preferably glioblastoma and medulloblastoma.

22. The pharmaceutical composition for use according to any one of claims 19 to 21, wherein said pharmaceutical composition is administered in combination with another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy.

23. The pharmaceutical composition for use according to any one of claims 19 to 22, wherein the compound is administered at a dose ranging from 0.001 mg / kg body weight to 100 mg / kg body weight.

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