Heterocyclic compounds as NUPR1 inhibitors for treating cancer

Abstract

The present invention relates to a compound of general formula (I), or the stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof. The invention also relates to the compound of general formula (I) or a pharmaceutical composition comprising the same, for use in a method for treating cancer.

Description

[0001] HETEROCYCLIC COMPOUNDS AS NUPR1 INHIBITORS FOR TREATING CANCER

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the field of medicine, in particular inhibitors of nuclear protein 1 (NUPR1) and their uses for treating cancer, including pancreatic cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] Pancreatic cancer has the highest mortality rate among all cancers, with a five-year relative survival rate of only 8%. It remains a significant concern in the global cancer burden1. According to Global Cancer Statistics 2020, 495,773 people were newly diagnosed with pancreatic cancer and 466,003 people died from this disease2. More than 90% of diagnosed pancreatic cancers cases are pancreatic ductal adenocarcinoma (PDAC). PDAC is normally treated with surgery, chemotherapy, and radiation therapy, but it is rarely curable. Less than 20% of PDAC patients can afford surgical removal of tumors due to late-stage detection or metastasis to other organs3,4. This makes chemotherapy become the primary treatment option for PDAC. The current first-line chemotherapy options include FOLFIRIN OX (5- fluorouracil, oxaliplatin, and irinotecan) and gemcitabine alone or in combination with nab-Paclitaxel5,6. However, the overall survival rate of PDAC patients remains poor and they are prone to relapse. Therefore, we urgently need to discover new therapeutic targets and drugs for this highly fatal disease.

[0006] The nuclear protein 1 (NUPR1) is an intrinsically disordered protein (IDP) that plays a crucial role in cellular stress7 7. Furthermore, NUPR1 is specifically overexpressed in PDAC compared to its negligible expression in normal tissues, highlighting NUPR1 as a potential therapeutic target in PDAC10. Numerous studies have demonstrated that NUPR1 is involved in various PDAC-related processes, including its occurrence, development and metastasis11. However, due to its disordered structure finding inhibitors for NUPR1 poses significant challenges to traditional structure -based drug design9, 12T To overcome these challenges, inventor have previously employed a mid-throughput screening procedure based on a thermal-shift assay, followed by computer modeling, chemical synthesis, biophysics, and biochemistry to develop ZZW-115, a potential NUPR1 inhibitor. This compound was able to effectively inhibit NUPR1, resulted in the suppression of tumor cell growth in vivo and in vitro16. However, as a trifluoperazine analogue, ZZW-115 has the potential to binds to the potassium ion channel encoded by the human Ether-a-go-go-Related Gene (hERG), leading to an inhibitory effect on this channel. As a results, there is a risk of cardiotoxicity associated with its use17,18. Specifically, trifluoperazine’s cardiotoxicity arises from its binding to the hERG, which blocks the fast delayed rectifier current I& of the heart. This therefore puts the patients at increased risk of experiencing torsades de pointes and even sudden death19,20.

[0007] For this reason, there is still a need to find and develop new NUPR1 inhibitors without cardiotoxicity effects. The present invention seeks to meet these and other needs. SUMMARY OF THE INVENTION

[0008] In this context, the inventors have provided NUPR1 inhibitors which exhibit a promising IC50 on several PDAC-derived as well as other cancer cell lines, with minimal binding to the hERG channel even at high concentrations. Notably, AJO compound primarily induced cell death through apoptosis and necroptosis, accompanied by mitochondrial metabolism failure resulting in a substantial decrease in ATP production.

[0009] The present invention thus provides new compounds of general formula (I), or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof: wherein: which the wave-shaped line indicates where said group is bound to X.

[0010] > Ri to R3 represent, independently of each other, a radical selected from a group consisting of:

[0011] • a hydrogen,

[0012] • a halogen,

[0013] • a(C1-C12) alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0014] • a C2-C6) alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0015] • a (Cj-Cslalkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,

[0016] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0017] • -NO2, and

[0018] • a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a (C1-C6)alkyl, a hydroxy, a halogen, a -SO2-(C1-C6)alkyl, and a (C1-C6)alkyloxy;

[0019] > R4, Rs and R7, independently of each other, represent a radical selected from a group consisting of:

[0020] • a hydrogen,

[0021] • a halogen,

[0022] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0023] • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0024] • a (C2-C6) alkynyl optionally substituted by a (C1-C6)alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,,

[0025] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0026] > R6 is a (C1-C6)alkyl optionally substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl; and

[0027] > X is -NHCONH- or -CONH-; provided that said compound is not a compound of following formula (AJO), (ED 18), (ED25), (LZX- 2-34), (LZX-2-40) or (IV): The invention also provides a pharmaceutical composition comprising a compound as defined herein, and a pharmaceutically acceptable excipient.

[0028] A further object of the invention is the compound as defined herein, for use as a medicine.

[0029] A further object of the invention is the compound as defined herein, or the pharmaceutical composition as defined herein, for use in a method for treating a cancer, in particular a cancer selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer, preferably for use in a method for treating a pancreatic cancer.

[0030] A further object of the invention is the compound as defined herein, or the pharmaceutical composition as defined herein, for use according to the invention, wherein the method comprises the combined administration of another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy, preferably immunotherapy; preferably the other antitumoral drug is sorafenib.

[0031] The invention further provides a compound of general formula (I), or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, for use in a method for treating a cancer, wherein formula (I) is: wherein: indicates where said group is bound to X.

[0032] > Ri to R3 represent, independently of each other, a radical selected from a group consisting of: • a hydrogen,

[0033] • a halogen,

[0034] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0035] • a C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,

[0036] • a C2-C6) alkynyl optionally substituted by a (1-6)alkvloxv. a hydroxy, at least one halogen, or a cycloalkyl,,

[0037] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0038] • -NO2, and

[0039] • a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a (C1-C6)alkyl, a hydroxy, a halogen, a -SO2- (C1-C6)alkyl, and a (C1-C6)alkyloxy;

[0040] > R4, R5 and R7, independently of each other, represent a radical selected from a group consisting of:

[0041] • a hydrogen,

[0042] • a halogen,

[0043] • a (C1-C12) alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0044] • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0045] • a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,

[0046] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0047] > R6 is a (C1-C6)alkyl optionally substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl; and

[0048] > X is -NHCONH- or -CONH-.

[0049] The present invention further relates to a combination product comprising:

[0050] (i) at least one compound of the invention, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising the same; and

[0051] (ii) sorafenib. BRIEF DESCRIPTION OF THE FIGURES

[0052] Figure 1. AJO compound inhibited pancreatic cancer proliferation in vitro due to NUPR1 inhibition. (A) IC5o of AJO on 1 NUPR1-WT clone and 2 NUPR1-KO clones treated for 72 h. (C) Viability of 11 primary patients-derived PDAC cell lines treated with AJO for 72 h. (D) Viability of cell lines HepG2, MDA-MB-231, H358, A375, HT29, U87, U2OS and PC-3 at increasing concentrations of AJO (n = 3).

[0053] Figure 2. AJO compound showed low hERG affinity. Representative graph of the concentrationresponse curve of E-4031, ZZW-115 and AJO for hERG binding using fluorescence polarization assay. Data are presented as mean ± SD, (n = 3).

[0054] Figure 3. AJO compound induces cancer cell death by necroptosis, apoptosis, and parthanatos. MIA PaCa-2 cells were treated with increasing concentrations of AJO for 24, 48 and 72 h and (A) LDH release and (B) caspase 3 / 7 activity were measured. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (2-way ANOVA, Dunnett’s test) (n = 3). (C) Flow cytometry analysis of annexin / PI staining following 24, 48 and 72 h of treatment with AJO. A representative experiment of the dot plot profile of cells is shown (n = 3). (D) Apoptotic rate, as the sum of the early apoptotic proportion and the late apoptotic / necrotic proportion * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (2 -way ANOVA, Dunnett’s test). (E) Viability upon a 24 h period of treatment with increasing concentrations of AJO in MIA PaCa-2 cells in the presence or absence of Z-VAD-FMK (20 pM), Nec-1 (40 pM), or Olaparib (25 pM). ** p < 0.01, *** p < 0.001, **** p < 0.0001 (1-way ANOVA, Dunnett’s test) (n = 3).

[0055] Figure 4. AJO compound treatment induced mitochondrial metabolic failure. (A) Total ATP content was measured in MIA PaCa-2 cells incubated with AJO for 24 h. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (2-way ANOVA, Dunnett’s test) (n = 3). Oxygen consumption rate was measured in MIA PaCa-2 cells using a Seahorse XF bioanalyzer after 24 h of treatment with increasing concentrations of AJO (B), and in the presence of AJO (10 pM) with increasing concentrations of Olaparib (C) (n = 3).

[0056] Figure 5. AJO compound treatment induced antitumoral effect in vivo. Crl:NU(Ico)-Fox«7"“ mice bearing pancreatic cancer MIA PaCa-2 cell lines xenograft were treated daily with the vehicle or 5, 10, 20 or 50 mg / kg AJO via i.p. administration (n = 5). A and B Tumor volume and (C) mice body weight were measured twice per week. * p < 0.05, *** p < 0.001, **** p < 0.0001 (1-way ANOVA, Dunnett’s test). (D) Representative images of tissues sections after TUNEL, Ki-67 or cleaved caspase-3 IHC staining of tumortissues are shown (n = 5) (scale bar: 100 pm).

[0057] Figure 6. LZX-2-73 and sorafenib combination showed synergistic anticancer effect. (A) Viability of MIAPaCa-2 cells upon a 72 hours treatment with sorafenib, LZX-2-73, or their combination. Data are shown as mean ± SEM. **** p < 0.0001 (1-way ANOVA, Dunnett’s test) (n = 4). (B) Representative images upon 78 hours of treatment with sorafenib, LZX-2-73, or their combination to MIAPaCa-2, HT- 29, MCF7, PDAC056T or PDAC088T cells (left) and the quantification of cell confluency in the images (right) by Incucyte device. Data are shown as mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (2-way ANOVA, Dunnett’s test) (n = 3), statistic shown on the last point of measurement. (C) Representative images upon 72 hours of treatment with sorafenib, LZX-2-73, ortheir combination to PDAC056T organoids and PDAC088T organoids (left) and the quantification of organoid diameters in the images (right). Data are shown as mean ± SEM. ** p < 0.01, *** p < 0.001, **** p < 0.0001 (1-way ANOVA, Dunnett’s test) (n = 3).

[0058] Figure 7. Synergistic antitumor effect of combined sorafenib and LZX-2-73 treatment in a tumor xenograft mouse model. Female Crl:NU(Ico)-Foxra7”“ mice implanted with pancreatic cancer MIAPaCa-2 cell lines xenografts and treated daily with sorafenib (25 mg / kg), LZX-2-73 (10 mg / kg), or a combination of both drugs (25 mg / kg + 10 mg / kg) via intraperitoneal injection. (A) Tumor volume were measured twice per week. Data are shown as mean ± SEM. * p < 0.05, **** p < 0.0001 (1-way ANOVA, Dunnett’s test). (B) Representative images of tissue sections following Ki-67 IHC staining and TUNEL assay from mice treated with sorafenib (25 mg / kg), LZX-2-73 (10 mg / kg), or their combination. Scale bar: 100 pm.

[0059] Figure 8. Combined sorafenib and LZX-2-73 treatment in a tumor xenograft mouse model induced no significant toxicity. Female Crl:NU(Ico)-Fox«7™ mice implanted with pancreatic cancer MIAPaCa-2 cell lines xenografts and treated daily with sorafenib (25 mg / kg), LZX-2-73 (10 mg / kg), or a combination of both drugs (25 mg / kg + 10 mg / kg) via intraperitoneal injection. (A) Body weight volume were measured twice per week. (B) Representative images of tissue sections following hematoxylin and eosin (H&E) staining of major organs from mice treated with sorafenib (25 mg / kg), LZX-2-73 (10 mg / kg), ortheir combination. Scale bar: 100 pm.

[0060] DETAILED DESCRIPTION OF THE INVENTION

[0061] Definitions

[0062] According to the present invention, the terms below have the following meanings:

[0063] The term “Cx-Cy” in which x and y are integers, as used in the present disclosure, means that the corresponding hydrocarbon chain comprises from x to y carbon atoms. If, for example, the term C1-C12 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 12 carbon atoms. If, for example, the term Ci-Ce is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C4 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 4 carbon atoms, especially 1, 2, 3 or 4 carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may compnse from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms. C0-C3 means that the corresponding hydrocarbon chain may comprise from 0 to 3 carbon atoms, especially 0, 1, 2 or 3 carbon atoms. In particular, when in the context of Co, the hydrocarbon chain is absent.

[0064] The term “alkyl” refers to a saturated, linear or branched aliphatic group. The term “(Cl-C6)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, butyl (n-butyl, i-butyl, sec-butyl and tert-butyl), pentyl, or hexyl. In a particular aspect, by “Me”, it refers to a methyl.

[0065] The term “alkenyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon double bound. The term “C2-C6 alkenyl” refers to an alkenyl having 2 to 6 carbon atoms. The term alkenyl (or C2-C6 alkenyl) includes for instance ethenyl, propenyl, butenyl, pentenyl, or hexenyl.

[0066] The term “alkynyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon triple bound. The term “C2-C6alkynyl” refers to an alkynyl having 2 to 6 carbon atoms. The term alkynyl (or C2-C6alkynyl) includes for instance ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

[0067] The term “alkoxy” or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -0- (ether) bond. (C1-C6)alkoxy or (C1-C6)alkyloxy includes methoxy or methyloxy, ethoxy or ethyloxy, propoxy or propyloxy, isopropoxy or isopropyloxy, butoxy or butyloxy, isobutoxy or isobutyloxy, pentoxy or pentyloxy, isopentoxy or isopentyloxy, and hexoxy or hexyloxy.

[0068] The term “3-14 membered ring” corresponds to a ring having between 3 and 14 atoms. Such a term includes, for instance, the term “5-14 membered ring” having between 5 and 14 atoms, and the term “5- 7 membered ring” having between 5 and 7 atoms. The term “ring” corresponds to a mono-, bi, or tricycle, which can be saturated, partially unsaturated or unsaturated, and optionally comprises at least one heteroatom. Particularly, the term “ring” includes a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl.

[0069] The term “cycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated mono-, bi- or tricyclic alkyl group comprising between 3 and 14, preferably between 3 and 10 atoms of carbons. It also includes fused, bridged, or spiro-connected cycloalkyl groups. The term “cycloalkyl” includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “spirocycloalkyl” includes for instance a spirocyclopentyl. In a particular aspect, the term “cycloalkyl” corresponds to a saturated monocycloalkyl group comprising between 3 and 7 atoms of carbons.

[0070] The term “heterocycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen (N- heterocycloalkyl), oxygen (O-heterocycloalkyl), or sulphur atom (S-heterocycloalkyl). An heterocycloalkyl is thus a saturated or unsaturated mono-, bi- or tri-cyclic group comprising between 5 and 20 cyclic atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulfur atom. It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to aziridinyl, azepanyl, diazepanyl, dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, phthalimidyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, pyrimidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiooxetanyl, thiopyranyl, thiomorpholinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, dihydrofuranyl, dihydrothiopyranyl, dihydrothiophenyl, dihydropiperidinyl, tetrahydropiperidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. In a particular aspect, the heterocycloalkyl group is for instance azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or pyrrolidinyl. In another particular aspect, the heterocycloalkyl group is morpholinyl.

[0071] "Cycloalkyl" and "heterocycloalkyl" also include cycloalkenyl and heterocycloalkenyl which correspond respectively to a partially unsaturated cycloalkyl and a partially unsaturated heterocycloalkyl such as cyclohexenyl, imidazolinyl, dihydropyranyl, for instance 3,6-dihydro-2H-pyranyl and 3,4- dihydro-2H-pyranyl, pyrazolinyl, azetinyl, pyranyl, and tetrahydropyridinyl, for instance 1,2, 3-6- tetrahydropyridinyl .

[0072] The term “aryl” corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term “aryl” includes phenyl, biphenyl, naphthyl and anthracenyl. In a particular embodiment, the aryl is a phenyl.

[0073] The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 5 and 14 cyclic atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulfur atom. As used herein, the term “heteroaryl” further includes the “fused arylheteroaryl”, “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl”. The terms “fused arylheteroaryl” may for instance include non-exhaustively quinolinyl, indole, or benzoxazole. The terms “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl” correspond to a bicyclic group in which an aryl as above defined or a heteroaryl is respectively bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons. In other terms, the aryl or the heteroaryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly-cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienopyridinyl, 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, benzothiazolyl, benzothiphenyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. In a particular aspect, the heteroaryl is for instance pyridinyl, pyrimidyl, 1,2,4-triazinyl or benzoxazolyl. In a particular aspect, the heteroaryl is for instance tetrazolyl or 1,2,3-trizolyl. In a particular aspect, the heteroaryl is for instance thiophenyl.

[0074] The term piperidinyl preferably encompasses 1-, 2-, 3- or 4-piperidinyl; considering that the 1- piperidinyl moiety refers to the piperidinyl moiety that is bound to the compound via the nitrogen atom.

[0075] The term pyridinyl preferably encompasses 2-, 3- or 4-pyridinyl, more preferably2-, 3- or 4-pyridinyl; considering that 1-pyridinyl moiety refers to the pyridinyl moiety that is bound to the compound via the nitrogen atom.

[0076] The term pyrrolidinyl preferably encompasses 1-, 2-, or 3-pyrrolidinyl; considering that the 1- pyrrolidinyl moiety refers to the pyrrolidinyl moiety that is bound to the compound via the nitrogen atom.

[0077] The term “fused” when applied to the description of two rings corresponds to a bicyclic group in which the first ring is respectively bounded to the second ring by at least two carbons.

[0078] The term “halogen” corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, chlorine or bromine.

[0079] The expression “substituted by at least” means that the radical is substituted by one or several groups of the list. For instance, the expression “a (C1-C6)alkyl substituted by at least one halogen, preferably a fluorine” may include a fluoromethyl (-CH2F), a difluoromethyl (-CHF2), or a trifluoromethyl (-CF3).

[0080] The expression “optionally substituted” means that the radical is not substituted or substituted by one or several groups of the list.

[0081] By “-CO-“ or “-C(O)-“, it refers to an oxo group. By “-SO-“ or “-S(O)-“, it refers to a sulfinyl group. By “-SO2-“ or “-S(O2)-“, it refers to a sulfonyl group.

[0082] 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. The “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons.

[0083] The “solvates” of the present disclosure include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. It can be for example an hydrate or an alcoholate such as an ethanolate.

[0084] The “hydrates” are compounds further comprising at least one molecule of water. For instance, if the compound comprises one molecule of water, it corresponds to a monohydrate form. If the compound comprises two molecules of water, it corresponds to a dihydrate form.

[0085] The “pharmaceutically salts” include 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, lactic, tartaric, methanesulfonic and the like. Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically 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. In a preferred embodiment, the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate. 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. Representative examples of suitable salts with an organic base includes for instance a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0086] 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.

[0087] As used herein, the terms “subj ecf ’, “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.

[0088] 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.

[0089] 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 disease or disorder, or to cure or to attenuate the effects of a disease or disorder; in particular, capable to prevent or to delay the appearance or development of a cancer, or to cure or to attenuate the effects of a cancer.

[0090] 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, etc. 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] In the context of the invention, the ranges of values expressed by “from X to XX” or “between X and XX” comprise the upper and lower limits.

[0097] New compounds of the invention

[0098] The present invention provides new compounds of the following formula (I), including the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, of therapeutic interest.

[0099] According to the invention, the compound has the following formula (I): indicates where said group is bound to X.

[0100] > Ri to Rg represent, independently of each other, a radical selected from a group consisting of:

[0101] • a hydrogen,

[0102] • a halogen,

[0103] • a(C1-C12) alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl, • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0104] • a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,

[0105] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0106] • -NO2, and

[0107] • a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a C1-C6alkyl . a hydroxy, a halogen, a -SO2-(C1-C6)alkyl, and a (C1-C6)alkyloxy;

[0108] > R4, R5 and R7, independently of each other, represent a radical selected from a group consisting of:

[0109] • a hydrogen,

[0110] • a halogen,

[0111] • a (C1-C6) alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0112] • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0113] • a C2-C6) alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,

[0114] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0115] > Rs is a (C1-C6)alkyl optionally substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl; and

[0116] > X is -NHCONH- or -CONH-.

[0117] In the context of the invention, the new compounds cannot be of following formula (AJO), (ED 18), (ED25), (LZX-2-34) or (LZX-2-40): and

[0118] In the context of the invention, the new compounds cannot be of following formula (IV): In the context of the invention, the compound of formula (I) is such that X is -NHCONH- or -CONH-. In a particular and preferred embodiment of the invention, the compound of formula (I) is such that X is -NHCONH-.

[0119] In another particular embodiment, the compound of formula (I) is such that X is -CONH-. In this embodiment, the nitrogen atom is preferably linked to the group A of formula (I). In the context of the invention, the compound of formula (I) is such that R is6 a (C1-C6)alkyl optionally substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl.

[0120] In a particular embodiment of the invention, R6 is a (C1-C6)alkyl optionally substituted with a 3-14 membered aryl group such as phenyl. Preferably, R6 is a (C1-C6)alkyl optionally substituted with a phenyl. Particularly, R6 is a methyl optionally substituted with a phenyl group, more preferably R i6s a methyl. In a particular embodiment, the compound of formula (I) is such that:

[0121] • X is -NHCONH-; and

[0122] • R6 is a methyl optionally substituted with a phenyl. In the context of the invention, the compound of formula (I) is such that A is: in which the wave-shaped line indicates where said group is bound to X.

[0123] The compound of formula (I) according to the invention can thus be of following formula (II) or (III):

[0124] In a particular and preferred embodiment, the compound of formula (I) is such that A is:

[0125] In another particular embodiment, the compound of formula (I) is such that A is: In a further particular embodiment, the compound of formula (I) is such that:

[0126] • X is -NHCONH-;

[0127] • R6 is a methyl optionally substituted with a phenyl; and

[0128] • A is of formula (Al).

[0129] In the context of the invention, when the compound of formula (I) is such that A is of formula (Al):

[0130] > Ri to R represent, independently of each other, a radical selected from a group consisting of:

[0131] • a hydrogen,

[0132] • a halogen,

[0133] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0134] • a C2-C6) alkenyl optionally substituted by a (C|-C, )alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,

[0135] • a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,

[0136] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0137] • -NO2, and

[0138] • a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a (C1-C6)alkyl, a hydroxy, a halogen, a -SO2-(C1-C6)alkyl, and a (C1-C6)alkyloxy; and

[0139] > R4 and R5, independently of each other, represent a radical selected from a group consisting of:

[0140] • a hydrogen,

[0141] • a halogen,

[0142] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0143] • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,

[0144] • a C2-C6) alkynyl optionally substituted by a (C1-C6)alkvloxv. a hydroxy, at least one halogen, or a cycloalkyl, and

[0145] • a (C1-C6)alkyloxy optionally substituted by at least one halogen.

[0146] In a particular embodiment, when the compound of formula (I) is such that A is of formula (Al), at least one of Ri to R5 are not hydrogen atom, particularly one, two or three of Ri to R5 are not hydrogen atom, preferably one or two of Ri to R5 are not hydrogen atom. In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R4 and R5 are hydrogen atoms. Preferably, R4 and R5 are hydrogen atoms, and at least one, preferably one or two, of Ri to R3 are not hydrogen atom.

[0147] In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R3 to R5 are hydrogen atom, and one or both of Ri and R2 are not hydrogen atom.

[0148] In a further particular embodiment, the compound of formula (I) is such that:

[0149] • X is -NHC0NH-;

[0150] • R„ is a methyl optionally substituted with a phenyl;

[0151] • A is of formula (Al);

[0152] • R4 and R5are hydrogen atoms; and

[0153] • at least one, preferably one or two, of Ri to R3 are not hydrogen atom.

[0154] In a further particular embodiment, the compound of formula (I) is such that:

[0155] • X is -NHCONH-;

[0156] • R<> is a methyl optionally substituted with a phenyl;

[0157] • A is of formula (Al);

[0158] • R3 to R5 are hydrogen atoms; and

[0159] • one or both of Ri and R2 are not hydrogen atom.

[0160] In a further particular embodiment, when the compound of formula (I) is such that A is of formula (Al), Ri to R3 represent, independently of each other, a radical selected from a group consisting of:

[0161] • a hydrogen,

[0162] • a halogen,

[0163] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0164] • a (C2-C6)alkenyl,

[0165] • a (C2-Cfi)alkynyl,

[0166] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0167] • -NO2, and

[0168] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that at least one, preferably one or two, of Ri to R3 is not a hydrogen atom.

[0169] In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R4 and R5 are hydrogen atoms, and Ri to R3 represent, independently of each other, a radical selected from a group consisting of:

[0170] • a hydrogen, • a halogen,

[0171] • a ( (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0172] • a (C2-C6)alkenyl,

[0173] • a (C2-C6)alkynyl.

[0174] • aC1-C6alkyloxy optionally substituted by at least one halogen,

[0175] • -NO2, and

[0176] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that at least one, preferably one or two, of Ri to R3 is not a hydrogen atom.

[0177] In a further particular embodiment, when the compound of formula (I) is such that A is of formula (Al), Ri and R2represent, independently of each other, a radical selected from a group consisting of:

[0178] • a hydrogen,

[0179] • a halogen,

[0180] • a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0181] • a (C2-C6)alkenyl,

[0182] • a (C2-C, )alkynyl.

[0183] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0184] • -NO2, and

[0185] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that one or both of Ri and R2is not a hydrogen atom.

[0186] In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R3to R5are hydrogen atoms, and Ri and R2represent, independently of each other, a radical selected from a group consisting of:

[0187] • a hydrogen,

[0188] • a halogen,

[0189] • a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0190] • a (C2-C6)alkenyl,

[0191] • a (C2-C6)alkynyl,

[0192] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0193] • -NO2, and

[0194] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that one or both, of Ri and R2is not a hydrogen atom. In a preferred embodiment, when the compound of formula (I) is such that A is of formula (Al), Rs to Rs are hydrogen atoms, and Ri and R2 represent, independently of each other, a radical selected from a group consisting of:

[0195] • a hydrogen,

[0196] • a halogen,

[0197] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0198] • a (C2-C6)alkenyl,

[0199] • a C2-C6) alkynyl,

[0200] • a (C1-C6)alkyloxy,

[0201] • -NO2,

[0202] • a (C3-C6) cycloalkyl; and

[0203] • a phenyl provided that one or both of R1 and R2 is not a hydrogen atom.

[0204] In a further particular embodiment, the compound of formula (I) is such that:

[0205] • X is -NHCONH-;

[0206] • R6 is a methyl optionally substituted with a phenyl;

[0207] • A is of formula (Al);

[0208] • R4 and R5 are hydrogen atoms;

[0209] • At least one, preferably one or two, of Ri to R3 are not hydrogen atom; and

[0210] • Ri to R3 represent, independently of each other, a radical selected from a group consisting of: o a hydrogen, o a halogen, o a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl, o a C2-C6) alkenyl, o a C2-C6) alkynyl, o a (C1-C6)alkyloxy, o -NO2, o a (C3-C6) cycloalkyl; and o a phenyl.

[0211] In a further particular embodiment, the compound of formula (I) is such that:

[0212] X is -NHC0NH-; R6 is a methyl optionally substituted with a phenyl; • A is of formula (Al);

[0213] • R3to R5are hydrogen atoms;

[0214] • one or both of R1 and R2are not hydrogen atom; and

[0215] • Ri and R2represent, independently of each other, a radical selected from a group consisting of: o a hydrogen, o a halogen, o a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl, o a (C2-C6)alkenyl, o a (C2-C6)alkynyl, o a (C1-C6)alkyloxy, o -NO2, o a (C3-C6) cycloalkyl; and o a phenyl.

[0216] In the context of the invention, when the compound of formula (I) is such that A is of formula (A2) or (A2’), R? is a radical selected from the group consisting of:

[0217] • a hydrogen,

[0218] • a halogen,

[0219] • a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,

[0220] • a (C2-C6)alkenyl optionally substituted by a (C1-C6) alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,

[0221] • aC2-C6) alkynyl optionally substituted by a (C1-C6) alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl, and

[0222] • a (C1-C6)alkyloxy optionally substituted by at least one halogen.

[0223] In a particular embodiment, when the compound of formula (I) is such that A is of formula (A2) or (A2’), R? is a radical selected from the group consisting of:

[0224] • a hydrogen,

[0225] • a halogen,

[0226] • a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0227] • a (C2-C6)alkenyl,

[0228] • a (C2-C6)alkynyl, and

[0229] • a (C1-C6 )alkyloxy optionally substituted by at least one halogen. Preferably, R? is a hydrogen, a halogen, or a (C1-C6)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a (C3-C6)cycloalkyl. More preferably, R7 is a hydrogen, a halogen or CF3, particularly CF3.

[0230] In a further particular embodiment, the compound of formula (I) is such that:

[0231] • X is -NHCONH-;

[0232] • R6 is a methyl optionally substituted with a phenyl;

[0233] • A is of formula (A2) or (A2’); and

[0234] • R7is a hydrogen, a halogen or CF3, particularly CF3.

[0235] In the context of the invention, the new compound of formula (I) according to the invention is preferably selected from compounds recited in Table 1 below, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof. Preferably, the new compound of formula (I) according to the invention is selected from compounds ED28, ED36, ED61, LZX-2-35, LZX-2-56, LZX-2-67 and LZX-2-73 of Table 1.

[0236] The invention also relates to a pharmaceutical composition comprising a new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof.

[0237] The invention also relates to a new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, for use as a drug.

[0238] The invention also relates to the use of a new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, for the manufacture of a medicament.

[0239] The invention further relates to a method for treating a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, to said subject.

[0240] The invention also relates to a new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, for use in a method for treating cancer. The invention also relates to the use of a new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, for the manufacture of a medicament for use in a method for treating cancer.

[0241] The invention further relates to a method for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, to said subject.

[0242] In a preferred embodiment of the invention, the cancer is selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer, preferably pancreatic cancer.

[0243] In a particular embodiment of the invention, the method for treating cancer further comprises the combined administration of another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy.

[0244] In a preferred embodiment, the other antitumoral drug is sorafenib.

[0245] The present invention also relates to a kit of parts and / or a combination product comprising (i) a compound of general formula (I) according to the invention, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, and (ii) an additional active ingredient, for separate, sequential or simultaneous use.

[0246] The present invention further relates to a combination product comprising:

[0247] (i) at least one new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it; and

[0248] (ii) sorafenib.

[0249] In a particular embodiment, compound (i) is selected from compounds ED28, ED36, ED61, LZX-2-35, LZX-2-56, LZX-2-67 and LZX-2-73 of Table 1.

[0250] In a particular embodiment, the combination product of the invention is a pharmaceutical composition comprising both components (i) and (ii), in a pharmaceutically acceptable carrier. In another embodiment, the combination product of the invention is a kit of parts comprising component (i) and component (ii), for sequential, separate or simultaneous use. In this embodiment, each of the components can be formulated in different pharmaceutical compositions.

[0251] The frequency and / or dose relative to the administration can be adapted by one of ordinary skill in the art, in function of the subject to be treated, the disease to be treated, the stage of the disease, the form of administration, etc. Typically, component (i) can be administered at a dose comprised between 5 mg / day to 50 mg / day. In another particular embodiment, component (ii) can be administered at a dose comprised between 10 mg / day and 50 mg / day.

[0252] In another aspect, the invention relates to the combination product of the invention, for use as a medicament.

[0253] The invention also relates to the combination product as defined above for use in a method for treating cancer.

[0254] The invention further relates to a method for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the combination product of the invention, to said subject.

[0255] The invention further relates to the use of the combination product of the invention for the manufacture of a medicament for use in a method for treating cancer.

[0256] In a preferred embodiment of the invention, the cancer is selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer, preferably pancreatic cancer. Com pounds for use

[0257] The invention also relates to a compound of general formula (I), or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, for use in a method for treating a cancer, wherein formula (I) is: wherein: indicates where said group is bound to X. Ri to RB represent, independently of each other, a radical selected from a group consisting of:

[0258] • a hydrogen,

[0259] • a halogen,

[0260] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0261] • a (C2-C6)alkenyl optionally substituted by a (CrC, )alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,

[0262] • a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,

[0263] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0264] • -NO2, and

[0265] • a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a (C1-C6)alkyl, a hydroxy, a halogen, a -SO2-(C1-C6)alkyl, and a (C1-C6)alkyloxy; R4, Rs and R7, independently of each other, represent a radical selected from a group consisting of:

[0266] • a hydrogen,

[0267] • a halogen,

[0268] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0269] • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0270] • a C2-C6) alkynyl optionally substituted by a (C1-C6)alkvloxv. a hydroxy, at least one halogen, or a cycloalkyl,,

[0271] • a (C1-C6)alkyloxy optionally substituted by at least one halogen, Re is a (C1-C6) alkyl optionally substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl; > X is -NHCONH- or -CONH-.

[0272] The invention further relates to a method for treating a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of general formula (I) as defined herein, especially one selected from the compounds recited in Table 1 or 2, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, to said subject.

[0273] The invention also relates to a compound of general formula (I) as defined herein, especially one selected from the compounds recited in Table 1 or 2, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it, for use in a method for treating cancer.

[0274] In a preferred embodiment of the invention, the cancer is selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer, preferably pancreatic cancer.

[0275] In the context of the invention, the compound of formula (I) is such that X is -NHCONH- or -CONH-. In a particular and preferred embodiment of the invention, the compound of formula (I) is such that X is -NHCONH-.

[0276] In another particular embodiment, the compound of formula (I) is such that X is -C0NH-. In this embodiment, the nitrogen atom is preferably linked to the group A of formula (I).

[0277] In the context of the invention, the compound of formula (I) is such that is a (C1-C6)alkyl optionally R6 substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl.

[0278] In a particular embodiment of the invention, is a (C1-C6)alk Ryl6 optionally substituted with a 3-14 membered aryl group such as phenyl.

[0279] Preferably, R6 is a (C1-C6)alkyl optionally substituted with a phenyl. Particularly, is a methyl R6 optionally substituted with a phenyl group, more preferably is a methyl. R6

[0280] In a particular embodiment, the compound of formula (I) is such that:

[0281] • X is -NHCONH-; and

[0282] • R6 is a methyl optionally substituted with a phenyl.

[0283] In the context of the invention, the compound of formula (I) is such that A is: in which the wave-shaped line indicates where said group is bound to X.

[0284] The compound of formula (I) according to the invention can thus be of following formula (II) or (III):

[0285] In a particular and preferred embodiment, the compound of formula (I) is such that A is:

[0286] In another particular embodiment, the compound of formula (I) is such that A is:

[0287] In a further particular embodiment, the compound of formula (I) is such that:

[0288] • X is -NHCONH-;

[0289] • R6 is a methyl optionally substituted with a phenyl; and • A is of formula (Al).

[0290] In the context of the invention, when the compound of formula (I) is such that A is of formula (Al): > Ri to Rj represent, independently of each other, a radical selected from a group consisting of

[0291] • a hydrogen,

[0292] • a halogen,

[0293] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0294] • a C2-C6) alkenyl optionally substituted by a (C1-C6) alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,

[0295] • a (C2-C6)alkynyl optionally substituted by a (C1-C6) alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,,

[0296] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0297] • -NO2, and

[0298] • a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a (C1-C6)alkyl, a hydroxy, a halogen, a -SO2-(C1-C6)alkyl, and a (C1-C6)alkyloxy; and

[0299] > R4 and R5, independently of each other, represent a radical selected from a group consisting of:

[0300] • a hydrogen,

[0301] • a halogen,

[0302] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0303] • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0304] • a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl, and

[0305] • a (C1-C6)alkyloxy optionally substituted by at least one halogen.

[0306] In a particular embodiment, when the compound of formula (I) is such that A is of formula (Al), at least one of Ri to R5are not hydrogen atom, particularly one, two or three of Ri to R5are not hydrogen atom, preferably one or two of Ri to R5are not hydrogen atom.

[0307] In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R4 and R5 are hydrogen atoms. Preferably, R4 and R5 are hydrogen atoms, and at least one, preferably one or two, of Ri to R3 are not hydrogen atom.

[0308] In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R3 to R5 are hydrogen atom, and one or both of Ri and R2 are not hydrogen atom. In a further particular embodiment, the compound of formula (I) is such that:

[0309] • X is -NHCONH-;

[0310] • R6 is a methyl optionally substituted with a phenyl;

[0311] • A is of formula (Al);

[0312] • R4 and Rs are hydrogen atoms; and

[0313] • at least one, preferably one or two, of Ri to R3are not hydrogen atom.

[0314] In a further particular embodiment, the compound of formula (I) is such that:

[0315] • X is -NHCONH-;

[0316] • R6 is a methyl optionally substituted with a phenyl;

[0317] • A is of formula (Al);

[0318] • R, to R5 are hydrogen atoms; and

[0319] • one or both of Ri and R2are not hydrogen atom.

[0320] In a further particular embodiment, when the compound of formula (I) is such that A is of formula (Al), Ri to R3 represent, independently of each other, a radical selected from a group consisting of:

[0321] • a hydrogen,

[0322] • a halogen,

[0323] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0324] • a C2-C6) alkenyl,

[0325] • a (C2-C6)alkynyl,

[0326] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0327] • -NO2, and

[0328] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that at least one, preferably one or two, of Ri to R3is not a hydrogen atom.

[0329] In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R4 and R5 are hydrogen atoms, and Ri to R3represent, independently of each other, a radical selected from a group consisting of:

[0330] • a hydrogen,

[0331] • a halogen,

[0332] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0333] • a (C2-C6)alkenyl,

[0334] • a (C2-C6)alkynyl,

[0335] • a (C1-C6)alkyloxy optionally substituted by at least one halogen, • -NO2, and

[0336] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that at least one, preferably one or two, of Ri to R3is not a hydrogen atom.

[0337] In a further particular embodiment, when the compound of formula (I) is such that A is of formula (Al), Ri and R3represent, independently of each other, a radical selected from a group consisting of:

[0338] • a hydrogen,

[0339] • a halogen,

[0340] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0341] • a (C2-C6)alkenyl,

[0342] • a (C2-C6)alkynyl,

[0343] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0344] • -NO2, and

[0345] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that one or both of Ri and R2 is not a hydrogen atom.

[0346] In another particular embodiment, when the compound of formula (I) is such that A is of formula (Al), R3to Rs are hydrogen atoms, and Ri and R2 represent, independently of each other, a radical selected from a group consisting of:

[0347] • a hydrogen,

[0348] • a halogen,

[0349] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0350] • a C2-C6) alkenyl,

[0351] • a (C2-C6)alkynyl,

[0352] • a (C1-C6)alkyloxy optionally substituted by at least one halogen,

[0353] • -NO2, and

[0354] • a 3-14 membered cycloalkyl or a 3-14 membered aryl; provided that one or both, of Ri and R2 is not a hydrogen atom.

[0355] In a preferred embodiment, when the compound of formula (I) is such that A is of formula (Al), R3to Rs are hydrogen atoms, and Ri and R2 represent, independently of each other, a radical selected from a group consisting of:

[0356] • a hydrogen,

[0357] • a halogen, • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0358] • a (C2-C6)alkenyl,

[0359] • a (C2-C6)alkynyl,

[0360] • a (C1-C6)alkyloxy,

[0361] • -NO2,

[0362] • a (C3-C6) cycloalkyl; and

[0363] • a phenyl provided that one or both of Ri and R2 is not a hydrogen atom.

[0364] In a further particular embodiment, the compound of formula (I) is such that:

[0365] • X is -NHC0NH-;

[0366] • R« is a methyl optionally substituted with a phenyl;

[0367] • A is of formula (Al);

[0368] • R and R5 are hydrogen atoms;

[0369] • At least one, preferably one or two, of Ri to R3 are not hydrogen atom; and

[0370] • Ri to R3represent, independently of each other, a radical selected from a group consisting of: o a hydrogen, o a halogen, o a(C1-C12) alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl, o a(C2-C6)alkenyl, o a(C2-C6)alkynyl, o a (C1-C6)alkyloxy, o -NO2, o a (Cg-Ce) cycloalkyl; and o a phenyl.

[0371] In a further particular embodiment, the compound of formula (I) is such that:

[0372] • X is -NHC0NH-;

[0373] • R is a methyl optionally substituted with a phenyl;

[0374] • A is of formula (Al);

[0375] • R3to R5are hydrogen atoms;

[0376] • one or both of Ri and R2 are not hydrogen atom; and

[0377] • Ri and R2 represent, independently of each other, a radical selected from a group consisting of: o a hydrogen, o a halogen, o a(C1-C12) alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl, o a(C2-C6)alkenyl, o aC2-C6) alkynyl, o a (C1-C6)alkyloxy, o -NO2, o a (C3-C6) cycloalkyl; and o a phenyl.

[0378] In the context of the invention, when the compound of formula (I) is such that A is of formula (A2) or (A2’)> R? is a radical selected from the group consisting of:

[0379] • a hydrogen,

[0380] • a halogen,

[0381] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0382] • a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0383] • a C2-C6) alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl, and

[0384] • a (C1-C6)alkyloxy optionally substituted by at least one halogen.

[0385] In a particular embodiment, when the compound of formula (I) is such that A is of formula (A2) or (A2’), R7is a radical selected from the group consisting of:

[0386] • a hydrogen,

[0387] • a halogen,

[0388] • a (C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,

[0389] • a C2-C6) alkenyl,

[0390] • a (C2-C6)alkynyl, and

[0391] • a (C1-C6)alkyloxy optionally substituted by at least one halogen.

[0392] Preferably, R7 is a hydrogen, a halogen, or a (C1-C6)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a (C3-C6)cycloalkyl. More preferably, R7 is a hydrogen, a halogen or CF3, particularly CF3.

[0393] In a further particular embodiment, the compound of formula (I) is such that: • X is -NHCONH-;

[0394] • R„ is a methyl optionally substituted with a phenyl;

[0395] • A is of formula (A2) or (A2’); and

[0396] • R? is a hydrogen, a halogen or CF3, particularly CF3.

[0397] In the context of the invention, the compound of formula (I) for use according to the invention is preferably selected from compounds recited in Table 1 or 2 below, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof. Preferably, the compound of formula (I) for use according to the invention is selected from compounds AJO, ED25, ED28, ED36, ED61, LZX-2-35, LZX-2-56, LZX-2-67 and LZX-2-73 of Table 1 or 2.

[0398] In a particular embodiment of the invention, the method for treating cancer further comprises the combined administration of another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy.

[0399] In a particular embodiment, the other antitumoral drug is sorafenib.

[0400] The present invention also relates to a kit of parts and / or a combination product comprising (i) a compound of general formula (I) according to the invention, especially one selected from the compounds recited in Table 1 or 2, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, and (ii) an additional active ingredient, for separate, sequential or simultaneous use

[0401] The present invention further relates to a combination product comprising:

[0402] (i) at least one new compound of general formula (I) as defined above, especially one selected from the compounds recited in Table 1 or 2 below, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising it; and

[0403] (ii) sorafenib.

[0404] In a particular embodiment, compound (i) is selected from compounds AJO, ED25, ED28, ED36, ED61, LZX-2-35, LZX-2-56, LZX-2-67 and LZX-2-73 of Table 1 or 2.

[0405] In a particular embodiment, the combination product of the invention is a pharmaceutical composition comprising both components (i) and (ii), in a pharmaceutically acceptable carrier.

[0406] In another embodiment, the combination product of the invention is a kit of parts comprising component (i) and component (ii), for sequential, separate or simultaneous use. In this embodiment, each of the components can be formulated in different pharmaceutical compositions. The frequency and / or dose relative to the administration can be adapted by one of ordinary skill in the art, in function of the subject to be treated, the disease to be treated, the stage of the disease, the form of administration, etc. Typically, component (i) can be administered at a dose comprised between 5 mg / day to 50 mg / day. In another particular embodiment, component (ii) can be administered at a dose comprised between 10 mg / day and 50 mg / day.

[0407] In another aspect, the invention relates to the combination product of the invention, for use as a medicament.

[0408] The invention also relates to the combination product as defined above for use in a method for treating cancer.

[0409] The invention further relates to a method for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the combination product of the invention, to said subject.

[0410] The invention further relates to the use of the combination product of the invention for the manufacture of a medicament for use in a method for treating cancer.

[0411] In a preferred embodiment of the invention, the cancer is selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer, preferably pancreatic cancer.

[0412] Therapeutics uses

[0413] As illustrated by examples, the inventors have demonstrated the therapeutic interest of the new compounds of the invention. The terms “new compound” or “new compound of general formula (I)” or “new compound according to the invention”, mean herein any compounds as defined in the section ■’A't’H' compounds of the invention" herein above. The terms “compound according to the invention” or “compound of general formula (I)”, mean herein any compounds of general formula (I) as defined in the present specification, in particular in the sections “Compounds for use” and “New compounds of the invention” herein above.

[0414] Accordingly, the present invention relates to compounds of general formula (I) as disclosed herein, especially one of those as disclosed in Tables 1 and 2, or a pharmaceutical composition comprising it, for use as anti-tumoral agent or for use for treating and / or preventing a cancer; and to the use of a compound of general formula (I) as disclosed herein, especially one of those as disclosed in Tables 1 and 2, or a pharmaceutical composition comprising it for the manufacture of a medicament useful as anti-tumoral agent or for treating and / or preventing a cancer. The invention further relates to the method for treating a subject suffering of a cancer, comprising administering a therapeutic effective amount of a compound of general formula (I) as disclosed herein, especially one of those as disclosed in Tables 1 and 2, or a pharmaceutical composition comprising it to said subject, thereby inducing an anti-tumoral effect.

[0415] As used herein, the term “cancer” refers to any cancer that may affect any one of the following tissues or organs: breast; liver; kidney; heart, mediastinum, pleura; floor of mouth; lip; salivary glands; tongue; gums; oral cavity; palate; tonsil; larynx; trachea; bronchus, lung; pharynx, hypopharynx, oropharynx, nasopharynx; esophagus; digestive organs such as stomach, intrahepatic bile ducts, biliary tract, pancreas, small intestine, colon; rectum; urinary organs such as bladder, gallbladder, ureter; rectosigmoid junction; anus, anal canal; skin; bone; joints, articular cartilage of limbs; eye and adnexa; brain; peripheral nerves, autonomic nervous system; spinal cord, cranial nerves, meninges; and various parts of the central nervous system; connective, subcutaneous and other soft tissues; retroperitoneum, peritoneum; adrenal gland; thyroid gland; endocrine glands and related structures; female genital organs such as ovary, uterus, cervix uteri; corpus uteri, vagina, vulva; male genital organs such as penis, testis and prostate gland; hematopoietic and reticuloendothelial systems; blood; lymph nodes; thymus.

[0416] The term “cancer” according to the invention comprises leukemias, seminomas, melanomas, teratomas, lymphomas, non-Hodgkin lymphoma, neuroblastomas, gliomas, adenocaminoma, mesothelioma (including pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and end stage mesothelioma), rectal cancer, endometrial cancer, thyroid cancer (including papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma and paraganglioma), skin cancer (including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi’s sarcoma, keratoacanthoma, moles, dysplastic nevi, lipoma, angioma and dermatofibroma), nervous system cancer, brain cancer (including astrocytoma, medulloblastoma, glioma, lower grade glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, glioma or sarcoma), skull cancer (including osteoma, hemangioma, granuloma, xanthoma or osteitis deformans), meninges cancer (including meningioma, meningiosarcoma or gliomatosis), head and neck cancer (including head and neck squamous cell carcinoma and oral cancer (such as, e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer or pharynx cancer)), lymph node cancer, gastrointestinal cancer, liver cancer (including hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma), colon cancer, stomach or gastric cancer, esophageal cancer (including squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma or lymphoma), colorectal cancer, intestinal cancer, small bowel or small intestines cancer (such as, e.g., adenocarcinoma lymphoma, carcinoid tumors, Karposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma or fibroma), large bowel or large intestines cancer (such as, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma or leiomyoma), pancreatic cancer (including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors or vipoma), ear, nose and throat (ENT) cancer, breast cancer (including HER2 -enriched breast cancer, luminal A breast cancer, luminal B breast cancer and triple negative breast cancer), cancer of the uterus (including endometrial cancer such as endometrial carcinomas, endometrial stromal sarcomas and malignant mixed Mullerian tumors, uterine sarcomas, leiomyosarcomas and gestational trophoblastic disease), ovarian cancer (including dysgerminoma, granulosa-theca cell tumors and Sertoli-Leydig cell tumors), cervical cancer, vaginal cancer (including squamous-cell vaginal carcinoma, vaginal adenocarcinoma, clear cell vaginal adenocarcinoma, vaginal germ cell tumors, vaginal sarcoma botryoides and vaginal melanoma), vulvar cancer (including squamous cell vulvar carcinoma, verrucous vulvar carcinoma, vulvar melanoma, basal cell vulvar carcinoma, Bartholin gland carcinoma, vulvar adenocarcinoma and erythroplasia of Queyrat), genitourinary tract cancer, kidney cancer (including clear renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, adenocarcinoma, Wilm’s tumor, nephroblastoma, lymphoma or leukemia), adrenal cancer, bladder cancer, urethra cancer (such as, e.g., squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), prostate cancer (such as, e.g., adenocarcinoma or sarcoma) and testis cancer (such as, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors or lipoma), lung cancer (including small cell lung carcinoma (SCLC), non-small cell lung carcinoma (NSCLC) including squamous cell lung carcinoma, lung adenocarcinoma (LUAD), and large cell lung carcinoma, bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lung sarcoma, chondromatous hamartoma and pleural mesothelioma), sarcomas (including Askin's tumor, sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma and soft tissue sarcomas), soft tissue sarcomas (including alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, plexiform fibrohistiocytic tumor, rhabdomyosarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma, cardiac cancer (including sarcoma such as, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma or liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma), bone cancer (including osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma and reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumors), hematologic and lymphoid cancer, blood cancer (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma and myelodysplasia syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma and hairy cell and lymphoid disorders, and the metastases thereof.

[0417] The term “cancer” according to the invention preferably comprises pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer. Preferably, the cancer is pancreatic cancer.

[0418] Pharmaceutical compositions

[0419] The pharmaceutical compositions contemplated herein may include a pharmaceutically acceptable carrier in addition to the active ingredient(s). The term "pharmaceutically acceptable carrier" is meant to encompass any carrier (e g., support, substance, solvent, etc.) which does not interfere with effectiveness of the biological activity of the active ingredient(s) and that is not toxic to the host to which it is administered. For example, for parental administration, the active compounds(s) may be formulated in a unit dosage form for injection in vehicles such as saline, dextrose solution, serum albumin and Ringer's solution.

[0420] The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicle, 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 suitable for parental 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. The pharmaceutical or veterinary composition as disclosed herein may further comprise an additional active ingredient or drug.

[0421] Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting. TABLES 1 and 2

[0422] TABLE 1

[0423] EXAMPLES Example 1 - Synthesis of AJO-derived compounds

[0424] AJO compound was obtained according to the synthetic route below.

[0425] Besides some general solvents and redox agents, the basic elements to construct of this family of compounds include cyclohexane- 1, 3-dione (source: Beijing MREDA Technology Co., Ltd.), ethyl-2- bromoacetate (source: Shanghai Titan Technology Co., Ltd.), and 3 -bromoaniline (source: Shanghai Meryer Biochemical Technology Co.).

[0426] Based on AJO compound, inventors have designed and synthesized AJO derivatives aiming to improve its cytotoxic activity against cancer cells. Their code, structures, synthetic protocol, molecular weight and characterization data are presented in Table 3 below . General Scheme

[0427] To a suspension of K2CO3in DMF at RT was added 1,3 -cyclohexanedione and the resulted slurry was stirred during 15min at RT. Then CS2was added at once and the reaction mixture was stirred at RT for 20min. A solution of ethyl chloroacetate in DMF was added added dropwise and the resulting mixture was stirred for further 30mm at RT. The reaction was then cooled to 0 °C and the required alkyl halide was added dropwise and the reaction mixture was stirred for additional Ih at 0 °C. The mixture was then allowed to warm up slowly to RT and stirred during the required time. The mixture was poured into ice / water and the aqueous layer was extracted several times with DCM. The combined organic extracts were washed once with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The crude residue was purified by FC (c-Hex / EtOAc gradient) to afford the required product.

[0428] General protocol 2 (GP-2) : Sulfide to sulfone oxidation

[0429] To a cooled solution of the required sulfide in DCM at 0 °C was added m-CPBA by portions. The resulting reaction mixture was stirred at 0 °C during 30min then allowed to slowly warmed up to RT and stirred during the required time. The reaction mixture was quenched slowly with a saturated aqueous solution of NaHCO3, then the separated organic layer was washed once with with a saturated aqueous solution of NaHCOs and once with water. The organic extract was then dried over Na2SO 4, filtered and concentrated under vacuum to afford the required crude product which was used in the next step without further purification.

[0430] General protocol 3 (GP-3) : Ketone to alcohol reduction

[0431] To a cooled solution of the required ketone in THF / MeOH at 0 °C was added NaBFU by portions. The reaction mixture was then stirred at 0 °C during the required time. The reaction mixture was quenched by the slow addition of a saturated aqueous solution of NH4CI. The aqueous layer was extracted three times with EtOAc. The combined extracted were washed once with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the required crude product which was used in the next step without further purification.

[0432] General protocol 4 (GP-4) : Alcohol acid elimination

[0433] To a solution of the required alcohol in toluene was added p-TsOH.H2O at RT. The reaction mixture was then refluxed and stirred during the required time. The mixture was then allowed to cool down to RT and concentrated under vacuum. The crude residue was purified by FC (c-Hex / EtOAc gradient) to afford the required product.

[0434] General protocol 5 (GP-5) : Ester saponification

[0435] To a solution of the required ester in MeOH / THF / H2O (1 / 1 / 1 mixture) was added LiOH H2O at RT. The reaction mixture was then stirred at RT during the required time. The mixture was acidified to pH = 3 by addition of a IM aqueous solution of HC1. The aqueous layer was then extracted twice with EtOAc. The combined organic extracts were washed once with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the require crude product which was used in the next step without further purification.

[0436] General protocol 6 (GP-6) : Urea synthesis via Curtins rearrangement

[0437] In a reaction tube, to a solution of the required carboxylic acid in toluene were added successively the required amine, DPPA and Et3N at room temperature. The tube was sealed and the reaction mixture was then heated at 105-110 °C during the require time. The mixture was then allowed to cool down to room temperature and concentrated under vacuum. The crude residue was then purified by FC (c-Hex / EtOAc or DCM / MeOH gradient) to afford the required purified product.

[0438] General protocol 7 (GP-7) : Amide formation with HATU

[0439] To a solution of the required carboxylic acid and the required amine in DMF were added successively HATU and DIPEA at room temperature. The reaction mixture was then stirred at room temperature during the required time. The mixture was concentrated under vacuum. The crude residue was purified by FC (c-Hex / EtOAc gradient) to afford the required product.

[0440] Table 3

[0441] Example 2 - Biological activity

[0442] Material and Methods

[0443] Cell lines and cell culture

[0444] Human pancreatic cancer cells MIA PaCa-2 and WT or NUPR1 KO Panc-1, human hepatocellular carcinoma cells HepG2, human breast adenocarcinoma cells MDA-MB-231, human melanoma cells A375, human colorectal cancer cells HT29, human primary glioblastoma cells U87 and human bone osteosarcoma epithelial cells U2OS were cultured in Dulbecco’s modified Eagle’s medium (DMEM) (Gibco, Invitrogen) containing 10% fetal bovine serum (FBS) (Biosera). Human lung carcinoma cells H358 and human prostate cancer cells PC-3 were cultured in RPMI 1640 medium (Gibco, Invitrogen) containing 10% FBS. Primary human PDAC cells were cultured in the serum-free DMEM / F12 medium adding 1.22 g / L nicotinamide, 5 g / L glucose, 5% Nu-Serum IV, 0.5% ITS+ Premix Universal Culture Supplement (containing insulin, human Transferrin and selenous acid), 1 pM dexamethasone, 10 ng / L cholera toxin, 50 nM 3,3’5-triiodo-L-Thyronine, 25.2 mg / L bovine pituitary extract, 20 pg / L epidermal growth factor. Cells were cultured in a humidified incubator with 5% CO2 at 37°C.

[0445] Cell viability assay

[0446] Cells were plated at 5,000 cells per well in 96-well plates and incubated 24h to attach. Cells were then incubated with increasing concentrations of the compounds for 72 hours. Cell viability was measured after addition of the PrestoBlue™ Cell Viability Reagent for 3 hours and quantified using the plate reader Tristar LB941. Untreated cells were used as control. All samples were performed in triplicate. Animals

[0447] Female Crl:NU(Ico)- / 'bxA? / "" mice (4 weeks old) were purchased from Charles River Company. Mice were kept in an agreed Experimental Animal House of the Centre de Cancerologie de Marseille, pole Luminy. All mice were fed under specific pathogen-free conditions and handled according to the principles of the laboratory animal care and recommendations to ethics laws. Ten million of MIA PaCa- 2 cells with 50 pL Matrigel (BD Pharmingen) were inoculated subcutaneously in nude mice of 5 weeks. Mice were treated daily with 0.5% DMSO in sunflower seed oil (vehicle), and 5, 10, 20, or 50 mg / kg AJO by intraperitoneal injection when the tumor size reached 200 mm3. Mice were weighed and the tumor volumes were measured twice per week with a caliper (tumor volume was calculated as an ellipsoid). Mice were sacrificed after 28 days of treatment. hERG channel binding assay

[0448] The propensity to block the hERG potassium channel was measured by using a Predictor™ hERG Fluorescence Polarization assay. Specifically, membrane fractions containing hERG channel protein were incubated with compounds to be tested at varying concentrations from 0.1 to 80 pM, and membrane polarization (mP) was measured and recorded. E-4031, a selective hERG potassium channel blocker, was used as the positive control in the assay. The test substances were prepared at lOOx in DMSO and then diluted to 4x (4% DMSO) in the assay buffer. The wells contained 5 pL assay buffer while 10 pL of the hERG membrane samples was used as negative control. Then, 5 pL of the test substances were dispensed into a 386-well plate at a final concentration of 0.1-80 pM into each well. Next, 10 pL of 2x Predictor hERG membranes were dispensed into each well, followed by 5 pL of 4x Predictor hERG Tracer Red. Each substance was tested in the absence and presence of 30 pM E-4031 to correct for possible test compound interference. The plates were incubated for at least 7 hours prior to measuring the fluorescence polarization using a BMG LABTECH (PHERAstar) at excitation and emission wavelengths of 540 and 573 nm, respectively.

[0449] LDH assay, caspase-3 / 7 activity assay and ATP production

[0450] MIA PaCa-2 cells were seeded in 96-well plates at a density of 10,000 cells per well. Cells were allowed to adhere for 24 h and then treated with AJO compound at increasing concentrations for 24, 48 or 72 h in triplicates. The LDH release, caspase 3 / 7 activity and ATP production were measured using CytoTox- ONE™, Caspase-Gio® 3 / 7 and CellTiter-Glo® assay, respectively.

[0451] In the case of the ATP assay, cells were normalized to untreated cells.

[0452] AnnexinV / PI staining

[0453] MIA PaCa-2 cells were harvested after incubating with AJO compound for 24 h, 48 h and 72 h. Cells were detached by Accutase and resuspended in 100 pL of Annexin-binding buffer. An amount of 5 pL of Pacific-Blue Annexin V was added to the cell suspension and incubated in the dark for 15 min. Five minutes before analysis by flow cytometry, 5 p L propidium iodide was added to the cell suspension. Ten thousand events per sample were collected and analyzed by MACSQuant-VYB (Miltenyi Biotec, Surrey, UK). Data analysis was performed using FlowJo 10.7.1 software.

[0454] Measurement of mitochondrial oxidative phosphorylation (OXPHOS)

[0455] Measurements were conducted using a Seahorse Bioscience XF24 Extracellular Flux Analyzer (Agilent). MIA PaCa-2 cells were plated at 30,000 cells / well onto Seahorse 24-well plates and incubated overnight. Cells were treated with AJO compound alone or in combination with Olaparib at indicated concentrations for 24 h. The cellular oxygen consumption rate (OCR, in pmol / min) was measured using the XF Cell Mito Stress Test Kit (Agilent) under basal conditions and in response to 1 pM oligomycin (a kind ofATPase Inhibitor), 0.5 pM carbonylcyanide p-(trifluoro-methoxy) phenylhydrazone (FCCP, a potent uncoupler of oxidative phosphorylation), and rotenone and antimycin A (0.5 pM each) (electron transport chain inhibitors).

[0456] In situ detection of apoptotic cells in tumor tissue

[0457] Serial 4 pm sections were obtained from each of the paraffin-embedded tumors using a Leica microtome. The TUNEL apoptosis assay kit (Abeam) was used to detect apoptotic cells in tumor samples from each group according to the manufacturer’s protocol. In brief, tumor sections were deparaffinized in xylene and rehydrated in gradient ethanol series before permeabilization with Proteinase K. Then inactivate endogenous peroxidases with 3% H2O2. Apoptotic cells were labelled with TdT Enzyme that binds to exposed 3 ’-OH ends of DNA fragments and catalyzes the addition of biotin-labeled deoxynucleotides, biotinylated nucleotides are bound with a streptavidin-horseradish peroxidase (HRP) conjugate. The signal was detected using 3,3 ’-diaminobenzidine (DAB) substrate, that reacts with the HRP labeled sample, and sections were counterstained with Methyl Green.To generate a negative control, TdT enzyme was replaced by the distilled water in the reaction mix. Treating one slide with 1 pg / pL DNase I for 20 minutes to add positive control. Finally, mount a glass coverslip using organic mounting media over the specimen. Images of the sections were taken by ZEISS Axio Imager Z2 microscope.

[0458] Immunoh istoch emistry

[0459] Immunohistochemistry staining was performed on 4 pm-thick paraffin-embedded tissue sections. After deparaffination, antigen retrieval was performed in a water bath at 96°C, in Buffer (Citrate) TRS pH 6 (Dako S1699) during 20 min. Blocking of endogenous peroxidases was performed and then, the following primary antibodies were used: rabbit anti-Ki67 (ab92742, 1: 100 dilution) and rabbit anticleaved caspase-3 (9661; Cell Signaling Technology, 1:400 dilution). Then, an incubation for 30 min with a biotinylated secondary antibody (1:400 dilution) followed by an incubation with Streptavidin- HRP (P0397) (1:500 dilution) was performed. Signal was detected with DAB (Dako, K3468) following the manufacturer’s protocol. Coloring of the samples was performed with Mayer’s Hematoxylin for 30 sec, followed by 0.1% sodium bicarbonate solution for 3 min. Finally, samples were dehydrated and assembled with mounting media.

[0460] Statistics

[0461] Statistical analyses were conducted by using 1-way ANOVA, Dunnett’s test or 2-way ANOVA, Dunnett’s test. The results were expressed as the mean ± SD of at least three independent experiments. A p-value of <0.05 was regarded as statistically significant.

[0462] Results

[0463] AJO compound is a specific and effective NUPR1 inhibitor with a high antitumoral effect

[0464] Inventors tested the cytotoxicity of AJO compound on PDAC cell lines with wild-type (NUPR1-WT) or inactivated NUPR1 by CRISPR-Cas system (NUPR1-KO). As shown in Figure 1A, the anticancer activity of AJO compound on NUPR1-WT cells was 2 to 3 times better than that on NUPR1-KO cells. It also proves that AJO compound exerted anticancer activity by targeting NUPR1.

[0465] Meanwhile, inventors tested the antitumor activity of AJO compound on MiaPaCa2 cells and 11 primary PDAC-derived cell lines and found that AJO compound exhibited potent activity against pancreatic cancer cells with IC50 in the range of 10.6 pM to 23.7 pM (Figure IB). As NUPR1 was also highly expressed in vanous cancer cells, inventors evaluated the antitumor activity of AJO compound on other cancer cells, such as HepG2 (hepatocarcinoma), MDA-MB-231 (breast cancer), H358 (lung cancer), A375 (melanoma), HT29 (colon cancer), U87 (glioblastoma), U2OS (osteosarcoma) and PC-3 (prostate cancer). The results indicated that AJO compound could effectively kill these cancer cells (Figure 1C). In summary, AJO compound is an efficient molecule to kill cancer cells by targeting NUPR1.

[0466] AJO compound displayed very low hERG binding ability

[0467] In the course of developing new drugs, one of the primary factors contributing to their failure in the market is the occurrence of cardiac arrhythmias, which is among the most common and severe side effects. This failure is primarily associated with the inhibition of hERG channels by the drug. Until now, around 17 FDA-approved drugs were withdrawn from the market because they block the hERG channel26,27. Hence, early identification of compounds with hERG inhibitory properties is very important. Inventors therefore measured the propensity of AJO compound to block the hERG channel using the Predictor™ hERG Fluorescence Polarization assay. Inventors compared AJO compound with E-4031, a positive control, as well as they compared it with their previous NUPR1 inhibitor, ZZW-115. The IC50 values of E-4031 and AJO compound were calculated to be 0.06 pM and more than 80 pM, respectively (Figure 2, table 4). AJO compound was 1,000 times less effective than E-4031 against hERG. Moreover, AJO compound showed lower hERG binding capacity compared to ZZW- 115. Based on these findings, AJO compound may not cause cardiotoxicity related to hERG binding.r-mr,_l inrichERG channel % Inhibition compounds

[0468] E-4031

[0469] ZZW-115 2 90%

[0470] AJ014 >80 4%

[0471] Table 4: Half-maximal inhibitory concentration (IC50) values on hERG channel inhibition byE-4031, ZZW-115 and AJO compound.

[0472] AJO compound kills pancreatic cancers by combining several cell death mechanisms

[0473] Although AJO compound could effectively kill cancer cells, the cell death mechanisms involved were unknown. Based on the previous results obtained with the ZZW-115 NUPR1 inhibitor, inventors first investigated whether AJO compound induced necroptosis and apoptosis in cancer cells, by testing LDH release and caspase 3 / 7 activity, respectively at different time points. The AJO-treated MIA PaCa-2 cells significantly increased LDH release compared with the control group and in a concentration- and timedependent manner (Figure 3A). Similarly, the caspase 3 / 7 activity of AJO-treated MIA PaCa-2 cells was still stronger than that of the control group (Figure 3B). Taken together, these results demonstrated that AJO compound can exert pro-necrotic and apoptotic effects. Inventors next measured cell apoptosis by flow cytometry with annexin V / PI double staining. MIA PaCa-2 cells treated with AJO compound exhibited a powerful pro-apoptotic effect in a time- and concentration-dependent manner. After MIA PaCa-2 cells treated with 80 LIM AJO compound for 72 hours, the proportion of apoptotic cells (early apoptosis and late apoptosis) reached 90.54% while the control group was only 4.1% (Figure 3C). Interestingly, pretreatment of MIA PaCa-2 cells with Z-VAD-FMK (a well-known pan-caspase inhibitor), olaparib (a parthanatos inhibitor) or Necrostatin (Nec-1), a necroptosis inhibitor, partially improve the cell viability of cancer cells treated with AJO compound (Figure 3D). These results further indicated that AJO compound can induce cancer cell necroptosis, parthanatos and apoptosis.

[0474] AJO compound treatment induced energetic metabolic failure by inducing a mitochondrial catastrophe

[0475] Intracellular ATP produced in mitochondria plays an important role in cell death28. In this regard, inventors tested the intracellular ATP content in MIA PaCa-2 cells after 24, 48 and 72h treatment with different concentrations of AJO compound. Remarkably, inventors observed that ATP level decreased significantly in a concentration-dependent manner (Figure 4A). Accordingly, inventors investigated whether reduced intracellular ATP production was the result of mitochondrial dysfunction. Inventors further examined the oxygen consumption rates (OCRs) for assessing OXPHOS activity of the mitochondria, by using the Seahorse XFe system. As expected, AJO-treatment induced a significant decrease in basal respiration and maximal respiration (Figure 4B). To further prove that mitochondrial dysfunction and hyperPARylation are related, inventors studied the OXPHOS activity after treatment with AJO compound alone or with the PARP inhibitor Olaparib. As shown in Figure 4C, Olaparib could reverse the strong mitochondrial metabolism failure caused by AJO compound. Altogether, these results proved that AJO compound treatment induced metabolic failure with a decrease in ATP production which can be rescued by Olaparib.

[0476] AJO compound inhibited PDAC tumor development in animal models

[0477] Next, inventor’s aim was to test the anticancer activity of AJO compound in vivo using the MIA PaCa- 2 cell as a xenografts mouse model, as previously described16. Mice were daily treated with 5, 10, 20 and 50 mg / kg AJO compound for up to 28 days intraperitoneally (i.p.) when tumors grew to 200 mm3The control group was treated with the corresponding volume of the vehicle. The tumor volumes in the control group increased exponentially during these 28 days (from 222.0 ± 18.2 mm3to 1589.2 ± 183.1 mm3) . On the contrary, mice treated with a 50 mg / kg dose of AJO compound showed slow tumor growth and significantly reduced tumor volume compared to the control group (from 246.4 ± 47.7 mm3to 224.98 ± 53.65 mm3). Moreover, the tumor growth of the other three groups treated with 5 mg / kg, 10 mg / kg and 20 mg / kg AJO compound displayed a clear dose-dependency. In detail, the tumor size grew from 269.7 ± 107.4 mm3to 1130.0 ± 389.8 mm3in mice treated with 5 mg / kg AJO compound, from 222.5 ± 37.1 mm3to 933.3 ± 199.9 mm3in mice treated with 10 mg / kg AJO compound and from 230.8 ± 81.9 mm3to 858.2 ± 196.9 mm3in mice treated with 10 mg / kg AJO compound (Figure 5A and B). These results clearly demonstrated that AJO compound potently suppressed tumor growth in a dosedependent effect. Additionally, in mice administrated with AJO compound, no matter the dose, there was no weight loss (Figure 5C). In addition, a lower Ki-67 number of positive cells, as well as a greater number of cells expressing cleaved-caspase-3 as well as TUNEL positive cells were found in the tumoral tissue of the 50 mg / kg treated mice (Figure 5D). Altogether, these data indicated that AJO compound showed effective tumor growth regression with no adverse effect.

[0478] Cytotoxic activity of the AJO-derived compounds

[0479] Inventors treated MIA PaCa-2 cells with increasing concentrations of AJO-derived compounds as prepared in Example 1 above. Their IC50 was calculated for each drug and each cell line and data presented in Table 5.

[0480] Table 5 30

[0481] Then the cytotoxicity of 8 of these compounds was tested on several PDAC-derived as well as other cancer cell lines and confirmed their superiority relative to AJO compound as presented in Table 6.

[0482] Table 6

[0483] Example 3 - Biological activity of the combination of sorafenib with the compounds of the invention

[0484] Material and Methods

[0485] Cell culture and patient-derived-organoids culture

[0486] Human PDAC cells MIAPaCa-2, human colorectal cancer cells HT-29, human lung carcinoma cells H1299, human breast adenocarcinoma cells MCF-7 and MDA-MB-231, human primary glioblastoma cells U87, human hepatocellular carcinoma cells HepG2 and Hep3B were cultured in Dulbecco’s modified Eagle’s medium (DMEM) from Gibco supplemented with 10% fetal bovine serum (FBS) from Biosera. Human prostate cancer cells PC-3, human lung carcinoma cells H358, human Burkitts lymphoma cells Daudi and human acute T cell leukemia cells Jurkat were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium from Gibco with 10% FBS. Cells were obtained from American Type Culture Collection (ATCC, USA). Primary human PDAC cell lines were cultured in DMEM / F12 medium supplemented with 1.22 g / L nicotinamide, 5 g / L glucose, 5% Nu-Serum IV, 0.5% ITS+ Premix Universal Culture Supplement (containing insulin, human transferrin, and selenous acid), 1 pM dexamethasone, 10 ng / L cholera toxin, 50 nM 3,3’5-triiodo-L-thyronine, 25.2 mg / L bovine pituitary extract, and 20 pg / L epidermal growth factor. Cells were maintained at 37°C with 5% CO2 in a humidified incubator.

[0487] Patient-derived organoids were obtained from a series of PDAC patients, including those with both resectable and unresectable tumors, as part of the PaCaOmics clinical trial NCT01692873. The organoids were cultured using Pancreatic Organoid Feeding Media (POFM), which consisted of Advanced DMEM / F12 with the addition of 10 mM HEPES, lx Glutamax, and penicillin / streptomycin from Thermo-Fisher. Supplements included 100 ng / ml Animal-Free Recombinant Human FGF10 and 50 ng / ml Animal-Free Recombinant Human EGF from Peprotech, 100 ng / ml Recombinant Human Noggin from Biotechne, 30% Wnt3a-conditioned medium, 10% RSPO1 -conditioned medium, 10 nM human Gastrin 1, 10 mM Nicotinamide, 1.25 mM N-acetylcysteine from Sigma Aldrich, lx B27 from Invitrogen, 500 nM A83-01, and 10.5 pM Y27632 from Tocris. The organoids were incubated at 37°C in a 5% CO2 atmosphere, with the media being refreshed every 3 to 4 days.

[0488] Drug combination assay

[0489] Drug combination assays were conducted to assess the synergistic effects of LZX-2-73 in combination with sorafenib on various cancer cell lines Cells were exposed to different doses of LZX-2-73 and the aforementioned compounds using a 5 x 5 dose matrix that included concentrations above and below their IC50, as determined from previous studies. Initially, cancer cells were seeded into clear 96-well plates at a density of 5000 cells per well and cultured for 24 hours. Serial dilutions from the main stock solutions of each compound were used to create the dosing matrix. After seeding for 24 hours, the compounds were applied to the cells in triplicate and incubated for 72 hours at 37°C with 5% CO2. Following incubation, PrestoBlue™ Cell Viability Reagent from Promega was added to each well, and the plates were incubated for an additional 3 hours under the same conditions. Cell viability and inhibition were quantified using the Tristar LB941 plate reader. Untreated cells served as the control. The SynergyFinder+ software (version 3.0) was utilized to calculate synergy scores for the drug combinations based on the HSA reference model. A synergy score below -10 indicated antagonistic interactions, scores between -10 and 10 indicated additive interactions, and scores above 10 indicated synergistic interactions29,30.

[0490] Proliferation assay

[0491] Cultures were plated at 5,000 cells per well in 96-well plates and allowed to incubate for 24 hours to adhere to the surface. Cells were then treated with sorafenib, LZX-2-73 or a combination of both for 72 hours. During the incubation period, cell growth was monitored using the Incucyte® S3 Live-Cell Analysis System (Sartorius, Germany), capturing phase contrast images every 4 hours and quantifying culture confluence with the integrated confluence algorithm. All experiments were conducted in triplicate.

[0492] Organoid imaging

[0493] Organoids were seeded at 1000 cells / well in 96 well plates (surface: BIOFLOAT™, round base) and incubated 2 days to form organoids. The following treatments were then applied for 72 hours: PDAC056T organoids were treated with 12.5 pM sorafenib alone, 25 pM LZX-2-73 alone, or a combination of both; PDAC088T organoids were treated with 10 pM sorafenib alone, 25 pM LZX-2- 73 alone, or a combination of both. Three days after drug treatment, the organoids were photographed using an EVOS cell imaging system (Invitrogen by ThermoFisher Scientific). The diameter of the organoids was analyzed using Image J software.

[0494] Xenografts development

[0495] Female Crl:NU(Ico)-Fox«7”" mice, aged 4 weeks, were obtained from Charles River Company. The mice were housed in the Experimental Animal House at the Centre de Cancerologie de Marseille, pole Luminy, under specific pathogen-free conditions. All procedures followed laboratory animal care guidelines and ethical regulations. At 5 weeks old, the mice were subcutaneously inoculated with 10 million MIAPaCa-2 cells mixed with 50 pL of Matrigel (BD Pharmingen). When tumors reached a size of 200 mm3, the mice received daily intraperitoneal injections of either 5% DMSO in sunflower seed oil (vehicle), 25 mg / kg sorafenib, 10 mg / kg LZX-2-73 or a combination of 25 mg / kg sorafenib and 10 mg / kg LZX-2-73. The mice were weighed and tumor volumes measured with calipers twice a week, with tumor volumes calculated assuming an ellipsoid shape. After 28 days of treatment, the mice were sacrificed.

[0496] Hematoxylin and Eosin Staining

[0497] Serial 4 pm sections were cut from each paraffin-embedded tissue sample using a Leica Histocore Biocut (Leica, Germany). These sections were then stained with hematoxylin and eosin according to the manufacturer's instructions using Leica Autostainer XL (Leica, Germany). Photomicrographs were captured using a ZEISS Axio Imager Z2 microscope (Zeiss, Germany).

[0498] In situ detection of apoptotic cells in tumor tissue

[0499] Serial 4 pm sections were prepared from each paraffin-embedded tumor sample using a Leica Histocore Biocut (Leica, Germany). Apoptotic cells were analyzed using the TUNEL apoptosis assay kit following the manufacturer’s protocol. Images of the sections were performed with a ZEISS Axio Imager Z2 microscope (Zeiss, Germany).

[0500] Immunoh istoch emistry

[0501] Four-micrometer paraffin sections of tumors were incubated for half an hour at 65 °C and then rehydrated. Antigen retrieval was performed by incubating the slides in Citrate Buffer TRS pH 6 (Dako) at 96°C for 20 minutes, followed by a 30-minute incubation at room temperature to cool them down. Endogenous peroxidases were blocked using 3% H2O2 for 10 minutes, and the slides were rinsed three times with PBS. The slides were then incubated with Monoclonal Rabbit Anti-Human Ki-67 antibody (Abeam, 1: 100) for 60 minutes at room temperature. After three washes in PBS, the slides were incubated with a biotinylated Goat anti-Rabbit Ig secondary antibody (Abeam, 1 :400) for 30 minutes at room temperature. Following anotherthree PBS washes, Streptavidin-HRP (Agilent; 1:500) was added and incubated for 30 minutes at room temperature. The staining was developed using diaminobenzidine (DAKO, Agilent) for 10 minutes at room temperature. The slides were rinsed in distilled water, counterstained with Mayer’s Hematoxylin for 30 seconds, and blued with 0.1% sodium bicarbonate solution for 3 minutes. Finally, the slides were dehydrated, cleared, and mounted with coverslips and permanent mounting medium. Images of the sections were captured using a ZEISS Axio Imager Z2 microscope (Zeiss, Germany).

[0502] Statistics

[0503] Statistical analyses were performed using one-way ANOVA, Dunnett’s test or two-way ANOVA, Dunnett’s test. Results were presented as the mean ± SEM from at least three independent experiments. A p- value of <0.05 was considered statistically significant. Results

[0504] The combination of sorafenib with LZX-2-73 showed strong synergism.

[0505] In this study, we evaluated the anticancer activity of sorafenib in combination with the novel NUPR1 inhibitor LZX-2-73. This evaluation was conducted on 15 cancer cell lines (commercial and primary cell lines) using a dose-response matrix. The antitumoral effects were analyzed using the SynergyFinder tool, which automatically calculates synergy scores of both drugs (Table 7). High synergy scores were found with sorafenib, indicating that a major contribution to improve the therapeutic effect of sorafenib could be done with this combination. In the Figure 6A, the combination of both drugs showed a massive synergic activity in cell viability.

[0506] Table 7 We selected six cancer cell lines -MIAPaCa-2, HT-29, MCF-7, HepG2, PDAC056T and PDAC088T- and specific drug concentrations that demonstrated the highest synergy scores for further study. These concentrations were chosen based on their ability to maximize the synergistic interaction between sorafenib and LZX-2-73. To assess the impact of this combination therapy on cell proliferation, we treated these cancer cells with sorafenib alone, LZX-2-73 alone, and the combination of both drugs, monitoring cell confluency in real-time using the Incucyte device. As shown in Figure 6B, the combination treatment significantly inhibited the proliferation of the six cancer cell lines compared to the individual treatments, underscoring the strong synergistic effect on cancer cell growth. Additionally, Figure 6C demonstrates that the combination of sorafenib and LZX-2-73 markedly reduced the diameter of primary PDAC organoids, indicating a substantial inhibitory effect on organoid formation. In conclusion, these results demonstrate that the sorafenib and LZX-2-73 combination consistently outperformed traditional chemotherapeutic agents, showing robust synergistic effects across all tested cancer cells.

[0507] Synergistic Antitumor Effects of Sorafenib and LZX-2-73 Combination Treatment in a PDAC Xenograft Model

[0508] To further explore the synergistic antitumor effects of LZX-2-73 and sorafenib in vivo, we established a subcutaneous xenograft tumor model in nude mice by injecting MIAPaCa-2 cells. As shown in Figure 7A, treatment with either sorafenib or LZX-2-73 alone resulted in moderate tumor growth inhibition. However, the combination of both drugs led to nearly complete suppression of tumor growth. To evaluate the effects of the combination therapy on tumor proliferation, we performed immunohistochemical (IHC) analysis using an anti-Ki-67 antibody, a marker for cell proliferation. The results demonstrated a significant reduction in the number of Ki-67-positive tumor cells in the combination treatment group compared to the monotherapy groups (Figure 7B), indicating a pronounced decrease in tumor cell proliferation. Additionally, TUNEL staining, used for in situ detection of apoptotic cells, revealed a higher incidence of apoptosis in tumors from the combination therapy group compared to those from the single-drug groups (Figure 7B). Collectively, these findings provide strong evidence of the synergistic antitumor effects of sorafenib and LZX-2-73 in vivo.

[0509] Importantly, no adverse effects were observed in the treated mice throughout the experiment. All mice exhibited a slight increase in body weight over time, with no significant differences between the treatment groups (Figure 8A). Histological analysis of major organs using hematoxylin and eosin (H&E) staining (Figure 8B) showed no signs of pathology or tissue damage in the heart, liver, spleen, lungs, or kidneys in any group. This indicates that both sorafenib and LZX-2-73 are non-toxic to mice, whether administered individually or in combination. Overall, the combination treatment of sorafenib and LZX- 2-73 demonstrates a powerful synergistic anticancer effect in vivo without causing toxic side effects. REFERENCES

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Claims

CLAIMS1- A compound of general formula (I), or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof:wherein:which the wave-shaped line indicates where said group is bound to X.> Ri to R3 represent, independently of each other, a radical selected from a group consisting of:• a hydrogen,• a halogen,• a(C1-C12) alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,• a (C1-C6)alkyloxy optionally substituted by at least one halogen,• -NO2, and• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a (C1-C6)alkyl. a hydroxy, a halogen, a -SO2-(C1-C6)alkyl, and a (C1-C6)alkyloxy;> R4, R5 and R7, independently of each other, represent a radical selected from a group consisting of: a hydrogen,• a halogen,• a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a(C2-C6) alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a(C2-C6) alkynyl optionally substituted by a (C1-C6)alkyloxy. a hydroxy, at least one halogen, or a cycloalkyl,,• a (C1-C6)alkyloxy optionally substituted by at least one halogen,> R6 is a (C1-C6)alkyl optionally substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl; and> X is -NHCONH- or -CONH-; provided that said compound is not a compound of following formula (AJO), (ED 18), (ED25), (LZX- 2-34), (LZX-2-40) or (IV):2- The compound according to claim 1, wherein X is a radical -NHCONH-.3- The compound according to claim 1 or 2, wherein is a (C1-C6)alkyl op Rt6ionally substituted with an aryl group, preferably a (C1-C6)alkyl optionally substituted with a phenyl.4- The compound according to any one of claims 1 to 3, wherein A is of formula5- The compound according to any one of claims 1 to 4, wherein A is of formula (Al), and at least one, preferably from one to three, of Ri to Rs are not hydrogen atom.6- The compound according to any one of claims 1 to 5, wherein A is of formula (Al), R4 and Rs are hydrogen atoms, and at least one, preferably one or two, of Ri to R3 are not hydrogen atom. 7- The compound according to claim 1, wherein said compound is selected from the group consisting of the compounds recited in the following table, and the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof:8- A pharmaceutical composition compnsing a compound as defined in any one of claims 1 to 7, and a pharmaceutically acceptable excipient.9- The compound according to any one of claims 1 to 7, for use as a medicine.10- The compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8, for use in a method for treating a cancer, preferably a cancer selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer; more preferably for use in a method for treating a pancreatic cancer.11- The compound or pharmaceutical composition for use according to claim 10, wherein said method for treating cancer comprises the combined administration of another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy; preferably the other antitumoral drug is sorafenib.12- A compound of general formula (I), or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, for use in a method for treating a cancer, wherein formula (I) is:wherein:which the wave-shaped line indicates where said group is bound to X.> Ri to R3represent, independently of each other, a radical selected from a group consisting of:• a hydrogen,• a halogen,• a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,• a (C1-C6)alkyloxy optionally substituted by at least one halogen,• -NO2, and• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3- 14 membered ring is optionally substituted by a (C1-C6)alkyl, a hydroxy, a halogen, a -SO2-(C1-C6)alkyl, and a (C1-C6)alkyloxy;> R4, R5 and R7, independently of each other, represent a radical selected from a group consisting of:• a hydrogen,• a halogen,• a ((C1-C12)alkyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a (C2-C6)alkenyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,• a (C2-C6)alkynyl optionally substituted by a (C1-C6)alkyloxy, a hydroxy, at least one halogen, or a cycloalkyl,,• a (C1-C6)alkyloxy optionally substituted by at least one halogen,> Rs is a (C1-C6)alkyl optionally substituted by a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected from a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl; and> X is -NHCONH- or -CONH-.13- The compound for use according to claim 12, wherein A, X and Ri to R7are as defined in any one of claims 2 to 6, preferably the compound is selected from the group consisting of the compounds as defined in claim 7 or as follows, and the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof:14- A combination product comprising:(i) at least one compound as defined in any one of claims 1 to 7 and 12 to 13, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising the same; and(ii) sorafenib.15- The compound as defined in claim 12 or 13 or a pharmaceutical composition comprising the same or the combination product according to claim 14, for use in a method for treating a cancer selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer, preferably for use in a method for treating a pancreatic cancer.16- The compound for use according to any one of claims 12, 13 or 15 or a pharmaceutical composition comprising the same or the combination product according to claim 14, wherein said method for treating cancer comprises the combined administration of another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy, preferably immunotherapy, preferably the other antitumoral drug is sorafenib.17- Use of compound as defined in any one of claims 1 to 7 and 12 to 13, orthe isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising the same or the combination according to claim 14, for the manufacture of a medicament.18- Use of compound as defined in any one of claims 1 to 7 and 12 to 13, orthe isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising the same or the combination according to claim 14, for the manufacture of a medicament for use in a method for treating a cancer, preferably a cancer selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer; more preferably for use in a method for treating a pancreatic cancer.19- The use according to claim 18, wherein said method for treating cancer comprises the combined administration of another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy.20- A method for treating a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of compound as defined in any one of claims 1 to 7 and 12 to 13, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising the same or the combination according to claim 14, to said subject.21- A method for treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of compound as defined in any one of claims 1 to 7 and 12 to 13, or the isomers, stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising the same or the combination according to claim 14, to said subject, wherein the cancer is preferably selected from the group consisting of: pancreatic cancer, hepatocarcinoma, breast cancer, lung cancer, melanoma, colon cancer, glioblastoma, osteosarcoma and prostate cancer; more preferably the cancer is a pancreatic cancer.22- The method of claim 21, further comprising the combined administration of another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and / or radiotherapy.

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