New anticancer compounds

Abstract

The present invention relates to the therapeutic field of cancer. In particular, the invention relates to a compound derived from an aliphatic diamine comprising at least one pyridine or pyrimidine moiety, for use as an anticancer agent, to a therapeutic composition comprising said compound, to a product comprising such a compound and another active ingredient, and to such a compound itself. Figure to be published: Figure 1

Description

Title of the invention: New anticancer compounds

[0001] The present invention applies to the therapeutic field of cancer. In particular, the invention relates to a compound derived from an aliphatic diamine comprising at least one pyridine or pyrimidine motif, for its use as an anticancer agent, to a therapeutic composition comprising said compound, to a product comprising such a compound and another active ingredient, as well as to such a compound.

[0002] Cancer is one of the leading causes of death worldwide. Treatments for cancer are varied and include surgery, radiotherapy, chemotherapy, hormone therapy, immunotherapy, and targeted therapy. Data from basic research show that the plasticity of tumor cells allows them to develop resistance mechanisms to evade these treatments.

[0003] In this context, given the relatively low efficacy of a large majority of conventional anticancer drugs in the treatment of cancers such as prostate, colon, breast, melanoma, and lymphoma, research is focusing on new therapeutic strategies. Indeed, successfully overcoming the resistance problems encountered in this type of disease represents a genuine public health issue and a challenge for research.

[0004] The reconfiguration of energy metabolism is one of the key steps involved in tumor development, particularly in cases of treatment resistance. Specifically, tumor cells adapt to the conditions of their microenvironment and to the selective pressure exerted by chemotherapeutic treatments by adjusting their metabolism. The development of new molecules targeting cellular metabolism is therefore a major therapeutic challenge.

[0005] Mitochondria are organelles that play a key role in cellular metabolism by centralizing ATP production from numerous substrates via oxidative phosphorylation (OXPHOS). The enzymatic reactions involved in this process regulate cell proliferation, differentiation, activation, and self-renewal. Much recent research has demonstrated a correlation between OXPHOS activity (i.e., the activation of mitochondrial metabolism) and chemoresistance and / or tumor progression. In particular, mitochondria are cellular organelles capable of integrating and relaying multiple signals and contributing not only to energy production in the form of ATP but also to the synthesis of macromolecules essential for tumor proliferation. Adaptation to increased OXPHOS activity is a frequently acquired characteristic. during tumor progression, particularly in cases of resistance to chemotherapy.

[0006] Molecules targeting OXPHOS metabolism via various processes have been developed and are being tested in various clinical trials; for example, those blocking the mitochondrial ribosome and indirectly inhibiting the synthesis of respiratory chain complexes (e.g., the antibiotic tigecycline), or those directly inhibiting complex I (e.g., metformin) or complex III (e.g., antimycin A) of the respiratory chain. They exert a synergistic cytotoxic effect with standard treatments. Other pharmacological approaches aimed at blocking 3-oxidation of fatty acids in the mitochondria, or at increasing oxidative stress in OXPHOS malignant cells, have also been proposed.

[0007] More recently, other OXPHOS inhibitors have been described. In particular, a complex I inhibitor known as "IACS-010759" is currently undergoing clinical trials, notably in the field of hematological cancers:

[0008] [Chem.l] ox D

[0009] Furthermore, international application WO2020 / 109506 describes compounds corresponding to the following formula:

[0010] [Chem.2] NH HH in which X1 and X2, identical or different, are NR5 or a sulfur atom, Y is a Ci-Cio alkanediyl group, Ar1 and Ar2, identical or different, are an aryl group possibly substituted, and R5 is a hydrogen atom or a Ci-C6 alkyl group, or a pharmaceutically acceptable salt and / or solvate thereof, for use in cancer treatment. These compounds are described as inhibitors of mitochondrial oxygen consumption and would notably allow the treatment of certain cancers with an "OXPHOS" mechanism.

[0011] In order to meet the growing needs within the framework of a per However, depending on the individual properties of each tumor, there is a persistent need to develop other anticancer agents effective against tumor cells, particularly those targeting the mitochondrial respiratory chain. and consequently having an inhibitory effect on the energy charge of cells. In particular, there is a need to develop molecules with different physicochemical characteristics, acting on other intracellular targets compared to the limited number of OXPHOS inhibitors already developed. These new molecules should be easy to prepare and have improved cytotoxicity properties while ensuring good pharmacokinetic properties such as good ADMET properties (Absorption, Distribution in the body, Elimination including biotransformation or Metabolism, and excretion, and Toxicity), especially in silico.

[0012] Thus, the object of the present invention is to overcome the disadvantages of the aforementioned prior art and to provide an anticancer agent with good performance in terms of anticancer activity, easy to prepare, and having low toxicity on non-tumor cells while ensuring good ADMET properties.

[0013] The object of the invention is achieved by the compounds which will be described below.

[0014] The present invention relates first to a compound selected from among the compounds corresponding to formula (I), their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates, said formula (I) having the following structure:

[0015] [Chem.3] (I) in which: * R1, R2, and R3 represent, independently of each other, a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN (cyano or carbonitrile), -CF3, -CHO (aldehyde), -NH-NH2 (hydrazine), -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR7, a group -NR8R9, a group -SR10, a group -C(O)Rn, a group -CH2OR12, and a group -CH2NR13R14, with R7, R8, R10, R11, R12, and R13 representing, independently of each other, an alkyl or cycloalkyl radical, and R9 and R14 representing, independently of each other, a hydrogen atom, or an alkyl or cycloalkyl radical, * X1 represents a nitrogen atom or a CR15 group, with R15 being a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group chosen from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR7, an -NR8R9 group, an -SR10 group, a -C(O)RH group, a -CH2OR12 group, and a -CH2NR13R14 group, * n is an integer from 1 to 20, * R4 represents a hydrogen atom, an alkyl radical, or a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is bonded, * R5 represents a hydrogen atom, an alkyl radical, or a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is bonded, * Y1 represents -CH2-, -NH-, or -O- when group R4 represents a hydrogen atom or an alkyl radical; and represents -CH- or -N- when group R4 represents a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is bonded. * Y2 represents -CH2-, -NH-, or -O- when group R5 represents a hydrogen atom or an alkyl radical; and represents -CH- or -N- when group R5 represents a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R4 is bonded, and * R6 represents one of the following two groups (lia) and (Ilb):

[0016] [Chem.4] in which R'1, R'2, and R'3 represent, independently of each other, a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR'7, a group -NR'8R'9, a group -SR'10, a group -C(O)R'H, a group -CH2OR'12, and a group -CH2NR'13R'14, with R'7, R'8, R'10, R'11, R'12, and R'13 representing, independently of each other, an alkyl or cycloalkyl radical, and R'9 and R'14 representing, independently of each other, a hydrogen atom, or a radical alkyl or cycloalkyl, and X2 represents a nitrogen atom or a CR'15 group, with R'15 being a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, a radical aryl, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2 H, -CH2OH, -CH2NH2, an alkoxy group -OR'7, a group -NR'8R'9, a group -SR'10, a group -C(O)R'H, a group -CH2OR'12, and a group -CH2NR'13R'14, for its use in the treatment of cancer.

[0017] The compounds (I) of the invention are derivatives of an aliphatic diamine comprising at least one pyridine or pyrimidine motif. The inventors have discovered that such compounds exhibit significant anticancer activity. Furthermore, these compounds are easy to prepare, have low toxicity to healthy cells, and good ADMET properties, particularly in silico.

[0018] The term "cancer" refers to all malignant neoplastic formations, regardless of their histological nature. There are two main categories of solid tumors: carcinomas, of epithelial origin, and sarcomas, of connective tissue origin. Solid tumors are composed of atypical, invasive, or disseminating cells, generally characterized by autonomous growth, indistinct borders, the ability to invade neighboring tissues and vessels, and a tendency to spread through metastasis. Examples include cancers of the breast, prostate, lung, esophagus, skin, bladder, stomach, liver, uterus, colon, and rectum. The other category of tumors encompasses the various types of hematological malignancies.

[0019] The invention has as its second object a compound as defined in the first object of the invention, for (targeted) use in the treatment of cancers having a modified metabolism, in particular in the treatment of cancers with an OXPHOS metabolism.

[0020] A cancer with an OXPHOS metabolism corresponds to a cancer which includes or is made up of cancer cells based mainly on oxidative phosphorylation (OXPHOS) for biosynthetic and / or bioenergetic processes.

[0021] Among such cancers with an OXPHOS metabolism, we find hematological cancers, lung cancers, cervical cancers, prostate cancers, neuroendocrine tumors, glial tumors and skin and eye cancers.

[0022] According to a preferred embodiment of the invention, the compound as defined in the first object of the invention is used in the treatment of lymphomas, in particular adult or pediatric B and T lymphomas; solid tumors such as sarcomas, in particular pediatric sarcomas (e.g. rhabdomyosarcoma type); and certain tumors that recur following chemotherapy treatments.

[0023] The compound as defined in the first object of the invention exerts antitumor activity in one or more preclinical models.

[0024] The term “lymphoma” means any tumor, generally malignant, due to a proliferation of formation of lymphoid tissue cells, developing in the spleen or lymph nodes, but also in many other organs or tissues.

[0025] The compound as defined in the first object of the invention thus exhibits the potential properties of a new anticancer drug targeting cellular metabolism.

[0026] In particular, it acts as a mitochondrial respiratory chain inhibitor and inhibits oxygen consumption. It can therefore be considered an OXPHOS inhibitor. Furthermore, it possesses: - cytotoxic activity in vitro, competitive with OXPHOS inhibitors already in clinical trials, particularly with "IACS-010759", and - a specificity of action linked to the cellular phenotype.

[0027] In the compound as defined in the first object of the invention, the alkyl radical may be linear or branched, and it is preferably linear.

[0028] In the compound as defined in the first object of the invention, the cy-cloalkyl radical may be linear or branched, and it is preferably linear.

[0029] In the context of the present invention, a halogen is chosen from F, Cl, Br and I, and particularly preferably from F and Cl.

[0030] Definition of R1, R2, R3

[0031] R1, R2, and R3 represent, independently of each other, an atom hydrogen, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN (carbonitrile or cyano), -CF3, -CO2H, -CH2OH, -CH2NH2, -CHO (aldehyde), -NH-NH2 (hydrazine), an alkoxy group -OR7, a group -NR8R9, a group -SR10, a group -C(O)Rn, a group -CH2OR12, and a group -CH2NR13R14, with R7, R8, R10, R11, R12, and R13 representing, independently of each other, an alkyl or cycloalkyl radical, and R9 and R14 representing, independently of each other, a hydrogen atom, or an alkyl or cycloalkyl radical.

[0032] The alkyl radical as group R1, R2 or R3 is preferably a Ci-C5 alkyl radical, and particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0033] The cycloalkyl radical as group R1, R2 or R3 is preferably a C3-C6 cycloalkyl radical, particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0034] The aryl radical as group R1, R2 or R3 is preferably a C5-C15 aryl radical, particularly preferably a phenyl, 2- or 3-thienyl, 2- or 3-furyl radical, and more particularly preferably a phenyl radical.

[0035] Definition of R7, R8, R9, R10, R11, R12, R13 and R14

[0036] The alkyl radical as group R7, R8, R9, R10, R11, R12, R13 or R14 is preferably a C1-C5 alkyl radical, and particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0037] The cycloalkyl radical as group R7, R8, R9, R10, R11, R12, R13 or R14 is preferably a C3-C6 cycloalkyl radical, particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0038] The -SR10 group is preferably a thiomethyl group.

[0039] The -NR8R9 group is preferably a methylamine or dimethylamine group.

[0040] The alkoxy group -OR7 is preferably a methoxy or ethoxy group.

[0041] According to a particularly preferred embodiment of the invention, R1 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR7, an -SR10 group, a -CN group, a -CF3 group, an -NR8 R9 group, an -NH-NH2 group, a -CO2H group, or a -CHO group.

[0042] According to a particularly preferred embodiment of the invention, R2 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR7, an -SR10 group, a -CN group, a -CF3 group, an -NR8 R9 group, an -NH-NH2 group, a -CO2H group, or a -CHO group.

[0043] According to a particularly preferred embodiment of the invention, R3 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR7, an -SR10 group, a -CN group, a -CF3 group, an -NR8 R9 group, an -NH-NH2 group, a -CO2H group, or a -CHO group.

[0044] Advantageously, R1, R2 and R3 are hydrogen atoms.

[0045] Definition of X1

[0046] X1 represents a nitrogen atom or a CR15 group, with R15 being a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR7, a group -NR8R9, a group -SR10, a group -C(O)Rn, a group -CH2OR12, and a group -CH2NR13R14.

[0047] Groups R7, R8, R9, R10, R11, R12, R13 and R14 are as defined in the invention.

[0048] According to a particularly preferred embodiment of the invention, R15 is a hydrogen atom, halogen atom, alkyl radical, cycloalkyl radical, alkoxy group -OR7, -SR10 group, -CN group, -CF3 group, -NR8 R9 group, -NH-NH2 group, -CO2H group, or -CHO group.

[0049] Advantageously, X1 represents a nitrogen atom or a CH group.

[0050] Definition of R4 and R5

[0051] R4 represents a hydrogen atom, an alkyl radical, or a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is connected.

[0052] The alkyl radical as group R4 is preferably a C1-C5 alkyl radical, and particularly preferably a methyl or ethyl radical.

[0053] The divalent alkylene radical forming a ring with Y1 and the nitrogen atom to which R4 is connected as group R4 is preferably an alkylene radical -(CH2)2- or -(CH2)3-, and particularly preferably an alkylene radical -(CH2)2-.

[0054] Preferably, R4 represents a hydrogen atom or a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is connected.

[0055] R5 represents a hydrogen atom, an alkyl radical, or a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is connected.

[0056] The alkyl radical as group R5 is preferably a Ci-C5 alkyl radical, and particularly preferably a methyl, ethyl, propyl or butyl radical.

[0057] The divalent alkylene radical forming a ring with Y2 and the nitrogen atom to which R2 is connected as group R2 is preferably an alkylene radical -(CH2)2- or -(CH2)3-, and particularly preferably an alkylene radical -(CH2)2-.

[0058] Preferably, R5 represents a hydrogen atom or a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is connected.

[0059] According to a particularly preferred embodiment of the invention, R4 represents a hydrogen atom or a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is connected: and R5 represents a hydrogen atom or a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is connected.

[0060] According to a particularly preferred embodiment of the invention, R4 and R5 are identical.

[0061] Definition of Y1 and Y2

[0062] Y1 represents -CH2-, -NH-, or -O- when the group R4 represents a hydrogen atom, or an alkyl radical; and represents -CH- or -N- when the group R4 represents a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is connected.

[0063] Preferably, Y1 represents -CH2- when the group R4 represents a hydrogen atom, or an alkyl radical; and represents -N- when the group R4 represents a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is connected.

[0064] Y2 represents -CH2-, -NH-, or -O- when the group R5 represents a hydrogen atom, or an alkyl radical; and represents -CH- or -N- when the group R5 represents a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is linked.

[0065] Preferably, Y2 represents -CH2- when group R5 represents a hydrogen atom, or an alkyl radical; and represents -N- when group R5 represents a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is attached.

[0066] According to a particularly preferred embodiment of the invention, Y1 represents -CH2- when group R4 represents a hydrogen atom, or an alkyl radical; and represents -N- when group R4 represents a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is connected; and Y2 represents -CH2- when group R5 represents a hydrogen atom, or an alkyl radical; and represents -N- when group R5 represents a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is connected.

[0067] According to a particularly preferred embodiment of the invention, Y1 and Y2 are identical.

[0068] Definition of n

[0069] n is an integer from 1 to 20, and preferably from 1 to 14.

[0070] Definition of Y1, Y2 in relation to n

[0071] According to a preferred embodiment of the invention: - when Y1 (respectively Y2) represents -CH2-, n preferably goes from 2 to 10, and particularly preferably from 3 to 9, - when Y1 (respectively Y2) represents -N-, -NH-, -CH- or -O-, n preferably goes from 6 to 18, and particularly preferably from 7 to 14.

[0072] This embodiment is particularly appropriate when R6 is a group of formula (Ha).

[0073] When Y1 and Y2 represent -CH-, and R6 is a group of formula (lia), then n is preferably such that n > 5 and / or R1, R'1, R2, R'2, R3, and R'3 are preferably different from -NH2

[0074] When Y1 and Y2 represent -N-, and R6 is a group of formula (Ha), then n is preferably such that n > 7.

[0075] According to a preferred embodiment of the invention, when Y1 and Y2 represent -CH-, and R6 is a group of formula (Ha), then n is such that n > 5 and / or R1, R'1, R2, R'2, R3, and R'3 are different from -NH2; and when Y1 and Y2 represent -N-, and R6 is a group of formula (lia), then n is such that n > 7.

[0076] Definition of R6

[0077] R6 represents one of the following two groups (lia) and (Ilb): (Ilb) in which R'1, R'2, and R'3 represent, independently of each other, a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR'7, a group -NR'8R'9, a group -SR'10, a group -C(O)R'H, a group -CH2OR'12, and a group -CH2NR'13R'14, with R'7, R'8, R'10, R'11, R'12, and R'13 representing, independently of each other, an alkyl or cycloalkyl radical, and R'9 and R'14 representing, independently of each other, a hydrogen atom, or a radical alkyl or cycloalkyl, and X2 represents a nitrogen atom or a CR'15 group, with R'15 being a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR'7, a group -NR'8R'9, a group -SR'10, a group -C(O)R'n, a group -CH2OR'12, and a group -CH2NR'13R'14.

[0079] R6 is preferably a formula group (Ilb).

[0080] Definition of R'1, R'2, R'3

[0081] The alkyl radical as group R'1, R'2 or R'3 is preferably a Ci-C5 alkyl radical, and particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0082] The cycloalkyl radical as group R'*, R'2 or R'3 is preferably a C3-C6 cycloalkyl radical, and particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0083] The aryl radical as group R'1, R'2 or R'3 is preferably a C5-C15 aryl radical, and particularly preferably a phenyl, 2- or 3-thienyl, 2- or 3-furyl radical, and more particularly preferably a phenyl radical.

[0084] Definition of R'7, R'8, R'9, R'10, R'11, R'12, R'13 and R'14

[0085] The alkyl radical as group R'7, R'8, R'9, R'10, R'11, R'12, R'13 or R'14 is preferably a C1-C5 alkyl radical, and particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0086] The cycloalkyl radical as group R'7, R'8, R'9, R'10, R'11, R'12, R'13 or R'14 is preferably a C3-C6 cycloalkyl radical, and particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0087] The -SR'10 group is preferably a thiomethyl group.

[0088] The -NR'8R'9 group is preferably a methylamine or dimethylamine group.

[0089] The alkoxy group -OR'7 is preferably a methoxy or ethoxy group.

[0090] According to a particularly preferred embodiment of the invention, R'1 is a hydrogen atom, halogen atom, alkyl radical, cycloalkyl radical, alkoxy group -OR7, -SR10 group, -CN group, -CF3 group, -NR8 R9 group, -NH-NH2 group, -CO2H group, or -CHO group.

[0091] According to a particularly preferred embodiment of the invention, R'2 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR7, an -SR10 group, a -CN group, a -CF3 group, an -NR8 R9 group, an -NH-NH2 group, a -CO2H group, or a -CHO group.

[0092] According to a particularly preferred embodiment of the invention, R'3 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR7, an -SR10 group, a -CN group, a -CF3 group, an -NR8 R9 group, an -NH-NH2 group, a -CO2H group, or a -CHO group.

[0093] Advantageously, R'1, R'2 and R'3 are hydrogen atoms.

[0094] Definition of X2

[0095] X2 represents a nitrogen atom or a CR'15 group, with R'15 being a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR'7, a group -NR'8R'9, a group -SR'10, a group -C(O)R'n, a group -CH2OR'12, and a group -CH2NR'13R'14.

[0096] Groups R'7, R'8, R'9, R'10, R'11, R'12, R'13 and R'14 are as defined in the invention.

[0097] According to a particularly preferred embodiment of the invention, R'15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR7, an -SR10 group, a -CN group, a -CF3 group, an -NR8 R9 group, an -NH-NH2 group, a -CO2H group, or a -CHO group.

[0098] Advantageously, X2 represents a nitrogen atom or a CH group.

[0099] According to a preferred embodiment of the invention, the compound of formula (I) is chosen from the following compounds:

[0100] [Tables] Name Expanded Formula Compound the NM ,,-x fs. Ij / -f 'V -X-- \ u. V—N (there) Compound Ib < K XS .-x -XA Xx X' -X.-' -V '-x' X-" '•X' XX- x^-' MCI HCi hf ''''t N OW Compound the '■N"' ■ • ' ' 'vz "x. •' XX vxN.x L .à. HC! HCI ''J: de)

[0101] The term "pharmaceutically acceptable" means that which is useful for the preparation of a pharmaceutical composition, and that which is generally safe and non-toxic, for pharmaceutical use.

[0102] By pharmaceutically acceptable salt or solvate of a compound is meant a salt or solvate that is pharmaceutically acceptable as defined above, and that possesses the pharmacological activity of said compound.

[0103] Pharmaceutically acceptable salts include: - acid addition salts formed with inorganic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid; or formed with organic acids such as formic acid, acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, propionic acid, succinic acid, muconic acid, 2-naphthalenesulfonic acid, tartaric acid, dibenzoyl acid L-tartaric acid, para-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, benzoic acid, citric acid, ethanesulfonic acid, lactic acid, mucic acid, pamoic acid, or pantothenic acid—salts formed when an acidic proton present in the compound is either replaced by a metal ion, such as an ion of an alkali metal, an alkali earth metal, or an aluminum ion; or coordinated with an inorganic or organic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, and tromethamine. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0104] Solvates acceptable for the therapeutic use of the compounds of the invention include conventional solvates such as those formed during the last step of preparation of these compounds due to the presence of solvents. Examples include solvates bound to the presence of water (these solvates are also called hydrates) or ethanol.

[0105] Due to their anticancer activity, the compounds as defined in the first object of the invention are useful in therapy.

[0106] The invention has as its third object a pharmaceutical composition comprising a compound as defined in the first object of the invention and at least one suitable pharmaceutical vehicle.

[0107] The appropriate pharmaceutical vehicle may be a pharmaceutically acceptable excipient for use in the treatment of cancer, and in particular in the treatment of cancers with altered metabolism, and preferably cancers with OXPHOS metabolism.

[0108] The pharmaceutical composition may be a solid composition or a liquid composition.

[0109] The solid composition may be in the form of tablets, capsules, powders, or granules.

[0110] The tablets may comprise the compound as defined in the first object of the invention mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, or similar substances. The resulting mixture may, in particular, be compressed.

[0111] The tablets may be coated with sucrose, sucrose, or other suitable materials or may be treated in such a way that they have a prolonged or delayed activity and continuously release a predetermined amount of compound.

[0112] The powders or granules may be dispersible in water. They may contain the compound as defined in the first object of the invention in a mixture with dispersing agents, wetting agents, or suspending agents, including taste correctors or sweeteners.

[0113] The capsules may comprise the compound as defined in the first object of the invention mixed with a diluent. The capsules may be soft or hard capsules.

[0114] The liquid composition may be in the form of an aqueous suspension or solution, a syrup, or an elixir.

[0115] It may in particular include the compound as defined in the first object of the invention in a solvent such as water, as well as optionally a sweetener, a flavoring agent, and / or a suitable color.

[0116] The liquid composition can in particular be obtained by dissolving or suspending a powder or granules such as the above in a liquid such as water, fruit juice, milk, etc.

[0117] The pharmaceutical composition is preferably sterile. It may be in the form of an isotonic solution (in particular compared to blood).

[0118] The compound as defined in the first object of the invention or the pharmaceutical composition according to the third object of the invention can thus be implemented in a method of therapeutic treatment of cancer, said method comprising the administration to an individual of an effective quantity of said compound as defined in the first object of the invention (or of a pharmaceutically acceptable salt or solvate of said compound) or the administration of an effective quantity of said pharmaceutical composition according to the third object of the invention.

[0119] The individual is the patient who requires treatment, such as a mammal, in particular a human.

[0120] The compound or pharmaceutical composition can be administered to mammals, including humans, by nasal, enteral (e.g., oral) or parenteral (e.g., intravenous) route.

[0121] The dosage varies according to the treatment and the condition involved. Appropriate unit forms of administration include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal forms of administration, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

[0122] The compound as defined in the first object of the invention can be used in therapy alone, or in combination with at least one other active agent.

[0123] The invention has as its fourth object a product comprising a compound as defined in the first object of the invention and another active agent.

[0124] The compound as defined in the first object of the invention and the other active agent are then used in combination, particularly for simultaneous, separate, or time-stretched use in therapy.

[0125] These other active agents are specifically chosen from among those suitable for the treatment of cancers. They may be adjuvants that enhance the activity of the compounds according to the invention, or other active agents known for their use in the treatment of said conditions. Such active agents are well known to those skilled in the art, are commercially available, or are described in reference works such as the Vidal Dictionary, published with annual updates, particularly the active agents grouped under the pharmacotherapeutic families "Cancer and Hematology".

[0126] Certain compounds as defined in the first object of the invention are novel in themselves and represent the fifth object of the invention: these compounds are chosen from among the compounds corresponding to formula (I'), their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates, said formula (I') having the following structure:

[0127] [Chem.6] in which: * R1, R2, R3, R4, R5, R6, X1, Y1, Y2, and n are as defined in the first object of the invention for formula (I), it being understood that: * when Y1 and Y2 represent -CH-, and R6 is a radical of formula (Ha), then n > 5 and / or R1, R'1, R2, R'2, R3, and R'3 are different from -NH2, and * when Y1 and Y2 represent -N-, and R6 is a radical of formula (Ha), then n > 7.

[0128] Other features, variants and advantages of the compound, its use, or the pharmaceutical composition according to the invention will become clearer from reading the following examples of embodiment, given by way of illustration and not limitation of the invention. Examples

[0129] Flash column chromatography was performed on silica gel 60 (0.063-200 mm).

[0130] Nuclear magnetic resonance spectra (¹H NMR and ¹³C NMR) have been in Recorded at 25 °C with a spectrometer (Bruker Avance III) (¹H NMR at 400 MHz, ¹³C NMR at 100 MHz) using CD30D as the reference solvent relative to residual CH3OH (ΔH = 3.31 ppm, ΔC = 49.00 ±0.01 ppm) and DMSO-t / 6 as the reference solvent relative to residual DMSO (ΔH = 2.50 ppm, ΔC = 39.52 ±0.06 ppm). Chemical shifts are given in ppm and coupling constants (J) in Hertz. The data for the 'H NMR spectra are reported as follows: chemical shift ppm (s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet of doublets of doublets, m = multiplet, coupling constants, integration). Brief description of the drawings

[0131] The accompanying drawings illustrate the invention.

[0132] [Fig-1] shows the oxygen consumption after treatment of cells from a cell line of human B lymphoma with compounds according to the invention and prior art compounds.

[0133] [Fig.2] shows the effect on cell growth of treating human tumor cells, a B lymphoma cell line with compounds according to the invention and prior art compounds.

[0134] [Fig.3] shows the effect on cell growth of treating human tumor cells from a wide range of B and T lymphoma cell lines with a compound according to the invention and a compound of the prior art.

[0135] [Fig.4] shows the antitumor efficacy of a compound of the invention in an in ovo model.

[0136] [Fig.5] shows the effect on cell growth of treating human cells from two sarcoma cell lines with compounds of the invention. Example 1: Synthesis of compound la

[0137] The compound was prepared according to the steps illustrated in the following diagram:

[0138] [Chem.7] : H8r NA i + NH. î / D' \ T rn -■ '•N"" VN

[0139] First step: synthesis of the derivative Af-pyrimidin-2-yldodecane-1,12-diamine

[0140] To a solution of 1 g (4.99 mmol) of 1,12-dodecanediamine in 30 mL of dioxane, 0.8 equivalents (3.99 mmol; 457.2 mg) of 2-chloropyrimidine and 5 equivalents (24.95 mmol; 3.45 g) of potassium carbonate are added. The reaction mixture is heated under reflux of dioxane for 16 h. After cooling, the dioxane is concentrated under reduced pressure. The residue obtained is resuspended in 50 mL of ethyl acetate, washed once with a saturated sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The derivative obtained is purified by silica gel chromatography with ethyl acetate / methanol / triethylamine as the eluent according to a gradient (98 / 0 / 2; 60 / 10 / 10; 70 / 20 / 10; 60 / 30 / 10).

[0141] The expected compound is obtained with a yield of 53% and is in the form of a yellow solid.

[0142] It has the following characteristics:

[0143] Melting point = 86°C

[0144] Molar mass = Ci6H3oN4: 278.43 g / mol

[0145] 'H NMR (CD3OD): 8.26 (d; J = 4.8 Hz; 2H); 6.59 (t; J = 4.9 Hz; 1H); 3.38-3.34 (m; 2H); 2.84-2.76 (m; 2H); 1.66-1.53 ​​(m; 4H); 1.41-1.33 (m; 16H).

[0146] 13C NMR (CD3OD): 162.1; 157.9 (2C); 109.6; 40.8; 40.1; 29.3; 29.3; 29.3; 29.3; 29.2; 29.1; 29.1; 29.0; 26.6; 26.3.

[0147] Second step: synthesis of the derivative A'-(4,5-dihydro-l / / -imidazol-2-yl)-A-pyrimidin-2-yl-dodecane-1,12-diamine

[0148] To a solution of 100 mg (0.36 mmol) of N' - Pyrimidin-2-yldodecane-1,12-diamine, as prepared in the previous step, is mixed with 1.05 equivalents (0.38 mmol) of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole hydrobromide. The reaction mixture is heated under reflux of ethanol for 3 days. After cooling, the reaction mixture is filtered, and the filtrate is concentrated under vacuum. The resulting derivative is purified by silica gel chromatography using dichloromethane / methanol (92 / 8) as the eluent.

[0149] The expected compound is obtained with a yield of 40% and is in the form of a yellow solid.

[0150] It has the following characteristics:

[0151] Melting point = 90 °C

[0152] Molar mass = Ci9H34N6: 346.51 g / mol

[0153] 'H NMR (CD3OD): 8.14 (d; J=4.9 Hz; 2H); 6.47 (t; J = 4.8 Hz; 1H); 3.61 (s; 4H); 3.25 - 3.22 (m; 2H); 3.14 - 3.06 (m; 2H); 1.53 - 1.45 (m; 4H); 1.31 - 1.18 (m; 16H).

[0154] 13C NMR (CD3OD): 162.1; 159.9; 157.8 (2C); 109.6; 42.6; 42.5; 40.8; 40.5; 29.3; 29.2; 29.2; 29.2; 29.1; 29.1; 28.9; 28.8; 26.6; 26.3. Example 2: Synthesis of compound Ib

[0155] Compound Ib was prepared according to the steps illustrated in the following diagram:

[0156] [Chem.8]

[0157] First step: synthesis of the derivative 2-[4-[12-(4-pyrimidin-2-ylpiperazin-l-yl)dodecyl]piperazin-l-yl]pyrimidine

[0158] To a solution of 700 mg (2.13 mmol) of 1,12-dibromododecane in 30 mL of dioxane, 2 equivalents (4.26 mmol; 700.5 mg) of 2-piperazin-l-ylpyrimidine and 7 equivalents (14.94 mmol; 2.1 g) of potassium carbonate are added. The reaction mixture is heated under reflux of dioxane for 20 h. After cooling, the dioxane is concentrated under reduced pressure. The resulting residue is resuspended in 50 mL of ethyl acetate, washed once with a saturated sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The derivative obtained is purified by silica gel chromatography with ethyl acetate / methanol / triethylamine (99 / 0.5 / 0.5) as the eluent.

[0159] The expected compound is obtained with a yield of 64% and is in the form of a white solid.

[0160] It has the following characteristics:

[0161] Melting point = 106°C

[0162] Molar mass = C28H46N8: 494.72 g / mol

[0163] 'H NMR (CD3OD): 8.23 ​​(d; J = 4.7 Hz; 4H); 6.40 (t; J = 4.7 Hz; 2H); 3.84 -3.67 (m; 8H); 2.49 - 2.35 (m; 8H); 2.35 - 2.21 (m; 4H); 1.54 - 1.37 (m; 4H); 1.32 - 1.11 (m; 16H).

[0164] 13C NMR (CD3OD): 161.7 (2C); 157.7 (4C); 109.8 (2C); 59.0 (2C); 53.2 (4C); 43.7 (4C); 29.6 (6C); 27.6 (2C); 26.9 (2C).

[0165] Second step: synthesis of the derivative 2-[4-[12-(4-pyrimidin-2-ylpiperazin-l-yl)dodecyl]piperazin-l-yl]pyrimidine dihydro- chloride

[0166] 150 mg (0.30 mmol) of 2-[4-[12-(4-pyrimidin-2-ylpiperazin-l-yl)dodecyl]piperazin-l-yl]pyrimidine are dissolved in 5-10 mL of ethanol. Hydrochloric acid gas is bubbled through the reaction mixture for 5 minutes. After stirring, the precipitate is collected by filtration, washed with diethyl ether, and dried. The expected compound is obtained in 87% yield and is a white solid.

[0167] It has the following characteristics:

[0168] Melting point = 252°C

[0169] Molar mass = C28H46N8.2HC1: 567.64 g / mol

[0170] 'H NMR (DMSO-d6): 11.49 (s; 2H); 8.44 (d; J = 4.8 Hz; 4H); 6.76 (t; J=4.8 Hz; 2H); 4.67 (d; J = 14.1 Hz; 4H); 3.52 (d; J = 12.4 Hz; 8H); 3.07 - 2.99 (m; 8H); 1.79 - 1.73 (m; 4H); 1.35 - 1.30 (m; 16H).

[0171] 13C NMR (DMSO-d6): 161.2 (2C); 158.5 (4C); 111.7 (2C); 56.2 (2C); 50.9 (4C); 40.8 (4C); 29.3 (2C); 29.1 (2C); 28.9 (2C); 26.6 (2C); 23.4 (2C). Example 3: Synthesis of compound le

[0172] The compound was prepared according to the steps illustrated in the following diagram:

[0173] [Chem.9] (ic)

[0174] First step: synthesis of the derivative l-(2-pyridyl)-4-[12-[4-(2-pyridyl)piperazin-l-yl]dodecyl]piperazine

[0175] To a solution of 700 mg (2.13 mmol) of 1,12-dibromododecane in 30 mL of dioxane, 2 equivalents (4.26 mmol; 696.3 mg) of l-(2-pyridyl)piperazine and 7 equivalents (14.94 mmol; 2.1 g) of potassium carbonate are added. The reaction mixture is heated under reflux of dioxane for 20 h. After cooling, the dioxane is concentrated under reduced pressure. The residue obtained is resuspended in 50 mL of ethyl acetate, washed once with a saturated sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The resulting derivative is purified by silica gel chromatography with ethyl acetate / methanol / triethylamine (99 / 0.5 / 0.5) as eluent.

[0176] The expected compound is obtained with a yield of 48% and is in the form of a white solid.

[0177] It has the following characteristics:

[0178] Melting point = 100°C

[0179] Molar mass = C30H48N6: 492.74 g / mol

[0180] 'H NMR (CD3OD): 8.12 (ddd; J=4.9; 2.0; 0.9 Hz; 2H); 7.40 (ddd; J= 8.9; 7.1; 2.0 Hz; 2H); 6.60 - 6.51 (m; 4H); 3.48 (dd; J = 6.2; 4.1 Hz; 8H); 2.54 - 2.42 (m; 8H); 2.34 - 2.25 (m; 4H); 1.52 - 1.38 (m; 4H); 1.30 - 1.14 (m; 16H).

[0181] 13C NMR (CD3OD): 159.6 (2C); 148.0 (2C); 137.1 (2C); 113.2 (2C); 107.0 (2C); 59.0 (2C); 53.2 (4C); 45.2 (4C); 29.6 (6C); 27.6 (2C); 26.9 (2C).

[0182] Second step: synthesis of the derivative l-(2-pyridyl)-4-[12-[4-(2-pyridyl)piperazin-l-yl]dodecyl]piperazine dihydrochloride

[0183] 150 mg (0.30 mmol) of l-(2-pyridyl)-4-[12-[4-(2-pyridyl)piperazin-l-yl]dodecyl]piperazine are dissolved in 5-10 mL of ethanol. Hydrochloric acid gas is bubbled through the reaction mixture for 5 minutes. After stirring, the precipitate is collected by filtration, washed with diethyl ether, and dried. The expected compound is obtained in 91% yield and is a white solid.

[0184] It has the following characteristics:

[0185] Melting point = 200°C

[0186] Molar mass = C30H48N6.2HCl: 565.66 g / mol

[0187] NMR *H (DMSO-J6): 11.41 (s; 2H); 8.13 (dd; J = 5.8; 1.8 Hz; 2H); 7.94 (t; J = 8.2 Hz; 2H); 7.30 (d; J = 9.0 Hz; 2H); 6.96 (t; J = 6.4 Hz; 2H); 4.48 (d; J = 8.2 Hz; 4H); 3.63 - 3.57 (m; 8H); 3.05 -3.17 (m; 8H); 1.82 - 1.68 (m; 4H); 1.31 - 1.28 (m; 16H).

[0188] 13C NMR (DMSO-J6): 155.3 (2C); 142.7 (2C); 141.7 (2C); 114.4 (2C); 110.9 (2C); 56.1 (2C); 50.5 (4C); 43.2 (4C); 29.3 (2C); 29.1 (2C); 28.9 (2C); 26.6 (2C); 23.4 (2C).

[0189] Example 4 of use of compounds (la), (Ib), and (le) as carcinogenic agents

[0190] 4.1 Analysis by Seahorse technology of oxygen consumption after treatment of cells from a human B-cell lymphoma cell line with compounds (a). (Ib) and (a)

[0191] The analyzer known as "Seahorse" allows for the real-time assessment of mitochondrial respiration by measuring oxygen consumption (also known by the acronym OCR for "oxygen consumption rate"). The experiments were performed following the supplier's recommendations ("Agilent_Seahorse"). XFe96”). To do this, 150,000 cells per well of a human B-cell lymphoma cell line (“RL cell line, CVCL_1660”) were seeded in 180 µL of “Agilent_Seahorse XF RPMI” medium (supplemented with pyruvate and glucose) on a dedicated “Agilent_Seahorse 96-well plate,” pre-treated with a “CellTak” solution according to the manufacturer’s (Corning) recommendations. After 30 min of incubation in a CO2-free incubator, the plate was analyzed with “Seahorse” using a protocol allowing the injection (indicated by arrows in [Fig. 1]) of increasing amounts of the compound to obtain a final cumulative concentration of 1.2 pM, 2.5 pM, 5 pM, and 10 pM, followed each time by an OCR reading (in pmol / min) for 10 min. Data normalization was performed by cell counting, using the device known as "Cytation 1 / 5 Cell Imaging Multi-Mode reader" (BioTek Instruments, Inc) coupled with the "Seahorse".

[0192] Figure 1 shows the effect on mitochondrial respiration of several compounds: a reference inhibitor, Rotenone (Fig. 1a, ROT, curve with inverted empty triangles), the inhibitor known as "IACS-010759" currently being evaluated in a clinical trial (Fig. 1a, IACS, curve with filled diamonds), compound (la) (Fig. 1b, curve with inverted filled triangles), compound (Ib) (Fig. 1b, curve with empty circles), and compound (le) (Fig. 1b, curve with filled circles). A control (DMSO, curve with filled squares) is used in each figure and corresponds to the medium studied without the addition of any compound (only its diluent, DMSO, was added). In [Fig.1] a, the injection of a concentration of 1.2 pM induces an instantaneous and almost total inhibition of OCR, similarly for the two comparative compounds not in accordance with the invention: Rotenone and "IACS-010759".Furthermore, the injection of increasing concentrations of compounds according to the invention induces a progressive inhibition of OCR, similarly and in stages for compounds (Ib) and (le), and progressively for compound (la). Near-total inhibition of OCR is obtained with a concentration of 10 pM.

[0193] In conclusion, compounds (la), (Ib) and (le) behave as inhibitors of mitochondrial respiration (= also known as OXPHOS inhibitors), with a moderate and gradual effect compared to rotenone or IACS-010759. Equivalent results are obtained for the various cell lines tested.

[0194] 4.2 Analysis of the effect of tumor cell treatment on cell growth human, from a B-cell lymphoma cell line with the compounds (la). (Ib) and (le)

[0195] Cells from a human B-cell lymphoma cell line (“Karpas422, CVCL_1325”) were seeded at a density of 100,000 cells per well in a 96-well plate in the presence of a 10 pM concentration of compound, in a volume of 100 µL of medium. After 48 hours of treatment, analyses of the effect on cell growth were carried out either by counting cells in flow cytometry ([Fig.2] a), or by using a live cell detection kit ([Fig.2] b).

[0196] Figure 2 shows the effect on cell growth of treating cells in a conventional "Gibco RPMI1640 / 10% SVF" medium (referred to as RPMI), with the compounds (la), (Ib), and (le) according to the invention ([Fig. 2] a); and in a "Gibco Human Like Plasma Medium" (Gibco HPLM_Thermo Fisher Scientific) (referred to as HLPM), mimicking the metabolic conditions of human plasma, with the compounds (la), (Ib), and (le) according to the invention and with four comparator compounds not according to the invention: "IACS-010759" (referred to as IACS), an inhibitor known under the reference "IM156" currently in clinical trial, Rotenone (referred to as ROT), and an apoptosis inducer staurosporine (referred to as STS) ([Fig. 2] b). In the classic “Gibco RPMI1640 / 10% SVF” medium, the number of live cells was determined after double AnnexinV / PI labeling, and cytometer analysis known as “ATTUNE” (Thermo Fisher Scientific).In the "Gibco Human Like Plasma Medium", the number of live cells was assessed using the kit. “CellTiterFluor” from Promega. The term noted DMSO on [Fig.2] corresponds to the control, i.e. identical medium without addition of compound.

[0197] According to [Fig. 2], compounds (a), (Ib), and (e) inhibit cell growth by reducing the number of live tumor cells after 48 hours of treatment, even under culture medium conditions mimicking human plasma. The efficacy is similar to that obtained with the inhibitor "IACS-010759" or rotenone. This effect is cell line dependent (see [Fig. 2] b).

[0198] 4.3 Analysis of the effect of tumor cell treatment on cell growth human from a wide range of B and T lymphoma cell lines with the compound (the)

[0199] Analysis of the effect on cell growth of the compound (la) according to the invention compared to the compound "IACS-010769" (referred to as IACS) not according to the invention was conducted on a large series of 31 human B and T lymphoma cell lines, after AnnexinV / PI labeling and analysis using the "ATTUNE" cytometer (Thermo Fisher Scientific). This technology allows, in parallel with the number of live cells shown in [Fig. 2], the evaluation of the percentage of cells undergoing apoptosis. The results are shown in [Fig. 3] as a heat map, with a black and white gradient, black representing the highest percentage of cells undergoing apoptosis.

[0200] According to [Fig. 3], the toxicity of compounds (la) and “IACS-010759” varies depending on the lymphoma cell lines analyzed. In particular, the toxicity of compound (la) is increased compared to that of “IACS-010759” for a subgroup of 8 cell lines highlighted in the diagram. These data confirm that these two compounds have different metabolic targeting and modes of action.

[0201] 4.4 Analysis of the antitumor efficacy of compound (la) in an in ovo model

[0202] Preclinical evaluation analyses of the anti-tumor efficacy of the compound (la) were conducted using the chicken embryo chorioallantoic membrane (CAM) xenograft model. Figure 4 shows the implantation of human tumor cells from a B-cell lymphoma cell line (“SUDHL-4, CVCL_0539”) onto the upper CAM of an embryo on day E9 (Fig. 4a), along with the indication of the presence or absence of a tumor mass (Fig. 4b), and the relative quantity of metastases (Fig. 4c). Treatments were performed on days E1, E13, E15, and E17. On day El8, the upper portions of CAM containing tumors were collected and weighed, and the lower CAM fragments were used to assess by RT-qPCR (polymerase chain reaction from an RNA sample) the presence of human cells indicative of metastases.Doxorubucine (DOXO) at 0.0097 mg / kg was used as a positive control for treatment efficacy. The compound was used at three different doses [1]: 0.05 mg / kg, [2]: 0.15 mg / kg, and [3]: 0.45 mg / kg, and IACS-010759 was used at two different doses [1]: 0.05 mg / kg, and [2]: 0.45 mg / kg. The negative control (denoted DMSO) represents treatment with the diluent of DMSO molecules.

[0203] In [Fig. 4] b, the effect of the treatment on tumor volume is directly observed. Treatment with doxorubucine induces a 90% regression of the primary tumor volume. Comparatively, treatment with "IACS-010759" (noted as IACS) induces a regression of 44% [1] and 82% [2], and treatment with the compound (la) induces a regression of 48% [1], 73% [2], and 70% [3].

[0204] In [Fig. 4] c, the effect of treatment on the relative quantity of metastases is directly observed. Treatment with doxorubucine induces a 99% regression in the number of metastases. Comparatively, treatment with "IACS-010759" (noted as IACS) induces a regression of 69% [1] and 73% [2], and treatment with the compound (la) induces a regression of 45% [1], 70% [2], and 72% [3].

[0205] In conclusion, the compound (a), which is chemically different and acts differently on OCR, has antitumor efficacy comparable to that of the molecule "IACS-010759" in the preclinical model used in this example. The compound (a) also inhibits tumor dissemination.

[0206] 4.5 Analysis of the effect on cell growth of human cell treatment of two sarcoma lines with compounds (la), (Ib) and (le)

[0207] Human tumor cells from two rhabdomyosarcoma-like sarcoma cell lines (“RD136, CVCL_1649”, [Fig. 5] a and “RH30, CVCL_0041”, [Fig. 5] b) were seeded in 96-well plates with a 10 pM concentration of compound, in a volume of 100 µL of “Gibco Human Like Plasma Medium” (Gibco HPLM_Thermo Fisher Scientific). The effect of compounds (a), (Ib) and (a) was compared to the inhibitors "IACS-010759" (noted as IACS) and "IM156" (a metformin analog) currently in clinical trials, Rotenone (noted as ROT), and the apoptosis inducer staurosporine (noted as STS). After 48 hours of treatment, the effect on the number of live cells was evaluated using Promega's "CellTiterFluor" kit.

[0208] Fig. 5a shows the effect of treatment with the compounds on the number of live cells of the RD136 cell line (in HLPM medium as defined above) and Fig. 5b shows the effect on the number of live cells of the RH30 cell line (in HLPM medium as defined above), represented as a percentage relative to the effect of the compound diluent (DMSO).

[0209] In conclusion, compounds (la), (Ib), and (le) inhibit cell growth in RD 136 and RH30 cell lines by reducing the number of live cells after 48 hours of treatment. Their effect is similar to that obtained with the inhibitor "IACS-010759" or rotenone. The scope of application for these compounds can therefore be extended beyond hematological cancers such as lymphomas, for example, to solid tumors such as the pediatric human sarcomas exemplified here.

[0210] 4.6 Analysis of 1TC50 of a compound Ha) according to the invention compared to that of a compound of the prior art

[0211] LTC5o of compound (la) was compared to that of a compound as described in WO2020 / 109506 corresponding to the following formula:

[0212] [Chem. 10] 1. ...... P « 'y '8' J. .... “ HtSr y.-”' •:

[0213] The results showed an IC50 of 1.5 pM for compound (la) and 15.1 pM for the compound as described in WO2020 / 109506. This demonstrates the improved performance of compound (la) compared to the prior art compound. These experiments were performed using cells from a human B-cell lymphoma cell line (“Karpas422, CVCL_1325”) that were seeded in “RPMI 1640” medium (11 mM glucose) supplemented with 10% serum, in the presence of increasing concentrations of the compounds.

[0214] After 48 hours of treatment, analyses of the effect on cell growth were carried out using a live cell detection kit known as "CellTiter-Fluor Cell Viability Assay" (Promega), and following the instructions of the supplier.

Claims

Claims

1. A compound selected from compounds of formula (I), their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates, said formula (I) having the following structure: [Chem. 11] (0 in which: * R1, R2, and R3 represent, independently of each other, a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group chosen from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR7, a group -NR8R9, a group -SR10, a group -C(O)RH, a group -CH2OR12, and a group -CH2NR13R14, with R7, R8, R10, R11, R12, and R13 representing, independently of each other, an alkyl or cycloalkyl radical, and R9 and R14 representing, independently of each other, a hydrogen atom, or an alkyl or cycloalkyl radical, * X1 represents a nitrogen atom or a CR15 group, with R15 being a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR7, a -NR8R9 group, a -SR10 group, a -C(O)RH group, a -CH2OR12 group, and a -CH2NR13R14 group, * n is an integer ranging from 1 to 20, * R4 represents a hydrogen atom, an alkyl radical, or a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is attached, * R5 represents a hydrogen atom, an alkyl radical, or a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is attached, * Y1 represents -CH2-, -NH-, or -O- when the group R4 represents a hydrogen atom, or an alkyl radical; and represents -CH- or -N- when the group R4 represents a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is attached, * Y2 represents -CH2-, -NH-, or -O- when the group R5 represents a hydrogen atom, or an alkyl radical; and represents -CH- or -N- when the group R5 represents a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R4 is attached, and * R6 represents one of the following two groups (IIa) and (IIb): [Chem. 12] (Ilb)

2. in which, R'1, R'2, and R'3 represent, independently of each other, a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group chosen from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR'7, a group -NR'8R'9, a group -SR'10, a group -C(O)R'H, a group -CH2OR'12, and a group -CH2NR'13R'14, with R'7, R'8, R'10, R'11, R'12, and R'13 representing, independently of each other, an alkyl or cycloalkyl radical, and R'9 and R'14 representing, independently of each other, a hydrogen atom, or a alkyl or cycloalkyl radical, and X2 represents a nitrogen atom or a CR'15 group, with R'15 being a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a group selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR'7, a -NR'8R'9 group, a -SR'10 group, a -C(O)R'n group, a -CH2OR'12 group, and a -CH2NR'13R'14 group, for use in the treatment of cancer. A compound as defined in claim 1, for use in the treatment of cancers having altered metabolism, in particular in the treatment of cancers with OXPHOS metabolism.

3.

4.

5.

6.

7.

8.

9.

10.

11. A compound as defined in claim 1, for use in the treatment of lymphomas; solid tumors; and certain tumors recurring following chemotherapy treatments. Compound for use according to any one of the preceding claims, characterized in that X1 represents a nitrogen atom or a CH group. A compound for use according to any one of the preceding claims, characterized in that R4 represents a hydrogen atom or a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is attached, and R5 represents a hydrogen atom or a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is attached. A compound for use according to any one of the preceding claims, characterized in that Y1 represents -CH2- when the group R4 represents a hydrogen atom, or an alkyl radical; and represents -N- when the group R4 represents a divalent alkylene group forming a ring with Y1 and the nitrogen atom to which R4 is attached; and Y2 represents -CH2- when the group R5 represents a hydrogen atom, or an alkyl radical; and represents -N- when the group R5 represents a divalent alkylene group forming a ring with Y2 and the nitrogen atom to which R5 is attached. Compound for use according to any one of the preceding claims, characterized in that Y1 and Y2 are identical. Compound for use according to any one of the preceding claims, characterized in that: - when Y1 represents -CH2-, n ranges from 2 to 10, - when Y2 represents -CH2-, n ranges from 2 to 10, - when Y1 represents -N-, -NH-, -CH- or -O-, n ranges from 6 to 18, - when Y2 represents -N-, -NH-, -CH- or -O-, n ranges from 6 to 18. A compound for use according to any one of the preceding claims, characterized in that when Y1 and Y2 represent -CH-, and R6 is a group of formula (IIa), then n is such that n > 5 and / or R1, R'1, R2, R'2, R3, and R'3 are other than -NH2; and when Y1 and Y2 represent -N-, and R6 is a group of formula (IIa), then n is such that n > 7. Compound for use according to any one of the preceding claims, characterized in that R6 is a group of formula (IIb). Compound for use according to any one of the claims preceding, characterized in that the compound of formula (I) is chosen from the following compounds: Name Structural formula Compound la fit! .. k jl / ' / f ' WH 'N'" \.—N (te! Compound Ib r-^' '"NL 1. "N" \ L - Xx ..-X. x'x •s.-- XX HC-I HO yf (ib; Compound le 'x -i'ï. x .-'XX Xx' xX X.,.,' x^,. x;N.. x( l  HCI HCl n H' (te}

12.

13.

14. Pharmaceutical composition comprising a compound as defined in any one of claims 1 and 4 to 11, and at least one vehicle appropriate pharmaceutical. Product comprising a compound as defined in any one of the claims 1 and 4 to 11 and another active agent. Compound chosen from the compounds corresponding to the formula (!), their pharmaceutically acceptable salts, and their pharmaceutical solvates tically acceptable, said formula (!) having the following structure: [Chem. 13] in which: * R1, R2, R3, R4, R5, R6, X1, Y1, Y2, and n are as defined in claim 1, it being understood that: * when Y1 and Y2 represent -CH-, and R6 is a radical of formula (IIa), then n > 5 and / or R1, R'1, R2, R'2, R3, and R'3 are different from -NH2, and * when Y1 and Y2 represent -N-, and R6 is a radical of formula (Ha), then n > 7.

15. Compound according to claim 14, characterized in that R6 is a group of formula (IIb).

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