OXPHOS inhibitors for use in the treatment of B-cell lymphoma

Abstract

The present invention is applied in the field of cancer treatment. The present invention particularly relates to compounds derived from aliphatic diamines containing at least one pyridine or pyrimidine unit and used as anticancer agents, to therapeutic compositions containing said compounds, to products containing such compounds and another active agent, and to such compounds.

Description

[Technical field]

[0001] The present invention is applied in the field of cancer treatment. It is particularly directed to compounds derived from aliphatic diamines containing at least one pyridine or pyrimidine unit and used as anticancer drugs, to therapeutic compositions containing said compounds, to products containing such compounds and another active agent, and to such compounds. [Background technology]

[0002] Cancer is one of the leading causes of death worldwide. Cancer treatments are diverse and include surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy and targeted therapy. Basic research data have demonstrated that the plasticity of tumor cells allows them to develop resistance mechanisms to evade these treatments.

[0003] In this context, the majority of conventional anticancer drugs have relatively low efficacy in the treatment of cancers such as T-cell lymphoma, pancreatic adenocarcinoma, and some pediatric brain tumors, whether or not they decline after first-line treatment, and research is focused on new treatment methods. Indeed, successfully overcoming the resistance problem faced in this type of disease represents a real public health problem and research challenge.

[0004] Reorganization of energy metabolism is one of the key steps involved in tumor growth, especially when resistant to treatment. In particular, tumor cells adjust their metabolism to adapt to the conditions of their microenvironment and to the selective pressure of chemotherapy treatments. Thus, the development of new molecules targeting cellular metabolism is a major therapeutic challenge.

[0005] Mitochondria are organelles that play a key role in cellular metabolism by concentrating ATP production from numerous substrates through oxidative phosphorylation (OXPHOS). The enzymatic reactions involved in this process control cell proliferation, differentiation, activation and self-renewal. Many recent studies have revealed a correlation between OXPHOS activity (i.e., mitochondrial metabolism) and chemotherapy resistance and / or tumor progression. In particular, mitochondria are organelles that can integrate and transmit many signals and contribute not only to energy production as ATP but also to the synthesis of macromolecules essential for tumor growth. Adaptation to increased OXPHOS activity is a property that is often acquired during tumor progression, especially during resistance to chemotherapy.

[0006] Molecules targeting OXPHOS metabolism have been developed by various processes and are undergoing various clinical trials, such as those that block mitochondrial ribosomes and indirectly block the synthesis of respiratory chain complexes (e.g., the antibiotic tigecycline) or directly inhibit respiratory chain complex I (e.g., metformin) or complex III (e.g., antimycin A). They have a synergistic cytotoxic effect with the reference treatment. Other pharmacological approaches aimed at blocking mitochondrial beta-oxidation of fatty acids or increasing oxidative stress in OXPHOS malignant cells are also offered.

[0007] More recently, other OXPHOS inhibitors have also been shown to be effective, in particular a complex I inhibitor known as "IACS-010759," which is currently in clinical trials, particularly in hematological cancers.

[0008] JPEG2025511996000002.jpg41170

[0009] WO 2020 / 109506 also describes a compound represented by the following formula, or a pharma- ceutically acceptable salt and / or solvate thereof, for use in treating cancer:

[0010] JPEG2025511996000003.jpg26170

[0011] In the formula, X 1 and X 2 are the same or different, NR 5 or a sulfur atom, and Y is C1-C 10 Alkanediyl group, Ar 1 and Ar 2 are the same or different, optionally substituted aryl groups; R 5 is a hydrogen atom or a C1-C6 alkyl group. These compounds are described as inhibitors of the rate of oxygen consumption by mitochondria, making it possible to treat some cancers, especially those that have an "OXPHOS" mechanism.

[0012] However, there is still a need to develop other anticancer drugs that are effective against tumor cells, in order to meet the increasing need for personalized medicine, based on the individual nature of each tumor. There is a need to develop those that target the mitochondrial respiratory chain, and therefore have an inhibitory effect on the energy charge of the cell. In particular, there is a need to develop molecules that act on other intracellular targets and have different physicochemical properties, compared to the limited number of OXPHOS inhibitors already developed. These new molecules should be easy to prepare, especially in silico, and have improved cytotoxicity, while ensuring good pharmacokinetics, such as good ADMET properties (absorption of the molecule, distribution in the body, excretion, including biotransformation or metabolism, and excretion, and toxicity). Summary of the Invention [Problem to be solved by the invention]

[0013] Therefore, the object of the present invention is to overcome the above-mentioned shortcomings of the prior art and to provide an anticancer agent having excellent performance in terms of anticancer activity, which is easy to prepare, ensures excellent ADMET properties, and has low toxicity to non-tumor cells. [Means for solving the problem]

[0014] The object of the present invention is achieved by the following compound.

[0015] A first subject of the present invention are compounds selected from the compounds of formula (I), their pharma- ceutically acceptable salts and their pharma- ceutically acceptable solvates, for use in the treatment of cancer. Formula (I) has the following structure:

[0016] JPEG2025511996000004.jpg67170

[0017] During the ceremony, * R 1 , R 2 and R 3 are each independently a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or one of the following radicals: -OH, -NH2, -SH, -CN (cyano or carbonitrile), -CF3, -CHO (aldehyde), -NH-NH2 (hydrazine), -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR 7 , -NR 8 R 9 Group, -SR 10 group, -C(O)R 11 group, -CH2OR 12 Group and -CHNR 13 R 14 R represents a group selected from the group 7 , R 8 , R 10 , R 11 , R 12 and R 13 are each independently an alkyl or cycloalkyl radical; R 9 and R 14 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl radical, * X 1 is a nitrogen atom or CR 15 represents a group, R 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical or an aryl radical, or -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR 7 , -NR 8 R9 Group, -SR 10 group, -C(O)R 11 group, -CH2OR 12 Group, and -CHNR 13 R 14 is a group selected from the group * n is an integer from 1 to 20, * R 4 is a hydrogen atom, an alkyl radical, or R 4 Y binds to 1 and a divalent alkylene group forming a ring together with a nitrogen atom, * R 5 is a hydrogen atom, an alkyl radical, or R 5 Y binds to 2 and a divalent alkylene group forming a ring together with a nitrogen atom, * Y 1 is R 4 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-, -NH- or -O-; R 4 Group is R 4 Y binds to 1 and when it represents a divalent alkylene group forming a ring together with a nitrogen atom, it represents -CH- or -N-; * Y 2 is R 5 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-, -NH- or -O-; R 5 Group is R 4 Y binds to 2 and when it represents a divalent alkylene group forming a ring together with a nitrogen atom, it represents -CH- or -N-; * R 6 represents one of the two groups (IIa) and (IIb) below:

[0018] JPEG2025511996000005.jpg53170

[0019] In the formula, R' 1 , R' 2 and R' 3are each independently a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR' 7 , -NR' 8 R' 9 Group, -SR' 10 group, -C(O)R' 11 group, -CH2OR' 12 Groups and -CHNR' 13 R' 14 R' represents a group selected from the group 7 , R' 8 , R' 10 , R' 11 , R' 12 and R' 13 R' are each independently an alkyl or cycloalkyl radical; 9 and R' 14 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl radical, X 2 is a nitrogen atom or CR' 15 R' represents a group; 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR' 7 , -NR' 8 R' 9 Group, -SR' 10 group, -C(O)R' 11 group, -CH2OR' 12 Groups and -CHNR' 13 R' 14 is a group selected from the group.

[0020] The compounds (I) of the present invention are derivatives of aliphatic diamines containing at least one pyridine or pyrimidine unit. The inventors have discovered that such compounds exhibit significant anticancer activity. In addition, these compounds are easy to prepare, have low toxicity to healthy cells, and have excellent ADMET properties, especially in silico.

[0021] "Cancer" refers to all malignant neoplasia of whatever histological nature (adult and pediatric). There are two main types of solid tumors: carcinomas of epithelial origin and sarcomas of connective origin. Solid tumors are formed by atypical cells, which may be invasive or diffuse, and are generally characterized by the ability for autonomous growth, poorly defined borders, the ability to invade adjacent tissues and blood vessels, and the tendency to spread and metastasize. Examples include breast, prostate, lung, esophageal, skin, bladder, stomach, liver, uterine, colon, and rectal cancers. There are also pancreatic endocrine and exocrine carcinomas, as well as pediatric tumors such as rhabdomyosarcoma and diffuse pontine glioma (DIPG). Other tumor types include various hematological malignancies.

[0022] A second subject of the present invention are compounds as defined in the first subject of the present invention for targeted use in the treatment of cancers with altered metabolism, in particular in the treatment of cancers with OXPHOS metabolism.

[0023] Cancers with OXPHOS metabolism correspond to cancers that contain or are composed of cancer cells that rely primarily on oxidative phosphorylation (OXPHOS) for their biosynthetic and / or bioenergetic processes.

[0024] Such cancers that have OXPHOS metabolism include hematological cancers, lung cancer, cervical cancer, prostate cancer, neuroendocrine tumors, glial tumors, and skin and eye cancers.

[0025] According to a preferred embodiment of the invention, the compounds defined in the first subject of the invention are used for the treatment of solid tumors such as lymphomas, in particular adult or pediatric B and T lymphomas; sarcomas, in particular pediatric sarcomas (e.g. rhabdomyosarcoma type); and some recurrent tumors after chemotherapy treatment.

[0026] The compounds defined in the first subject matter of the present invention have antitumor activity in one or more preclinical models.

[0027] "Lymphoma" refers to any tumor, usually malignant, caused by proliferation of lymphatic tissue cells and occurring not only in the spleen or lymph nodes but also in many other organs or tissues.

[0028] Thus, the compounds defined in the first subject matter of the present invention have potential properties as new anti-cancer drugs targeting cellular metabolism.

[0029] In particular, it acts as an inhibitor of the mitochondrial respiratory chain and inhibits the rate of oxygen consumption. Thus, it can be considered an OXPHOS inhibitor. - in vitro cytotoxic activity comparable to OXPHOS inhibitors already in clinical trials, in particular IACS-010759; and - specificity of action with respect to cell phenotype.

[0030] In the compounds defined in the first subject of the invention, the alkyl radical may be straight-chain or branched, preferably straight-chain.

[0031] In the compounds defined in the first subject of the invention, the cycloalkyl radical may be straight-chain or branched, preferably straight-chain.

[0032] For the purposes of the present invention, halogen is selected from F, Cl, Br and I, particularly preferably F and Cl.

[0033] R 1 、R 2 R 3 Definition of R 1 , R 2 and R 3 are each independently a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or one of the following radicals: -OH, -NH2, -SH, -CN (carbonitrile or cyano), -CF3, -CO2H, -CH2OH, -CH2NH2, -CHO (aldehyde), -NH-NH2 (hydrazine), an alkoxy group -OR 7, -NR 8 R 9 Group, -SR 10 group, -C(O)R 11 group, -CH2OR 12 Group and -CHNR 13 R 14 R represents a group selected from the group 7 , R 8 , R 10 , R 11 , R 12 and R 13 are each independently an alkyl or cycloalkyl radical; R 9 and R 14 represent independently of each other a hydrogen atom or an alkyl or cycloalkyl radical.

[0034] R 1 , R 2 or R 3 Alkyl radicals as groups are preferably C1-C5 alkyl radicals, particularly preferably methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radicals.

[0035] R 1 , R 2 or R 3 Cycloalkyl radicals as groups are preferably C3-C6 cycloalkyl radicals, particularly preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals, more particularly preferably cyclopropyl radicals.

[0036] R 1 , R 2 or R 3 The aryl radical as a group is preferably a C5-C 15 Aryl radicals, particularly preferred are phenyl, 2- or 3-thienyl, 2- or 3-furyl radicals, more particularly preferred are phenyl radicals.

[0037] R 7 、R 8 、R 9 、R10 、R 11 、R 12 、R 13 and R 14 Definition of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 Alkyl radicals as groups are preferably C1-C5 alkyl radicals, particularly preferably methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radicals.

[0038] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 Cycloalkyl radicals as groups are preferably C3-C6 cycloalkyl radicals, particularly preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals, more particularly preferably cyclopropyl radicals.

[0039] -SR 10 The group is preferably a thiomethyl group.

[0040] -NR 8 R 9 The group is preferably a methylamine or dimethylamine group.

[0041] Alkoxy group -OR 7 is preferably a methoxy or ethoxy group.

[0042] According to a particularly preferred embodiment of the present invention, R 1 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR10 group, -CN group, CF3 group, -NR 8 R 9 group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0043] According to a particularly preferred embodiment of the present invention, R 2 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR 10 group, -CN group, CF3 group, -NR 8 R 9 group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0044] According to a particularly preferred embodiment of the present invention, R 3 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR 10 group, -CN group, CF3 group, -NR 8 R 9 group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0045] Advantageously, R 1 , R 2 and R 3 is a hydrogen atom.

[0046] X 1 Definition of X 1 is a nitrogen atom or CR 15 represents a group, R 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical or an aryl radical, or -OH, -NH2, -SH, -CN, -CF3, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR 7 , -NR 8 R 9 Group, -SR 10 group, -C(O)R 11 group, -CH2OR 12 Group and -CHNR 13 R 14is a group selected from the group.

[0047] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 The groups are as defined in the present invention.

[0048] According to a particularly preferred embodiment of the present invention, R 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR 10 group, -CN group, -CF3 group, -NR 8 R 9 group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0049] Advantageously, X 1 represents a nitrogen atom or a CH group.

[0050] R 4 and R 5 Definition of R 4 is a hydrogen atom, an alkyl radical, or R 4 Y binds to 1 and a divalent alkylene group which forms a ring together with the nitrogen atom.

[0051] R 4 Alkyl radicals as groups are preferably C1-C5 alkyl radicals, particularly preferably methyl or ethyl radicals.

[0052] R 4 R as a group 4 Y binds to 1 The divalent alkylene radical which forms a ring together with the nitrogen atom is preferably the alkylene radical -(CH2)2- or -(CH2)3-, particularly preferably the alkylene radical -(CH2)2-.

[0053] Preferably, R 4 is a hydrogen atom, or R 4 Y binds to 1 and a divalent alkylene group which forms a ring together with the nitrogen atom.

[0054] R 5 is a hydrogen atom, an alkyl radical, or R 5 Y binds to 2 and a divalent alkylene group which forms a ring together with the nitrogen atom.

[0055] R 5 Alkyl radicals as groups are preferably C1-C5 alkyl radicals, particularly preferably methyl, ethyl, propyl or butyl radicals.

[0056] R 2 R as group 2 Y binds to 2 The divalent alkylene radical which forms a ring together with the nitrogen atom is preferably the alkylene radical -(CH2)2- or -(CH2)3-, particularly preferably the alkylene radical -(CH2)2-.

[0057] Preferably, R 5 is a hydrogen atom, or R 5 Y binds to 2 and a divalent alkylene group which forms a ring together with the nitrogen atom.

[0058] According to a particularly preferred embodiment of the present invention, R 4 is a hydrogen atom, or R 4 Y binds to 1 and a divalent alkylene group which forms a ring together with the nitrogen atom; R 5 is a hydrogen atom, or R 5 Y binds to 2 and a divalent alkylene group which forms a ring together with the nitrogen atom.

[0059] According to a particularly preferred embodiment of the present invention, R 4 and R 5 are identical.

[0060] Y 1 and Y 2 Definition of Y 1 is R 4 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-, -NH- or -O-; R 4 Group is R 4 Y binds to 1 and when it represents a divalent alkylene group forming a ring together with a nitrogen atom, it represents -CH- or -N-.

[0061] Preferably, Y 1 is R 4 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-; R 4 Group is R 4 Y binds to 1 and when it represents a divalent alkylene group which forms a ring together with a nitrogen atom, it represents --N--.

[0062] Y 2 is R 5 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-, -NH- or -O-; R 5 Group is R 5 Y binds to 2 and when it represents a divalent alkylene group forming a ring together with a nitrogen atom, it represents -CH- or -N-.

[0063] Preferably, Y 2 is R 5 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-; R 5 Group is R 5 Y binds to 2 and when it represents a divalent alkylene group which forms a ring together with a nitrogen atom, it represents --N--.

[0064] According to a particularly preferred embodiment of the present invention, Y 1 is R 4 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-; R 4 Group is R 4 Y binds to 1and when Y represents a divalent alkylene group forming a ring together with a nitrogen atom, it represents -N-; 2 is R 5 When the group represents a hydrogen atom or an alkyl radical, it represents -CH2-; R 5 Group is R 5 Y binds to 2 and when it represents a divalent alkylene group which forms a ring together with a nitrogen atom, it represents --N--.

[0065] According to a particularly preferred embodiment of the present invention, Y 1 and Y 2 are identical.

[0066] Definition of n n is an integer from 1 to 20, preferably from 1 to 14.

[0067] Y related to n 1 、Y 2 Definition of According to a preferred embodiment of the present invention, - Y 1 (and Y 2 When —CH—, n is preferably 2 to 10, particularly preferably 3 to 9. - Y 1 (and Y 2 When —N—, —NH—, —CH— or —O—, n is preferably 6 to 18, particularly preferably 7 to 14.

[0068] This embodiment is R 6 is particularly preferred when is a group of formula (IIa).

[0069] Y 1 and Y 2 represents -CH-, and R 6 is a group of formula (IIa), n is preferably n≧5, and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R' 3is preferably different from -NH2.

[0070] Y 1 and Y 2 represents -N-, and R 6 When is a group of formula (IIa), n is preferably n≧7.

[0071] According to a preferred embodiment of the present invention, Y 1 and Y 2 represents -CH-, and R 6 is a group of formula (IIa), n is greater than or equal to 5, and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R' 3 is different from -NH2; Y 1 and Y 2 represents -N-, and R 6 is a group of formula (IIa), n is greater than or equal to 7.

[0072] R 6 Definition of R 6 represents one of the following two groups (IIa) and (IIb):

[0073] JPEG2025511996000006.jpg52170

[0074] In the formula, R' 1 , R' 2 and R' 3 are each independently a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR' 7 , -NR' 8 R' 9 Group, -SR' 10 group, -C(O)R' 11 group, -CH2OR' 12 Groups and -CHNR' 13 R'14 R' represents a group selected from the group 7 , R' 8 , R' 10 , R' 11 , R' 12 and R' 13 R' are each independently an alkyl or cycloalkyl radical; 9 and R' 14 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl radical, X 2 is a nitrogen atom or CR' 15 R' represents a group; 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH2, -SH, -CN, -CF3, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR' 7 , -NR' 8 R' 9 Group, -SR' 10 group, -C(O)R' 11 group, -CH2OR' 12 Groups and -CHNR' 13 R' 14 is a group selected from the group.

[0075] R 6 is preferably a group of formula (IIb).

[0076] R’ 1 、R’ 2 、R’ 3 Definition of R' 1 , R' 2 , R' 3 Alkyl radicals as groups are preferably C1-C5 alkyl radicals, particularly preferably methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radicals.

[0077] R' 1 , R' 2 , R' 3Cycloalkyl radicals as groups are preferably C3-C6 cycloalkyl radicals, particularly preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals, more particularly preferably cyclopropyl radicals.

[0078] R' 1 , R' 2 , R' 3 The aryl radical as a group is preferably a C5-C 15 Aryl radicals, particularly preferred are phenyl, 2- or 3-thienyl, 2- or 3-furyl radicals, more particularly preferred are phenyl radicals.

[0079] R’ 7 、R’ 8 、R’ 9 、R’ 10 、R’ 11 、R’ 12 、R’ 13 and R' 14 Definition of R' 7 , R' 8 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 or R' 14 Alkyl radicals as groups are preferably C1-C5 alkyl radicals, particularly preferably methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radicals.

[0080] R' 7 , R' 8 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 or R' 14Cycloalkyl radicals as groups are preferably C3-C6 cycloalkyl radicals, particularly preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals, more particularly preferably cyclopropyl radicals.

[0081] -SR' 10 The group is preferably a thiomethyl group.

[0082] -NR' 8 R' 9 The group is preferably a methylamine or dimethylamine group.

[0083] Alkoxy group -OR' 7 is preferably a methoxy or ethoxy group.

[0084] According to a particularly preferred embodiment of the present invention, R' 1 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR 10 group, -CN group, -CF3 group, -NR 8 R 9 group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0085] According to a particularly preferred embodiment of the present invention, R' 2 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR 10 group, -CN group, -CF3 group, -NR 8 R 9 group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0086] According to a particularly preferred embodiment of the present invention, R' 3 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR 10 group, -CN group, -CF3 group, -NR 8 R 9group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0087] Advantageously, R' 1 , R' 2 and R' 3 is a hydrogen atom.

[0088] X 2 Definition of X 2 is a nitrogen atom or CR' 15 R' represents a group; 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH2, -SH, -CN, -CF3, -CO2H, -CH2OH, -CH2NH2, an alkoxy group -OR' 7 , -NR' 8 R' 9 Group, -SR' 10 group, -C(O)R' 11 group, -CH2OR' 12 Groups and -CHNR' 13 R' 14 is a group selected from the group.

[0089] R' 7 , R' 8 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 and R' 14 The groups are as defined in the present invention.

[0090] According to a particularly preferred embodiment of the present invention, R' 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an alkoxy group -OR 7 , -SR 10 group, -CN group, -CF3 group, -NR 8 R 9 group, a -NH-NH2 group, a -CO2H group or a -CHO group.

[0091] Advantageously, X 2represents a nitrogen atom or a CH group.

[0092] According to a preferred embodiment of the invention, the compound of formula (I) is selected from the following compounds:

[0093] JPEG2025511996000007.jpg234170

[0094] The term "pharmaceutical acceptable" means useful in the preparation of pharmaceutical compositions and generally safe and non-toxic for pharmaceutical use.

[0095] A pharma- ceutically acceptable salt or solvate of a compound means a salt or solvate which is pharma- ceutically acceptable as defined above and which possesses the pharmacological activity of said compound.

[0096] 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 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-L-tartaric acid, paratoluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, benzoic acid, citric acid, ethanesulfonic acid, lactic acid, mucic acid, pamoic acid or pantothenic acid, - Including salts formed when an acidic proton present in the compound is replaced with a metal ion, such as an alkali metal, alkaline earth metal, or aluminum ion; or is 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.

[0097] Acceptable solvates for the therapeutic use of the compounds of the invention include conventional solvates, such as those formed during the final steps of the preparation of these compounds due to the presence of solvents, such as those involving the presence of water (these solvates are also called hydrates) or ethanol.

[0098] Due to their anti-cancer activity, the compounds defined in the first subject matter of the present invention are useful in therapy.

[0099] A third subject of the present invention is a pharmaceutical composition comprising a compound as defined in the first subject of the present invention and at least one suitable pharmaceutical carrier.

[0100] A suitable pharmaceutical carrier may be a pharma- ceutically acceptable excipient used in the treatment of cancer, in particular in the treatment of cancers with altered metabolism, preferably cancers with OXPHOS metabolism.

[0101] The pharmaceutical composition may be a solid composition or a liquid composition.

[0102] The solid composition may be in the form of a tablet, capsule, powder, or granules.

[0103] The tablets may contain the compound defined in the first subject of the invention in admixture with a pharmaceutical carrier such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic, etc. The resulting mixture can in particular be compressed.

[0104] The tablets may be coated with saccharose, sucrose or other suitable materials and may be treated to prolong or delay activity and to continuously release a predetermined amount of the compound.

[0105] The powders or granules may be water-dispersible. They may contain the compounds as defined in the first subject of the invention in admixture with dispersing, wetting or suspending agents, in particular flavor correctors or sweeteners.

[0106] The capsules may contain a compound as defined in the first subject of the invention in admixture with a diluent. The capsules may be soft or hard capsules.

[0107] Liquid compositions may be in the form of an aqueous suspension or solution, a syrup or an elixir.

[0108] A liquid composition may in particular contain a compound as defined in the first subject of the invention in a solvent such as water, and optionally suitable sweeteners, flavourings and / or colouring agents.

[0109] Liquid compositions can be obtained in particular by dissolving or suspending powders or granules as described above in a liquid such as water, fruit juice, milk or the like.

[0110] The pharmaceutical composition is preferably sterile and may be in the form of an isotonic solution (especially compared to blood).

[0111] Thus, a compound as defined in the first aspect of the invention or a pharmaceutical composition according to the third aspect of the invention may be used in a method for the treatment of cancer, which method comprises administering to an individual an effective amount of a compound as defined in the first aspect of the invention (or a pharma- ceutically acceptable salt or solvate of said compound) or an effective amount of a pharmaceutical composition according to the third aspect of the invention.

[0112] The individual is a patient in need of treatment, such as a mammal, particularly a human.

[0113] The compound or pharmaceutical composition may be administered to a mammal, including a human, via the nasal, enteral (eg, oral) or parenteral (eg, intravenous) routes.

[0114] Dosages vary depending on the treatment and condition. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules, and oral liquids or suspensions, sublingual and buccal dosage forms, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms, and rectal dosage forms.

[0115] The compounds defined in the first subject of the present invention can be used in monotherapy or in combination with at least one other active agent.

[0116] Thus, the present invention relates to a method for treating cancer in a patient in need thereof, comprising administering to the patient a compound as defined in the first aspect of the invention (or a pharma- ceutically acceptable salt or solvate of said compound) or a pharmaceutical composition according to the third aspect of the invention.

[0117] The cancer is as defined in the first subject of the present invention.

[0118] The present invention also relates to a method for treating a metabolically altered cancer, in particular a cancer with OXPHOS metabolism, in a patient in need thereof, comprising administering to the patient a compound as defined in the first aspect of the invention (or a pharma- ceutically acceptable salt or solvate of said compound) or a pharmaceutical composition according to the third aspect of the invention.

[0119] The cancer with altered metabolism, in particular a cancer with OXPHOS metabolism, is as defined in the first subject of the present invention.

[0120] The present invention also relates to the use of a compound as defined in the first subject of the invention (or a pharma- ceutically acceptable salt or solvate of said compound), or a pharmaceutical composition according to the third subject of the invention, for the manufacture of a medicament for the treatment of cancer or a metabolically altered cancer, in particular a cancer with OXPHOS metabolism, in a subject in need thereof.

[0121] The present invention also relates to the use of a compound as defined in the first object of the invention (or a pharma- ceutically acceptable salt or solvate of said compound), or a pharmaceutical composition according to the third object of the invention, for treating cancer or a cancer with altered metabolism, in particular a cancer with OXPHOS metabolism, in a subject in need thereof.

[0122] The term "patient" refers to an animal, generally a warm-blooded animal, preferably a mammal. As used herein, the term "mammal" refers to any mammal, including humans, domestic and farm animals, as well as zoo animals, sports animals or pets, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is a primate, more preferably a human.

[0123] The term "human" refers to a male or female human subject at any stage of development, including neonates, infants, juveniles, adolescents and adults.

[0124] A fourth subject of the invention is a product comprising a compound as defined in the first subject of the invention and another active agent.

[0125] That is to say, the compound as defined in the first object of the invention and the other active agent are combined, in particular used concomitantly in a treatment, used separately or used one after the other.

[0126] These other active agents are selected from those suitable in particular for the treatment of cancer. They may be adjuvants that improve the activity of the compounds of the invention or other active agents known to be used in the treatment of said conditions. Such active agents are well known to those skilled in the art and are commercially available or described in reference works such as Le Dictionnaire Vidal, published and updated annually, and in particular those active agents classified in the drug therapy family "Cancerology Haematology".

[0127] Some compounds defined in the first subject of the present invention are new per se and are the fifth subject of the present invention. These compounds are selected from the compounds of formula (I'), their pharma- ceutically acceptable salts and their pharma- ceutically acceptable solvates, The formula (I') has the following structure:

[0128] JPEG2025511996000008.jpg62170

[0129] During the ceremony, * R1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , Y 1 , Y 2 and n is as defined in the first subject of the invention for formula (I), * Y 1 and Y 2 represents -CH-, and R 6 is a radical of formula (IIa), n≧5, and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R' 3 is different from -NH2, * Y 1 and Y 2 represents -N-, and R 6 When is a radical of formula (IIa), it is understood that n≧7.

[0130] Further properties, alternatives and advantages of the compounds, their uses or pharmaceutical compositions according to the invention will become clearer upon examination of the following examples of embodiments, which are intended to illustrate but not limit the scope of the invention.

[0131] The present invention will now be described with reference to the accompanying drawings. [Brief description of the drawings]

[0132] [Figure 1] FIG. 1 shows the rate of oxygen consumption following treatment of cells derived from a human B cell lymphoma line with compounds of the invention and prior art compounds. [Diagram 2] FIG. 2 shows the effect on cell proliferation of human tumor cells from a B-cell lymphoma line treated with compounds of the invention and prior art compounds. [Diagram 3] FIG. 3 shows the effect on cell proliferation of human tumor cells from a broad range of B and T cell lymphoma lines treated with compounds according to the invention and prior art compounds. [Figure 4] FIG. 4 shows the antitumor efficacy of compounds of the invention in an in ovo model. [Diagram 5] FIG. 5 shows the effect on cell proliferation of human cells derived from two pediatric sarcoma lines treated with compounds of the invention. [Figure 6] FIG. 6 shows the effect on cell proliferation of human tumor cells derived from a B cell lymphoma line treated with compounds of the invention. [Figure 7] FIG. 7 shows the effect on cell proliferation of human tumor cells derived from a pediatric sarcoma line treated with a compound of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0133] Example 1: Synthesis of Compound Ia Working Example Flash column chromatography was performed on silica gel 60 (0.063200 mm).

[0134] The chromatograms were recorded at 25 °C using a spectrometer (Bruker Avance III) ( 1 HNMR is 400MHz, 13 Nuclear magnetic resonance spectrum (CNMR 100MHz) 1 HNMR and 13 C NMR spectra were recorded. Chemical shifts are given in ppm and coupling constants (J) in Hertz. 1 H NMR spectral data are reported as: chemical shift in ppm (s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet doublet, td=doublet triplet, ddd=doublet doublet of doublets, m=multiplet, coupling constant, integral).

[0135] Example 1: Synthesis of Compound Ia Compound Ia was prepared according to the steps outlined in the following scheme.

[0136] JPEG2025511996000009.jpg67170

[0137] Step 1: Synthesis of N'-pyrimidin-2-yldodecane-1,12-diamine derivatives 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 were added. The reaction mixture was heated under reflux in dioxane for 16 hours. After cooling, the dioxane was concentrated under reduced pressure. The residue obtained was taken up in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative obtained was purified by silica gel chromatography using as eluent a gradient of ethyl acetate / methanol / triethylamine (98 / 0 / 2; 60 / 10 / 10; 70 / 20 / 10; 60 / 30 / 10).

[0138] The expected compound was obtained as a yellow solid in 53% yield.

[0139] This compound has the following properties: Melting point = 86℃ Molar mass = C 16 H 30 N4: 278.43 g / mol 1 HNMR(CD3OD):8.26(d;J=4.8Hz;2H);6.59(t;J=4.9Hz;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). 13 CNMR(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.

[0140] Second step: Synthesis of N'-(4,5-dihydro-1H-imidazol-2-yl)-N-pyrimidin-2-yl-dodecane-1,12-diamine derivatives To a solution of 100 mg (0.36 mmol) of N'-pyrimidin-2-yldodecane-1,12-diamine prepared in the previous step in an ethanol / triethylamine mixture (12 mm / 0.1 mm), 1.05 equivalents (0.38 mmol) of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole hydrobromide were added. The reaction medium was heated under ethanol reflux for 3 days. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuum. The derivative obtained was purified by silica gel chromatography using dichloromethane / methanol (92 / 8) as eluent.

[0141] The expected compound was obtained as a yellow solid in 40% yield.

[0142] This compound has the following properties: Melting point = 90℃ Molar mass = C 19 H 34 N6: 346.51 g / mol 1 HNMR(CD3OD):8.14(d;J=4.9Hz;2H);6.47(t;J=4.8Hz;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). 13 CNMR(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.

[0143] Example 2: Synthesis of Compound Ib Compound Ib was prepared according to the steps outlined in the following scheme.

[0144] JPEG2025511996000010.jpg54170

[0145] First step: Synthesis of 2-[4-[12-(4-pyrimidin-2-ylpiperazin-1-yl)dodecyl]piperazin-1-yl]pyrimidine derivatives 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-1-ylpyrimidine and 7 equivalents (14.94 mmol; 2.1 g) of potassium carbonate were added. The reaction mixture was heated under reflux in dioxane for 20 hours. After cooling, the dioxane was concentrated under reduced pressure. The residue obtained was taken up in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative obtained was purified by silica gel chromatography using ethyl acetate / methanol / triethylamine (99 / 0.5 / 0.5) as eluent.

[0146] The expected compound was obtained as a white solid in 64% yield.

[0147] This compound has the following properties: Melting point = 106 °C Molar mass = C 28 H 46 N8: 494.72 g / mol 1 HNMR(CD3OD):8.23(d;J=4.7Hz;4H);6.40(t;J=4.7Hz;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). 13 CNMR(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).

[0148] Second step: Synthesis of 2-[4-[12-(4-pyrimidin-2-ylpiperazin-1-yl)dodecyl]piperazin-1-yl]pyrimidine dihydrochloride derivative 150 mg (0.30 mmol) of 2-[4-[12-(4-pyrimidin-2-ylpiperazin-1-yl)dodecyl]piperazin-1-yl]pyrimidine was dissolved in 5-10 mL of ethanol. Hydrochloric acid gas was bubbled through the reaction medium for 5 min. After stirring, the precipitate was collected by filtration, washed with diethyl ether and dried. The expected compound was obtained as a white solid in 87% yield.

[0149] This compound has the following properties: Melting point = 252 °C Molar mass = C 28 H 46 N8.2HCl: 567.64 g / mol 1 HNMR(DMSO-d6):11.49(s;2H);8.44(d;J=4.8Hz;4H);6.76(t;J=4.8Hz;2H);4.67(d;J=14. 1Hz;4H);3.52(d;J=12.4Hz;8H);3.07-2.99(m;8H);1.79-1.73(m;4H);1.35-1.30(m;16H). 13 CNMR(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).

[0150] Example 3: Synthesis of Compound Ic Compound Ic was prepared according to the steps outlined in the following scheme.

[0151] JPEG2025511996000011.jpg60161

[0152] First step: Synthesis of 1-(2-pyridyl)-4-[12-[4-(2-pyridyl)piperazin-1-yl]dodecyl]piperazine derivatives To a solution of 700 mg (2.13 mmol) of 1,12-dibromododecane in 30 mL of dioxane were added 2 equivalents (4.26 mmol; 696.3 mg) of 1-(2-pyridyl)piperazine and 7 equivalents (14.94 mmol; 2.1 g) of potassium carbonate. The reaction mixture was heated under reflux in dioxane for 20 hours. After cooling, the dioxane was concentrated under reduced pressure. The residue obtained was taken up in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative obtained was purified by silica gel chromatography using ethyl acetate / methanol / triethylamine (99 / 0.5 / 0.5) as eluent.

[0153] The expected compound was obtained as a white solid in 48% yield.

[0154] This compound has the following properties: Melting point = 100℃ Molar mass = C 30 H 48 N6: 492.74 g / mol 1 HNMR(CD3OD):8.12(ddd;J=4.9;2.0;0.9Hz;2H);7.40(ddd;J=8.9;7.1;2.0Hz;2H);6.60-6.51(m;4H);3 .48(dd;J=6.2;4.1Hz;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). 13 CNMR(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).

[0155] Second step: Synthesis of 1-(2-pyridyl)-4-[12-[4-(2-pyridyl)piperazin-1-yl]dodecyl]piperazine dihydrochloride derivative 150 mg (0.30 mmol) of 1-(2-pyridyl)-4-[12-[4-(2-pyridylpiperazin-1-yl]dodecyl]piperazine was dissolved in 5-10 mL of ethanol. Hydrochloric acid gas was bubbled through the reaction medium for 5 min. After stirring, the precipitate was collected by filtration, washed with diethyl ether, and dried. The expected compound was obtained as a white solid in 91% yield.

[0156] This compound has the following properties: Melting point = 200 °C Molar mass = C 30 H 48 N6.2HCl: 565.66 g / mol 1 HNMR(DMSO-d6):11.41(s;2H);8.13(dd;J=5.8;1.8Hz;2H);7.94(t;3=8.2Hz;2H);7.30(d;3=9.0Hz;2H);6.96(t; 3=6.4Hz;2H);4.48(d;J=8.2Hz;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). 13 CNMR(DMSO-d6):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).

[0157] Example 4: Use of compounds (Ia), (Ib) and (Ic) as cancer agents 4.1 Seahorse Technology Analysis of Oxygen Consumption Rates Following Treatment of Human B Cell Lymphoma Cells with Compounds (Ia), (Ib) and (Ic) The analyzer, known as "Seahorse", allows the evaluation of mitochondrial respiration in real time by measuring the oxygen consumption rate (OCR). The experiments were carried out according to the supplier's recommendations ("Agilent's Seahorse XFe96"). To achieve this, a dedicated Agilent Seahorse 96-well plate was pretreated with CellTak's solution according to the supplier's recommendations (Corning) and 150,000 cells of a human B-cell lymphoma line ("RL line, CVCL_1660") were seeded per well in 180 μL of Agilent's Seahorse XF RPMI medium (supplemented with pyruvate and glucose). After 30 minutes of incubation in a CO2-free oven, the plates were analyzed on a "Seahorse" using a protocol in which increasing amounts of compound were injected (indicated by arrows in Figure 1) to give final cumulative concentrations of 1.2 μM, 2.5 μM, 5 μM, and 10 μM, and then the OCR (pmol / min) was read for 10 minutes each time. Data were normalized by counting cell numbers using an instrument known as the "Cytation1 / 5 Cell Imaging Multimode Reader" (BioTek) in combination with the "Seahorse."

[0158] FIG. 1 shows the effect of several compounds on mitochondrial respiration: the reference inhibitor rotenone (FIG. 1a, ROT, curve shown by the open inverted triangles), an inhibitor currently being evaluated in clinical trials and known as "IACS010759" (FIG. 1a, IACS, curve shown by the closed diamonds), compound (Ia) (FIG. 1b, curve shown by the closed inverted triangles), compound (Ib) (FIG. 1b, curve shown by the open circles) and compound (Ic) (FIG. 1b, curve shown by the closed circles). A control was used in each graph (DMSO, curve shown by the closed squares) and corresponds to the vehicle used in the study without the addition of compound (only DMSO dilutions from the molecular stock were added). In FIG. 1a, when injected at a concentration of 1.2 μM, the two comparative compounds not of the present invention, rotenone and "IACS-010759", similarly induced an immediate and almost complete inhibition of OCR. In addition, injection of increasing concentrations of the compounds of the present invention similarly induces a progressive inhibition of OCR, stepwise with compounds (Ib) and (Ic) and continuously with compound (Ia), with OCR being virtually completely inhibited at a concentration of 10 μM.

[0159] FIG. 1 shows the standard deviation (SD).

[0160] In summary, compounds (Ia), (Ib) and (Ic) act as mitochondrial respiration inhibitors (also known as OXPHOS inhibitors) with moderate and continuous effects compared to rotenone or "IACS-010759". Comparable results were obtained in the various strains tested.

[0161] 4.2 Analysis of the effect on cell proliferation of the treatment of human tumor cells derived from a B-cell lymphoma line with compounds (Ia), (Ib) and (Ic) Cells from human B-cell lymphoma cell lines (Karpas422, CVCL_1325) were seeded at a density of 100,000 cells per well in 96-well plates in the presence of compounds at a concentration of 10 μM in a volume of 100 μL of medium. After 48 hours of treatment, the effect on cell proliferation was analyzed either by counting viable cell numbers using flow cytometry (FIG. 2a) or by using a biochemical fluorescence detection kit for live cells (FIG. 2b).

[0162] FIG. 2 shows the effect on cell proliferation of cells treated with compounds (Ia), (Ib) and (Ic) of the present invention in conventional "Gibco RPMI1640 / 10%SVF" medium (denoted as RPMI) (FIG. 2a); and with compounds (Ia), (Ib) and (Ic) of the present invention, four comparative compounds not of the present invention, "IACS-010759 (IACS) currently undergoing clinical trials, an inhibitor known as "IM156", rotenone (ROT) and staurosporine (STS), an apoptosis inducer, in "Gibco Human Like Plasma Medium" (Gibco HPLM, Thermo Fisher Scientific) (denoted as HLPM), which reproduces the metabolic conditions of human plasma (FIG. 2b). Viable cell counts were determined in conventional "Gibco RPMI1640 / 10° / 0SVF" medium after double labeling with Annexin V / PI and analysis using a flow cytometer known as "ATTUNE" (Thermo Fisher Scientific). The viable cell number was assessed after measurement of relative fluorescence units (RFU) in "Gibco Human Like Plasma Medium" using the "CellTiterFluor" kit according to the supplier's recommendations (Promega). The term DMSO in Figure 2 corresponds to the control, which is the same medium without the addition of compound.

[0163] FIG. 2 shows the standard deviation (SD).

[0164] Based on Figure 2, compounds (Ia), (Ib) and (Ic) inhibit cell proliferation by reducing the number of viable tumor cells after 48 hours of treatment, even in culture medium conditions that mimic human plasma. The efficacy is similar to that obtained with the inhibitor "IACS010759" or rotenone. The effect is strain-dependent (see Figure 3).

[0165] 4.3 Analysis of the effect on cell proliferation of treatment of human tumor cells derived from a broad range of B and T cell lymphoma cell lines with compound (Ia) The effect of the compound of the invention (Ia) compared to the non-inventive compound "IACS-010769" (denoted as IACS) on cell proliferation was analyzed on 31 broad lineage human B and T cell lymphoma lines after labeling with Annexin V / PI and analysis using an "ATTUNE" cytometer (Thermo Fisher Scientific). This technique allows the assessment of the % of cells undergoing apoptosis in addition to the number of live cells shown in Figure 2a. The results are presented in Figure 3 as a "heat map" with a black and white gradient, with black representing the highest % of cells undergoing apoptosis.

[0166] Based on FIG. 3, the toxicity of compound (Ia) and "IACS-010759" differs depending on the lymphoma strain analyzed. In particular, the toxicity of compound (Ia) is higher than that of "IACS-010759" for the subgroup of 8 strains boxed in the figure. These data confirm that these two compounds have different targeting and modes of action.

[0167] 4.4 Analysis of the Antitumor Efficacy of Compound (Ia) in an In Ovo Model A preclinical evaluation of the antitumor efficacy of compound (Ia) on chicken embryo chorioallantoic membrane (CAM) was performed using a xenograft model. Figure 4 shows human tumor cells of a B-cell lymphoma line ("SUDHL-4, CVCL_0539") implanted on the CAM of embryos on day E9 (Figure 4a), as well as indication of the presence or absence of tumor mass (Figure 4b) and the relative amount of metastasis (Figure 4c). Treatment was performed on days E11, E13, E15 and E17. On day E18, the upper CAM containing the tumor was removed and weighed, and the lower CAM fragment was used to evaluate the presence of human cells representing metastasis by RT-qPCR (polymerase chain reaction from RNA samples). Doxorubicin (DOXO) 0.0097 mg / kg was used as a positive control for therapeutic effect, compound (Ia) 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 as DMSO) represents treatment with DMSO molecular diluent.

[0168] In Figure 4b, the effect of treatment on tumor volume is directly observed. Treatment with doxorubicin induced a 90% reduction in the initial tumor volume. In comparison, treatment with "IACS010759" (IACS) induced a 44% [1] and 82% [2] reduction, and treatment with compound (Ia) induced a 48% [1], 73% [2] and 70% [3] reduction.

[0169] In figure 4c, the effect of treatment on the relative number of metastases is directly observed. Treatment with doxorubicin induced a 99% regression of the number of metastases. In comparison, treatment with "IACS010759" (IACS) induced a 69% [1] and 73% [2] reduction, and treatment with compound (Ia) induced a 45% [1], 70% [2] and 72% [3] reduction.

[0170] FIG. 4 shows the standard deviation (SD).

[0171] In summary, compound (Ia) is chemically different from the "IACS-010759" molecule and acts differently on the OCR, but has comparable antitumor efficacy in the preclinical model used in this example. Compound (Ia) also inhibits tumor metastasis.

[0172] 4.5 Analysis of the effect on cell proliferation of the treatment of human cells from two sarcoma lines with compounds (Ia), (Ib) and (Ic) Human tumor cells from two pediatric rhabdomyoid sarcoma lines (RD136, CVCL_1649 in Fig. 5a and RH3O, CVCL_0041 in Fig. 5b) were seeded in 96-well plates in the presence of compounds at 10 μM concentration in a volume of 100 μL in "Gibco Human Like Plasma Medium" (Gibco HPLM, Thermo Fisher Scientific). The effects of compounds (Ia), (Ib) and (Ic) were compared with the inhibitors IACS-010759 (IACS) and IM156 (metformin analogue), currently in clinical trials, rotenone (ROT) and the apoptosis inducer staurosporine (STS). After 48 h of treatment, the effect on viable cell number was assessed using the Promega "CellTiterFluor" kit as in Fig. 2b.

[0173] Figure 5a shows the effect of compound treatment on viable cell counts of strain RD136 (in HLPM medium as above) and Figure 5b shows the effect on viable cell counts of strain RH30 (in HLPM medium as above), compared to the effect of compound diluent (DMSO) and expressed as % relative fluorescence units (RFU).

[0174] FIG. 5 shows the standard deviation (SD).

[0175] In summary, compounds (Ia), (Ib) and (Ic) inhibit cell proliferation of RD136 and RH30 lines by reducing the number of viable cells after 48 hours of treatment. These effects are similar to those obtained with the inhibitor "IACS-010759" or rotenone. Thus, the field of application of these compounds can be expanded beyond blood cancers such as lymphomas to solid tumors such as human pediatric sarcomas exemplified herein.

[0176] 4.6 IC of compound (Ia) of the present invention compared to conventional compounds 50 Analysis of IC of compound (Ia) 50 was compared with the compound described in WO 2020 / 109506, which has the following formula:

[0177] JPEG2025511996000012.jpg36170

[0178] As a result, compound (Ia) has an IC 50 The compound described in WO 2020 / 109506 showed a 1.5 μM and the compound described in WO 2020 / 109506 showed a 15.1 μM. This indicates an improved performance of compound (Ia) compared to the prior art compounds. These experiments were carried out using cells derived from a human B cell lymphoma cell line ("Karpas422, CVCL_1325") seeded in "RPMI1640" medium (11 mM glucose) supplemented with 10% serum in the presence of increasing concentrations of the compounds.

[0179] After 48 h of treatment, the effect on cell proliferation was analyzed using the “CellTiter-Fluor Cell Viability Assay” (Promega) viable cell detection kit as in Fig. 2b, according to the supplier's instructions.

[0180] Example 5: Synthesis of Compound Id

[0181] JPEG2025511996000013.jpg38170

[0182] To a solution of 700 mg (3.49 mmol) of 1,12-dodecanediamine in 30 mL of dioxane, 2.2 equivalents (7.69 mmol; 880 mg) of 2-chloropyrimidine and 5 equivalents (17.47 mmol; 2.4 g) of potassium carbonate were added. The reaction mixture was heated under reflux in dioxane for 20 hours. After cooling, the dioxane was concentrated under reduced pressure. The residue obtained was taken up in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative obtained was purified by silica gel chromatography using ethyl acetate / cyclohexane (90 / 10) as eluent.

[0183] The expected compound was obtained as a white solid in 26% yield.

[0184] This compound has the following properties: Melting point Mp=105℃, C 20 H 32 N6 = 356.50 g / mol 1 HNMR(CDCl3):8.20(d;J=4.8Hz;4H);6.43(t;J=4.8Hz;2H);5.11(bs;2H);3.32(td;J=7.1;5.7Hz;4H);1.57-1.50(m,4H);1.35-1.18(m;16H). 13 CNMR(CDCl3):162.4(2C);158.0(4C);110.3(2C);41.5(2C);29.6(2C);29.5(2C);29.4(2C);27.0(2C).

[0185] Example 6: Synthesis of Compound Ie

[0186] JPEG2025511996000014.jpg41170

[0187] To a solution of 800 mg (3.10 mmol) of 1,7-dibromoheptane in 30 mL of dioxane, 2 equivalents (6.20 mmol; 1.0 g) of 2-piperazin-1-ylpyrimidine and 7 equivalents (21.70 mmol; 3.0 g) of potassium carbonate were added. The reaction mixture was heated under reflux in dioxane for 20 h. After cooling, the dioxane was concentrated under reduced pressure. The residue obtained was taken up in 50 mL of dichloromethane, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative obtained was purified by silica gel chromatography using dichloromethane / methanol / triethylamine (98 / 1 / 1) as eluent.

[0188] The expected compound was obtained as a white solid in 30% yield.

[0189] This compound has the following properties: Melting point Mp=86℃, C 23 H 36 N8 = 424.58 g / mol 1HNMR(CDCl3):8.23(d;J=4.7Hz;4H);6.40(t;J=4.7Hz;2H),3.78-3.75(m;8H) ;2.44-2.41(m;8H);2.31-2.27(m;4H);1.50-1.43(m;4H);1.28-1.24(m;6H). 13 CNMR(CDCl3):161.7(2C);157.7(4C);109.8(2C);58.9(2C);53.2(4C);46.2(2C);43.7(2C);29.5;27.6(2C);26.9(2C).

[0190] Example 7: Synthesis of Compound If

[0191] JPEG2025511996000015.jpg37170

[0192] To a solution of 800 mg (3.10 mmol) of 1,7-dibromoheptane in 30 mL of dioxane were added 2 equivalents (6.20 mmol; 1.0 g) of 1-(2-pyridyl)piperazine and 7 equivalents (21.70 mmol; 3.0 g) of potassium carbonate. The reaction mixture was heated under reflux in dioxane for 20 hours. After cooling, the dioxane was concentrated under reduced pressure. The residue obtained was taken up in 50 mL of dichloromethane, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative obtained was purified by silica gel chromatography using dichloromethane / methanol / triethylamine (98 / 1 / 1) as eluent.

[0193] 150 mg (0.354 mmol) of 1-(2-pyridyl)-4-[7-[4-(2-pyridylpiperazin-1-yl]heptyl]piperazine was dissolved in 5-10 mL of ethanol. Hydrochloric acid gas was bubbled through the reaction medium for 2 min. After stirring, the precipitate was collected by filtration, washed with diethyl ether, and dried.

[0194] The expected compound was obtained as a white solid in 82% yield.

[0195] This compound has the following properties: Melting point Mp = 210 ° C, C 25 H 38 N6.2HCl = 495.53 g / mol 1 HNMR(D2O):8.06(m;2H);7.93(d;J=6.3Hz;2H);7.30(d;J=9.2Hz;2H);7.06(t;J=6.7Hz;2H);4.28(d;J=1 4.5Hz;4H);3.73(d;J=12.8Hz;4H);3.59(t;J=13.5Hz;4H);3.30-3.13(m;8H);1.71(m;4H);1.34(m;6H). 13 CNMR(D2O):152.1(2C);145.6(2C);136.6(2C);115.0(2C);113.3(2C);57.1(2C);50.5(4C);43.2(4C);27.7;25.5(2C);23.3(2C).

[0196] Example 8: Use of compounds (Id), (Ie) and (If) as cancer agents Cells from a human B cell lymphoma cell line ("RL, CVCL_1660") were seeded at a density of 100,000 cells per well in 96-well plates in the presence of compounds at 5 μM or 10 μM concentrations in a volume of 100 μL of RPMI medium. After 48 hours of treatment, the effect on cell proliferation was analyzed by counting viable cells using flow cytometry, as in Figure 2a.

[0197] FIG. 6 shows the inhibitory effect on cell proliferation when cells are treated with compounds (Ia) and (Id) of the present invention in a conventional "Gibco RPMI1640 / 10% SVF" medium (denoted as RPMI).

[0198] FIG. 6 shows the standard deviation (SD).

[0199] Human tumor cells from a pediatric rhabdomyosarcoma line ("RH30, CVCL_0041") were seeded in 96-well plates in the presence of compounds at 10 μM or 25 μM concentration in a volume of 100 μL of "Gibco Human Like Plasma Medium" (Gibco HPLM, Thermo Fisher Scientific). After 48 hours of treatment, the effect of compounds (Ia), (Ie) and (If) on cell proliferation was evaluated using the Promega "CellTiterFluor" kit as in Figure 2b. Figure 7 shows the effect of treatment with these compounds on RH30 line proliferation (in HLPM medium as above) and is expressed as % relative fluorescence units (RFU) compared to the effect of compound diluent (DMSO).

[0200] FIG. 7 shows the standard deviation (SD).

[0201] In summary, compounds (Ia), (Ie) and (If) inhibit cell proliferation of the RH30 line by reducing the number of viable cells 48 hours after treatment. Thus, the field of application of these compounds can be expanded beyond hematological cancers such as lymphomas to solid tumors, such as the human pediatric sarcomas exemplified herein.

Claims

1. A compound selected from compounds represented by formula (I) used in cancer treatment, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof, Formula (I) has the following structure: [Chemical formula 1] During the ceremony, * R ２ 、R ２ and R ３ are each independently a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH ２ 、-SH, -CN, -CF ３ 、-CHO, -NH-NH ２ 、-CO ２ H, -CH ２ OH, -CH ２ NH ２ 、an alkoxy group -OR ７ 、-NR ８ R ９ group, -SR １０ group, -C(O)R １１ group, -CH ２ OR １２ group and -CH ２ NR １３ R １４ group, and R ７ 、R ８ 、R １０ 、R １１ 、R １２ and R １３ are each independently an alkyl or cycloalkyl radical, and R ９ and R １４ are each independently a hydrogen atom, or an alkyl or cycloalkyl radical, * X １ is a nitrogen atom or CR １５ Represents the base, R １５ is a hydrogen atom, halogen atom, alkyl radical, cycloalkyl radical, aryl radical, or -OH, -NH ２ , -SH, -CN, -CF ３ , -CHO, -NH-NH ２ , -CO ２ H, -CH ２ OH, -CH ２ NH ２ alkoxy group -OR ７ , -NR ８ R ９ Base, -SR １０ group, -C(O)R １１ group, -CH ２ OR １２ The group and -CH ２ NR １３ R １４ It is a base selected from the bases, * n is an integer from 1 to 20, * R ４ is a hydrogen atom, an alkyl radical, or R ４ Y that generates １ And represents a divalent alkylene group that forms a ring with a nitrogen atom, * R ５ is a hydrogen atom, an alkyl radical, or R ５ Y that generates ２ And represents a divalent alkylene group that forms a ring with a nitrogen atom, * Y １ is the aforementioned R ４ When the group represents a hydrogen atom or an alkyl radical, -CH ２ -, -NH- or -O-; the above R ４ The base is R ４ Y that generates １ And when representing a divalent alkylene group that forms a ring with the nitrogen atom, it represents -CH- or -N-, * Y ２ is the aforementioned R ５ When the group represents a hydrogen atom or an alkyl radical, -CH ２ -, -NH- or -O-; the above R ５ The base is R ４ Y that generates ２ And when representing a divalent alkylene group that forms a ring with the nitrogen atom, it represents -CH- or -N-, * R ６ This represents one of the following two groups, (IIa) and (IIb): [Chemical 2] wherein, R' １ , R' ２ and R' ３ are each independently a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH ２ , -SH, -CN, -CF ３ , -CHO, -NH-NH ２ , -CO ２ H, -CH ２ OH, -CH ２ NH ２ , an alkoxy group -OR' ７ , -NR' ８ R' ９ group, -SR' １０ group, -C(O)R' １１ group, -CH ２ OR' １２ group and -CH ２ NR' １３ R' １４ group, and R' ７ , R' ８ , R' １０ , R' １１ , R' １２ and R' １３ each independently represent an alkyl or cycloalkyl radical, and R' ９ and R' １４ each independently represent a hydrogen atom, or an alkyl or cycloalkyl radical, X ２ represents a nitrogen atom or CR' １５ group, and R' １５ is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or -OH, -NH ２ , -SH, -CN, -CF ３ , -CHO, -NH-NH ２ , -CO ２ H, -CH ２ OH, -CH ２ NH ２ , an alkoxy group -OR' ７ , -NR' ８ R' ９ group, -SR' １０ group, -C(O)R' １１ group, -CH ２ ​​​​​​​​​ compound.

2. The compound according to claim 1, for use in the treatment of cancer with altered metabolism, particularly in the treatment of cancer having OXPHOS metabolism.

3. The compound according to claim 1, for use in the treatment of lymphoma; solid tumors; and certain recurrent tumors after chemotherapy.

4. X １ The compound used according to claim 1, characterized in that represents a nitrogen atom or a CH group.

5. R ４ is a hydrogen atom, or R ４ Y that generates １ and represents a divalent alkylene group that forms a ring with the nitrogen atom, R ５ is a hydrogen atom, or R ５ Y that generates ２ The compound used according to claim 1, characterized in that it represents a divalent alkylene group that forms a ring together with the nitrogen atom.

6. Y １ is the aforementioned R ４ When the group represents a hydrogen atom or an alkyl radical, -CH ２ - represents; the above R ４ The base is R ４ Y that generates １ And when representing a divalent alkylene group that forms a ring with the nitrogen atom, it represents -N-; Y ２ is the aforementioned R ５ When the group represents a hydrogen atom or an alkyl radical, -CH ２ - represents; the above R ５ The base is R ５ Y that generates ２ The compound used according to claim 1, characterized in that when representing a divalent alkylene group that forms a ring with the nitrogen atom, it represents -N-.

7. Y １ and Y ２ The compound used according to claim 1, characterized in that it is identical.

8. - Y １ ga-CH ２ When representing -, n is from 2 to 10, - Y ２ ga-CH ２ When representing -, n is from 2 to 10, - Y １ When n represents -N-, -NH-, -CH-, or -O-, n is between 6 and 18. - Y ２ The compound used according to claim 1, characterized in that when represents -N-, -NH-, -CH-, or -O-, n is between 6 and 18.

9. Y １ and Y ２ represents -CH-, R ６ When is the basis of equation (IIa), then n is, for example, n ≥ 5, and / or R １ , R' １ , R ２ , R' ２ , R ３ and R' ３ ga-NH ２ Unlike; Y １ and Y ２ represents -N-, R ６ The compound used according to claim 1, characterized in that when is a base of formula (IIa), n is, for example, n ≥ 7.

10. R ６ The compound used according to claim 1, characterized in that is a group of formula (IIb).

11. The compound used according to claim 1, characterized in that the compound of formula (I) is selected from the following compounds. [Table 1]

12. A pharmaceutical composition comprising a compound according to any one of claims 1 and 4 to 11 and at least one suitable pharmaceutical carrier.

13. A product comprising the compound according to any one of claims 1 and 4 to 11, and another activator.

14. A compound selected from the compounds represented by formula (I'), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof, The above formula (I') has the following structure, [Chemical 3] During the ceremony, * R １ , R ２ , R ３ , R ４ , R ５ , R ６ , X １ , Y １ , Y ２ And n is as described in claim 1, * Y １ and Y ２ represents -CH-, R ６ When is a radical of formula (IIa), n ≥ 5 and / or R １ , R' １ , R ２ , R' ２ , R ３ and R' ３ ga-NH ２ Unlike, * Y １ and Y ２ represents -N-, R ６ A compound in which n ≥ 7, where is a radical of formula (IIa).

15. R ６ The compound according to claim 14, characterized in that is a group of formula (IIb).

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