Diamine derivative mitochondrial activity inhibitors for cancer treatment

Abstract

The invention is applicable to the field of cancer treatment. In particular, the present invention relates to compounds derived from aliphatic diamines comprising at least one pyridine unit or pyrimidine unit for use as anti-cancer agents, therapeutic compositions comprising said compounds, products comprising such compounds and another active agent, and such compounds.

Description

[0001] The present invention is applicable to the field of cancer treatment. In particular, the present invention relates to compounds derived from aliphatic diamines containing at least one pyridine unit or pyrimidine unit for use as anticancer agents, therapeutic compositions containing said compounds, products containing such compounds and another active agent, and such compounds.

[0002] Cancer is one of the leading causes of death worldwide. Treatments for cancer are diverse, including surgery, radiotherapy, chemotherapy, hormone therapy, immunotherapy, and targeted therapy. Basic research data suggest that the plasticity of tumor cells enables them to develop resistance mechanisms to evade these treatments.

[0003] In this context, research is focusing on new therapeutic strategies in the face of the relatively low efficacy of most conventional anticancer drugs in cancers that have failed or not failed after first-line treatment, such as T-cell lymphoma, pancreatic cancer, and some pediatric brain tumors. In fact, successfully overcoming the drug resistance encountered in such diseases represents a real public health problem and a challenge for research.

[0004] Remodeling of energy metabolism is one of the key steps in tumor development, especially in the context of resistance to therapy. In particular, tumor cells adapt to the conditions of their microenvironment and the selective pressure imposed by chemotherapy by modulating their metabolism. Therefore, the development of novel molecules targeting cellular metabolism represents a major therapeutic challenge.

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

[0006] Molecules targeting OXPHOS metabolism have been developed through a variety of processes and are being tested in various clinical trials; for example, those molecules that block mitochondrial ribosomes and indirectly block the synthesis of respiratory chain complexes (e.g., the antibiotic tigecycline), or those molecules that directly inhibit complex I (e.g., metformin) or complex III (e.g., antimycin A) of the respiratory chain. They have synergistic cytotoxic effects on reference treatments. Other pharmacological approaches aimed at blocking β-oxidation of fatty acids in mitochondria or increasing oxidative stress in OXPHOS malignant cells are also provided.

[0007] Recently, other OXPHOS inhibitors have been described. In particular, a complex I inhibitor named "IACS-010759" is currently undergoing clinical trials, especially in hematological cancers.

[0008]

[0009] In addition, international application WO2020 / 109506 describes a compound for cancer treatment having the following formula or a pharmaceutically acceptable salt and / or solvate thereof:

[0010]

[0011] Where X 1 and X 2 Same or different, NR 5 or sulfur atom, Y is C 1 To C 10 Alkanediyl, Ar l and Ar 2 are the same or different, are optionally substituted aryl, R 5 A hydrogen atom or C 1 To C 6 These compounds are described as inhibitors of mitochondrial oxygen consumption rate and are particularly useful in treating some cancers that have an "OXPHOS" mechanism.

[0012] However, in order to meet the growing demand for personalized medicine, according to the individual characteristics of each type of tumor, there is a need to continue to develop other anticancer drugs that are effective against tumor cells, especially those that target the mitochondrial respiratory chain and thus have an inhibitory effect on the cellular energy charge. In particular, compared with the limited number of OXPHOS inhibitors that have been developed, it is necessary to develop molecules with other physicochemical characteristics that act on other intracellular targets. These new molecules should be easy to prepare and have improved cytotoxic properties, while ensuring good pharmacokinetic properties, such as good ADMET properties (absorption of molecules, distribution in the body, elimination including biotransformation or metabolism, excretion and toxicity), especially in computer simulations.

[0013] Therefore, the object of the present invention is to overcome the above-mentioned defects of the prior art and provide an anticancer agent with good performance in anticancer activity, which is easy to prepare, has low toxicity to non-tumor cells, and ensures good ADMET properties.

[0014] The objects of the present invention are achieved by the following compounds.

[0015] The first object of the present invention is a compound selected from the group consisting of compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvates thereof for use in the treatment of cancer,

[0016] The formula (I) has the following structure:

[0017]

[0018] in:

[0019] *R 1 , R 2 and R 3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical or a radical selected from -OH, -NH 2 , -SH, -CN (cyano or carbonitrile), -CF 3 、-CHO(aldehyde), -NH-NH 2 (Hydrazine), -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-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 A group of groups, where R 7 , R 8 , R 10 , R 11 , R 12 and R 13 independently represent an alkyl group or a cycloalkyl group, and R 9 and R 14 independently of one another represent a hydrogen atom or an alkyl or cycloalkyl radical,

[0020] *X 1 Represents nitrogen atom or CR 15 Group, where R 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical or an aryl radical, or is selected from -OH, -NH 2 、-SH、-CN、-CF 3 , -CHO, -NH-NH 2 , -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-OR 7 、-NR 8 R9 Group, -SR 10 Group, -C(O)R 11 Group, –CH 2 OR 12 Group, and -CH 2 NR 13 R 14 Group of groups,

[0021] *n is an integer from 1 to 20,

[0022] *R 4 represents a hydrogen atom, an alkyl radical or a divalent alkylene group, wherein the divalent alkylene group and Y 1 and R 4 The nitrogen atoms connected form a ring,

[0023] *R 5 represents a hydrogen atom, an alkyl radical or a divalent alkylene group, wherein the divalent alkylene group and Y 2 and R 5 The nitrogen atoms connected form a ring,

[0024] * When R 4 When the group represents a hydrogen atom or an alkyl radical, Y 1 Indicates -CH 2 -, -NH- or -O-; and when R 4 Group representation and Y 1 and R 4 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 1 Indicates -CH- or -N-,

[0025] * When R 5 When the group represents a hydrogen atom or an alkyl radical, Y 2 Indicates -CH 2 -, -NH- or -O-; and when R 5 Group representation and Y 2 and R 4 When the nitrogen atom I to which it is connected forms a cyclic divalent alkylene group, Y 2 Indicates -CH- or -N-,

[0026] *R 6 represents one of the following two groups (IIa) and (IIb):

[0027]

[0028] Where R' 1 , R' 2 and R' 3independently represent a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical or a radical selected from -OH, -NH 2 、-SH、-CN、-CF 3 , -CHO, -NH-NH 2 , -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-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 A group of groups, where R' 7 , R' 8 , R' 10 , R' 11 , R' 12 and R' 13 independently represent an alkyl or cycloalkyl radical, and R' 9 and R' 14 independently of one another represent a hydrogen atom or an alkyl or cycloalkyl radical, and

[0029] X 2 Represents nitrogen atom or CR' 15 Group, where R' 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a radical selected from -OH, -NH 2 、-SH、-CN、-CF 3 , -CHO, -NH-NH 2 , -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-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 of groups.

[0030] Compounds (I) of the present invention are derivatives of aliphatic diamines containing at least one pyridine unit or pyrimidine unit. The inventors have found that such compounds exhibit significant anticancer activity. In addition, these compounds are easy to prepare, have low toxicity to healthy cells, and have good ADMET properties, especially in computer simulations.

[0031] "Cancer" refers to all malignant tumor formations, regardless of their histological nature (adults and children). Solid tumors are mainly divided into two categories: carcinomas of epithelial origin and sarcomas of connective origin. Solid tumors are formed by invasive or diffusible atypical cells and are characterized by their ability to grow autonomously, poorly defined borders, the ability to invade adjacent tissues and blood vessels, and the tendency to spread by producing metastases. Examples include breast cancer, prostate cancer, lung cancer, esophageal cancer, skin cancer, bladder cancer, stomach cancer, liver cancer, uterine cancer, colon cancer and rectal cancer. In addition, there are pancreatic endocrine cancer and pancreatic exocrine cancer as well as childhood tumors such as rhabdomyosarcoma and diffuse intrinsic pontine glioma (DIPG). Another category of tumors includes various types of hematological malignancies.

[0032] A second object of the present invention is a compound as defined in the first object of the present invention for use in the targeted treatment of cancers with metabolic alterations, in particular in the treatment of cancers with OXPHOS metabolism.

[0033] A cancer with OXPHOS metabolism corresponds to a cancer comprising or consisting of cancer cells that primarily rely on oxidative phosphorylation (OXPHOS) for biosynthetic and / or bioenergetic processes.

[0034] Such cancers with OXPHOS metabolism include hematological cancers, lung cancer, cervical cancer, prostate cancer, neuroendocrine tumors, glial tumors, and skin and eye cancers.

[0035] According to a preferred embodiment of the present invention, the compounds defined in the first object of the present invention are used to treat lymphoma, especially B lymphoma and T lymphoma in adults or children; solid tumors such as sarcoma, especially childhood sarcoma (e.g. rhabdomyosarcoma type); and some recurrent tumors after chemotherapy.

[0036] The compounds defined in the first object of the present invention have antitumor activity in one or several preclinical models.

[0037] "Lymphoma" refers to any tumor, usually malignant, arising from the proliferation of lymphohistiocytic cells, which develops in the spleen or lymph nodes but also in many other organs or tissues.

[0038] Therefore, the compounds defined in the first object of the present invention have the potential properties of new anticancer drugs targeting cellular metabolism.

[0039] The compound acts in particular as an inhibitor of the mitochondrial respiratory chain and inhibits the oxygen consumption rate. Therefore, it can be considered an OXPHOS inhibitor. The compound also has:

[0040] - In vitro cytotoxic activity comparable to existing OXPHOS inhibitors in clinical trials, particularly IACS-010759, and

[0041] -Specificity of the effect in relation to the cellular phenotype.

[0042] In the compounds defined in the first aspect of the present invention, the alkyl radical may be linear or branched, and is preferably linear.

[0043] In the compounds defined in the first aspect of the present invention, the cycloalkyl radical may be linear or branched, and is preferably linear.

[0044] For the purposes of the present invention, halogen is selected from F, Cl, Br and I and particularly preferably from F and Cl.

[0045] R 1 , R 2 , R 3 Definition of

[0046] R 1 , R 2 and R 3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical or a radical selected from -OH, -NH 2 , -SH, -CN (carbonitrile or cyano), -CF 3 , -CO 2 H, -CH 2 OH, CH 2 NH 2 、-CHO(aldehyde), -NH-NH 2 (Hydrazine), alkoxy-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 A group of groups, where R 7 , R 8 , R 10 , R 11 , R 12 and R 13 independently represent an alkyl or cycloalkyl radical, and R 9 and R 14independently of one another represent a hydrogen atom or an alkyl or cycloalkyl radical.

[0047] As R 1 , R 2 or R 3 The alkyl radical of the group is preferably C 1 To C 5 The alkyl radical is particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0048] As R 1 , R 2 or R 3 The cycloalkyl radical of the group is preferably C 3 To C 6 The cycloalkyl radical is particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0049] As R 1 , R 2 or R 3 The aromatic radical of the group is preferably C 5 To C 15 The aryl radical is particularly preferably a phenyl radical, a 2-thienyl radical or a 3-thienyl radical, a 2-furyl radical or a 3-furyl radical, and more particularly preferably a phenyl radical.

[0050] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 Definition of

[0051] As R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 The alkyl radical of the group is preferably C 1 To C 5 The alkyl radical is particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0052] As R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 The cycloalkyl radical of the group is preferably C 3 To C 6 The cycloalkyl radical is particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0053] -SR 10 The group is preferably thiomethyl.

[0054] -NR 8 R 9 The group is preferably a methylamino group or a dimethylamino group.

[0055] Alkoxy group -OR 7 Preferred is a methoxy group or an ethoxy group.

[0056] 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 radical -OR 7 、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0057] 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 radical -OR 7 、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0058] 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 radical -OR 7 、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0059] Advantageously, R 1 , R 2 and R 3 A hydrogen atom.

[0060] X 1 Definition of

[0061] X 1Represents nitrogen atom or CR 15 Group, where R 15 is a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group or an aryl group, or is selected from -OH, -NH 2 、-SH、-CN、-CF 3 , -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-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 of groups.

[0062] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 The groups are as defined herein.

[0063] 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 radical -OR 7 、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0064] Advantageously, X 1 represents a nitrogen atom or a CH group.

[0065] R 4 and R 5 Definition

[0066] R 4 represents a hydrogen atom, an alkyl radical or a divalent alkylene group, wherein the divalent alkylene group and Y 1 and R 4 The attached nitrogen atoms form a ring.

[0067] As R 4 The alkyl radical of the group is preferably C1 To C 5 The alkyl radical is particularly preferably a methyl or ethyl radical.

[0068] As R 4 Group and Y 1 and R 4 The divalent alkylene radical to which the nitrogen atom is attached to form a ring is preferably an alkylene radical -(CH 2 ) 2 -or-(CH 2 ) 3 -, particularly preferably an alkylene radical -(CH 2 ) 2 -.

[0069] Preferably, R 4 represents a hydrogen atom or a divalent alkylene group, wherein the divalent alkylene group and Y 1 and R 4 The attached nitrogen atoms form a ring.

[0070] R 5 represents a hydrogen atom, an alkyl radical or a divalent alkylene group, wherein the divalent alkylene group and Y 2 and R 5 The attached nitrogen atoms form a ring.

[0071] As R 5 The alkyl radical of the group is preferably C 1 To C 5 The alkyl radical is particularly preferably a methyl, ethyl, propyl or butyl radical.

[0072] As R 2 Group and Y 2 and R 2 The divalent alkylene radical to which the nitrogen atom is attached to form a ring is preferably an alkylene radical -(CH 2 ) 2 -or-(CH 2 ) 3 -, particularly preferably an alkylene radical -(CH 2 ) 2 -.

[0073] Preferably, R 5 represents a hydrogen atom or a divalent alkylene group, wherein the divalent alkylene group and Y 2 and R 5 The attached nitrogen atoms form a ring.

[0074] According to a particularly preferred embodiment of the present invention, R 4 represents a hydrogen atom or a divalent alkylene group, wherein the divalent alkylene group and Y 1 and R4 The nitrogen atom connected forms a ring; R 5 represents a hydrogen atom or a divalent alkylene group, wherein the divalent alkylene group and Y 2 and R 5 The attached nitrogen atoms form a ring.

[0075] According to a particularly preferred embodiment of the present invention, R 4 and R 5 are the same.

[0076] Y 1 and Y 2 Definition of

[0077] When R 4 When the group represents a hydrogen atom or an alkyl radical, Y 1 Indicates -CH 2 -, -NH- or -O-; and when R 4 Group representation and Y 1 and R 4 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 1 It represents -CH- or -N-.

[0078] Preferably, when R 4 When the group represents a hydrogen atom or an alkyl radical, Y 1 Indicates -CH 2 -; and when R 4 Group representation and Y 1 and R 4 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 1 Means -N-.

[0079] When R 5 When the group represents a hydrogen atom or an alkyl radical, Y 2 Indicates -CH 2 -, -NH- or -O-; and when R 5 Group representation and Y 2 and R 5 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 2 It represents -CH- or -N-.

[0080] Preferably, when R 5 When the group represents a hydrogen atom or an alkyl radical, Y 2 Indicates -CH 2 -; and when R 5 Group representation and Y 2 and R 5 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 2 Means -N-.

[0081] According to a particularly preferred embodiment of the present invention, when R 4 When the group represents a hydrogen atom or an alkyl radical, Y 1 Indicates -CH 2 -; and when R 4 Group representation and Y 1 and R 4 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 1 Indicates -N-; when R 5 When the group represents a hydrogen atom or an alkyl radical, Y 2 Indicates -CH 2 -; and when R 5 Group representation and Y 2 and R 5 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 2 Means -N-.

[0082] According to a particularly preferred embodiment of the present invention, Y 1 and Y 2 are the same.

[0083] Definition of n

[0084] n is an integer of 1-20, preferably an integer of 1-14.

[0085] n and Y 1 , n and Y 2 Definition of relationship

[0086] According to a preferred embodiment of the present invention:

[0087] -When Y 1 (or Y 2 ) indicates -CH 2 -, n is preferably 2 to 10, particularly preferably 3 to 9,

[0088] -When Y 1 (or Y 2 ) represents -N-, -NH-, -CH- or -O-, n is preferably 6 to 18, particularly preferably 7 to 14.

[0089] When R 6 This embodiment applies in particular when it is a group of the formula (IIa).

[0090] When Y 1 and Y 2 represents -CH-, and R 6 When it is a group of formula (IIa), n is preferably such that n≥5 and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R'3 Preferably different from -NH 2 .

[0091] When Y 1 and Y 2 Represents -N-, and R 6 When it is a group of formula (IIa), n is preferably such that n≥7.

[0092] According to a preferred embodiment of the present invention, when Y 1 and Y 2 represents -CH-, and R 6 When it is a group of formula (IIa), n is preferably such that n≥5 and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R' 3 Preferably different from -NH 2 ; When Y 1 and Y 2 Represents -N-, and R 6 When it is a group of formula (IIa), n is preferably such that n≥7.

[0093] R 6 Definition

[0094] R 6 represents one of the following two groups (IIa) and (IIb):

[0095]

[0096] Where R' 1 , R' 2 and R' 3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a radical selected from -OH, -NH 2 、-SH、-CN、-CF 3 , -CHO, -NH-NH 2 , -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-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 A group of groups, where R' 7 , R' 8 , R' 10 , R' 11 , R' 12 and R' 13 independently represent an alkyl or cycloalkyl radical, and R' 9 and R' 14 independently of one another represent a hydrogen atom, or an alkyl or cycloalkyl radical, and

[0097] X 2 Represents nitrogen atom or CR' 15 Group, where R' 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a radical selected from -OH, -NH 2 、-SH、-CN、-CF 3 , -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-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 of groups.

[0098] R 6 Preferred are groups of the formula (IIb).

[0099] R' 1 , R' 2 , R' 3 Definition

[0100] As R' 1 , R' 2 or R' 3 The alkyl radical of the group is preferably C 1 To C 5 The alkyl radical is particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0101] As R' 1 , R' 2 or R' 3 The cycloalkyl radical of the group is preferably C 3 To C 6The cycloalkyl radical is particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0102] As R' 1 , R' 2 or R' 3 The aromatic radical of the group is preferably C 5 To C 15 The aryl radical is particularly preferably a phenyl radical, a 2-thienyl radical or a 3-thienyl radical, a 2-furyl radical or a 3-furyl radical, and more particularly preferably a phenyl radical.

[0103] R' 7 , R' 8 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 and R' 14 Definition of

[0104] As R' 7 , R' 8 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 or R' 14 The alkyl radical of the group is preferably C 1 To C 5 The alkyl radical is particularly preferably a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl radical.

[0105] As R' 7 , R' 8 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 or R' 14 The cycloalkyl radical of the group is preferably C 3 To C 6 The cycloalkyl radical is particularly preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical, and more particularly preferably a cyclopropyl radical.

[0106] -SR' 10 The group is preferably thiomethyl.

[0107] -NR' 8 R' 9 The group is preferably a methylamino group or a dimethylamino group.

[0108] Alkoxy-OR' 7 Preferred is a methoxy group or an ethoxy group.

[0109] 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 radical -OR 7、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0110] 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 radical -OR 7 、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0111] 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 radical -OR 7 、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0112] Advantageously, R' 1 , R' 2 and R' 3 A hydrogen atom.

[0113] X 2 Definition of

[0114] X 2 Represents nitrogen atom or CR' 15 Group, where R' 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical, or a radical selected from -OH, -NH 2 、-SH、-CN、-CF 3 , -CO 2 H, -CH 2 OH, -CH 2 NH 2 , alkoxy-OR' 7 、-NR' 8 R' 9 Group, -SR' 10Group, -C(O)R' 11 Group, -CH 2 OR' 12 Group and -CH 2 NR' 13 R' 14 Group of groups.

[0115] R' 7 , R' 8 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 and R' 14 The groups are as defined herein.

[0116] 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 radical -OR 7 、-SR 10 group, -CN group, -CF 3 Group, -NR 8 R 9 Group, -NH-NH 2 Group, -CO 2 H group or -CHO group.

[0117] Advantageously, X 2 represents a nitrogen atom or a CH group.

[0118] According to a preferred embodiment of the present invention, the compound of formula (I) is selected from the following compounds:

[0119]

[0120]

[0121] The term "pharmaceutically acceptable" means useful in preparing pharmaceutical compositions and generally safe and non-toxic for pharmaceutical use.

[0122] A pharmaceutically acceptable salt or solvate of a compound refers to a pharmaceutically acceptable salt or solvate as defined above, which has the pharmacological activity of the compound.

[0123] Pharmaceutically acceptable salts include:

[0124] - 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, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, benzoic acid, citric acid, ethanesulfonic acid, lactic acid, mucic acid, pamoic acid or pantothenic acid.

[0125] -Salts formed when acidic protons present in the compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions; or salts formed by coordination with inorganic bases or organic bases. 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.

[0126] Acceptable solvates for therapeutic use of the compounds of the invention include conventional solvates, such as those formed during the final step of the preparation of these compounds due to the presence of a solvent. Mention may be made of solvates associated with the presence of water (these solvates are also called hydrates) or solvates associated with the presence of ethanol.

[0127] The compounds defined in the first object of the invention are useful in therapy due to their anticancer activity.

[0128] A third object of the present invention is a pharmaceutical composition comprising the compound defined in the first object of the present invention and at least one suitable pharmaceutical carrier.

[0129] A suitable pharmaceutical carrier may be a pharmaceutically acceptable excipient for treating cancer, in particular for treating cancers with altered metabolism, preferably for treating cancers with OXPHOS metabolism.

[0130] The pharmaceutical composition may be a solid composition or a liquid composition.

[0131] The solid composition may be in the form of tablets, capsules, powders or granules.

[0132] Tablets may comprise a mixture of the compound as defined in the first object of the present invention and a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. The mixture may be particularly compressed.

[0133] Tablets may be coated with saccharose, sucrose or other suitable material, or may be treated so that they have prolonged or delayed activity and continuously release a predetermined amount of the compound.

[0134] The powders or granules may be water dispersible. They may contain a compound as defined in the first object of the invention in admixture with a dispersant, wetting agent or suspending agent, especially a flavoring or sweetening agent.

[0135] The capsule may contain a mixture of the compound as defined in the first object of the present invention and a diluent. The capsule may be a soft capsule or a hard capsule.

[0136] Liquid compositions may be in the form of aqueous suspensions or solutions, syrups or elixirs.

[0137] It may in particular comprise the compounds defined in the first object of the invention in a solvent such as water and optionally suitable sweetening, flavouring and / or colouring agents.

[0138] The liquid composition can be obtained in particular by dissolving or suspending the above-mentioned powder or granules in a liquid such as water, juice, milk or the like.

[0139] The pharmaceutical composition is preferably sterile. It may be in the form of an isotonic solution (especially compared to blood).

[0140] Therefore, the compound defined in the first purpose of the present invention or the pharmaceutical composition according to the third purpose of the present invention can be used for a method of treating cancer, which method comprises administering to an individual an effective amount of the compound defined in the first purpose of the present invention (or a pharmaceutically acceptable salt or solvate of the compound) or administering an effective amount of the pharmaceutical composition according to the third purpose of the present invention.

[0141] A subject is a patient in need of treatment, such as a mammal, particularly a human.

[0142] The compound or pharmaceutical composition can be administered to mammals, including humans, nasally, enterally (eg, orally), or parenterally (eg, intravenously).

[0143] The dosage varies with the treatment and the condition. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms and rectal administration forms.

[0144] The compounds defined in the first object of the present invention may be used in therapy alone or in combination with at least one other active agent.

[0145] Therefore, 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 object of the present invention (or a pharmaceutically acceptable salt or solvate of the compound) or a pharmaceutical composition according to the third object of the present invention.

[0146] Cancer is as defined in the first object of the present invention.

[0147] The present invention also relates to a method for treating cancer with metabolic alterations, in particular cancer with OXPHOS metabolism, in a patient in need thereof, the method comprising administering to the patient a compound as defined in the first object of the present invention (or a pharmaceutically acceptable salt or solvate of the compound) or a pharmaceutical composition according to the third object of the present invention.

[0148] Cancers with altered metabolism, in particular cancers with OXPHOS metabolism, are as defined in the first object of the present invention.

[0149] The present invention also relates to the use of a compound as defined in the first object of the present invention (or a pharmaceutically acceptable salt or solvate of the compound) or a pharmaceutical composition according to the third object of the present invention in the preparation of a medicament for treating cancer or a cancer with metabolic changes, in particular a cancer with OXPHOS metabolism, in a subject in need thereof.

[0150] The present invention also relates to the use of a compound as defined in the first object of the present invention (or a pharmaceutically acceptable salt or solvate of the compound) or a pharmaceutical composition according to the third object of the present invention in treating cancer or a cancer with metabolic changes, in particular a cancer with OXPHOS metabolism, in a subject in need thereof.

[0151] The term "patient" refers to an animal, typically a warm-blooded animal, preferably a mammal. The term "mammal" herein refers to any mammal, including humans, domestic animals and farm animals, and zoo, sports or companion animals, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is a primate, more particularly a human.

[0152] The term "human" refers to male or female human subjects at any stage of development, including neonates, infants, juveniles, adolescents, and adults.

[0153] A fourth object of the present invention is a product comprising a compound as defined in the first object of the present invention and another active agent.

[0154] The compounds defined in the first object of the invention are then used in combination with other active agents, in particular simultaneously, separately or alternatingly in therapy.

[0155] These other active agents are particularly selected from those suitable for treating cancer. They may be adjuvants for improving the activity of the compounds of the invention, or other active agents known for treating the condition. Such active agents are well known to those skilled in the art, commercially available or described in references, such as Le Dictionnaire Vidal, which is published and updated annually, in particular those grouped in the pharmacotherapy section "Cancerology Haematology".

[0156] Certain compounds defined in the first object of the present invention are novel per se and represent a fifth object of the present invention: these compounds are selected from compounds having formula (I'), pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvates thereof,

[0157] The formula (I') has the following structure:

[0158]

[0159] in:

[0160] *R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , Y 1 , Y 2 and n are defined as in the first object of the present invention for formula (I), it should be understood that:

[0161] *When Y 1 and Y 2 represents -CH-, and R 6 When it is a free radical of formula (IIa),

[0162] n≥5 and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R' 3 Different from

[0163] -NH 2 ,and

[0164] *When Y 1 and Y 2 Represents -N-, and R 6 When it is a free radical of formula (IIa), n≥7.

[0165] Other characteristics, alternatives and advantages of the compounds of the invention, their uses or pharmaceutical compositions will become more apparent on reading the following examples of embodiments, which are given for the purpose of illustrating and not limiting the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0166] The accompanying drawings illustrate the invention.

[0167] Figure 1 Shown are the oxygen consumption rates of cells of a human B-cell lymphoma line treated with compounds according to the invention and compounds from the prior art.

[0168] Figure 2 The effect on cell growth of treating human tumor cells from a B-cell lymphoma line with compounds according to the invention and compounds from the prior art is shown.

[0169] Figure 3 The effect on cell growth of treating human tumor cells from various B-cell and T-cell lymphoma lines with compounds according to the invention and compounds from the prior art is shown.

[0170] Figure 4 The anti-tumor efficacy of the compounds of the invention in an in vitro model was shown.

[0171] Figure 5 The effect on cell growth of human cells from two childhood sarcoma lines treated with compounds of the invention is shown.

[0172] Figure 6 The effect of treatment of human tumor cells from a B-cell lymphoma line with compounds according to the invention on cell growth is shown.

[0173] Figure 7 The effect on cell growth of treating human tumor cells from a childhood sarcoma line with compounds according to the invention is shown.

[0174] Example 1: Synthesis of Compound Ia Example

[0175] Flash column chromatography was performed on silica gel 60 (0.063200 mm).

[0176] The NMR spectra were recorded at 25 °C using a Bruker Avance III spectrometer. 1 H NMR and 13 C NMR) (at 400 MHz 1 H NMR, at 100 MHz 13 C NMR), using CD 3 OD as a function of residual CH 3OH (δH = 3.31 ppm, δC = 49.00 ± 0.01 ppm) as the reference solvent, using DMSO-d 6 As a reference solvent relative to residual DMSO (δH=2.50 ppm, δC=39.52±0.06 ppm), chemical shifts are in ppm and coupling constants (J) are in Hertz. 1 1H NMR spectral data are reported as follows: chemical shift in ppm (s = singlet, d = doublet, t = triplet, q = quartet, dd = double of doublet, td = double of triplet, ddd = double of doublets, m = multiplet, coupling constant, integral).

[0177] Example 1: Synthesis of Compound Ia

[0178] Compound Ia was prepared according to the steps shown in the following scheme:

[0179]

[0180] The first step: synthesizing N'-pyrimidin-2-yldodecane-1,12-diamine derivatives.

[0181] To a solution of 1 g (4.99 mmol) of 1,12-dodecanediamine in 30 mL of 1,4-dioxane was added 0.8 equivalents (3.99 mmol; 457.2 mg) of 2-chloropyrimidine and 5 equivalents (24.95 mmol; 3.45 g) of potassium carbonate. The reaction mixture was heated under reflux in 1,4-dioxane for 16 h. After cooling, the 1,4-dioxane was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative was purified by silica gel chromatography using a gradient of ethyl acetate / methanol / triethylamine (98 / 0 / 2; 60 / 10 / 10; 70 / 20 / 10; 60 / 30 / 10) as eluent.

[0182] The expected compound was obtained as a yellow solid with a yield of 53%.

[0183] It has the following characteristics:

[0184] Melting point = 86°C

[0185] Molar mass = C 16 H 30 N 4 : 278.43 g / mole

[0186] RMN 1 H(CD 3OD): 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). RMN 13 C(CD 3 OD): 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.

[0187] Step 2: Synthesis of N′-(4,5-dihydro-1H-imidazol-2-yl)-N-pyrimidin-2-yl-dodecane-1,12-diamine derivatives

[0188] To a solution of 100 mg (0.36 mmol) of N'-pyrimidin-2-yldodecane-1,12-diamine in a mixture of ethanol / triethylamine (12 mm / 0.1 mm) prepared in the previous step was added 1.05 equivalents (0.38 mmol) of 1-(4,5-dihydro-1H-imidazole-2-yl)-3,5-dimethyl-1H-pyrazole hydrobromide. The reaction medium was heated under ethanol reflux for 3 days. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting derivative was purified by silica gel chromatography using dichloromethane / methanol (92 / 8) as eluent.

[0189] The expected compound was obtained as a yellow solid with a yield of 40%.

[0190] It has the following characteristics:

[0191] Melting point = 90°C

[0192] Molar mass = C 19 H 34 N 6 : 346.51 g / mole

[0193] RMN 1 H(CD 3 OD): 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).

[0194] RMN 13 C(CD 3OD): 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.

[0195] Example 2: Synthesis of Compound Ib

[0196] Compound Ib was prepared according to the steps shown in the following scheme:

[0197]

[0198] Step 1: Synthesis of 2-[4-[12-(4-pyrimidin-2-ylpiperazin-1-yl)dodecyl]piperazin-1-yl]pyrimidine derivatives

[0199] To a solution of 700 mg (2.13 mmol) of 1,12-dibromododecane in 30 mL of 1,4-dioxane was added 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. The reaction mixture was heated under reflux in 1,4-dioxane for 20 hours. After cooling, the 1,4-dioxane was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative was purified by silica gel chromatography using ethyl acetate / methanol / triethylamine (99 / 0.5 / 0.5) as eluent.

[0200] The expected compound was obtained as a white solid with a yield of 64%.

[0201] It has the following characteristics:

[0202] Melting point = 106°C

[0203] Molar mass = C 28 H 46 N 8 :494.72g / mole

[0204] RMN 1 H(CD 3 OD): 8, 23 (d; J = 4, 7Hz; 4H); 6, 40 (t; J = 4, 7Hz; 2H); 3, 84-3, 67 (m; 8H); 2, 4 9-2, 35 (m; 8H); 2, 35-2, 21 (m; 4H); 1, 54-1, 37 (m; 4H); 1, 32-1, 11 (m; 16H).

[0205] RMN 13 C(CD3 OD): 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).

[0206] Step 2: Synthesis of 2-[4-[12-(4-pyrimidin-2-ylpiperazin-1-yl)dodecyl]piperazin-1-yl]pyrimidine dihydrochloride derivatives

[0207] 150 mg (0.30 mmol) of 2-[4-[12-(4-pyrimidin-2-ylpiperazin-1-yl)dodecyl]piperazin-1-yl]pyrimidine was dissolved in 5 mL to 10 mL of ethanol. Hydrochloric acid gas was bubbled through the reaction medium for 5 minutes. After stirring, the precipitate was collected by filtration, washed with ether and dried. The desired compound was obtained as a white solid with a yield of 87%.

[0208] It has the following characteristics:

[0209] Melting point = 252°C

[0210] Molar mass = C 28 H 46 N 8 .2HCl: 567.64 g / mole

[0211] RMN 1 H(DMSO-d 6 ): 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).

[0212] RMN 13 C(DMSO-d 6 ): 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).

[0213] Example 3: Synthesis of Compound Ic

[0214] Compound Ic was prepared according to the steps shown in the following scheme:

[0215]

[0216] Step 1: Synthesis of 1-(2-pyridyl)-4-[12-[4-(2-pyridyl)piperazin-1-yl]dodecyl]piperazine derivatives

[0217] To a solution of 700 mg (2.13 mmol) of 1,12-dibromododecane in 30 mL of 1,4-dioxane was 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 1,4-dioxane for 20 hours. After cooling, the 1,4-dioxane was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative was purified by silica gel chromatography using ethyl acetate / methanol / triethylamine (99 / 0.5 / 0.5) as eluent.

[0218] The expected compound was obtained as a white solid with a yield of 48%.

[0219] It has the following characteristics:

[0220] Melting point = 100°C

[0221] Molar mass = C 30 H 48 N 6 :492.74g / mole

[0222] RMN 1 H(CD 3 OD): 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).

[0223] RMN 13 C(CD 3 OD): 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).

[0224] Step 2: Synthesis of 1-(2-pyridyl)-4-[12-[4-(2-pyridyl)piperazin-1-yl]dodecyl]piperazine dihydrochloride derivatives

[0225] 150 mg (0.30 mmol) of 1-(2-pyridyl)-4-[12-[4-(2-pyridylpiperazin-1-yl]dodecyl]piperazine was dissolved in 5 mL to 10 mL of ethanol. Hydrochloric acid gas was bubbled through the reaction medium for 5 minutes. After stirring, the precipitate was collected by filtration, washed with diethyl ether and dried. The desired compound was obtained as a white solid with a yield of 91%.

[0226] It has the following characteristics:

[0227] Melting point = 200°C

[0228] Molar mass = C 30 H 48 N 6 .2HCl: 565.66 g / mole

[0229] RMN 1 H(DMSO-d 6 ): 11, 41 (s; 2H); 8, 13 (dd; J = 5, 8; 1, 8Hz; 2H); 7, 94 (t; J = 8, 2Hz; 2H); 7, 30 (d; J = 9, 0Hz; 2H); 6, 96 (t; J = 6, 4H z; 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).

[0230] RMN 13 C(DMSO-d 6 ): 155, 3 (2C); 142, 7 (2C); 141, 7 (2C); 114, 4 (2C); 110, 9 (2C); 56, 1 (2C); 5 0, 5 (4C); 43, 2 (4C); 29, 3 (2C); 29, 1 (2C); 28, 9 (2C); 26, 6 (2C); 23, 4 (2C).

[0231] Example 4: Use of compounds (Ia), (Ib) and (1c) as anticancer agents

[0232] 4.1 Seahorse technology analysis of oxygen in human B cell lymphoma cells treated with compounds (Ia), (Ib) and (Ic) Consumption rate

[0233] The analyzer called "Seahorse" allows real-time assessment of mitochondrial respiration by measuring the oxygen consumption rate (OCR). The experiments were performed according to the instructions of the supplier ("Agilent_Seahorse XFe96"). For this purpose, a human B-cell lymphoma line ("RL line, CVCL_1660") was seeded at 150,000 cells per well in a dedicated Agilent_Seahorse 96-well plate in 180 μL of Agilent_Seahorse XF RPMI medium (supplemented with pyruvate and glucose) and pretreated with CellTak solution according to the instructions of the supplier (Corning). In the absence of CO 2 After incubation in an oven for 30 min, the plates were analyzed with the "Seahorse" using injections that allowed increasing amounts of compound ( Figure 1 The protocol (indicated by arrows in the figure) was followed to obtain final cumulative concentrations of 1.2 μM, 2.5 μM, 5 μM and 10 μM, followed by OCR readings (in picomoles / minute) for 10 minutes each. Data were normalized by cell counting using a device called "Cytation 1 / 5 Cell Imaging Multi-Mode reader" (BioTek Instruments, Inc) in conjunction with "Seahorse".

[0234] Figure 1 The effects of several compounds on mitochondrial respiration are shown: the reference inhibitor rotenone ( Figure 1 a, ROT, the curve is an inverted hollow triangle), the inhibitor "IACS010759" currently being evaluated in clinical trials ( Figure 1 a, IACS, the curve is a solid diamond), compound (Ia) ( Figure 1 b, the curve is an inverted solid triangle), compound (Ib) ( Figure 1 b, curve is open circle) and compound (Ic) ( Figure 1 b, curves are solid circles). In each figure, a control (DMSO, curves are solid squares) was used, corresponding to the culture medium studied without the addition of the compound (only the DMSO diluent from the molecule stock solution was added). Figure 1 In a, the drug injected at a concentration of 1.2 μM can instantly and almost completely inhibit OCR, and the same is true for two non-comparative compounds of the present invention: rotenone and "IACS-010759". In addition, the compounds of the present invention can gradually inhibit OCR as the injection concentration increases, and the same is true for compounds (Ib) and (Ic), and the inhibition is staged, while compound (Ia) is progressive. At a concentration of 10 μM, OCR is almost completely inhibited.

[0235] exist Figure 1 In the figure, the standard deviation (SD) is shown.

[0236] In summary, compounds (Ia), (Ib) and (Ic) act as mitochondrial respiration inhibitors (also known as OXPHOS inhibitors) with moderate and progressive effects compared to rotenone or "IACS-010759". The same results were obtained for the various cell lines tested.

[0237] 4.2 Analysis of the effects of treatment of human tumor cells from a B-cell lymphoma line with compounds (Ia), (Ib) and (Ic) on the cells The impact of growth

[0238] Cells of human B-cell lymphoma cell line ("Karpas422, CVCL_1325") were seeded at a density of 100,000 cells per well in 96-well plates with a compound concentration of 10 μM in a medium volume of 100 μL. After 48 h of treatment, live cells were counted by flow cytometry ( Figure 2 a) or use the living cell biochemical fluorescence detection kit ( Figure 2 b) The effect on cell growth was analyzed.

[0239] Figure 2 The effect of treating cells with compounds (Ia), (Ib) and (Ic) of the present invention on cell growth in conventional "Gibco RPMI1640 / 10% SVF" medium (denoted as RPMI) is shown. Figure 2 a); and the effects of treating cells with compounds (Ia), (Ib) and (Ic) of the present invention and the following four non-comparative compounds of the present invention on cell growth in "Gibco human plasma-like medium" (Gibco HPLM_Thermo Fisher Scientific) (expressed as HLPM) simulating the metabolic conditions of human plasma ( Figure 2 b): IACS-010759 (IACS), an inhibitor called "IM156" currently in clinical trials, rotenone (ROT) and apoptosis inducer staurosporine (STS). The number of viable cells was determined in the conventional "Gibco RPMI1640 / 10° / 0SVF" medium after double AnnexinV / PI labeling and analysis using the flow cytometer "ATTUNE" (Thermo Fisher Scientific). The number of viable cells was assessed in the "Gibco human plasma analog medium" after measuring relative fluorescence units (RFU) using the "CellTiterFluor" kit according to the supplier's instructions (Promega). Figure 2 The term DMSO in corresponds to the control, ie the same medium without addition of the compound.

[0240] exist Figure 2In the figure, the standard deviation (SD) is shown.

[0241] according to Figure 2 Compounds (Ia), (Ib) and (Ic) inhibited cell growth by reducing the number of viable tumor cells after 48 hours of treatment, even in medium conditions that simulated human plasma. Their efficacy was similar to that obtained using the inhibitor "IACS010759" or rotenone. This effect was cell line-dependent (see Figure 3 ).

[0242] 4.3 Analysis of the effects of compound (Ia) on the human tumor cells of various B-cell and T-cell lymphoma cell lines The impact of growth

[0243] The effect of the compound (Ia) of the present invention on cell growth was analyzed after Annexin V / PI labeling of 31 human B-cell and T-cell lymphoma lines and analysis using an "ATTUNE" cytometer (Thermo Fisher Scientific) and compared with the non-inventive compound "IACS-010769" (denoted as IACS). Figure 2 In addition to the number of live cells shown in a, this technique can also assess the percentage of cells undergoing apoptosis. The results are shown in a black and white gradient "heat map" format. Figure 3 In the figure, black represents the highest percentage of apoptotic cells.

[0244] according to Figure 3 , the toxicity of compound (Ia) and "IACS-010759" varies with the lymphoma cell lines analyzed. Specifically, for the 8 cell line subgroups framed in the figure, the toxicity of compound (Ia) is increased relative to the toxicity of "IACS-010759". These data confirm that the two compounds have different metabolic targets and modes of action.

[0245] 4.4 Analysis of the anti-tumor efficacy of compound (Ia) in the embryonic model

[0246] The antitumor efficacy of compound (Ia) was evaluated preclinically using the chick chorioallantoic membrane (CAM) xenograft model. Figure 4 Human tumor cells of a B-cell lymphoma line ("SUDHL-4, CVCL_0539") are shown to be implanted into the upper CAM of the embryo at day E9 ( Figure 4 a), and an indication of the presence or absence of a tumor mass ( Figure 4 b), and the relative amount of transfer ( Figure 4c). Treatments were performed on days E11, E13, E15 and E17. On day E18, the upper CAM portion containing the tumor was removed and weighed, and the lower CAM fragment was used to assess the presence of human cells indicative of metastasis by RT-qPCR (polymerase chain reaction from RNA samples). 0.0097 mg / kg doxorubicin (DOXO) has been used as a positive control for the efficacy of treatment, compound (Ia) has been used at 3 different doses [1]: 0.05 mg / kg, [2]: 0.15 mg / kg and [3]: 0.45 mg / kg, and "IACS-010759" has been used at 2 different doses [1]: 0.05 mg / kg and [2]: 0.45 mg / kg. Negative controls (expressed as DMSO) represent treatment with DMSO molecular diluent.

[0247] exist Figure 4 In b, the effect of treatment on tumor volume was directly observed. Treatment with doxorubicin induced a 90% reduction in primary tumor volume. In contrast, treatment with "IACS010759" (IACS) induced a 44% [1] and 82% [2] reduction in primary tumor volume, while treatment with compound (Ia) induced a 48% [1], 73% [2] and 70% [3] reduction in primary tumor volume.

[0248] exist Figure 4 c, the effect of treatment on the relative number of metastases was directly observed. Treatment with doxorubicin induced a 99% reduction in the number of metastases. In contrast, treatment with "IACS 010759" (IACS) induced a 69% [1] and 73% [2] reduction in the number of metastases, while treatment with compound (Ia) induced a 45% [1], 70% [2] and 72% reduction in the number of metastases [3].

[0249] exist Figure 4 In the figure, the standard deviation (SD) is shown.

[0250] In summary, compound (Ia) has different chemical properties from the "IACS-010759" molecule and different effects on OCR, but in the preclinical model used in this example, its anti-tumor efficacy is comparable to that of the "IACS-010759" molecule. Compound (Ia) also inhibits tumor spread.

[0251] 4.5 Analysis of the effects of treatment of human cells from two sarcoma lines with compounds (Ia), (Ib) and (Ic) on cell growth Impact

[0252] Two childhood rhabdomyosarcoma-like sarcoma lines ("RD136, CVCL_1649, Figure 5 a and "RH3O,CVCL_0041", Figure 5b) Human tumor cells were seeded in 96-well plates in the presence of 10 μM concentration of compounds, 100 μL of "Gibco Human Plasma Analog 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 analogs) currently in clinical trials, rotenone (ROT) and the apoptosis inducer staurosporine (STS). After 48 h of treatment, the effect on the number of viable cells was assessed using the "CellTiterFluor" kit from Promega, compared to Figure 2 b is the same.

[0253] Figure 5 a shows the effect of treatment with compounds on the number of viable cells of the RD136 line (in HLPM medium as defined above), Figure 5 b shows the effect of treatment with compounds on the number of viable cells of the RH30 line (in HLPM medium as defined above), expressed as percentage of relative fluorescence units (RFU) compared to the effect of the compound diluent (DMSO).

[0254] exist Figure 5 In the figure, the standard deviation (SD) is shown.

[0255] In summary, compounds (Id), (Ib) and (Ic) inhibited cell growth in RD136 and RH30 cell lines by reducing the number of viable cells after 48 hours of treatment. Their efficacy is similar to that obtained using the inhibitor "IACS-010759" or rotenone. Therefore, the application field of these compounds can be extended beyond blood cancers such as lymphomas, for example, solid tumors such as pediatric human sarcomas listed herein.

[0256] 4.6 Compared with the prior art compounds, the IC of the compound (Ia) of the present invention is 50 analyze

[0257] IC of compound (Ia) 50 IC of a compound having the formula 50 A comparison was made:

[0258]

[0259] The results showed that the IC 50 is 1.5 μM, while the IC of the compound described in WO2020 / 109506 is 5015.1 μM. This shows that the performance of compound (Ia) is improved over the compounds of the prior art. These experiments were carried out with cells from a human B-cell lymphoma cell line ("Karpas422, CVCL_1325"), which had been seeded in "RPMI 1640" medium (11 mM glucose) supplemented with 10% serum, at increasing concentrations of the compound.

[0260] After 48 h of treatment, the live cell detection kit "CellTiter-Fluor Cell Viability Assay" (Promega) was used ( Figure 2 b) and the effect on cell growth was analyzed according to the supplier's instructions.

[0261] Example 5: Synthesis of Compound Id

[0262]

[0263] To a solution of 700 mg (3.49 mmol) of 1,12-dodecanediamine in 30 mL of 1,4-dioxane was added 2.2 equivalents (7.69 mmol; 880 mg) of 2-chloropyrimidine and 5 equivalents (17.47 mmol; 2.4 g) of potassium carbonate. The reaction mixture was heated under reflux in 1,4-dioxane for 20 h. After cooling, the 1,4-dioxane was concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative was purified by silica gel chromatography using ethyl acetate / cyclohexane (90 / 10) as eluent.

[0264] The expected compound was obtained as a white solid with a yield of 26%.

[0265] It has the following characteristics: melting point Mp = 105 ° C, C 20 H 32 N 6 =356.50 g / mole.

[0266] RMN 1 H(CDCl 3 ): 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).

[0267] RMN 13 C(CDCl 3): 162, 4 (2C); 158, 0 (4C); 110, 3 (2C); 41, 5 (2C); 29, 6 (2C); 29, 5 (2C); 29, 5 (2C); 29, 4 (2C); 27, 0 (2C).

[0268] Example 6: Synthesis of Compound Ie

[0269]

[0270] To a solution of 800 mg (3.10 mmol) of 1,7-dibromoheptane in 30 mL of 1,4-dioxane was added 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. The reaction mixture was heated under reflux in 1,4-dioxane for 20 hours. After cooling, the 1,4-dioxane was concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative was purified by silica gel chromatography using dichloromethane / methanol / triethylamine (98 / 1 / 1) as eluent.

[0271] The expected compound was obtained as a white solid with a yield of 30%.

[0272] It has the following characteristics: melting point Mp = 86 ° C, C 23 H 36 N 8 =424.58 g / mole.

[0273] RMN 1 H(CDCl 3 ): 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).

[0274] RMN 13 C(CDCl 3 ): 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).

[0275] Example 7: Synthesis of Compound If

[0276]

[0277] To a solution of 800 mg (3.10 mmol) of 1,7-dibromoheptane in 30 mL of 1,4-dioxane was 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 1,4-dioxane for 20 hours. After cooling, the 1,4-dioxane was concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane, washed once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The derivative was purified by silica gel chromatography using dichloromethane / methanol / triethylamine (98 / 1 / 1) as eluent.

[0278] 150 mg (0.354 mmol) of 1-(2-pyridyl)-4-[7-[4-(2-pyridylpiperazin-1-yl]heptyl]piperazine was dissolved in 5 mL to 10 mL of ethanol. Hydrochloric acid gas was bubbled through the reaction medium for 2 minutes. After stirring, the precipitate was collected by filtration, washed with diethyl ether and dried.

[0279] The expected compound was obtained as a white solid with a yield of 82%.

[0280] It has the following characteristics: melting point Mp = 210 ° C, C 25 H 38 N 6 .2HCl=495.53 g / mole.

[0281] RMN 1 H(D 2 O): 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=14,5 Hz; 4H); 3, 73 (d; J = 12, 8 Hz; 4H); 3, 59 (t; J = 13, 5 Hz; 4H); 3, 30-3, 13 (m; 8H); 1, 71 (m; 4H); 1, 34 (m; 6H).

[0282] RMN 13 C(D 2 O): 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).

[0283] Example 8: Use of compounds (Id), (Ie) and (ID) as anticancer agents

[0284] Cells from a human B-cell lymphoma cell line ("RL, CVCL 1660") were seeded at a density of 100,000 cells per well in a 96-well plate, and the compounds were present at a concentration of 5 μM or 10 μM in a volume of 100 μL of RPMI medium. After 48 h of treatment, the effect on cell growth was analyzed by counting viable cells using flow cytometry, as Figure 2 As shown in a.

[0285] Figure 6 The inhibitory effect on cell growth of cells treated with compounds (Ia) and (Id) of the present invention in conventional "Gibco RPMI1640 / 10% SVF" medium (denoted as RPMI) is shown.

[0286] exist Figure 6 In the figure, the standard deviation (SD) is shown.

[0287] Human tumor cells of a childhood rhabdomyosarcoma sarcoma line ("RH30, CVCL_0041") were seeded in 96-well plates in the presence of 10 μM or 25 μM concentrations of compounds in a volume of 100 μL of "Gibco Human Plasma-Like Medium" (Gibco HPLM_ThermoFisherScientific). After 48 h of treatment, the effects of compounds (Ia), (Ie) and (If) on cell growth were evaluated using the Promega "CellTiterFluor" kit, as shown in Table 1. Figure 2 As shown in b. Figure 7 Shown are the effects of compound treatment on the growth of the RH30 cell line (in HLPM medium as defined above) expressed as % relative fluorescence units (RFU) compared to the effect of the compound diluent (DMSO).

[0288] exist Figure 7 In the figure, the standard deviation (SD) is shown.

[0289] In summary, compounds (Ia), (Ie) and (If) inhibited cell growth in the RH30 cell line by reducing the number of viable cells after 48 hours of treatment. Therefore, the application areas of these compounds can be extended beyond blood cancers such as lymphoma, for example, solid tumors such as pediatric human sarcomas listed herein.

Claims

1. A compound selected from the group consisting of a compound of formula (I), a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solvate thereof for use in treating cancer, The formula (I) has the following structure: in: *R 1 , R 2 and R 3 Each independently represents a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical or a radical selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, alkoxy-OR 7 、-NR 8 R 9 Group, -SR 10 Group, -C(O)R 11 Group, -CH2OR 12 Group and -CH2NR 13 R 14 A group of groups, where R 7 , R 8 , R 10 , R 11 , R 12 and R 13 independently represent an alkyl radical or a cycloalkyl radical, and R 9 and R 14 independently of one another represent a hydrogen atom or an alkyl radical or a cycloalkyl radical, *X 1 Represents nitrogen atom or CR 15 Group, where R 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical or a radical selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, CH2NH2, alkoxy-OR 7 、-NR 8 R 9 Group, -SR 10 Group, -C(O)R 11 Group, -CH2OR 12 Group and -CH2NR 13 R 14 Group of groups, *n is an integer from 1 to 20, *R 4 represents a hydrogen atom, an alkyl radical or a divalent alkylene group, wherein the divalent alkylene group and Y 1 and R 4 The nitrogen atoms connected form a ring, *R 5 represents a hydrogen atom, an alkyl radical or a divalent alkylene group, wherein the divalent alkylene group and Y 2 and R 5 The nitrogen atoms connected form a ring, * When R 4 When the group represents a hydrogen atom or an alkyl radical, Y 1 represents -CH2-, -NH- or -O-; and when R 4 Group representation and Y 1 and R 4 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 1 Indicates -CH- or -N-, * When R 5 When the group represents a hydrogen atom or an alkyl radical, Y 2 represents -CH2-, -NH- or -O-; and when R 5 Group representation and Y 2 and R 4 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 2 represents -CH- or -N-, and *R 6 represents one of the following two groups (IIa) and (IIb): Where R' 1 , R' 2 and R' 3 Each independently represents a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical or a radical selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, alkoxy-OR' 7 、-NR' 8 R' 9 Group, -SR' 10 Group, -C(O)R' 11 Group, -CH2OR' 12 Group and -CH2NR' 13 R' 14 A group of groups, where R' 7 , R' 8 , R' 10 , R' 11 , R' 12 and R' 13 independently represent an alkyl radical or a cycloalkyl radical, and R' 9 and R' 14 independently of one another represent a hydrogen atom or an alkyl radical or a cycloalkyl radical, and X 2 Represents nitrogen atom or CR' 15 Group, where R' 15 is a hydrogen atom, a halogen atom, an alkyl radical, a cycloalkyl radical, an aryl radical or a radical selected from -OH, -NH2, -SH, -CN, -CF3, -CHO, -NH-NH2, -CO2H, -CH2OH, -CH2NH2, alkoxy, -OR' 7 、-NR' 8 R' 9 Group, -SR' 10 Group, -C(O)R' 11 Group, -CH2OR' 12 Group and -CH2NR' 13 R' 14 Group of groups.

2. A compound as defined in claim 1 for use in the treatment of cancers with altered metabolism, in particular cancers with OXPHOS metabolism.

3. A compound as defined in claim 1 for use in the treatment of lymphoma; solid tumors; and some recurrent tumors after chemotherapy.

4. A compound for use according to any one of the preceding claims, characterized in that X 1 represents a nitrogen atom or a CH group.

5. A compound for use according to any one of the preceding claims, characterized in that R 4 represents a hydrogen atom or a divalent alkylene group, wherein the divalent alkylene group and Y 1 and R 4 The nitrogen atoms connected form a ring, and R 5 represents a hydrogen atom or a divalent alkylene group, wherein the divalent alkylene group and Y 2 and R 5 The attached nitrogen atoms form a ring.

6. A compound for use according to any one of the preceding claims, characterized in that When R 4 When the group represents a hydrogen atom or an alkyl radical, Y 1 represents -CH2-; and when R 4 Group representation and Y 1 and R 4 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 1 represents -N-; and when R 5 When the group represents a hydrogen atom or an alkyl radical, Y 2 represents -CH2-; and when R 5 Group representation and Y 2 and R 5 When the nitrogen atom to which it is connected forms a divalent alkylene ring, Y 2 Means -N-.

7. A compound for use according to any one of the preceding claims, characterized in that Y 1 and Y 2 same.

8. A compound for use according to any one of the preceding claims, characterized in that: -When Y 1 When it represents -CH2-, n is 2 to 10, -When Y 2 When it represents -CH2-, n is 2 to 10, -When Y 1 When it represents -N-, -NH-, -CH- or -O-, n is 6 to 18, -When Y 2 When it represents -N-, -NH-, -CH- or -O-, n is 6 to 18.

9. A compound for use according to any one of the preceding claims, characterized in that When Y 1 and Y 2 represents -CH- and R 6 When it is a group of formula (IIa), n is, for example, n≥5 and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R' 3 Different from -NH2; and when Y 1 and Y 2 Represents -N- and R 6 When it is a group of formula (IIa), n is, for example, n≥7.

10. Compound for use according to any one of the preceding claims, characterized in that R 6 It is a group of formula (IIb).

11. Compound for use according to any one of the preceding claims, characterized in that The compound of formula (I) is selected from the following compounds: 。 12. A pharmaceutical composition comprising a compound as defined in any one of claims 1 and 4 to 11 and at least one suitable pharmaceutical carrier.

13. A product comprising a compound as defined in any one of claims 1 and 4 to 11 and another active agent.

14. A compound selected from the group consisting of a compound of formula (I'), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof, The formula (I') has the following structure: in: *R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , Y 1 , Y 2 and n as defined in claim 1, it should be understood that: *When Y 1 and Y 2 represents -CH- and R 6 When it is a free radical of formula (IIa), n≥5 and / or R 1 , R' 1 , R 2 , R' 2 , R 3 and R' 3 Unlike -NH2, and *When Y 1 and Y 2 Represents -N- and R 6 When it is a free radical of formula (IIa), n≥7.

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

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