Pannexin-1 inhibitors and uses thereof

Abstract

The present invention relates to 4-bis(sulfonyl)aniline derivatives of formula (I) and the isomers, stereoisomers and pharmaceutical acceptable salts thereof. The compounds of the invention are useful as inhibitors or blocker of pannexin-1. The invention further relates to pharmaceutical compositions comprising such compounds of formula (I) and their use for treating diseases.

Description

[0001] PANNEXIN-1 INHIBITORS AND USES THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the field of medicine, in particular 2,4-bis(sulfonyl)aniline derivatives and their uses for treating diseases. More particularly, the invention provides inhibitors or blockers of pannexin-1 (Panxl) channels, preferably inhibitors of the activated form of Panxl channels, more preferably inhibitors or blockers specific to the activated form of Panxl channels.

[0004] BACKGROUND OF THE INVENTION

[0005] Panxl channels are transmembrane proteins that play an important role in intercellular communication. They are widely expressed in throughout the body, including in nervous system tissues. Panxl channels can be closed or opened with low conductance properties under physiological conditions, and activated, i.e. higher conductance properties, by different stimuli mostly pathological, including mechanical stress, increased extracellular K+concentration or increased intracellular Ca2+level, proteolytic cleavage, pro-inflammatory processes and changes in extracellular pH.

[0006] The Panxl channel is involved in various diseases, such as for instance, epilepsy, ischemic stroke, cancer, Parkinson’s disease, neuropathic pain, and make Panxl an interesting biological target.

[0007] Several molecules were proposed to inhibit or block Panxl, such as carbenoxolone (CBX), probenecid (PBN), and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB):

[0008] 5-nitro-2-(3-phenylpropylamino)benzoic acid

[0009] (NPPB)

[0010] Further Panxl inhibitors or Panxl blockers were developed in the last years, such as indole derivatives (Crocetti et al., Eur. J. Med. Chem., 2021, 223, 113650) and additional chemical scaffolds naphthalene and pyrazole (Crocetti et al. Int. J. Mol. Sci., 2022, 23, 4827).

[0011] However, there remains a need to identify further Panxl inhibitors or blockers, particularly compounds able to inhibit or block the activated form of Panxl, for treating diseases associated with this target. The present invention seeks to meet these and other needs.

[0012] SUMMARY OF THE INVENTION

[0013] In this context, the inventors have provided new 2,4-bis(sulfonyl)aniline derivatives as efficient Panxl inhibitors or blockers, demonstrating thereby the therapeutic interest of such derivatives in medicine.

[0014] The present invention thus provides new compounds of formula (I): wherein: Ri and R2 represent independently a (Ci-Ce)alkyl or a -NRaRb with Ra and Rb represent independently a hydrogen or a (Ci-Ce)alkyl; and R3 and R4 represent independently a radical selected in a group consisting of:

[0015] • a hydrogen,

[0016] • a (Ci-C6)alkyl,

[0017] • a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of: - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A,

[0018] - a hydroxy,

[0019] - a carboxy,

[0020] - a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl, and

[0021] - a halogen,

[0022] • a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:

[0023] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0024] - a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0025] - a halogen,

[0026] - a hydroxy,

[0027] - a 3-8 membered ring selected in a group consisting of cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,

[0028] - a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl,

[0029] - a nitro,

[0030] - a cyano,

[0031] - a -CO-cycloalkyl, and

[0032] - a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl, with the proviso that the compound of formula (I) is not a compound having the formula selected in a group consisting of: and the isomers, stereoisomers and pharmaceutical acceptable salts thereof.

[0033] In a particular embodiment, the compound of formula (I) is such that Ri and R2 represent independently a methyl, a -NRaRb with Raand Rb represent a hydrogen, or a -NRaRb with Raand Rb represent a methyl.

[0034] In a further particular embodiment, the 3-14 cycloalkyl or 3-14 cycloalkenyl, which can be optionally substituted by at least one radical A, has a formula selected in a group consisting of:

[0035] In a further particular, embodiment, the 3-14 heterocycloalkyl, which can be optionally substituted by at least one group A, has a formula selected in a group consisting of:

[0036]

[0037] In a further particular embodiment, R3 represents a hydrogen or a (Ci-Ce)alkyl.

[0038] In a further particular embodiment, the at least one radical A is selected in a group consisting of: - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen and a hydroxy, preferably a methyl, a methyl substituted by a hydroxy, an isopropyl, a tert-butyl, a -CHF2, and

[0039] - a phenyl. In a particular embodiment, the compound of the invention has the following formula selected in a group consisting of:

[0040] Particularly, the compound of the invention is a pannexin-1 inhibitor or a pannexin-1 blocker, preferably an inhibitor or a blocker of pannexin-1 in its activated form, more preferably an inhibitor or a blocker specific to pannexin-1 in its activated form.

[0041] A further object of the invention is a compound of formula (I) as defined herein for use as a medicine. A further object of the invention is a pharmaceutical composition comprising a compound of formula (I) as defined herein and a pharmaceutically acceptable excipient.

[0042] Another object of the invention is a pharmaceutical composition comprising a compound of formula (I), the isomers, stereoisomers and pharmaceutical acceptable salts thereof: wherein: Ri and R2 represent independently a (Ci-Ce)alkyl or a -NRaRb with Ra and Rb represent independently a hydrogen or a (Ci-Ce)alkyl; and R3 and R4 represent independently a radical selected in a group consisting of:

[0043] • a hydrogen,

[0044] • a (Ci-C6)alkyl,

[0045] • a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:

[0046] - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, and a heteroaryl, said 3-14 membered ring being optionally substituted by at least one radical A,

[0047] - a hydroxy, - a carboxy,

[0048] - a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl,

[0049] - a halogen,

[0050] - a (Ci-Ce)alkyloxy,

[0051] - a -C(O)-O-(Ci-C6)alkyl, and

[0052] - a -S-phenyl, and

[0053] • a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:

[0054] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0055] - a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0056] - a halogen,

[0057] - a hydroxy,

[0058] - a 3-8 membered ring selected in a group consisting of cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least radical selected in group consisting of a (Ci-C6)alkyl,

[0059] - a -NReRf with Re and Rf represent independently a hydrogen or a (Ci-Ce)alkyl,

[0060] - a nitro,

[0061] - a cyano,

[0062] - a -CO-cycloalkyl, and

[0063] - a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl.

[0064] A further object of the invention is a pharmaceutical composition as defined herein for use for treating a disease associated with the Pannexin 1 channel, the use of a pharmaceutical composition as defined herein for the manufacture of a medicine for treating a disease associated with the Pannexin 1 channel, or a method for treating a disease associated with the Pannexin 1 channel in a subject comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition as defined herein.

[0065] Particularly, the disease associated with the Pannexin 1 channel is selected in a group consisting of:

[0066] - an inflammatory disease, preferably ischemia, sepsis associated encephalopathy, pneumonia, Crohn’s disease, and wound healing;

[0067] - a chronic neurological disease with crisis, preferably epilepsy, pain, multiple sclerosis, acute disseminated encephalomyelitis, migraine, headache, neuropathies, and glaucoma;

[0068] - a neurodegenerative disease, preferably Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease;

[0069] - a psychiatric and developmental disorder, preferably autism, schizophrenia, major depressive disorder, bipolar disorder, Rett syndrome, and Angelman syndrome;

[0070] - withdrawal syndrome upon stopping drug use such as opioid;

[0071] - cancer;

[0072] - cardiovascular disease, preferably hypertension, cardiomyocyte fibrosis, and cardiac ischemia;

[0073] - tinnitus, hearing loss, deficiency of the inner ear development, vertigo, Meiniere disease, taste and / or olfaction loss, glaucoma, optic neuritis, retinal ischemia, lacrimal gland injury neuropathic pain, Wallerian degeneration, allodynia, nerve injury repair, thermal hyperalgesia, dentinal and / or pulpal pain;

[0074] - a urogenital disease, preferably an overactive bladder disorder, infertility oogenesis, vaginal dysfunction, risk for impaired genital arousal; and

[0075] - a viral infection, preferably a SARS Cov-2 and human immunodeficiency virus.

[0076] In a particular embodiment, the pharmaceutical composition and the pharmaceutical composition for use comprise a compound of formula (I) wherein: Ri and R2 represent a (Ci-Ce)alkyl, preferably a methyl; R3 represents a hydrogen; and R4 represents a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:

[0077] - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, an aryl, and a heteroaryl, said 3-14 membered ring being optionally substituted by at least one radical A, - a (Ci-Ce)alkyloxy,

[0078] - a -C(O)-O-(Ci-C6)alkyl, and

[0079] - a -S-phenyl, in which said radical A is selected in a group consisting of: - a (Ci-Ce)alkyl optionally substituted by at least one a halogen,

[0080] - a (Ci-Ce)alkyloxy optionally substituted by at least one a halogen,

[0081] - a halogen,

[0082] - a hydroxy,

[0083] - a nitro, - a cyano, and

[0084] - a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl.

[0085] More particularly, the pharmaceutical composition and the pharmaceutical composition for use comprise a compound of formula (I) having the following formula selected in a group consisting of:

[0086] In a further particular embodiment, the pharmaceutical composition as defined herein is such that the compound is administered at a dose ranging from 0.001 mg / kg body weight to 100 mg / kg body weight. In a further particular embodiment, the pharmaceutical composition as defined herein is administered by oral, topical, or parenteral route.

[0087] DETAILED DESCRIPTION OF THE INVENTION

[0088] Definitions

[0089] According to the present invention, the terms below have the following meanings:

[0090] The terms mentioned herein with prefixes such as for example Ci-Ce, can also be used with lower numbers of carbon atoms such as C1-C2. If, for example, the term Ci-Ce is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms.

[0091] The term “alkyl” refers to a saturated, linear or branched aliphatic group. The term “(Ci- C6)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, or hexyl.

[0092] The term “alkoxy” or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond. (Ci-Ce)alkoxy or (Ci-Ce)alkyloxy includes methoxy or methyloxy, ethoxy or ethyloxy, propoxy or propyloxy, isopropoxy or isopropyloxy, butoxy or butyloxy, isobutoxy or isobutyloxy, pentoxy or pentyloxy, isopentoxy or isopentyloxy, and hexoxy or hexyl oxy

[0093] The term “3-14 membered ring” corresponds to a ring having between 3 and 14 atoms. Such a term includes, for instance, the term “5-14 membered ring” having between 5 and 14 atoms, and the term “5-8 membered ring” having between 5 and 8 atoms. The term “ring” corresponds to a mono-, bi, or tricycle, which can be saturated, partially unsaturated or unsaturated, and optionally comprises at least one heteroatom. Particularly, the term “ring” includes a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl.

[0094] The term “cycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 14, preferably between 3 and 10 atoms of carbons. It also includes fused, bridged, or spiro-connected cycloalkyl groups. The term “cycloalkyl” includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “cycloalkyl” further includes fused, bridged, or spiro-connected cycloalkyl groups having, without limitation, the following formulae:

[0095] The term “heterocycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen (N-heterocycloalkyl), oxygen (O-heterocycloalkyl), or sulphur atom (S-heterocycloalkyl). It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. The term “heterocycloalkyl” further includes fused, bridged, or spiro-connected heterocycloalkyl groups having, without limitation, the following formulae:

[0096] The terms “cycloalkenyl” and “heterocycloalkenyl” correspond respectively to a partially unsaturated cycloalkyl and a partially unsaturated heterocycloalkyl such as cyclohexenyl, imidazolinyl, dihydropyranyl, pyrazolinyl, azetinyl, pyranyl, and tetrahydropyridinyl.

[0097] The term “aryl” corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term “aryl” includes phenyl, biphenyl, naphthyl and anthracenyl. In a particular embodiment, the aryl is a phenyl.

[0098] The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 3 and 20 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom. As used herein, the term “heteroaryl” further includes the “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl”. The terms “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl” correspond to a bicyclic group in which an aryl as above defined or a heteroaryl is respectively bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons. In other terms, the aryl or the heteroaryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly-cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, chromenyl, xanthenyl, phenoxanthinyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotri azolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydrobenzodi oxepinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. A fused arylheterocycloalkyl is for instance an indolinyl (phenyl fused to a pyrrolidinyl) and a dihydrobenzofuranyl (phenyl fused to a dihydrofuranyl).

[0099] The term “halogen” corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, chlorine or bromine.

[0100] The expression “substituted by at least” means that the radical is substituted by one or several groups of the list. For instance, the expression “a (Ci-Ce)alkyl substituted by at least one halogen, preferably a fluorine” may include a fluoromethyl (-CH2F), a difluoromethyl (-CHF2), or a trifluoromethyl (-CF3).

[0101] The expression “optionally substituted” means that the radical is not substituted or substituted by one or several groups of the list.

[0102] The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers, and anomers. In a particular embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers.

[0103] The “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons.

[0104] The “hydrates” are compounds further comprising at least one molecule of water. For instance, if the compound comprises one molecule of water, it corresponds to a monohydrate form. If the compound comprises two molecules of water, it corresponds to a dihydrate form. The “pharmaceutically salts” include inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like. Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. In a particular embodiment, the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate. The “pharmaceutically salts” also include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt.

[0105] As used herein, the terms “treatment”, “treat” or “treating” refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease. In certain embodiments, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other embodiments, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease.

[0106] By “pannexin-1” or “Panxl” both is intended to refer to a channel involved in the exchange of molecules such as ions such as chloride and / or small molecules, especially ATP, between the intra and the extra cellular spaces. Pannexin-1 from Homo sapiens is described in Uniprot under access number Q96RD7. NCBI Reference nucleic acid and amino acid sequences of human Panexin-1 are disclosed respectively NM_015368.3 and NP_056183.2. Panxl channels display two stimulation dependent conductance states, namely a small-pore small conductance (~ 70 pS) conformation that is permeable to ions and molecules up to 250 Da (named the nonactivated form), and a large-pore non-selective high-conductance (~ 500 pS) state which allows the exchange of molecules up to 1.5 kDa between the cytoplasm and the extracellular space (named the activated form). Panxl channels can be activated by different stimuli such as and not limited to mechanical pressure, glutamate activation, low oxygen level, voltage changes or cleavage at C-terminus (e.g., removal of amino acids 380-426 by caspase, especially caspase 3 or 7). Accordingly, Panxl exists in three forms: a closed form, a low-conductance form (i.e., non-activated form) and a high-conductance form (i.e. activated form). As used herein, the terms “pannexin-1 inhibitor” or “pannexin-1 blocker” refer to a molecule, a chemical, or a substance targeting or having an effect on the pannexin-1 channel. The “pannexin-1 inhibitor” or “pannexin-1 blocker” may be an inhibitor or a blocker of the pannexin-1 channel including closed, non-activated and activated forms. Preferably, the “pannexin-1 inhibitor” or “pannexin- 1 blocker” is an inhibitor or a blocker of the pannexin-1 channel in its activated form. More preferably, the “pannexin-1 inhibitor” or “pannexin-1 blocker” is an inhibitor or a blocker of the pannexin-1 channel specific to its activated form. In other words, it has no or only a weak effect on the closed and non-activated form.

[0107] By “blocker of Panxl” is intended to refer to a molecule, a chemical, or a substance which prevents or reduces the exchange of ions and / or small molecules between the intra and the extra cellular spaces by acting directly on the pore and blocking it. The blocker can be able to prevent or reduce or stop the exchange of both non-activated and activated Panxl. Alternatively, the blocker can be specific to activated form and is only able to prevent or reduce or stop the exchange of the activated Panxl.

[0108] By “inhibitor of Panxl”, it is intended to refer to a molecule, a chemical, or a substance which acts on a site out of the pore (intra or extra cellular part of the Panxl channel) and which is able to prevent or reduce its opening under non-activated and / or activated form; and / or induce its closure and / or internalisation; and / or control its opening in non-activated and / or activated form.

[0109] By inhibitor of pannexin-1 channel in its activated form, it may refer to an inhibitor which prevents or reduces or stops the activation of Panxl. By doing so, an inhibitor prevents or reduces or stops the exchange of ions and / or small molecules between the intra and the extra cellular spaces.

[0110] The effect of the inhibitor or blocker can be measured using a variety of in vitro models known to a skilled artisan. For instance, models to evaluate ATP release by Human Embryonic Kidney (HEK)-293 cells or Xenopus Oocytes genetically transformed to overexpress Panxl hemichannels are available (Locovei, et al. (2006). FEBS letters, 580(1), 239-244; Vanden Abeele, et al. (2006). The Journal of cell biology, 174(4), 535-546). Models based on cells naturally expressing Panxl are also known. For instance, the skilled artisan would know that human subcutaneous fibroblasts release ATP via Panxl upon mechanical or histamine stimulation (Yang, et al. (2022). International Journal of Molecular Sciences, 23(3), 1523; Pinheiro, A. R., et al. (2013). Journal of Biological Chemistry, 288(38), 27571-27583). A patent application KR20200143858 describes a high-throughput method for measuring Panxl activity. Alternatively, the effect of the inhibitor or blocker can be assessed by measuring a current following the stimulation of Panxl (e.g., by a slow voltage ramp) in the presence and the absence of the inhibitor or blocker and the effect can be expressed as % blockade in the presence of the compound (e.g., % blockade = measured current in presence of the compound / measured current in absence of the compound) (for instance, see Bao et al, 2004, FEBS Letters, https: / / doi.Org / 10.1016 / j.febslet.2004.07.009). In a particular aspect, the effect of the inhibitor or blocker can be determined by the protocol detailed in Example 1, section II. More precisely, the effect of the inhibitor or blocker can be expressed as following: % blockage of compound (at a defined concentration, e.g., 100pM) / % blockage of positive control (e.g., at 200pM). Optionally, the positive control is CBX or PBN.

[0111] Optionally, the inhibitor or blocker of Pannexin-1 is capable of decreasing the activity of Pannexin-1 (i.e., blockage) by at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100% compared to the activity in absence of the inhibitor or blocker. Optionally, when normalizing with a positive control such as CBX or PBN (corresponding to 100% inhibition), the inhibitor or blocker of Pannexin-1 is capable of a blockage of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%.

[0112] In a particular aspect, the effect of the inhibitor or blocker can be determined by the protocol detailed in Example 1, section II.

[0113] In a particular aspect, the inhibitor or blocker is specific to the activated form of Pannexin-1. Optionally, the inhibitor or blocker inhibits the activity of the activated form of Pannexin-1 and has no or less effect of the closed and the non-activated form. For instance, it has 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 fold less effect on the non-activated form than on the activated form. Optionally, the inhibitor or blocker has to be used at a concentration / dose at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 fold higher with the nonactivated form to present the same effect than with the activated form. Optionally, at a same concentration / dose, the effect of the inhibitor or blocker is reduced by at least 10, 20, 30, 40, 50, 60, 70, 80 or 90% on the non-activated form compared to the effect on the activated form. As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to a mammal, even more preferably to a human, including adult, elderly, child, newborn and human at the prenatal stage. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.

[0114] The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule. As used herein, the terms "active principle", "active ingredient", "active pharmaceutical ingredient", “medicine”, and “drug” are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect. Particularly, these terms refer to a compound of formula (I) as defined herein.

[0115] As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease, or to cure or to attenuate the effects of a disease.

[0116] As used herein, the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of a disease. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the disease, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.

[0117] As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.

[0118] Compounds

[0119] The present invention provides new compounds of the following formula (I), including isomers, stereoisomers, and pharmaceutical acceptable salts thereof, of therapeutic interest.

[0120] According to the invention, a compound has the following formula (I): wherein: Ri and R2 represent independently a (Ci-Ce)alkyl or a -NRaRb with Ra and Rb represent independently a hydrogen or a (Ci-Ce)alkyl; and R3 and R4 represent independently a radical selected in a group consisting of:

[0121] • a hydrogen,

[0122] • a (Ci-C6)alkyl,

[0123] • a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:

[0124] - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A,

[0125] - a hydroxy,

[0126] - a carboxy,

[0127] - a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl, and

[0128] - a halogen,

[0129] • a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:

[0130] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0131] - a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0132] - a halogen,

[0133] - a hydroxy,

[0134] - a 3-8 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,

[0135] - a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl,

[0136] - a nitro,

[0137] - a cyano,

[0138] - a -CO-cycloalkyl, and - a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl, with the proviso that the compound of formula (I) is not a compound having the formula selected in a group consisting of:

[0139] According to the invention, a compound of formula (I) is not a compound having the formula and the isomers and stereoisomers thereof. Particularly, a compound of formula corresponds to a racemic mixture comprising the isomers having the formulae These compounds are outside the scope of the present invention.

[0140] According to the invention, Ri and R2 represent independently a (Ci-Ce)alkyl or a -NRaRb with Ra and Rb represent independently a hydrogen or a (Ci-Ce)alkyl. In a particular embodiment, Ri and R2 represent independently a methyl, a -NRaRb with Raand Rb represent a hydrogen (i.e, a -NH2), or a -NRaRb with Raand Rb represent a methyl. In an embodiment, Ri is a methyl and R2 is a -NRaRb with Raand Rb represent a hydrogen. In an embodiment, Ri is a -NRaRb with Raand Rb represent a hydrogen and R2 is a methyl. In an embodiment, Ri is a -NRaRb with Raand Rb represent a methyl and R2 is a -NRaRb with Raand Rb represent a hydrogen. In an embodiment, Ri is a methyl and R2 is a methyl.

[0141] According to the invention, R3 and R4 represent independently a radical selected in a group consisting of:

[0142] • a hydrogen,

[0143] • a (Ci-C6)alkyl,

[0144] • a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:

[0145] - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A,

[0146] - a hydroxy,

[0147] - a carboxy,

[0148] - a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl, and

[0149] - a halogen,

[0150] • a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A.

[0151] Particularly, a 3-14 cycloalkyl or a 3-14 cycloalkenyl, optionally substituted by at least one radical A has a formula selected in a group consisting of:

[0152] Preferably, a 3-14 cycloalkyl optionally substituted by at least one radical A has a formula selected in a group consisting of:

[0153] Particularly, 3-14 heterocycloalkyl optionally substituted by at least one group A has a formula selected in a group consisting of: Preferably, a 3-14 heterocycloalkyl optionally substituted by at least one radical A has a formula selected in a group consisting of:

[0154] According to the invention, said 3-14 cycloalkyl and 3-14 heterocycloalkyl are optionally substituted by at least one radical A.

[0155] In a particular embodiment, said 3-14 cycloalkyl, 3-14 cycloalkenyl, 3-14 heterocycloalkyl, and 3-14 heterocycloalkenyl are not substituted.

[0156] In a further particular embodiment, said 3-14 cycloalkyl, 3-14 cycloalkenyl, 3-14 heterocycloalkyl, and 3-14 heterocycloalkenyl are substituted by at least one radical A.

[0157] Said radical A is selected in a group consisting of:

[0158] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0159] - a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0160] - a halogen,

[0161] - a hydroxy,

[0162] - a 3-8 membered ring selected in a group consisting of cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,

[0163] - a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl,

[0164] - a nitro,

[0165] - a cyano,

[0166] - a -CO-cycloalkyl, and

[0167] - a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl.

[0168] In a particular embodiment, said radical A is selected in a group consisting of:

[0169] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen and a hydroxy, preferably a methyl, a methyl substituted by a hydroxy, an isopropyl, a tert-butyl, a -CHF2, and

[0170] - a phenyl. In a particular embodiment, R3 represents a hydrogen or a (Ci-Ce)alkyl.

[0171] In a further particular embodiment, R3 represents a hydrogen or a (Ci-Ce)alkyl and R4 represents a radical selected in a group consisting of:

[0172] • a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:

[0173] - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A,

[0174] - a hydroxy,

[0175] - a carboxy,

[0176] - a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl, and

[0177] - a halogen,

[0178] • a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:

[0179] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0180] - a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0181] - a halogen,

[0182] - a hydroxy,

[0183] - a 3-8 membered ring selected in a group consisting of cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,

[0184] - a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl,

[0185] - a nitro,

[0186] - a cyano,

[0187] - a -CO-cycloalkyl, and

[0188] - a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl. In a further particular embodiment, R3 represents a hydrogen or a (Ci-Ce)alkyl and R4 represents a radical selected in a group consisting of:

[0189] • a (Ci-Cio)alkyl substituted by at least one 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl as defined herein, said 3-14 membered ring being optionally substituted by at least one radical A,

[0190] • a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl as defined herein, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:

[0191] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0192] - a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0193] - a halogen,

[0194] - a hydroxy,

[0195] - a 3-8 membered ring selected in a group consisting of cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,

[0196] - a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl,

[0197] - a nitro,

[0198] - a cyano,

[0199] - a -CO-cycloalkyl, and

[0200] - a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl.

[0201] Preferably, said radical A is selected in a group consisting of:

[0202] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen and a hydroxy, preferably a methyl, a methyl substituted by a hydroxy, an isopropyl, a tert-butyl, a -CHF2, and

[0203] - a phenyl.

[0204] A preferred compound of the invention has the following formula selected in a group consisting of:

[0205] A more preferred compound of the invention is selected in a group consisting of: Compound 005 8-(2,4-bis(methylsulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride;

[0206] Compound 006 A-((l -methyl -4-phenylpiperidin-4-yl)methyl)-2, 4- bi s(m ethyl sulfonyl)aniline;

[0207] - Compound 007 : A-((lR,2S)-2-isopropylcyclopentyl)-2,4-bis(methylsulfonyl)aniline;

[0208] - Compound 008 : A-(2,4-bis(methylsulfonyl)phenyl)-3,5-dimethyladamantan-l-amine;

[0209] Compound 009 4-(((l-(difluoromethyl)cyclobutyl)methyl)amino)-3-

[0210] (methylsulfonyl)benzenesulfonamide;

[0211] Compound 010 4-(((l-azabicyclo[3.3.1]nonan-5-yl)methyl)amino)-3-

[0212] (methylsulfonyl)benzenesulfonamide; Compound 011 2-(((l-(hydroxymethyl)-4,4-dimethylcyclohexyl)methyl)amino)-5- (methylsulfonyl)benzenesulfonamide; Compound 012 2-((2-(3-azaspiro[5.5]undecan-3-yl)ethyl)(methyl)amino)-5-

[0213] (methylsulfonyl)benzenesulfonamide; Compound 013 2-((2-(4-(tert-butyl)piperazin-l-yl)ethyl)amino)-5-

[0214] (methylsulfonyl)benzenesulfonamide;

[0215] - Compound 014 : N1,7V1-dimethyl-4-((2-methyl-2-(piperidin-4-yl)propyl)amino)benzene-l,3- disulfonamide hydrochloride;

[0216] - Compound 015 : (5)-A-((l-methylpiperidin-2-yl)methyl)-2,4-bis(methylsulfonyl)aniline;

[0217] - Compound 016 : 2,4-bis(methylsulfonyl)-7V-(l-(piperidin-l-ylmethyl)cyclobutyl)aniline;

[0218] - Compound 017 : (2A,35)-A-(2,4-bis(methylsulfonyl)phenyl)-l-methyl-2-phenylpyrrolidin-3- amine; - Compound 018 : / f-(2, 4-bis(methyl sulfonyl )phenyl)adamantan- l -amine ;

[0219] - Compound 019 : (5£,65)-6-(((2,4-bis(methylsulfonyl)phenyl)amino)methyl)spiro[3.5] nonan- 5-ol; and

[0220] - Compound 020 : (35,5A,75)-A-(2,4-bis(methylsulfonyl)phenyl)octahydrobenzofuran-5- amine.

[0221] In a particular embodiment, a compound of the invention is a pannexin-1 inhibitor or a pannexin-1 blocker. In a further particular embodiment, a compound of the invention is an inhibitor or a blocker of pannexin-1 in its activated form. In a more specific aspect, the compound of the invention is inhibitor or a blocker of pannexin-1 specific to its activated form.

[0222] Therapeutic applications

[0223] The inventors have provided the new compounds of formula (I). As illustrated by examples, the inventors have demonstrated the therapeutic interest of the compounds of the invention. A further object of the invention is a pharmaceutical or veterinary composition comprising a compound of formula (I), the isomers, stereoisomers and pharmaceutical acceptable salts thereof wherein: Ri and R2 represent independently a (Ci-Ce)alkyl or a -NRaRb with Ra and Rb represent independently a hydrogen or a (Ci-Ce)alkyl; and R3 and R4 represent independently a radical selected in a group consisting of

[0224] • a hydrogen,

[0225] • a (Ci-C6)alkyl,

[0226] • a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of

[0227] - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, and a heteroaryl, said 3-14 membered ring being optionally substituted by at least one radical A, - a hydroxy,

[0228] - a carboxy,

[0229] - a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl,

[0230] - a halogen,

[0231] - a (Ci-Ce)alkyloxy,

[0232] - a -C(O)-O-(Ci-C6)alkyl, and

[0233] - a -S-phenyl, and

[0234] • a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:

[0235] - a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0236] - a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,

[0237] - a halogen,

[0238] - a hydroxy,

[0239] - a 3-8 membered ring selected in a group consisting of cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,

[0240] - a -NReRf with Re and Rf represent independently a hydrogen or a (Ci-Ce)alkyl,

[0241] - a nitro,

[0242] - a cyano,

[0243] - a -CO-cycloalkyl, and

[0244] - a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl.

[0245] A particular object of the invention is a pharmaceutical or veterinary composition comprising a new compound of formula (I) including any particular or preferred embodiments as above described, the isomers, stereoisomers and pharmaceutical acceptable salts. A further particular object of the invention is a pharmaceutical or veterinary composition comprising a compound of formula (I), the isomers, stereoisomers and pharmaceutical acceptable salts thereof: wherein: Ri and R2 represent a (Ci-Ce)alkyl, preferably a methyl; R3 represents a hydrogen; and R4 represents a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:

[0246] - a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, and a heteroaryl, said 3-14 membered ring being optionally substituted by at least one radical A,

[0247] - a (Ci-Ce)alkyloxy,

[0248] - a -C(O)-O-(Ci-C6)alkyl, and

[0249] - a -S-phenyl, in which said radical A is selected in a group consisting of:

[0250] - a (Ci-Ce)alkyl optionally substituted by at least one a halogen,

[0251] - a (Ci-Ce)alkyloxy optionally substituted by at least one a halogen,

[0252] - a halogen,

[0253] - a hydroxy,

[0254] - a nitro,

[0255] - a cyano, and

[0256] - a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl. In a particular embodiment, said compound of formula (I) is a pannexin-1 inhibitor or a pannexin-1 blocker. In a further particular embodiment, a compound of the invention is an inhibitor or a blocker of pannexin-1 in its activated form. In a more specific aspect, the compound of the invention is inhibitor or a blocker of pannexin-1 specific to its activated form. Particularly, said compound of formula (I) has the following formula selected in a group consisting of:

[0257]

[0258] More specifically, said compound of formula (I) is selected in a group consisting of: - 7V-(3-(lH-imidazol-l-yl)-2-methylpropyl)-2,4-bis(methylsulfonyl) aniline;

[0259] - (5)-7V-(2-(4-methylpiperidin-l-yl)propyl)-2,4-bis(methylsulfonyl)aniline;

[0260] - 2,4-bis(methylsulfonyl)-7V-(2-(pyridin-2-yl)ethyl)aniline; and - 7V-(2-ethoxyethyl)-2,4-bis(methylsulfonyl)aniline.

[0261] The present invention further relates to a pharmaceutical or veterinary composition comprising a compound of formula (I) according to the invention or any particular compound as disclosed herein. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient.

[0262] The present invention further relates to the use of a compound of formula (I) according to the invention or any particular compound as disclosed herein as a drug or a medicine.

[0263] The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a compound of formula (I) according to the invention or any particular compound as disclosed herein, is administered to said subject in need thereof. The invention also relates to the use of a compound of formula (I) according to the invention or any particular compound as disclosed herein, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising a compound of formula (I) according to the invention or any particular compound as disclosed herein for use as a drug or a medicine.

[0264] The present invention also concerns:

[0265] - a compound of formula (I) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound for preventing and / or treating or for use for preventing and / or treating a disease associated with the pannexin-1 channel; and / or

[0266] - the use of a compound of formula (I) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the prevention and / or the treatment of a disease associated with the pannexin-1 channel; and / or

[0267] - a method for treating a disease associated with the pannexin-1 channel, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound.

[0268] As used herein, “a disease associated with the pannexin-1 channel” refers to a disease or disorder characterized by inappropriate Panxl activity. Inappropriate Panxl activity refers to an increase in Panxl activity as measured by cellular assays, for example compared to the activity in a healthy cell or subject. Inappropriate activity could also be due to overexpression of Panxl in diseased tissue compared with healthy adjacent tissue. In a particular aspect, the disease or disorder may be characterized by an increase of activated Panxl, for instance an increased activity specific to activated Panxl or an increased amount of activated Panxl.

[0269] Panxl has been associated to several diseases, for instance and non-exhaustively inflammatory disorders and diseases such as Chron’s disease, inflammatory bowel disease, viral and bacterial infections and sepsis, CNS diseases and disorders including epilepsy, seizure, stroke, migraine headache, chronic pain such as neuropathic and orofacial pain, spinal cord injury, traumatic brain injury, sciatic nerve injury, brain ischemia, cancer such as leukemia, glioma, melanoma, and breast cancer, and metabolic disorder such as diabetes (e.g. and, see Rusiecka et al, 2022, Front. Cell Dev. Biol., Sec. Signaling, Volume 10, https: / / doi.org / 10.3389 / fcell.2022.1020826; Crespo et al, 2017, Biochim Biophys Acta., 1864(1): 51-61; Chen et al, 2023, Front. Immunol., Sec. Inflammation, Volume 14, https: / / doi.org / 10.3389 / fimmu.2023.1217366; Yeung et al, 2020, Journal of Neurochemistry, Vol 154, pages 468-485, https: / / doi.org / 10.l l l l / jnc.15004; Seo et al, 2021, Int J Mol Sci., 22(10): 5189, doi: 10.3390 / ijms22105189).

[0270] As used herein, “a disease associated with the pannexin-1 channel” comprises, without limitation, an inflammatory disease, a chronic neurological disease, a neurodegenerative disease, a psychiatric and development disorder, a cancer, a cardiovascular disease, tinnitus, hearing loss, deficiency of the inner ear development, vertigo, Meiniere’s disease, taste and / or olfaction loss, glaucoma, optic neuritis, retinal ischemia, lacrimal gland injury, neuropathic pain, Wallerian degeneration, allodynia, nerve injury repair, thermal hyperalgesia, dentinal and / or pulpal pain, a urogenital disease, or a viral infection.

[0271] An inflammatory disease may include, without limitation, ischemia, sepsis associated encephalopathy, pneumonia, Crohn’s disease, and wound healing.

[0272] A chronic neurological disease with crisis may include, without limitation, epilepsy, pain, multiple sclerosis, acute disseminated encephalomyelitis, migraine, headache, neuropathies, and glaucoma.

[0273] A neurodegenerative disease may include, without limitation, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

[0274] A psychiatric and developmental disorder may include, without limitation, autism, schizophrenia, major depressive disorder, bipolar disorder, Rett syndrome, and Angelman syndrome.

[0275] A cancer may include, without limitation, to, solid tumors and hematological cancers, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, lung cancer, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, bile duct cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, melanoma, skin cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, oesophagal cancer, colon cancer, head and neck cancer, brain cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia, mastocytosis and any symptom associated with mastocytosis.

[0276] A cardiovascular disease may include but is not limited to hypertension, cardiomyocyte fibrosis, and cardiac ischemia.

[0277] Further diseases associated with the pannexin-1 channel - tinnitus include, without limitation, hearing loss, deficiency of the inner ear development, vertigo, Meiniere’s disease, taste and / or olfaction loss, glaucoma, optic neuritis, retinal ischemia, lacrimal gland injury, neuropathic pain, Wallerian degeneration, allodynia, nerve injury repair, thermal hyperalgesia, dentinal and / or pulpal pain.

[0278] A urogenital disease may include but is not limited to an overactive bladder disorder, infertility oogenesis, vaginal dysfunction, risk for impaired genital arousal.

[0279] A viral infection may include but is not limited to a SARS Cov-2 and human immunodeficiency virus.

[0280] A particular object of the invention is a pharmaceutical composition as defined herein for use for treating a disease, preferably associated with the Pannexin 1 channel, which is selected in a group consisting of:

[0281] - an inflammatory disease, preferably ischemia, sepsis associated encephalopathy, pneumonia, Crohn’s disease, and wound healing;

[0282] - a chronic neurological disease with crisis, preferably epilepsy, pain, multiple sclerosis, acute disseminated encephalomyelitis, migraine, headache, neuropathies, and glaucoma;

[0283] - a neurodegenerative disease, preferably Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease;

[0284] - a psychiatric and developmental disorder, preferably autism, schizophrenia, major depressive disorder, bipolar disorder, Rett syndrome, and Angelman syndrome; - withdrawal syndrome upon stopping drug use such as opioid;

[0285] - cancer;

[0286] - cardiovascular disease, preferably hypertension, cardiomyocyte fibrosis, and cardiac ischemia;

[0287] - tinnitus, hearing loss, deficiency of the inner ear development, vertigo, Meiniere’s disease, taste and / or olfaction loss, glaucoma, optic neuritis, retinal ischemia, lacrimal gland injury, neuropathic pain, Wallerian degeneration, allodynia, nerve injury repair, thermal hyperalgesia, dentinal and / or pulpal pain;

[0288] - a urogenital disease, preferably an overactive bladder disorder, infertility oogenesis, vaginal dysfunction, risk for impaired genital arousal; and

[0289] - a viral infection, preferably a SARS Cov-2 and human immunodeficiency virus.

[0290] A further object is a use of is a pharmaceutical composition as defined herein for the manufacture of a drug for treating said disease. A further object is a method for treating said disease comprising administering a pharmaceutical composition as defined herein in a subject in need thereof.

[0291] The administration route can be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumor or parenteral (including subcutaneous, intramuscular, intravenous and / or intradermal). Preferably, the administration route is parental, oral or topical. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition is preferably administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.

[0292] The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets or capsules that contain solid vehicles in a way known in the art. Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.

[0293] Pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.

[0294] Preferably, the treatment with the compound according to the invention or the pharmaceutical composition according to the invention starts no longer than a month, preferably no longer than a week, after the diagnosis of the disease. In a particular embodiment, the treatment starts the day of the diagnosis.

[0295] The compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses.

[0296] Preferably, the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day.

[0297] The duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably comprised between 1 day and 50 weeks, more preferably between 1 day and 30 weeks, still more preferably between 1 day and 15 weeks, even more preferably between 1 day and 10 weeks. In a particular embodiment, the duration of the treatment is of about 1 week. Alternatively, the treatment may last as long as the disease persists. The amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient. In a particular embodiment, the compound according to the invention is administered at a dose ranging from 0.001 mg / kg body weight to 100 mg / kg body weight, preferably from 0.001 mg / kg body weight to 30 mg / kg body weight.

[0298] Further aspects and advantages of the invention will be disclosed in the following experimental section, which should be regarded as illustrative and not limiting.

[0299] BRIEF DESCRIPTION OF THE FIGURES

[0300] Figure 1: percentage of Panxl inhibition by tested compounds compared to positive control (Carbenoxolone, 200pM) in the oocyte model expressing the human Panxl (hPanxl) channel following a voltage ramp.

[0301] EXAMPLES

[0302] I. CHEMISTRY EXAMPLES

[0303] The compounds according to the invention can be prepared by the general method illustrated in the scheme 1 below and were prepared by the method A.

[0304] Scheme 1:

[0305] X = Halogen

[0306] General Nucleophilic Aromatic Substitution procedure:

[0307] To a solution of l-halogeno-2,4-bis(sulfonyl)benzene 1 (0.5 mmol, 1 eq.) and the appropriate amine 2 (0.5 mmol, 1 eq.) in DMSO (1 mL) was added DIPEA (0.75 mmol, 1.5 eq.). The solution was stirred at 50 °C overnight then concentrated under reduced pressure. The mixture was then diluted with H2O (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by flash chromatography.

[0308] Method A: Aromatic Nucleophilic Substitution reaction (S\Ar)

[0309] To a solution of aryl halide (1 equivalent) and amine (1.2 equivalents) in acetonitrile (3 mL) is added triethylamine (2 equivalents), at room temperature under an argon atmosphere. The mixture is stirred at reflux of the solvent. After completion of the reaction, the progress of which is monitored by TLC, the crude is directly concentrated under reduced pressure. It is then purified by chromatography on a silica gel column or on a silica preparative layer plate.

[0310] Compound 001 : \-(3-( 1 H-imidazol-l-yl)-2-methylpropyl)-2,4-bis(methylsulfonyl) aniline

[0311] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with 3-(lH-imidazol-l-yl)-2-methylpropan-l-amine (33 mg, 0.237 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent DCM / MeOH 90 / 10) shows the completion of the reaction. After concentration of the crude under reduced pressure, a yellow amorphous solid weighing 110 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 90 / 10) to give the compound 001, in the form of a light yellow solid (52 mg, yield: 71%).

[0312] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.32 (d, J= 2.3 Hz, 1H), 7.92 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 6.99 (br t, 1H), 6.92 (s, 1H), 6.69 (d, J= 9.0 Hz, 1H), 3.97 (d, J = 6.8 Hz, 2H), 3.22-3.11 (m, 2H), 3.07 (s, 3H), 3.05 (s, 3H), 2.39-2.26 (m, 1H), 1.11 (d, J= 6.8 Hz, 3H).

[0313] LC-MS : Retention time : 2.46 min ; observed m / z : 372.0860 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0314] Compound 002 : (N)-A-(2-(4-methylpiperidin-l-yl)propyl)-2,4-bis(methylsulfonyl)aniline

[0315] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with (5)-2-(4-methyl-l-piperidinyl)propylamine (38 mg, 0.243 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at the reflux for 2 hours. At this stage, a TLC (eluent DCM / MeOH 90 / 10) shows the completion of the reaction. After concentrating the crude under reduced pressure, a white solid weighing 92 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 95 / 5 to 90 / 10) to give compound 002, in the form of a white powder (64 mg, yield: 83%).

[0316] ’H NMR 5 (300 MHz, CDCI3) (ppm) : 8.32 (d, J= 2.3 Hz, 1H), 7.90 (dd, J= 8.8 Hz, 2.3 Hz, 1H), 7.55 (br d, J= 5.2 Hz, 1H), 6.76 (d, J= 8.8 Hz, 1H), 3.19-3.10 (m, 1H), 3.06 (s, 3H), 3.03 (s, 3H), 3.02-2.95 (m, 2H), 2.70-2.59 (m, 2H), 2.53 (td, J= 11.1 Hz, 2.6 Hz, 1H), 2.09 (td, J = 11.1 Hz, 2.6 Hz, 1H), 1.70-1.58 (m, 2H), 1.45-1.29 (m, 2H), 1.27-1.14 (m, 1H), 1.05 (d, J = 6.4 Hz, 3 H), 0.93 (d, J= 6.0 Hz, 3H).

[0317] LC-MS : Retention time : 2.92 min ; observed m / z : 389.1509 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0318] Compound 003 : 2,4-bis(methylsulfonyl)-7V-(2-(pyridin-2-yl)ethyl)aniline

[0319] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with 2-(2pyridyl)ethylamine (29 mg, 0.237 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent DCM / MeOH 90 / 10) shows the completion of the reaction. After concentration of the crude under reduced pressure, a yellowish amorphous solid weighing 92 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 95 / 5 to 90 / 10) to give compound 003, in the form of a white powder (41 mg, yield: 58%).

[0320] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.57 (ddd, J= 4.5 Hz, 2.3 Hz, 0.7 Hz, 1H), 8.29 (d, J= 9.0 Hz, 2.3 Hz, 1H), 7.91 (dd, J= 8.9 Hz, 2.3 Hz, 1H), 7.64 (td, J= 7.6 Hz, 1.9 Hz, 1H), 7.23- 7.11 (m, 3H), 6.90 (d, J= 8.9 Hz, 1H), 3.71 (td, J = 6.4 Hz, 5.3 Hz, 2H), 3.16 (t, J= 6.4 Hz, 2H), 3.02 (s, 3H), 2.94 (s, 3H).

[0321] LC-MS : Retention time : 2.98 min ; observed m / z: 355.0807 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0322] Compound 004 : 7V-(2-ethoxyethyl)-2,4-bis(methylsulfonyl)aniline

[0323] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with 2-ethoxyethylamine (21 mg, 0.236 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent DCM / MeOH 95 / 5) shows the completion of the reaction. After concentration of the crude under reduced pressure, a white amorphous solid weighing 65 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 98 / 2 to 95 / 5) to give compound 004, in the form of a white powder (49 mg, yield: 77%).

[0324] ’H NMR 5 (300 MHz, CDCI3) (ppm) : 8.32 (d, J= 2.3 Hz, 1H), 7.92 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 7.02 (br t, J= 4.3 Hz, 1H), 6.86 (d, J= 9.0 Hz, 1H), 3.70 (t, J= 5.3 Hz, 2H), 3.56 (q, J= 7.0 Hz, 2H), 3.44 (q, J= 5.3 Hz, 2H), 3.07 (s, 3H), 3.04 (s, 3H), 1.22 (t, J= 7.0 Hz, 3H) LC-MS : Retention time : 5.25 minutes ; observed m / z : 322.0791 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm). tert-butyl 8-(2,4-bis(methylsulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0325] According to the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (51 mg, 0.240 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 4 hours. At this stage, TLC (eluent hexane / AcOEt 60 / 40 - double elution) shows the completion of the reaction. After concentration of the crude under reduced pressure, a white solid weighing 96 mg is obtained. It is purified on a silica gel column (eluent cyclohexane / AcOEt 40 / 60 to 10 / 90) to give tert-butyl 8-(2,4- bis(methylsulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, in the form of a white powder (60 mg, yield: 68%).

[0326] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.67 (d, J= 2.3 Hz, 1H), 8.06 (dd, J= 8.7 Hz, 2.3 Hz, 1H), 7.21 (d, J= 8.7 Hz, 1H), 4.11 (br s, 2H), 3.99 (d, J= 12.6 Hz, 1H), 3.84 (d, J= 12.6 Hz, 1H), 3.4 (d, J= 12.6 Hz, 1H), 3.33 (s, 3H), 3.22 (d, J= 12.6 Hz, 1H), 3.08 (s, 3H), 2.09-1.80 (m, 4H), 1.48 (s, 9H).

[0327] Compound 005 8-(2,4-bis(methylsulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride To a solution of tert-butyl 8-(2,4-bis(methylsulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (110 mg, 0.247 mmol) in anhydrous dioxane (4.5 mL) is added a solution of hydrochloric acid in dioxane (1.24 mL of 4 M, 4.96 mmol, 20 equiv.), at room temperature under an argon atmosphere. The mixture is stirred in these conditions for 48 hours. At this stage, a TLC (eluent AcOEt / cyclohexane 70 / 30) shows that the progress of the reaction is almost complete. The white precipitate formed is filtered over sintered glass and washed with ether. The precipitate is collected to give compound 005 in the form of a white powder (38 mg, yield: 40 %).

[0328] ’H NMR 5 (300 MHz, (CD3)2SO) (ppm) : 9.32 (br s, 1H), 8.39 (s, 1H), 8.11 (br t, J= 8.7 Hz, 1H), 7.48 (br t, J= 9.8 Hz, 1H), 4.21-4.01 (m, 2H), 3.76 (br t, J= 14.4 Hz, 1H), 3.40 (s, 3H), 3.26 (s, 3H), 2.10 (s, 2H), 2.00-1.87 (m, 1H), 1.73-1.62 (m, 1H), 1.43 (s, 4H).

[0329] LC-MS : Retention time : 1.07 min ; observed m / z : 345.0934 [M-C1]+; Purity : 43 % (based on the integration of the UV peak at 254 nm).

[0330] Compound 006 : 7V-((l-methyl-4-phenylpiperidin-4-yl)methyl)-2,4- bis(methylsulfonyl)aniline

[0331] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with (l-methyl-4-phenylpiperidin-4-yl)m ethanamine (49 mg, 0.240 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent AcOEt / cyclohexane 70 / 30) shows the completion of the reaction. After concentration of the crude under reduced pressure, a colourless amorphous solid weighing 114 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 95 / 5 to 90 / 10) to give compound 006, in the form of a beige powder (88 mg, quantitative yield).

[0332] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.19 (d, J= 2.3 Hz, 1H), 7.82 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 7.45-7.37 (m, 4H), 7.30-7.27 (m, 1H), 6.67 (d, J = 9.0 Hz, 1H), 6.52 (br t, J = 4.5 Hz, 1H), ;3.55 (d, J= 4.5 Hz, 2H), 2.99 (s, 3H), 2.88-2.76 (m, 2H), 2.62 (s, 3H), 2.50-2.35 (m, 4H), 2.34 (s, 3H), 2.18-2.06 (m, 2H). LC-MS : Retention time : 2.45 min ; observed m / z : 437.1557 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0333] Compound 007 : 7V-((ll?,2»S)-2-isopropylcyclopentyl)-2,4-bis(methylsulfonyl)aniline

[0334] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl) benzene (50 mg, 0.198 mmol) is reacted with (lA,25)-2-isopropylcyclopentan-l-amine (30 mg, 0.236 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 eq.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent cyclohexane / AcOEt 50 / 50) shows the completion of the reaction. After concentration of the crude under reduced pressure, a light yellow amorphous solid weighing 77 mg is obtained. It is purified on a silica gel column (eluent cyclohexane / AcOEt 60 / 40 to 40 / 60) to give compound 007, in the form of a white powder (64 mg, yield: 90%).

[0335] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.3 (d, J= 2.2 Hz, 1H), 7.9 (dd, J= 9.0 Hz, 2.2 Hz, 1H), 6.88 (d, J= 6.9 Hz, 1H), 6.84 (d, J= 9.0 Hz, 1H), 3.63-3.53 (m, 1H), 3.04 (s, 6H), 2.11-2.01 (m, 1H), 1.99-1.87 (m, 1H), 1.78-1.48 (m, 6H), 1.43-1.27 (m, 2H), 0.96 (d, J= 6.3 Hz, 3H), 0.93 (d, J= 6.3 Hz, 3H).

[0336] LC-MS : Retention time : 6.40 min ; observed m / z : 360.1294 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0337] Compound 008 : 7V-(2,4-bis(methylsulfonyl)phenyl)-3,5-dimethyladamantan-l-amine

[0338] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with l,3-Dimethyl-5-adamantanamine hydrochloride (51 mg, 0.236 mmol, 1.2 equiv.) in the presence of tri ethylamine (85 pL, 0.610 mmol, 3.1 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent cyclohexane / AcOEt 50 / 50) shows the partial progress of the reaction, which is nevertheless stopped. After concentration of the crude under reduced pressure, a white solid weighing 114 mg is obtained. It is purified on a silica gel column (eluent cyclohexane / AcOEt 60 / 40) to 50 / 50 to give compound 008, in the form of a white powder (33 mg, yield: 36%).

[0339] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.3 (d, J= 2.3 Hz, 1H), 7.84 (dd, J = 9.0 Hz, 2.3 Hz, 1H), 7.12 (d, J= 9.0 Hz, 1H), 6.88 (br s, 1H), 3.04 (s, 3H), 3.03 (s, 3H), 2.29-2.23 (m, 1H), 1.9 (d, J= 2.7 Hz, 2H), 1.67 (dd, J= 30.5 Hz, 12 Hz, 4H), 1.47-1.34 (m, 4H), 1.29-1.20 (m, 2H), 0.91 (s, 6H).

[0340] LC-MS : Retention time : 7.30 min ; observed m / z : 823.3138 [2M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0341] Compound 009 : 4-(((l-(difluoromethyl)cyclobutyl)methyl)amino)-3-

[0342] (methylsulfonyl)benzenesulfonamide

[0343] In accordance with the method A, 4-fluoro-3-(methanesulfonyl)benzenesulfonamide (50 mg, 0.197 mmol) is reacted with [l-(difluoromethyl)cyclobutyl]methanamine hydrochloride (41 mg, 0.239 mmol, 1.2 equiv.) in the presence of triethylamine (90 pL, 0.646 mmol, 3.3 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent cyclohexane / AcOEt 30 / 70) shows the completion of the reaction. After concentration of the crude under reduced pressure, a white amorphous solid weighing 130 mg is obtained. It is purified on a silica gel column (eluent cyclohexane / AcOEt 30 / 70) to give compound 009 in the form of a white powder (60 mg, yield: 82%).

[0344] ’H NMR 5 (300 MHz, CDCI3) (ppm) : 8.17 (d, J= 2.3 Hz, 1H), 7.85 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 6.79 (d, J= 9.0 Hz, 1H), 6.66 (br t, J= 4.0 Hz, 1H), 5.79 (t, J= 56.2 Hz, 1H), 3.66 (br s, 2H), 3.39 (d, J= 4.0 Hz, 2H), 2.97 (s, 3H), 2.24-2.12 (m, 2H), 2.03-1.80 (m, 4H).

[0345] LC-MS : Retention time : 4.88 minutes ; observed m / z : 369.0744 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0346] Compound 010 : 4-(((l-azabicyclo[3.3.1]nonan-5-yl)methyl)amino)-3-

[0347] (methylsulfonyl)benzenesulfonamide

[0348] In accordance with the method A, 4-fluoro-3-(methanesulfonyl)benzenesulfonamide (60 mg, 0.237 mmol, 1.2 equiv.) is reacted with l-azabicyclo[3.3.1]non-5-ylmethanamine (30 mg, 0.194 mmol, 1 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent DCM / MeOH 90 / 10 + 2% TEA) shows the completion of the reaction. After concentrating the crude under reduced pressure, a white solid weighing 92 mg is obtained. It is purified on a silica preparative plate (eluent DCM / MeOH 90 / 10 + 2% TEA, double elution) to give compound 010, in the form of a white powder (40 mg, yield: 53%).

[0349] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.09 (d, J= 1.9 Hz, 1H), 7.76 (dd, J= 9.0 Hz, 1.9 Hz, 1H), 6.71 (d, J = 9.0 Hz, 1H), 6.64 (br t, J = 5.0 Hz, 1H), 3.62 (t, J = 6.0 Hz, 1H), 3.08-2.98 (m, 3H), 2.95 (s, 3H), 2.91-2.80 (m, 3H), 2.72 (br s, 2H), 2.29 (t, J= 6.0 Hz, 1H), 2.16-1.98 (m, 2H), 1.85-1.71 (m, 2H), 1.69-1.45 (m, 4H).

[0350] LC-MS : Retention time : 1.53 min ; observed m / z : 388.1358 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0351] Compound Oil : 2-(((l-(hydroxymethyl)-4,4-dimethylcyclohexyl)methyl)amino)-5- (methylsulfonyl)benzenesulfonamide

[0352] In accordance with the method A, 2-fluoro-5-(methylsulfonyl)benzenesulfonamide (50 mg, 0.197 mmol) is reacted with [l-(aminomethyl)-4,4-dimethylcyclohexyl]methanol (41 mg, 0.239 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent AcOEt / cyclohexane 50 / 50) shows the completion of the reaction. After concentration of the crude under reduced pressure, a whitish amorphous solid weighing 100 mg is obtained. It is purified on a silica gel column (eluent cyclohexane / AcOEt 50 / 50 to 30 / 70) to give compound OH, in the form of a white powder (71 mg, yield: 89%). ’H NMR 5 (300 MHz, (CD3)2SO) (ppm) : 8.17 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 8.9 Hz, 2.1 Hz, 1H), 6.93 (br t, J= 4.3 Hz, 1H), 6.82 (br s, 2H), 6.75 (d, J = 8.9 Hz, 1H), 5.05 (br s, 1H), 3.12 (d, .7= 4.3 Hz, 2H), 2.94 (s, 3H), 2.91-2.85 (m, 2H), 1.46-1.29 (m, 4H), 1.27-1.11 (m, 4H), 0.84 (s, 3H), 0.83 (s, 3H).

[0353] LC-MS : Retention time : 5.44 min ; observed m / z : 405.1504 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0354] Compound 012 : 2-((2-(3-azaspiro[5.5]undecan-3-yl)ethyl)(methyl)amino)-5-

[0355] (methylsulfonyl)benzenesulfonamide

[0356] In accordance with the general procedure, 2-fluoro-5-(methylsulfonyl)benzenesulfonamide (50 mg, 0.197 mmol) is reacted with / V-[2-(3-azaspiro[5.5]undec-3-yl)ethyl]- / V-methylamine (50 mg, 0.238 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent AcOEt / cyclohexane 50 / 50) shows the completion of the reaction. After concentration of the crude under reduced pressure, a yellow amorphous solid weighing 109 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 95 / 5 to 90 / 10) to give compound 012, in the form of a white powder (75 mg, yield: 86%).

[0357] ’H NMR 5 (300 MHz, (CD3)2SO) (ppm) : 8.55 (d, J= 2.3 Hz, 1H), 8.10 (dd, J= 8.3 Hz, 2.3 Hz, 1H), 7.51 (d, J= 8.3 Hz, 1H), 3.20-3.13 (m, 2H), 3.09 (s, 3H), 2.81 (s, 3H), 2.61-2.34 (m, 6H), 1.51-1.27 (m, 16H).

[0358] LC-MS : Retention time : 3.09 min ; observed m / z : 444.1980 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0359] Compound 013 : 2-((2-(4-(terf-butyl)piperazin-l-yl)ethyl)amino)-5-

[0360] (methylsulfonyl)benzenesulfonamide In accordance with the method A, 2-fluoro-5-(methylsulfonyl)benzenesulfonamide (50 mg, 0.197 mmol) is reacted with 2-(4- / c77-butylpiperazin- l -yl)ethan- l -amine (44 mg, 0.237 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent cyclohexane / AcOEt 50 / 50) shows the completion of the reaction. After concentration of the crude under reduced pressure, a white solid weighing 101 mg is obtained. It is purified on a silica preparative plate (eluent DCM / MeOH 90 / 10, triple elution) to give compound 013, in the form of a beige powder (30 mg, yield: 36%).

[0361] ’H NMR 5 (300 MHz, (CD3)2SO) (ppm) : 8.09 (d, J= 2.3 Hz, 1H), 7.82 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 7.54 (br s, 2H), 6.96 (d, J= 9.0 Hz, 1H), 6.86 (t, J= 4.3 Hz, 1H), 3.40-3.28 (m, 2H), 3.12 (s, 3H), 2.87-2.51 (m, 10H), 1.11 (s, 9H).

[0362] LC-MS : Retention time : 1.54 min ; observed m / z : 419.1782 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm). tert-butyl 4-( l-((4-( \.\-diniethylsiilf:inioyl)-2-siilf:inioylphenyl):iinino)-2-niethylpropan- 2-yl)piperidine-l-carboxylate

[0363] In accordance with the method A, 4-Chloro-A;,A;-dimethyl-l,3-benzenedisulfonamide (100 mg, 0.372 mmol) is reacted with tert-butyl 4-(l-amino-2-methylpropan-2-yl)piperidine-l- carboxylate (114 mg, 0.445 mmol, 1.2 equiv.) in the presence of triethylamine (105 pL, 0.753 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 48 hours. At this stage, a TLC (eluent cyclohexane / AcOEt 50 / 50) shows the partial progress of the reaction, which is nevertheless stopped. After concentration of the crude under reduced pressure, a yellow solid weighing 217 mg is obtained. It is purified on 2 preparative plates of silica (eluent cyclohexane / AcOEt 50 / 50, double elution) to give tert-butyl 4-(l-((4-(7V,7V- dimethylsulfamoyl)-2-sulfamoylphenyl)amino)-2-methylpropan-2-yl)piperidine-l- carboxylate, in the form of a white powder (77 mg, yield: 40%).

[0364] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.17 (d, J= 2.2 Hz, 1H), 7.74 (dd, J= 8.7 Hz, 2.2 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.52 (br t, J= 4.9 Hz, 1H), 4.97 (br s, 2H), 4.17 (br d, J= 11.0 Hz, 2H), 3.05 (d, J= 4.9 Hz, 2H), 2.69 (s, 6H), 2.65-2.57 (m, 1H), 1.69-1.57 (m, 3H), 1.44 (s, 9H), 1.42-1.18 (m, 3H), 1.01 (s, 6H). Compound 014 : A^1^V1-dimethyl-4-((2-methyl-2-(piperidin-4-yl)propyl)amino)benzene- 1,3-disulfonamide hydrochloride

[0365] To a solution of tert-butyl 4-(l -((4-(A,A-dimethyl sulfamoyl )-2-sulfamoylphenyl )amino)-2- methylpropan-2-yl)piperidine-l -carboxylate (68 mg, 0.131 mmol) in anhydrous dioxane (2 mL) is added a solution of hydrochloric acid in dioxane (327 pL of 4 M, 1.31 mmol, 10 equiv.), at room temperature in an argon atmosphere. The mixture is stirred under these conditions for 42 hours. At this stage, a TLC (eluent AcOEt / cyclohexane 70 / 30) shows that the reaction is fully advanced. The white precipitate formed is filtered over sintered glass and washed with ether. The precipitate is collected to give compound 014 in the form of a white powder (27 mg, yield: 45%).

[0366] ’H NMR 5 (300 MHz, (CD3)2SO) (ppm) : 8.71 (br s, 2H), 7.95 (d, J= 1.9 Hz, 1H), 7.75 (br s, 2H), 7.65 (dd, J= 9.0 Hz, 1.9 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 6.55 (br t, J= 4.2 Hz, 1H), 3.28 (br s, 2H), 3.12 (br d, J= 4.9 Hz, 2H), 2.77 (t, J= 11.0 Hz, 2H), 2.57 (s, 6H), 1.76 (br d, J = 9.4 Hz, 2H), 1.59-1.43 (m, 3H), 0.92 (s, 6 H).

[0367] LC-MS : Retention time : 2.61 minutes ; observed m / z : 419.1775 [M-C1]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0368] Compound 015 : (5)-A-((l-methylpiperidin-2-yl)methyl)-2,4-bis(methylsulfonyl)aniline

[0369] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with [(25)-l-methyl-2-piperidinyl]methanamine (30 mg, 0.234 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent DCM / MeOH 95 / 5) shows the completion of the reaction. After concentration of the crude under reduced pressure, a white solid weighing 82 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 95 / 5) to give compound 015, in the form of a white powder (65 mg, yield: 91%). ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.31 (d, J= 2.3 Hz, 1H), 7.91 (dd, J= 8.9 Hz, 2.3 Hz, 1H), 7.22 (br s, 1H), 6.76 (d, J= 8.9 Hz, 1H), 3.48-3.38 (m, 1H), 3.20-3.10 (m, 1H), 3.08 (s, 3H), 3.03 (s, 3H), 2.98-2.88 (m, 1H), 2.26 (s, 3H), 2.21-2.10 (m, 1H), 1.83-1.73 (m, 1H), 1.69- 1.48 (m, 4H), 1.39-1.23 (m, 2H).

[0370] LC-MS : Retention time : 1.62 min ; observed m / z : 361.1273 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0371] Compound 016 : 2,4-bis(methylsulfonyl)-7V-(l-(piperidin-l-ylmethyl)cyclobutyl)aniline

[0372] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with l-(piperidin-l-ylmethyl)cyclobutan-l -amine dihydrochloride (57 mg, 0.236 mmol, 1.2 equiv.) in the presence of triethylamine (110 pL, 0.789 mmol, 4 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent DCM / MeOH 95 / 5) shows the partial progress of the reaction, which is nevertheless stopped. After concentration of the crude under reduced pressure, a greyish amorphous solid weighing 148 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 95 / 5) to give compound 016, in the form of a beige amorphous solid (35 mg, yield: 44%).

[0373] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.32 (d, J= 2.3 Hz, 1H), 7.83 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 7.11 (br s, 1H), 6.80 (d, J= 9.0 Hz, 1H), 3.10 (s, 3H), 3.04 (s, 3H), 2.70 (br s, 2H), 2.47- 2.37 (m, 4H), 2.30-2.22 (m, 4H), 2.08-1.84 (m, 2H), 1.54-1.43 (m, 4H), 1.41-1.33 (m, 2H).

[0374] LC-MS : Retention time : 2.98 min ; observed m / z : 401.1620 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0375] Compound 017 (21?,3>S)-^-(2,4-bis(methylsulfonyl)phenyl)-l-methyl-2- phenylpyrrolidin-3-amine

[0376] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with (2A,35)-l-methyl-2-phenylpyrrolidin-3-amine (42 mg, 0.238 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (eluent AcOEt / cyclohexane 70 / 30) shows the completion of the reaction. After concentration of the crude under reduced pressure, an orange viscous oil weighing 105 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 98 / 2) to give compound 017, in the form of a white powder (60 mg, yield: 74%).

[0377] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.24 (d, J= 2.3 Hz, 1H), 7.76 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 7.42-7.28 (m, 5H), 7.09 (d, J= 6.8 Hz, 1H), 6.51 (d, J= 9.0 Hz, 1H), 3.90-3.78 (m, 1H), 3.38-3.28 (m, 1H), 2.99 (s, 3H), 2.94 (s, 3H), 2.62-2.49 (m, 2H), 2.20 (s, 3H), 1.76-1.56 (m, 2H).

[0378] LC-MS : Retention time : 3.33 min ; observed m / z : 409.1243 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0379] Compound 018 : 7V-(2,4-bis(methylsulfonyl)phenyl)adamantan-l-amine

[0380] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with 1-adamantylamine hydrochloride (45 mg, 0.239 mmol, 1.2 equiv.) in the presence of triethylamine (90 pL, 0.646 mmol, 3.3 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 4 hours. At this stage, a TLC (eluent cyclohexane / AcOEt 50 / 50) shows the partial progress of the reaction, which is nevertheless stopped. After concentration of the crude under reduced pressure, a white solid weighing 104 mg is obtained. It is purified on a silica gel column (eluent cyclohexane / AcOEt 60 / 40 to 50 / 50) to give compound 018, in the form of a white powder (23 mg, yield: 30%).

[0381] ’H NMR 5 (300 MHz, CDCI3) (ppm) : 8.31 (d, J= 2.3 Hz, 1H), 7.82 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 7.15 (d, J= 9.0 Hz, 1H), 6.89 (br s, 1H), 3.05 (s, 3H), 3.03 (s, 3H), 2.20 (br s, 3H), 2.09- 2.03 (m, 6H), 1.81-1.68 (m, 6H).

[0382] LC-MS : Retention time : 7.87 min ; observed m / z : 767.2649 [2M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0383] Compound 019 : (5N,65)-6-(((2,4-bis(methylsulfonyl)phenyl)amino)methyl)spiro[3.5] nonan-5-ol

[0384] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with (55,65)-6-(aminomethyl)spiro[3.5]nonan-5-ol hydrochloride (49 mg, 0.238 mmol, 1.2 equiv.) in the presence of triethylamine (90 pL, 0.646 mmol, 3.3 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 2 hours. At this stage, a TLC (DCM / MeOH 98 / 2 elutant) shows the completion of the reaction. After concentration of the crude under reduced pressure, a colourless amorphous solid weighing 130 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 98 / 2 to 96 / 4) to give compound 019, in the form of a white powder (74 mg, yield: 93%).

[0385] ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.30 (d, J= 2.3 Hz, 1H), 7.90 (dd, J= 8.8 Hz, 2.3 Hz, 1H), 7.10 (br t, J= 4.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.73 (br s, 1H), 3.51-3.32 (m, 1H), 3.28-3.09 (m, 2H), 3.08 (s, 3H), 3.04 (s, 3H), 2.21-2.07 (m, 1H), 2.03-1.71 (m, 6H), 1.70-1.45 (m, 4H), 1.45-1.24 (m, 2H).

[0386] LC-MS : Retention time : 6.81 min ; observed m / z : 402.1427 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0387] Compound 020 : (35,51?,75)-A-(2,4-bis(methylsulfonyl)phenyl)octahydrobenzofuran-5- amine

[0388] In accordance with the method A, l-fluoro-2,4-bis(methylsulfonyl)benzene (50 mg, 0.198 mmol) is reacted with (35,5A,75)-octahydrobenzofuran-5-amine 37 (34 mg, 0.241 mmol, 1.2 equiv.) in the presence of triethylamine (55 pL, 0.396 mmol, 2 equiv.) in acetonitrile (3 mL). The mixture is stirred at reflux for 3h30. At this stage, a TLC (eluting DCM / MeOH 98 / 2) shows the completion of the reaction. After concentration of the crude under reduced pressure, a light yellow amorphous solid weighing 115 mg is obtained. It is purified on a silica gel column (eluent DCM / MeOH 99 / 1 to 98 / 2) to give compound 020, in the form of a white solid (74 mg, quantitative yield). ’H NMR 5 (300 MHz, CDC13) (ppm) : 8.3 (d, J= 2.3 Hz, 1H), 7.9 (dd, J= 9.0 Hz, 2.3 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.73 (br d, J = 7.1 Hz, 1H), 3.99 (t, J = 7.9 Hz, 1H), 3.92-3.78 (m, 2H), 3.46-3.30 (m, 1H), 3.04 (s, 3H) 3.03 (s, 3 H), 2.32-2.15 (m, 3H), 1.98-1.62 (m, 6H).

[0389] LC-MS : Retention time : 5.64 min ; observed m / z : 374.0810 [M+H]+; Purity : 100% (based on the integration of the UV peak at 254 nm).

[0390] II. BIOLOGY EXAMPLES

[0391] Model description:

[0392] Xenopus oocytes expressing human Panxl using cDNA or RNA injection.

[0393] Injections of cDNA or mRNAs encoding for the human Panxl (accession # NM_015368), were performed in at least 95 oocytes using a proprietary automated injection device (Hogg et al., J. Neurosci. Methods, 2008, 169, 65-75) and receptor expression was examined at least 24h later or more.

[0394] All recordings were performed at 18 C and cells super fused with OR2 medium containing in mM: NaCl 82.5, KC1 2.5, HEPES 5, CaCl2.2H2O 1.8, MgCl2.6H2O 1, pH 7.4.

[0395] Currents were recorded using an automated process equipped with standard two-electrode voltage-clamp configuration (TEVC). Data were captured and analyzed using a proprietary data acquisition and analysis software running under Matlab (Mathworks Inc.).

[0396] First, the system uploads the oocytes and assess the resting potential of the cell. The cell is then maintained throughout the experiment at a holding potential of -60 mV and slow voltage ramps are applied first in control (i.e. OR2 medium without any compound) then in presence of the tested compound (successive concentrations as appropriate or same concentration several time), then the positive control (probenecid or carb enoxol one, 200pM) and finally the negative control (e.g., OR2 medium). The cells are washed with OR2 medium between each test.

[0397] To induce the activation of the panxl channels, a slow voltage ramp ranging from -120 to +120 mV is applied in each of the conditions. The process repeats itself for the different compound conditions and an additional voltage ramp is applied in control conditions. The process repeats itself for the desired number of oocytes.

[0398] Test of compounds:

[0399] Compounds were prepared in stock solution at lOOmM in DMSO. A first putative final concentration in the medium of lOOpM was tested, ensuring that the final concentration of DMSO do not exceed 0.1%. Efficacy was measured as the capacity of the compound to block the measured current following the ramp activation of the cells. To compare data between experiments and between compounds, the results are expressed as the following ratio: % blockage of compound (related concentration) / % blockage of positive control (200 pM). To obtain mean measurements with standard deviations, all experiments were carried out using at least three cells. Experiments were reproduced from 2 to 6 times for each compound.

[0400] Results

[0401] The results showed in Figure 1 demonstrated the inhibition potential of 4 molecules on the hPanxl after a ramp voltage (001, 002, 003 and 004) at a concentration of 100 pM in the medium. These results are also indicated in the table 1 in addition to the results of 10 supplemental molecules.

[0402] Table 1 :

Claims

CLAIMS1. A compound of formula (I):wherein: Ri and R2 represent independently a (Ci-Ce)alkyl or a -NRaRb with Ra and Rb represent independently a hydrogen or a (Ci-Ce)alkyl; and R3 and R4 represent independently a radical selected in a group consisting of:• a hydrogen,• a (Ci-C6)alkyl,• a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:- a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A,- a hydroxy,- a carboxy,- a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl, and- a halogen,• a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:- a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,- a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,- a halogen,- a hydroxy,- a 3-8 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,- a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl,- a nitro,- a cyano,- a -CO-cycloalkyl, and- a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl, with the proviso that the compound of formula (I) is not a compound having the formula selected in a group consisting of:and the isomers, stereoisomers and pharmaceutical acceptable salts thereof.

2. The compound according to claim 1, wherein Ri and R2 represent independently a methyl, a -NRaRb with Raand Rb represent a hydrogen, or a -NRaRb with Raand Rb represent a methyl.

3. The compound according to claim 1 or 2, wherein said 3-14 cycloalkyl or 3-14 cycloalkenyl optionally substituted by at least one radical A has a formula selected in a group consisting of:

4. The compound according to claim 1 or 2, wherein said 3-14 heterocycloalkyl optionally substituted by at least one group A has a formula selected in a group consisting of:

5. The compound to any one of claims 1 to 4, wherein R3 represents a hydrogen or a (Ci-Ce)alkyl.

6. The compound according to any one of claims 1 to 5, wherein said at least one radical A is selected in a group consisting of:- a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of a halogen and a hydroxy, preferably a methyl, a methyl substituted by a hydroxy, an isopropyl, a tert-butyl, a -CHF2, and- a phenyl.

7. The compound according to claim 1, wherein said compound has the following formula selected in a group consisting of:

8. The compound according to any one of claims 1 to 7, wherein said compound is a pannexin- 1 inhibitor or blocker, preferably an inhibitor or blocker of pannexin-1 in its activated form, more preferably an inhibitor or blocker specific to pannexin-1 in its activated form.

9. The compound according to any one of claims 1 to 8, for use as a medicine.

10. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 8, and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising a compound of formula (I), the isomers, stereoisomers and pharmaceutical acceptable salts thereof:wherein: Ri and R2 represent independently a (Ci-Ce)alkyl or a -NRaRb with Ra and Rb represent independently a hydrogen or a (Ci-Ce)alkyl; and R3 and R4 represent independently a radical selected in a group consisting of:• a hydrogen,• a (Ci-C6)alkyl,• a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:- a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, and a heteroaryl, said 3-14 membered ring being optionally substituted by at least one radical A,- a hydroxy,- a carboxy,- a -NRcRa with Re and Rd represent independently a hydrogen or a (Ci- Ce)alkyl,- a halogen,- a (Ci-Ce)alkyloxy,- a -C(O)-O-(Ci-C6)alkyl, and- a -S-phenyl, and• a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, and a heterocycloalkenyl, said 3-14 membered ring being optionally substituted by at least one radical A, in which said radical A is selected in a group consisting of:- a (Ci-Ce)alkyl optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,- a (Ci-Ce)alkyloxy optionally substituted by at least one radical selected in a group consisting of an aryl, a hydroxy, a carboxy, and a halogen,- a halogen,- a hydroxy,- a 3-8 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, and an aryl, said 3-8 membered ring being optionally substituted by at least one (Ci-Ce)alkyl,- a -NReRf with Re and Rf represent independently a hydrogen or a (Ci-Ce)alkyl,- a nitro,- a cyano,- a -CO-cycloalkyl, and- a -CO-NRgRh with Rgand Rh represent independently a hydrogen or a (Ci- Ce)alkyl.

12. A pharmaceutical composition according claims 10 or 11, for use for treating a disease associated with the pannexin 1 channel.

13. The pharmaceutical composition for use according to claim 12, wherein: Ri and R2 represent a (Ci-Ce)alkyl, preferably a methyl; R3 represents a hydrogen; and R4 represents a (Ci-Cio)alkyl substituted by at least one radical selected in a group consisting of:- a 3-14 membered ring selected in a group consisting of a cycloalkyl, a cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, and a heteroaryl, said 3-14 membered ring being optionally substituted by at least one radical A, and- a (Ci-Ce)alkyloxy,- a -C(O)-O-(Ci-C6)alkyl, and- a -S-phenyl, in which said radical A is selected in a group consisting of:- a (Ci-Ce)alkyl optionally substituted by at least one a halogen,- a (Ci-Ce)alkyloxy optionally substituted by at least one a halogen,- a halogen,- a hydroxy,- a nitro,- a cyano, and- a -NReRfwith Reand Rf represent independently a hydrogen or a (Ci-Ce)alkyl.

14. The pharmaceutical composition for use according to claim 12 or 13, wherein said compound has the following formula selected in a group consisting of:

15. The pharmaceutical composition for use according to any one of claims 12 to 14, wherein the disease associated with the Pannexin 1 channel is selected in a group consisting of:- an inflammatory disease, preferably ischemia, sepsis associated encephalopathy, pneumonia, Crohn’s disease, and wound healing;- a chronic neurological disease with crisis, preferably epilepsy, pain, multiple sclerosis, acute disseminated encephalomyelitis, migraine, headache, neuropathies, and glaucoma;- a neurodegenerative disease, preferably Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease;- a psychiatric and developmental disorder, preferably autism, schizophrenia, major depressive disorder, bipolar disorder, Rett syndrome, and Angelman syndrome;- withdrawal syndrome upon stopping drug use such as opioid;- cancer;- cardiovascular disease, preferably hypertension, cardiomyocyte fibrosis, and cardiac ischemia;- tinnitus, hearing loss, deficiency of the inner ear development, vertigo, Meiniere’s disease, taste and / or olfaction loss, glaucoma, optic neuritis, retinal ischemia, lacrimal gland injury, neuropathic pain, Wallerian degeneration, allodynia, nerve injury repair, thermal hyperalgesia, dentinal and / or pulpal pain;- a urogenital disease, preferably an overactive bladder disorder, infertility oogenesis, vaginal dysfunction, risk for impaired genital arousal; and- a viral infection, preferably a SARS Cov-2 and human immunodeficiency virus.

16. The pharmaceutical composition for use according to any one of claims 12 to 15, wherein the compound is administered at a dose ranging from 0.001 mg / kg body weight to 100 mg / kg body weight, and wherein said composition is administered by oral, topical, or parenteral route.

17. A method for treating a disease associated with the Pannexin 1 channel comprising administering a pharmaceutical composition as defined in claim 10 or 11 in a subject in need thereof.18 A use of pharmaceutical composition as defined in claim 10 or 11 for the manufacture of a drug for the prevention and / or the treatment of a disease associated with the pannexin-1 channel

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