(1,2,4-triazol-3-YL)-2-pyridyl-1-isoindolinone for use in the treatment of sepsis

Abstract

The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of sepsis in a subject in need thereof. The compounds of the present invention can be used in monotherapy or in combination with another antimicrobial agent.

Description

[0001] (1,2,4-TRIAZOL-3-YL)-2-PYRIDYL-1-ISOINDOLINONE FOR USE IN THE TREATMENT OF SEPSIS

[0002] FIELD OF THE INVENTION

[0003] The present invention is in the medical field and relates to compounds for use in the treatment of sepsis.

[0004] BACKGROUND OF THE INVENTION

[0005] Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. It develops as the result of a complex, dysregulated host response to infection, a bacterial infection in most cases. This dysregulated host response is characterized not only by increased inflammation but also by immune suppression. The effects of this inappropriate response to infection lead to cellular dysfunction and, ultimately, organ failure. Single organ dysfunction in sepsis is rare, and several organs are usually affected. Mortality in patients with sepsis correlates with the number of organs that are affected.

[0006] Sepsis and the resultant multiple organ failure that it induces are the most common causes of death in many intensive care units. The annual global incidence of sepsis is estimated at approximately 49 million cases with 11 million deaths worldwide (Rudd KE et al, Lancet, 2020, 395, 200-211). It is estimated that 750,000 cases of severe sepsis occur each year in the United States, with a high mortality rate. Sepsis is now the 12th most common cause of death in America. As a matter of fact, sepsis is defined as “the systemic inflammatory response syndrome due to infection” and reflects the concept that sepsis is the result of an uncontrolled inflammatory cascade.

[0007] Septic shock is defined as a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality. The 2001 task force definitions described septic shock as “a state of acute circulatory failure” (Singer M et al, JAMA. 2016; 315(8): 801-810).

[0008] Polymicrobial sepsis is associated with immunosuppression caused by the predominance of anti-inflammatory mediators and profound loss of lymphocytes through apoptosis, and so deaths directly related to sepsis are twofold higher in polymycrobial sepsis. (Abed N et al, Critical Care, 2010, 14(Suppl 1), p62). Compared to monomicrobial sepsis, polymicrobial sepsis is associated with higher illness severity, higher progression rates to severe sepsis and septic shock, longer hospital stays and higher mortality rates in all age groups.

[0009] Factors that contribute to these differences may include variations in the anatomical source of infection, the relative proportion of immunocompromised hosts and the adequacy of first-line antimicrobial therapy. Polymicrobial sepsis can be described as life-threatening organ dysfunction caused by a dysregulated host response to infection involving more than one pathogen (Doualeh M et al, Int. J. Mol. Sci. 2022, 23(9), 4484).

[0010] Increasing evidence now suggests that extensive apoptotic death results in immune cell depletion and may compromise the ability of the patient to eradicate infections.

[0011] Current treatment for sepsis aims to limit the development of organ dysfunction by providing rapid control of infection, haemodynamic stabilization and organ support when possible to ensure recovery of organ function. But treatment of sepsis, in particular polymicrobial sepsis and septic shock remains a substantial unmet medical need.

[0012] SUMMARY OF THE INVENTION

[0013] The experimental data of the examples have surprisingly shown that a compound according to the invention improves survival in CLP-induced polymicrobial sepsis in mice. These results explicitly show the efficacy of a compound according to the invention for treating sepsis.

[0014] The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of sepsis in a subject in need thereof, wherein the compound of formula (I) is of the following general formula: wherein

[0015] Ri and R2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic group or a bridged-heterocycloalkyl group, said groups having from 4 to 9 cyclic atoms, and said groups being optionally substituted with one, two, or three substituents selected from the group consisting of halogen, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Ce)alkyl;

[0016] R3 and R4 are independently selected from the group consisting of hydrogen and (C1- Ce)alkyl;

[0017] Rs is selected from a group consisting of halogen and (Ci-Ce)alkyl; and p is 0 or 1. In a particular embodiment, the compound of the invention is for use in a method for the treatment of polymicrobial sepsis in a subject in need thereof.

[0018] In a particular embodiment, the compound of the invention is administered to a subject who suffers from or is at risk of sepsis with multiple organ failure. In another embodiment, the subject suffers from or is at risk of septic shock.

[0019] In particular embodiment, the compound of the invention is for use as a single active agent in said method.

[0020] In another embodiment, the compound of the invention is for use in combination with an antimicrobial agent in the method disclosed herein. In particular, the antimicrobial agent is an antibiotic, typically a carbapenem antibiotic, such as ertapenem.

[0021] DESCRIPTION OF THE FIGURES

[0022] Figure 1 : Survival curves following cecal ligation and puncture over 168 hours (7 days) in mice that received Cpd.A treatment (dotted grey line) or the vehicle (black line). ** for p<0.01 using Brehan-Breslow-Wilcoxon test. Compound according to the invention reduces mortality induced by sepsis in mice.

[0023] Figure 2: Survival curves following cecal ligation and puncture over 168 hours (7 days) in mice that received Cpd. A treatment (dotted grey line) or selonsertib (dotted grey line with marks) treatments, or the vehicle (black line). ** for p<0.01 comparing the survival curves between Cpd. A and selonsertib groups, in one hand, and Cpd. A and vehicle groups on the other, using Gehan-Breslow- Wilcoxon test.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention relates to a compound of formula (I) as defined below, or a pharmaceutically acceptable salt of a compound of formula (I), for use in the treatment of sepsis.

[0026] Definitions

[0027] In the context of the present invention, the terms below have the following meanings.

[0028] The term “Cx-Cy” in which x and y are integers, as used in the present disclosure, means that the corresponding hydrocarbon chain comprises from x to y carbon atoms. If, for example, the term C1-C12 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 12 carbon atoms. If, for example, the term Ci-Ce is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1 , 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C4 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 4 carbon atoms, especially 1 , 2, 3 or 4 carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1 , 2, or 3 carbon atoms. C0-C3 means that the corresponding hydrocarbon chain may comprise from 0 to 3 carbon atoms, especially 0, 1 , 2 or 3 carbon atoms. In particular, when in the context of Co, the hydrocarbon chain is absent.

[0029] The term “alkyl” refers to a saturated, linear or branched aliphatic group. The term “(C1- C6)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, butyl (n-butyl, i-butyl, secbutyl and tert-butyl), pentyl, or hexyl.

[0030] The term “alkenyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon double bound. The term “C2-C6 alkenyl” refers to an alkenyl having 2 to 6 carbon atoms. The term alkenyl (or C2-C6 alkenyl) includes for instance ethenyl, propenyl, butenyl, pentenyl, or hexenyl.

[0031] The term “alkynyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon triple bound. The term “C2-C6 alkynyl” refers to an alkynyl having 2 to 6 carbon atoms. The term alkynyl (or C2-C6 alkynyl) includes for instance ethynyl, propynyl, butynyl, pentynyl, or hexynyl.

[0032] 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 hexyloxy. In a preferred embodiment, the “alkoxy” or “alkyloxy” is a methoxy, an ethoxy, a propoxy, an isopropyloxy, more preferably a methoxy.

[0033] The term “alkylthio” corresponds to the alkyl group as above defined bonded to the molecule by an -S- (thioether) bond. (Ci-Ce)alkylthio includes thiomethyl, thioethyl, thiopropyl, thioisopropyl, thiobutyl, thiopentyl, or thiohexyl. In a preferred embodiment, the “alkylthio” is a thiomethyl, a thioethyl, a thiopropyl, a thioisopropyl, more preferably a thiomethyl.

[0034] A "cyclic group” corresponds to an aryl group, a cycloalkyl group or a heterocyclic group.

[0035] A “cyclic atom” corresponds to an atom included in a cyclic group as defined above. The cyclic atoms are bound together to form the cyclic group.

[0036] 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, naphthyl, or anthracenyl. In a preferred embodiment, the aryl is a phenyl. The term “cycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 20 atoms of carbons. It also includes fused, bridged, or spiro-connected cycloalkyl groups. The term “cycloalkyl” includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl. The term “spirocycloalkyl” includes for instance a spirocyclopropyl.

[0037] The term “heterocycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen (N-heterocycloalkyl), oxygen (O-heterocycloalkyl), or sulphur atom (S-heterocycloalkyl). An heterocycloalkyl is thus a saturated or unsaturated mono-, bi- or tri-cyclic group comprising between 5 and 20 cyclic atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulfur atom. It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to aziridinyl, azepanyl, diazepanyl, dioxolanyl, benzo[1 ,3]dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1 ,4-dioxanyl, imidazolinyl, phthalimidyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1 ,4-dithianyl, pyrimidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, dithiolanyl, thiooxetanyl, thiopyranyl, thiomorpholinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, di hydropyranyl, dihydrofuranyl, dihydrothiopyranyl, dihydrothiophenyl, dihydropiperidinyl, tetrahydropiperidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl.

[0038] "Cycloalkyl" and "heterocycloalkyl" also include cycloalkenyl and heterocycloalkenyl which correspond respectively to a partially unsaturated cycloalkyl and a partially unsaturated heterocycloalkyl such as cyclohexenyl, imidazolinyl, dihydropyranyl, for instance 3,6-dihydro- 2H-pyranyl and 3,4-dihydro-2H-pyranyl, pyrazolinyl, azetinyl, pyranyl, and tetrahydropyridinyl, for instance 1 ,2,3-6-tetrahydropyridinyl.

[0039] The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 5 and 14 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 respectively shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly-cyclic heteroaryl groups may be: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. In a preferred embodiment, a heteroaryl is a thiazolyl, pyridinyl, pyrimidinyl, furanyl, thiophenyl, quinolinyl, and isoquinolinyl, more preferably a thiazolyl and thiophenyl.

[0040] The term “heterocyclic” refers to a heterocycloalkyl group or a heteroaryl group as above defined.

[0041] The term “fused” when applied to the description of two rings corresponds to a bicyclic group in which the first ring is respectively bounded to the second ring by at least two carbons.

[0042] The term “bridged” when applied to the description of two rings corresponds to a bicyclic group in which the two cyclic groups share three or more cyclic atoms, separating the two bridgehead atoms by a bridge containing at least one atom.

[0043] The term “halogen” corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

[0044] 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).

[0045] The expression “optionally substituted” means that the radical is not substituted or substituted by one or several groups of the list.

[0046] By “-CO” or “-C(O)- ”, it refers to an oxo group. By “-SO-" or “-S(O)-“, it refers to a sulfinyl group. By “-SO2-” or “-S(O2)- ”, it refers to a sulfonyl group.

[0047] The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers, and anomers. In a particular embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers. The “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons.

[0048] The “solvates” of the present disclosure include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. It can be for example a hydrate or an alcoholate such as an ethanolate.

[0049] 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.

[0050] The term “pharmaceutically acceptable salts” includes 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 acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable 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. The “pharmaceutically acceptable salts” also include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt. Representative examples of suitable salts with an organic base includes for instance a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0051] 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. In a particular embodiment, the invention is used to reduce the mortality associated to sepsis. In other embodiments, the invention can be used to slow or stop the progression of sepsis. In particular, the invention can be used to prevent the progression of sepsis, in particular to prevent the progression of sepsis to septic shock in a subject suffering from sepsis. In other embodiments, the invention can be used to prevent organ failure, in particular multiple organ failure, in a subject suffering from sepsis.

[0052] As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult, child, newborn and human at the prenatal stage. However, the term "subject" can also refer to nonhuman animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheeps and non-human primates, among others.

[0053] The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule.

[0054] 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.

[0055] As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder; in particular, capable to prevent or to delay the appearance or development of sepsis, or to cure or to attenuate the effects of sepsis.

[0056] 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 sepsis. 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 disease stage, 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.

[0057] 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.

[0058] The terms “kit”, “product” or "combined preparation", as used herein, defines especially a "kit of parts" in the sense that the combination partners (a) and (b), as defined in the present application can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit of parts can then be administered simultaneously or chronologically staggered, that is at different time points for any part of the kit of parts. The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied. The combination partners (a) and (b) can be administered by the same route or by different routes. As used herein, the term “simultaneous” refers to a pharmaceutical composition, a kit, a product or a combined product according to the invention in which the active ingredients are used or administered simultaneously, i.e. , at the same time.

[0059] As used herein, the term “sequential” refers to a pharmaceutical composition, a kit, a product or a combined product according to the invention in which the active ingredients are used or administered sequentially, i.e., one after the other. Preferably, when the administration is sequential, all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute.

[0060] As used herein, the term “separate” refers to a pharmaceutical composition, a kit, a product or a combined product according to the invention in which the active ingredients are used or administered at distinct time of the day. Preferably, when the administration is separate, the active ingredients are administered with an interval of about 1 hour to about 24 hours, preferably with an interval of about 1 hour and 15 hours, more preferably with an interval of about 1 hour and 8 hours, even more preferably with an interval of about 1 hour and 4 hours.

[0061] In the context of the invention, the ranges of values expressed by “from X to XX” or “between X and XX” comprise the upper and lower limits.

[0062] In the context of the present invention, the term "about" applied to a numerical value means the value + / - 10%. For the sake of clarity, this means that "about 100" refers to values comprised in the 90-110 range. In addition, in the context of the present invention, the term "about X", wherein X is a numerical value, also discloses specifically the X value, but also the lower and higher value of the range defined as such, more specifically the X value.

[0063] Compounds for use according to the present invention

[0064] The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of sepsis in a subject in need thereof, wherein the compound of formula (I) is of the following general formula:

[0065] Wherein

[0066] Ri and R2are taken together with the nitrogen atom to which they are attached to form a heterocyclic group or a bridged-heterocycloalkyl group, said groups having from 4 to 9 cyclic atoms, and said groups being optionally substituted with one, two, or three substituents selected from the group consisting of halogen, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Ce)alkyl;

[0067] R3 and R4 are independently selected from the group consisting of hydrogen and (C1- Ce)alkyl;

[0068] Rs is selected from a group consisting of halogen and (Ci-Ce)alkyl; and p is 0 or 1 ;

[0069] In the context of the invention, in the compound of general formula (I), R1 and R2are taken together with the nitrogen atom to which they are attached to form a heterocyclic group or a bridged-heterocycloalkyl group, said groups having from 4 to 9 cyclic atoms, and said groups being optionally substituted with one, two, or three substituents selected from the group consisting of halogen, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Ce)alkyl; in which R3and R4are independently selected from the group consisting of hydrogen and (Ci-Ce)alkyl. Preferably, R3 and R4 are independently a hydrogen atom or a methyl.

[0070] In a specific embodiment, in the compound of general formula (I), R1 and R2are taken together with the nitrogen atom to which they are attached to form a heterocyclic group or a bridged- heterocycloalkyl group, said groups having from 4 to 9 cyclic atoms, and said groups being optionally substituted with one, two, or three substituents selected from the group consisting of halogen, oxo, -OH, -OCH3, -C(O)CH3, -NH2, -N(CH3)2, and -CH3.

[0071] In a specific embodiment, in the compound of general formula (I), R1 and R2are taken together with the nitrogen atom to which they are attached to form a heterocyclic group or a bridged- heterocycloalkyl group, said groups having from 4 to 9 cyclic atoms, and said groups being optionally substituted with one or two substituents selected from the group consisting of halogen, oxo, -OH, -OCH3, -C(O)CH3, -NH2, -N(CH3)2, and -CH3, preferably one or two substituents selected from the group consisting of -OH, -OCH3 and -CH3.

[0072] In a specific embodiment, in the compound of general formula (I), R1 and R2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic group or a bridged- heterocycloalkyl group, said groups having from 4 to 9 cyclic atoms, and said groups being unsubstituted.

[0073] According to the invention, in the compound of general formula (I), the heterocyclic group or bridged-heterocycloalkyl group advantageously comprises one or two cyclic heteroatom(s), the first heteroatom being the nitrogen atom to which R1 and R2 are attached, and the optional second heteroatom being a nitrogen atom or an oxygen atom.

[0074] In a specific embodiment of the invention, in the compound of general formula (I), R1 and R2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic group comprising 4 to 9 cyclic atoms, including one or two cyclic heteroatom (s), the first cyclic heteroatom being the nitrogen atom to which R1 and R2 are attached, and the optional second cyclic heteroatom being a nitrogen atom or an oxygen atom.

[0075] In particular, R1 and R2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic group comprising advantageously 4 to 6 cyclic atoms, including one or two cyclic heteroatom(s), the first cyclic heteroatom being the nitrogen atom to which R1 and R2 are attached, and the optional second cyclic heteroatom being a nitrogen atom or an oxygen atom.

[0076] In particular, the heterocyclic group advantageously comprises 4 to 6 cyclic atoms, preferably 5 or 6 cyclic atoms, including only one cyclic heteroatom being the nitrogen atom to which R1 and R2are attached.

[0077] In another embodiment, the heterocyclic group advantageously comprises 4 to 6 cyclic atoms, preferably 5 or 6 cyclic atoms, including two cyclic heteroatoms, the first cyclic heteroatom being the nitrogen atom to which R1 and R2 are attached, and the second cyclic heteroatom being a nitrogen atom or an oxygen atom.

[0078] In another specific embodiment of the invention, in the compound of general formula (I), R1 and R2 are taken together with the nitrogen atom to which they are attached to form a bridged- heterocycloalkyl group comprising 4 to 9 cyclic atoms, including one or two cyclic heteroatom(s), the first cyclic heteroatom being the nitrogen atom to which R1 and R2 are attached, and the optional second cyclic heteroatom being a nitrogen atom or an oxygen atom. In particular, R1 and R2 are taken together with the nitrogen atom to which they are attached to form a bridged-heterocycloalkyl group comprising advantageously 5 to 8 cyclic atoms, including one or two cyclic heteroatom(s), the first cyclic heteroatom being the nitrogen atom to which R1 and R2 are attached, and the optional second cyclic heteroatom being a nitrogen atom or an oxygen atom.

[0079] In particular, the bridged-heterocycloalkyl group advantageously comprises 5 to 8 cyclic atoms, preferably 7 or 8 cyclic atoms, including only one cyclic heteroatom being the nitrogen atom to which R1 and R2are attached.

[0080] In another embodiment, the bridged-heterocycloalkyl group advantageously comprises 5 to 8 cyclic atoms, preferably 7 or 8 cyclic atoms, including two cyclic heteroatoms, the first cyclic heteroatom being the nitrogen atom to which R1 and R2are attached, and the second cyclic heteroatom being a nitrogen atom or an oxygen atom.

[0081] In the context of the invention, in the compound of general formula (I), Rs is selected from a group consisting of halogen and (Ci-Cs)alkyl.

[0082] In a specific embodiment, in the compound of general formula (I), Rs is selected from a group consisting of halogen and methyl.

[0083] In the context of the invention, in the compound of general formula (I), p is 0 or 1.

[0084] In a specific embodiment, in the compound of general formula (I), p is 0.

[0085] In a specific aspect, the compound of the invention is of the following general formula (II) or a pharmaceutically acceptable salt thereof: wherein

[0086] X is -CH2-, -N- or -O-; and

[0087] Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halogen, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Cs)alkyl; R3 and R4 being as defined for compounds of formula (I); or Rais a hydrogen atom and, Rb and Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms; or Rb is a hydrogen atom and, Raand Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms.

[0088] In the context of the invention, in the compound of formula (II), X is -CH2-, -N- or -O-. Preferably X is CH2- or -O-. More preferably, X is -O-.

[0089] In a specific embodiment of the invention, in the compound of formula (II), Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halogen, oxo, -OR3, - C(O)CH3, -N(R4)2, and (Ci-Ce)alkyl; R3 and R4 being independently selected from the group consisting of hydrogen and (Ci-Cs)alkyl.

[0090] Preferably, Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halogen, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Cs)alkyl; R3 and R4 being independently selected from the group consisting of hydrogen and methyl.

[0091] Preferably, one or two of Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halogen, oxo, -OH, -OCH3, -C(O)CH3, -NH2, -N(CH3)2, and CH3, and the other(s) are hydrogen atom. For example, Raand Rb are CH3 and Rcis a hydrogen atom.

[0092] Preferably, Ra, Rb and Rcare all hydrogen atoms.

[0093] In another specific embodiment of the invention, in the compound of formula (II), Rais a hydrogen atom and, Rb and Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms, preferably one or two carbon atoms.

[0094] In another specific embodiment of the invention, in the compound of formula (II), Rbis a hydrogen atom and, Raand Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms, preferably one or two carbon atoms.

[0095] In the context of the invention, in the compound of general formula (II), Rs is selected from a group consisting of halogen and (Ci-Cs)alkyl.

[0096] In a specific embodiment, in the compound of general formula (II), Rs is selected from a group consisting of halogen and methyl.

[0097] In the context of the invention, in the compound of general formula (II), p is 0 or 1 .

[0098] In a specific embodiment, in the compound of general formula (II), p is 0.

[0099] In a specific embodiment of the invention, in the compound of formula (II): X is -CH2- or -O-, preferably O;

[0100] Ra, b and Rcare hydrogen atoms; and p is 0.

[0101] In a specific embodiment of the invention, in the compound of formula (II):

[0102] X is -CH2- or -O-, preferably O;

[0103] Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halogen, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Ce)alkyl; R3and R4being independently selected from the group consisting of hydrogen and (Ci-Ce)alkyl; and p is 0.

[0104] In a specific embodiment of the invention, in the compound of formula (II):

[0105] X is -CH2- or -O-, preferably -O-;

[0106] Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halogen, oxo, -OH, -OCH3, -C(O)CH3, -NH2, -N(CH3)2, and CH3; and p is 0.

[0107] In a specific embodiment of the invention, in the compound of formula (II):

[0108] X is -CH2- or -O-, preferably -O-; one or two of Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halogen, oxo, -OH, -OCH3, -C(O)CH3, -NH2, -N(CH3)2, and CH3, and the other(s) are hydrogen atom; and p is 0.

[0109] In a specific embodiment of the invention, in the compound of formula (II):

[0110] X is -CH2- or -O-, preferably -O-;

[0111] Raand Rbare CH3and Rcis a hydrogen atom; and p is 0.

[0112] In a specific embodiment of the invention, in the compound of formula (II):

[0113] X is -CH2- or -O-, preferably -O-;

[0114] Rais a hydrogen atom;

[0115] Rb and Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms, preferably one or two carbon atoms; and p is 0.

[0116] In a specific embodiment of the invention, in the compound of formula (II): X is -CH2- or -O-, preferably -O-;

[0117] Rb is a hydrogen atom;

[0118] Raand Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms, preferably one or two carbon atoms; and - p is 0.

[0119] In a specific aspect of the invention, the compound of general formula (I) is advantageously selected from the group consisting of the compounds listed hereinbelow and any pharmaceutically acceptable salt thereof:

[0120]

[0121] (P).

[0122] In a specific embodiment of the invention, the compound of general formula (I) is advantageously of the following formula A or a pharmaceutically acceptable salt thereof:

[0123] Therefore, the present invention also relates to the compound of formula (A) for use in a method for the treatment of sepsis in a subject in need thereof.

[0124] In a specific embodiment of the invention, the compound of general formula (I) is advantageously of the following formula B or a pharmaceutically acceptable salt thereof:

[0125] Therefore, the present invention also relates to the compound of formula (B) for use in a method for the treatment of sepsis in a subject in need thereof.

[0126] The compound of formula (I) can be in the form of a pharmaceutically acceptable salt, particularly acid or base salts compatible with pharmaceutical use. Salts of compounds of formula (I) include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. These salts can be obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound.

[0127] In the context of the invention, the compound of formula (I) is for use in a method for the treatment of sepsis in a subject in need thereof.

[0128] As mentioned above, the term "sepsis" as used herein refers to a deleterious systemic inflammatory response to infection, formally defined as the presence of infection together with systemic manifestations of infection. The term sepsis as used herein encompasses sepsis, at any degree of severity, and complications thereof such, such as sepsis with multiple organ failure and septic shock.

[0129] In a particular embodiment of the invention, the subject suffers or is at risk of suffering from sepsis or complications thereof.

[0130] In another particular embodiment, the subject suffers from sepsis caused by one or more microbial species. In particular, the subject may suffer from sepsis caused by a bacterial, fungal or viral infection. In yet another embodiment, said sepsis is caused by a bacterial infection.

[0131] In another particular embodiment, the subject suffers from or is at risk of sepsis with multiple organ failure.

[0132] In another particular embodiment, the subject suffers from or is at risk of septic shock.

[0133] In a particular embodiment, the compound of the invention is for use in a method for treating polymicrobial sepsis in a subject in need thereof.

[0134] In a particular embodiment, the compound of the invention is for use in a method for treating a sepsis caused by a bacterial infection in a subject in need thereof. In a particular embodiment, the compound of the invention is for use in a method for treating sepsis with multiple organ failure.

[0135] In a particular embodiment, the compound of the invention is for use in a method for treating a septic shock.

[0136] The invention further relates to a method for the treatment of sepsis in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of a compound of general formula (I) according to the invention to said subject.

[0137] In a particular embodiment, the invention further relates to a method for the treatment of polymicrobial sepsis in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of a compound of general formula (I) according to the invention to said subject.

[0138] In a particular embodiment, the invention further relates to a method for the treatment of a sepsis caused by a bacterial infection in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of a compound of general formula (I) according to the invention to said subject.

[0139] In a particular embodiment, the invention further relates to a method for the treatment of a sepsis with multiple organ failure in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of a compound of general formula (I) according to the invention to said subject.

[0140] In a particular embodiment, the invention further relates to a method for the treatment of a septic shock in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of a compound of general formula (I) according to the invention to said subject.

[0141] The invention further relates to the use of a compound of general formula (I) according to the invention for the preparation of a medicament for the treatment of sepsis.

[0142] In a particular embodiment, the invention further relates to the use of a compound of general formula (I) according to the invention for the preparation of a medicament for the treatment of polymicrobial sepsis.

[0143] In a particular embodiment, the invention further relates to the use of a compound of general formula (I) according to the invention for the preparation of a medicament for the treatment of sepsis caused by a bacterial infection. In a particular embodiment, the invention further relates to the use of a compound of general formula (I) according to the invention for the preparation of a medicament for the treatment of a sepsis with multiple organ failure.

[0144] In a particular embodiment, the invention further relates to the use of a compound of general formula (I) according to the invention for the preparation of a medicament for the treatment of septic shock.

[0145] In the context of the present invention, the compound of general formula (I) is administered to a subject, in a therapeutically effective amount. A "therapeutically effective amount" refers to an amount of the drug effective to achieve a desired therapeutic result. A therapeutically effective amount of a drug may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of drug to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of agent are outweighed by the therapeutically beneficial effects. The effective dosages and dosage regimens for drug depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of drug employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable dose of a composition of the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above.

[0146] The compound of the invention can be formulated in a pharmaceutical composition further comprising one or several pharmaceutically acceptable excipients or vehicles (e.g. saline solutions, physiological solutions, isotonic solutions, etc.), compatible with pharmaceutical usage and well-known by one of ordinary skill in the art. These compositions can also further comprise one or several agents or vehicles chosen among dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles useful for these formulations (liquid and / or injectable and / or solid) are particularly methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc. These compositions can be formulated in the form of injectable suspensions, syrups, gels, oils, ointments, pills, tablets, suppositories, powders, gel caps, capsules, aerosols, etc., eventually by means of galenic forms or devices assuring a prolonged and / or slow release. For this kind of formulations, agents such as cellulose, carbonates or starches can advantageously be used.

[0147] The compound of the invention may be administered by different routes and in different forms. Suitable routes of administration include, but are not limited to oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. Of course, the route of administration will be adapted to the form of the drug according to procedures well known by those skilled in the art.

[0148] In a particular embodiment, the compound is administered orally.

[0149] In a particular embodiment, the compound is formulated as a tablet.

[0150] In another particular embodiment, the compound is formulated as an injectable. In another particular embodiment, the compound is administered parenterally.

[0151] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

[0152] The frequency and / or dose relative to the administration can be adapted by one of ordinary skill in the art, in function of the patient, the pathology, the form of administration, etc. Typically, the compound of the invention can be administered at a dose comprised between 0.01 mg / day to 4000 mg / day, such as from 50 mg / day to 2000 mg / day, such as from 100 mg / day to 2000 mg / day; and particularly from 100 mg / day to 1000 mg / day. Administration can be performed daily or even several times per day, if necessary. In one embodiment, the compound is administered at least once a day, such as once a day, twice a day, or three times a day. In a particular embodiment, the compound of the invention is administered once or twice a day. In particular, oral administration may be performed once a day, during a meal, for example during breakfast, lunch or dinner, by taking a tablet comprising the compound of the invention. Suitably, the course of treatment with the compound of the invention is for at least 1 week, in particular for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 24 weeks or more. In a particular embodiment, the course of treatment is for at least 1 month, at least 2 months or at least 3 months. In a particular embodiment, the course of treatment is for at least 1 year, or more depending on the condition of the subject being treated.

[0153] In a particular embodiment, the method of treatment consists of the administration of a compound of the invention as a single active ingredient.

[0154] In another particular embodiment, the administration of the compound of the invention is performed in combination with another active ingredient, preferably with an antimicrobial agent such as an antibiotic, an antifungal or an antiviral. Of course, the most suitable antimicrobial agent will be selected depending on the organism or virus responsible for the infection, as is well known in the art. In a particular embodiment, the sepsis is caused by a bacterial infection, and the antimicrobial is an antibiotic. Antibiotics useful in the treatment of bacterial infections are well known in the art. Illustrative antibiotic families include, without limitation, beta-lactam antibiotics (such as penicillins), tetracyclines, cephalosporins, quinolones, lincomycins, macrolides, sulfonamides, glycopeptides, aminoglycosides and carbapenems. In a particular embodiment, the compound of the invention can be combined to an antibiotic of the carbapenem family, such as ertapenem.

[0155] The compound of the invention and the antimicrobial agent can be administered to the subject in the same or separate pharmaceutical compositions. In a particular embodiment, the invention provides a pharmaceutical composition comprising the composition of the invention, an antimicrobial agent and a pharmaceutically acceptable excipient. This pharmaceutical composition can be used in the method of the invention, for the treatment of sepsis.

[0156] In another embodiment, the invention provides a method wherein: a first pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable excipient; and a second pharmaceutical composition comprising the antimicrobial agent; are both administered to the subject for the treatment of sepsis.

[0157] The first and second pharmaceutical compositions can be used simultaneously, separately or sequentially (i.e. the first pharmaceutical composition can be administered before or after the second pharmaceutical composition). As such, the invention also provides a kit-of-parts comprising: a first pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable excipient; and a second pharmaceutical composition comprising the antimicrobial agent; for simultaneous, separate or sequential use in the treatment of sepsis.

[0158] The following examples serve to illustrate the invention and must not be considered as limiting the scope thereof.

[0159] EXAMPLES

[0160] Chemistry

[0161] Chemical names follow IUPAC nomenclature. Starting materials and solvents were purchased from commercial suppliers (Acros Organic, Sigma Aldrich, Combi-Blocks, Fluorochem, Fluka, Alfa Aesar or Lancaster) and were used as received without further purification. Some starting materials can be readily synthesized by a person skilled in the art. Air and moisture sensitive reactions were carried out under an inert atmosphere of nitrogen, and glassware was oven- dried. No attempts were made to optimize reaction yields.

[0162] Animals

[0163] Manipulation of animals was conducted carefully in order to reduce stress at the minimum. All the experiments were performed in compliance with the guidelines of French Ministry of Agriculture for experiments with laboratory animals (law 87-848). The study was conducted in compliance with Animal Health Regulation (Council directive No. 2010 / 63 / UE of September 22rd 2010 and French decree no. 2013-118 of February 1st 2013 on protection of animals).

[0164] Compounds

[0165] Compounds of formula (I) can be synthetized following general procedures disclosed in WO2018 / 187506.

[0166] Compound A (Cpd. A) is 2-[6-(4-cyclopropyl-4H-1 ,2,4-triazol-3-yl)-2-pyridyl]-5- morpholinocarbonyl-1-isoindolinone of the following formula (A): Example 1 : the compounds according to the invention improves survival in CLP- induced polymicrobial sepsis in mice

[0167] Aim of the study

[0168] Polymicrobial sepsis induced by cecal ligation and puncture (CLP) is characterized by dysregulated systemic inflammatory responses followed by immunosuppression. The CLP model in mice mimics the progression and features of human sepsis (Rittirsch D et al, Nature Protocol, 2009, 4, p31-36) and is thus also useful to determine whether a drug would be efficient in the treatment of prevention of transition from sepsis to septic shock. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model because it closely resembles the progression and characteristics of human sepsis (Dejager L et al, Trends in Microbiology, 2011 , 19(4), p198-208).

[0169] This study aims to investigate the efficacy of Cpd. A in CLP model in C57BL / 6J mice. The efficacy of the test compound was evaluated based on the analysis of the survival curves over the study period (7 days after CLP surgery). This study also aims to compare Cpd. A to another ASK1 inhibitor. Selonsertib (GS-4997) is an ASK1 inhibitor that has been developed by Gilead Sciences Inc for the treatment of liver fibrosis in patients with NASH (phase 3) as well as diabetic nephropathy (phase 2 trial). Selonsertib alleviates liver and kidney injury and fibrosis, notably via anti-inflammatory and anti-fibrotic properties, across several conditions (Lou et al, Cell Biosci. 2021 , 11 , p9; Wang et al, Int J Mol Sci 2024, 25(6), p3086). The efficacy of the compounds was evaluated based on the analysis of the survival curves over the study period (7 days after CLP surgery).

[0170] Cecal ligation and puncture surgery

[0171] C57BL / 6J male mice (supplier Janvier - France) at 9 weeks of age and weighing 23-28 g on arrival were anesthetized with 250 pL of xylazine / ketamine solution (6.75 mg / kg for ketamine (Imalgene, Boehringer, Germany) et 2.5 mg / kg for xylazine (Rompund 2%, Bayer, Germany)) by intraperitoneal route. A 1-1.5 cm abdominal midline incision was made, and the cecum was located and tightly ligated at half the distance between distal pole and the base of the cecum with 4-0 silk suture (mild grade). The caecum was punctured through-and-through once with a 21-gauge needle from mesenteric toward antimesenteric direction after medium ligation. A small amount of stool was extruded to ensure that the wounds were patent. Then the cecum was replaced in its original position within the abdomen, which was closed with sutures and wound clips. Mice were followed for body weight evolution and mortality rate until Day 7.

[0172] Treatment scheme

[0173] Cpd. A (Aptuit, USA) was administered by oral gavage at 10 mg / kg BID (20 mg / kg / day). Cpd. A treatment was initiated on the day of the CLP surgery (Day 0) 30 min before and 5h30 after surgery, then BID until Day 6. Mice receiving Cpd. A vehicle (5% NMP + 10% Kolliphore EL + 55% PEG400 + 30% H2O) BID served as controls (n=20 / group).

[0174] Cpd. A was administered by oral gavage at 10 mg / kg BID (20 mg / kg / day). Selonsertib (Ontario Chemicals, Canada) was administered by oral gavage at 15 mg / kg BID (30 mg / kg / day). Cpd. A and selonsertib treatments were initiated on the day of the CLP surgery (Day 0) 30 min before and 5h30 after surgery, then BID until Day 6. Cpd. A and selonsertib were administered using the same vehicle, ie 5% NMP, 10% Kolliphore EL, 55% PEG400, 30% H2O. Previous internal studies showed that this vehicle allowed selonsertib efficacy in acute liver failure models at the doses of 1 to 30 mg / kg (data not shown). Mice receiving the vehicle BID served as controls (n=20-40 / group).

[0175] Results

[0176] CLP induced 70% mortality at 55h (3 days) and 85% mortality at 168h (7 days), respectively, after surgery in the group of mice receiving the vehicle only (Figure 1). On the contrary, only 30% mortality was observed at 55h and 35% mortality at 168h, respectively, in mice that received Cpd. A treatment. In conclusion, Cpd. A significatively improves survival in CLP- induced polymicrobial sepsis in mice.

[0177] In another comparative study, CLP induced high mortality, with only 50% survival at 48h and 12.5% survival at 168h (7 days) after surgery, respectively, in the group of mice receiving the vehicle (Figure 2). On the contrary, 70% survival at 48h and 52.5% survival at 168h, respectively, was observed in mice that received Cpd. A treatment (p=0.0026 using Gehan- Breslow-Wilcoxon test for comparison of survival curves between Cpd. A treatment and vehicle groups). Surprisingly, selonsertib treatment (15 mg / kg BID) had no effect on mortality in this model, reaching 85% at Day 7, while similar or lower doses of selonsertib have been reported efficient in different pathological models (Lou et al, Cell Biosci. 2021 , 11 , p9; Legry et al, J Hepatol. 2019; Plonowski et al, Hepatology 2020).

[0178] The survival curves between Cpd. A and selonsertib groups were significantly different (p=0.0061 using Gehan-Breslow-Wilcoxon test). These results demonstrate that all ASK1 inhibitors do not have the same efficacy to protect from sepsis.

Claims

CLAIMS1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of sepsis in a subject in need thereof, wherein the compound of formula (I) is of the following general formula:whereinRi and R2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic group or a bridged-heterocycloalkyl group, said groups having from 4 to 9 cyclic atoms, and said groups being optionally substituted with one, two, or three substituents selected from the group consisting of halo, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Ce)alkyl;R3and R4are independently selected from the group consisting of hydrogen and (C1- C6)alkyl;R5is selected from a group consisting of halogen and (Ci-Ce)alkyl; and p is 0 or 1.

2. The compound for use according to claim 1 , wherein p is 0.

3. The compound for use according to claim 1 or 2, wherein said heterocyclic group or bridged- heterocycloalkyl group comprises one or two heteroatom(s), the first heteroatom being the nitrogen atom to which R1 and R2 are attached, and the optional second heteroatom being a nitrogen atom or an oxygen atom.

4. The compound for use according to any one of claims 1 to 3, wherein R1 and R2 are taken together with the nitrogen atom to which they are attached to form a heterocyclic group comprising 4 to 9 cyclic atoms, preferably 4 to 6 cyclic atoms.

5. The compound for use according to any one of claims 1 to 3, wherein R1 and R2are taken together with the nitrogen atom to which they are attached to form a bridged-heterocycloalkyl group comprising 4 to 9 cyclic atoms, preferably 5 to 8 cyclic atoms.

6. The compound for use according to claim 1 , wherein said compound is of the following general formula (II) or a pharmaceutically acceptable salt thereof:wherein- X is -CH2-, -N- or -O-Ra, b and Rcare independently selected from the group consisting of hydrogen atom, halo, oxo, -OR3, -C(0)CH3, -N(R4)2, and (Ci-Ce)alkyl; R3 and R4 being as defined in claim 1 ; or Rais a hydrogen atom and, Rb and Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms; or Rb is a hydrogen atom and, Raand Rcare taken together to form a hydrocarbon chain comprising from 1 to 3 carbon atoms.

7. The compound for use according to claim 6, wherein Ra, Rb and Rcare independently selected from the group consisting of hydrogen atom, halo, oxo, -OR3, -C(O)CH3, -N(R4)2, and (Ci-Ce)alkyl; R3and R4being as defined in claim 1.

8. The compound for use according to claim 1 , wherein said compound is selected from the group consisting of:

9. The compound for use according to any one of claims 1 to 8, wherein said compound is 2- [6-(4-cyclopropyl-4H-1 ,2,4-triazol-3-yl)-2-pyridyl]-5-morpholinocarbonyl-1-isoindolinone of the following formula A or a pharmaceutically acceptable salt thereof:

10. The compound for use according to any one of claims 1 to 9, for use in a method for the treatment of polymicrobial sepsis in a subject in need thereof.

11. The compound for use according to any one of claims 1 to 10, wherein said subject suffers from or is at risk of sepsis with multiple organ failure or of septic shock.

12. The compound for use according to any one of claims 1 to 11 , wherein said compound is for use as a single active agent in said method.

13. The compound for use according to any one of claims 1 to 11 , wherein said compound is for use in combination with an antimicrobial agent in said method.

14. The compound for use according to claim 13, wherein said antimicrobial agent is an antibiotic.

15. The compound for use according to claim 13 or 14, wherein said antimicrobial agent is a carbapenem antibiotic, preferably said antimicrobial agent is ertapenem.

16. A method for the treatment of sepsis in a subject in need thereof, said method comprising the administration of a therapeutically effective amount of a compound of general formula (I) as defined in any one of claims 1 to 9, to said subject.

17. The method according to claim 16, for the treatment of polymicrobial sepsis, sepsis caused by a bacterial infection, sepsis with multiple organ failure, and / or septic shock.

18. Use of a compound of general formula (I) as defined in any one of claims 1 to 9 for the preparation of a medicament for the treatment of sepsis.

19. Use according to claim 18, wherein the medicament is for the treatment of polymicrobial sepsis, sepsis caused by a bacterial infection, sepsis with multiple organ failure, and / or septic shock.

20. The method according to claims 16 or 17 or the use according to claims 18 or 19, wherein said compound is combined with an antimicrobial agent, preferably with an antibiotic, more preferably with ertapenem.

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