Combination of obefazimod and its derivatives with a α4β7 Anti-integrin

Abstract

The present invention relates to pharmaceutical combinations, pharmaceutical compositions, kits comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, and a α4β7 anti-integrin. The present invention also relates to said pharmaceutical combination for use in the treatment of an inflammatory disease, disorder, or condition. The compound of formula (I) has the following formula: (I).

Description

[0001] COMBINATION OF OBEFAZIMOD AND ITS DERIVATIVES WITH A α4β7 ANTI-INTEGRIN

[0002] TECHNICAL FIELD

[0003] The present disclosure relates to compounds, pharmaceutical compositions, kits, and methods for treating an inflammatory disease, disorder, or condition.

[0004] BACKGROUND

[0005] Some quinoline derivatives have been described in WO2010 / 143169, W02012 / 080953, WO2016 / 009065, W02016 / 009066 and WO2020 / 127843, the contents of which are incorporated herein by reference in their entireties.

[0006] Obefazimod or one of its pharmaceutically acceptable salts was among all disclosed in such patent applications as well as its use in the treatment of inflammatory diseases, in particular in the treatment of Inflammatory Bowel Disease (IBD), namely Ulcerative Colitis and Crohn’s disease. Its glucuronide metabolite was in particular disclosed in WO 2016 / 135052. Obefazimod is tested in a Phase 3 program (known as ABTECT) in adults with moderately to severely active ulcerative colitis (UC) and in a Phase 2b trial in Crohn’s disease (known as ENHANCE-CD).

[0007] The most well-known a4p7 anti-integrins are a class of biologic agents, i.e. monoclonal antibodies that target the a4p7 integrin.

[0008] Some side effects have been revealed in the literature when using a4p7 anti-integrins such as infections of the nose and throat, skin rash, and theoretical risk of progressive multifocal leukoencephalopathy (PML) (one known case in a patient with HIV and a boxed warning in US FDA prescribing information).

[0009] In addition, in the treatment of Inflammatory Bowel Disease (IBD), namely Ulcerative Colitis and Crohn’s disease, it has been observed that many patients do not respond, lose response, or develop intolerance to currently marketed products, such as mesalamine, corticosteroids, azathioprine, anti-tumor necrosis factor a (TNF-a) agents, a4p7 anti-integrin agents, and Janus kinase inhibitors (JAK inhibitors).

[0010] Thus, unmet clinical need remains for additional treatments.

[0011] None of the hereabove cited documents disclose a synergistic activity of a combination of compounds of formula (I) as defined herein after, in particular Obefazimod,or one of their pharmaceutically acceptable salt or metabolite thereof with a a4p7 anti-integrin nor the advantage of this combination for decreasing the hereabove mentioned sideeffects.

[0012] The mechanisms of action and side effects of a4p7 anti-integrin being different from Obefazimod’s, assessing synergistic efficacy on inflammation is of interest, for example by demonstrating a reduction of cytokines level decrease in blood or in the colon tissue and / or prevention of weight loss.

[0013] There is still a need for alternative or complementary therapies efficient in the treatment of inflammatory diseases, disorders or conditions such as inflammatory bowel disease.

[0014] There also remains a need for compounds with no or limited side-effects.

[0015] SUMMARY

[0016] The present disclosure relates to compounds, pharmaceutical compositions, kits, and methods for treating an inflammatory disease, disorder, or condition. The method includes administering to a patient in need thereof: an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, and an effective amount of a a4p7 anti-integrin, to treat the inflammatory disease, disorder, or condition. The compound of formula (I) has the following formula:

[0017] Rnf X X J]Rn

[0018]

[0019] R" (I).

[0020] DETAILED DESCRIPTION

[0021] It has now been found that a combination of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug or a metabolite thereof, in particular Obefazimod, with a a4p7 anti-integrin can be useful for the treatment and / or prevention of a variety of inflammatory diseases, disorders or conditions.

[0022] In particular, the present disclosure relates to compounds to be used to reduce the dose of a a4p7 anti-integrin, and thereby limiting its side effects, while preserving orincreasing the said efficacy and / or safety to treat said variety of inflammatory diseases, disorders or conditions, as detailed herein after of said a4p7 anti-integrin.

[0023] In particular, the present disclosure relates to compounds to be used to reduce the dose of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt, prodrug or metabolite thereof, and particularly of its glucuronide metabolite and thereby limiting its side effects, while preserving or increasing the said efficacy and / or safety to treat said variety of inflammatory diseases, disorders or conditions, as detailed herein after of said compound of formula (I), or pharmaceutically acceptable salt, prodrug or metabolite thereof.

[0024] Herein is provided a combination therapy for treating inflammatory diseases, disorders or conditions as detailed herein after and in particular inflammatory bowel disease, including ulcerative colitis and of Crohn’s disease, rheumatoid arthritis, psoriasis and dermatitis.

[0025] It is more particularly herein provided a pharmaceutical combination of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt, prodrug or metabolite thereof, and particularly of its glucuronide metabolite, with a a4p7 anti-integrin.

[0026] Herein is also provided a pharmaceutical combination of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite, with a a4p7 anti-integrin for use in the treatment of inflammatory diseases, disorders or conditions as detailed herein after and in particular inflammatory bowel disease, including ulcerative colitis and of Crohn’s disease, rheumatoid arthritis, psoriasis and dermatitis.

[0027] The compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite, and the a4p7 anti-integrin may be used simultaneously, separately or may be spread out over time, and preferably simultaneously.Accordingly, herein is provided a pharmaceutical combination of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite, and of a a4p7 anti-integrin for separate administration, administration spread out over time or simultaneous administration to patients suffering from inflammatory diseases, disorders or conditions as detailed herein after and in particular inflammatory bowel disease, including ulcerative colitis and of Crohn’s disease, rheumatoid arthritis, psoriasis and dermatitis.

[0028] Herein is further provided a pharmaceutical composition or kit comprising a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite with a a4p7 anti-integrin and at least one pharmaceutically acceptable excipient.

[0029] Herein is further provided a pharmaceutical composition or kit comprising Obefazimod or one of its pharmaceutically acceptable salts and Vedolizumab and at least one pharmaceutically acceptable excipient.

[0030] Herein is further provided a pharmaceutical composition, wherein the pharmaceutical composition is for oral administration and comprises:

[0031] Obefazimod or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof,

[0032] Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP10000 PN 10943A or PTG-100 / PN-943, and

[0033] the at least one pharmaceutically acceptable excipient.

[0034] Herein is further provided a pharmaceutical composition or kit comprising Obefazimod glucuronide metabolite and Vedolizumab and at least one pharmaceutically acceptable excipient.

[0035] The pharmaceutical combination comprises an effective amount, as implemented in the present combination, of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salts or one of itsmetabolite and an effective amount, as implemented in the present combination, of a a4p7 anti-integrin.

[0036] Herein is further provided a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite for increasing the efficacy and / or safety of a a4p7 anti-integrin, in particular for its anti-inflammatory activity, and hereby reducing the a4p7 anti-integrin dose while maintaining its efficacy, in a subject suffering from inflammatory diseases, disorders or conditions as detailed herein after, and in particular inflammatory bowel disease, including ulcerative colitis and of Crohn’s disease rheumatoid arthritis, psoriasis and dermatitis, in need thereof.

[0037] Herein is further provided a a4p7 anti-integrin for increasing the efficacy and / or safety of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite, in particular for its anti-inflammatory activity, and hereby reducing the compound of formula (I) or pharmaceutically acceptable salt, prodrug or metabolite thereof or dose while maintaining its efficacy, in a subject suffering from inflammatory diseases, disorders or conditions as detailed herein after, and in particular inflammatory bowel disease, including ulcerative colitis and of Crohn’s disease rheumatoid arthritis, psoriasis and dermatitis, in need thereof.

[0038] Herein is further provided a pharmaceutical kit, in particular intended for treating inflammatory diseases, disorders or conditions as detailed herein after, and in particular inflammatory bowel disease, including ulcerative colitis and of Crohn’s disease, rheumatoid arthritis, psoriasis and dermatitis, comprising:

[0039] (i) a first galenical formulation comprising a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite, and

[0040] (ii) a second galenical formulation comprising a α4β7 anti-integrin.Herein is further provided a method for treating an inflammatory disease, disorder, or condition. The method includes administering to a patient in need thereof: an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, and an effective amount of a a4p7 anti-integrin, to treat the inflammatory disease, disorder, or condition.

[0041] In the framework of the present disclosure, the following definitions may be given:

[0042] • effective amount: amount of a pharmaceutical compound which produces an effect on the disease treated;

[0043] • the separate administration, simultaneous administration or administration spread out over time of a medicinal combination means that the elementary constituents of the combination, can be administered at the same time, each in one go at distinct moments, or repeatedly, or else at different moments and anyway in the same course of treatment, in particular during cycles or respectively during an induction sequence and during a following long term treatment sequence or maintenance phase, as detailed herein after. The elementary constituents can, in order to do this, be formulated as mixtures, only if they are administered simultaneously, or else formulated separately for the other administration schemes and regimens as detailed herein after;

[0044] • As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, excipients, compositions or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem complications commensurate with a reasonable benefit / risk ratio; and

[0045] • The term “patient” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0046] • As used herein, the term “side effects” has its general meaning in the art and refers to unintended effect occurring at normal dose related to the pharmacological properties.

[0047] In the framework of the present disclosure, for a sake of simplification, the term “a combination according to the present disclosure” or “a pharmaceutical combination” means a pharmaceutical combination of a compound of formula (I) as defined hereinafter, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite, with a a4p7 anti-integrin. As detailed herein after, said combination may be implemented in a unique dosage form also named fixed dose drug combination, or under the form of separate dosage forms, or under the form of a kit.

[0048] The “efficacy” or “therapeutic efficacy” on inflammation as used herein, may typically be assessed by measuring cytokines level, such as TNFa, IL-6, IFNg (or IFNγ), and IL 17, in blood or in the colon tissue and / or measuring prevention of weight loss. Such efficacy assessment is in particular illustrated in example 3 herein after.

[0049] “Synergy” or “synergistic effect” of a combination of drugs means that the combined effect is greater than that predicted by the individual potencies or efficacy of said drugs. A synergistic interaction may allow a greater therapeutic efficacy, and / or the use of lower doses of said drugs, for example of at least one of them, and may reduce adverse reactions or side effects. In particular, synergy may be demonstrated by a superior effect of the combination in comparison to the sum of the effects induced by administering the compounds of the combination alone. The synergy may typically be assessed in in vivo models by measuring the reduction of cytokines level, such as TNFα, IL-6, IFNγ, IL-1α, MCP-1, GM-CSF, IL-27 and IL 17, in blood or in the colon tissue and / or by measuring the weight loss.

[0050] The synergy may typically be assessed in patients by assessing efficacy on clinical remission, on endoscopic improvement, on clinical response as per Modified Mayo Score (MMS), on symptomatic remission, on histologic-endoscopic mucosal improvement (HEMI) and / or on Fecal Calprotectin (FCP).

[0051] As a way of illustration, assessment of drug combinations synergy is discussed in Genes Cancer. 2011 Nov; 2(11): 1003–1008 (doi: 10.1177 / 1947601912440575). It is among all stated that “If the combined effect observed is significantly greater than the expected (additive) effect, there is synergism Said assessment of drug combinations synergy in the framework of the present disclosure is not limited to the use of a unique method but rather can be based on the use of any method well known to the man skilled in the art.

[0052] In particular, synergy may typically be demonstrated by the following effects: (i) the reduction of cytokines level of at least one, more particularly at least two or three, forexample the reduction of four, of the cytokine levels selected from TNFa, IL-6, IFNg and IL 17 in blood or in the colon tissue, and / or

[0053] (ii) the prevention of weight loss.

[0054] By way of illustration, for a combination A+B, wherein A and B are the active ingredients, synergy of the combination A+B may be demonstrated by measuring separately:

[0055] - (a) the effect of A at a dose x,

[0056] - (b) the effect of B at a dose y,

[0057] - (c) the effect of A+B, wherein A is at a dose x and B is at a dose y, and by demonstrating that the effect of the combination A+B measured in (c) is superior to the sum of the effect (a) + the effect (b), the effect being for example at least one of the effects described above.

[0058] The compound of formula (I) that may be implemented in the framework of the present disclosure may be represented herein after:

[0059]

[0060] or a pharmaceutically acceptable salt thereof or prodrug thereof or a metabolite thereof, wherein:

[0061] Z is C or N;

[0062] V is C or N;

[0063] means an aromatic ring wherein V is C or N, and when V is N, V is ortho, meta

[0064]

[0065] or para relative to Z;

[0066] each R is independently hydrogen, halogen, -CN, hydroxyl, (C₁-C₃)haloalkyl, (C₁-C₃)haloalkoxy, -NO₂, -NR₁R₂, (C₁-C₄)alkoxy unsubstituted or substituted by a (C₃-C₆)cycloalkyl group, said (C₃-C₆)cycloalkyl group being unsubstituted or substituted by one or two halogen atoms, a (C₃-C₆)cycloalkyl group unsubstituted or substituted by one substituent which is selected from a halogen atom, a (C₁-C₄)haloalkyl group, a (C₁-C₄)haloalkoxy group, a hydroxyl group, and a (C₁-C₄)alkoxy group, a (C₃-C₆)cycloalkoxy group unsubstituted or substituted by one or two halogen atoms, a 3- to 6-memberedmonocyclic heterocycloalkyl ring comprising from 2 to 5 carbon atoms and comprising 1 or 2 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atom, said 3- to 6-membered monocyclic heterocycloalkyl ring being unsubstituted or substituted by one substituent which is selected from a halogen atom, a (Ci-C4)haloalkyl group, a (Ci-C4)haloalkoxy group, a hydroxyl group, and a (Ci-C4)alkoxy group, phenoxy, -NR₁-SO₂-NR₁R₂, -NR₁-SO₂-R1, -NR₁-C(=O)-R₁, -NR₁-C(=O)-NR₁R₂, -SO₂-NR₁R₂, -SO₃H, -O-SO₂-OR₃, -O-P(=O)-(OR₃)(OR₄),

[0067] -O-CH₂-COOR₃, (C₁-C₃)alkyl, said alkyl being optionally mono- or di-substituted by a hydroxyl group, a group of formula (IIa): Ra

[0068] or a group of formula

[0069]

[0070] (Illa),

[0071] Q is N or O, provided that R” does not exist when Q is O;

[0072] each of R₁ and R₂ is independently hydrogen or (C₁-C₃)alkyl;

[0073] each of R₃ and R₄ is independently hydrogen, Li⁺, Na⁺, K⁺, N⁺(Ra)₄ or benzyl; n is 1, 2 or 3;

[0074] n’ is 1, 2 or 3;

[0075] each R’ is independently hydrogen, (C1-C3)alkyl, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (Ci-C3)fluoroalkyl, (Ci-C4)alkoxy,-OP(=O)-(-OR3)(OR4),- CN,

[0076] a group of formula (IIa):

[0077]

[0078] A is a covalent bond, oxygen, or NH;

[0079] B is a covalent bond or NH;

[0080] m is 1, 2, 3, 4 or 5;

[0081] p is 1, 2 or 3; each of Ra and Rb is independently hydrogen, (C₁-C₅)alkyl, or (C₃-C₆)cycloalkyl, orRa and Rb form together with the nitrogen atom to which they are attached a saturated 5- or 6- membered heterocycle, said heterocycle being optionally substituted by one or more Ra, provided that when R’ is a group (Ila) or (Illa), n’ may be 2 or 3 only if other R’ groups are different from said group (Ila) or (Illa); and

[0082] R” is hydrogen, (Ci-C4)alkyl, or a group of formula (Ila) as defined herein.

[0083] The compound of formula (I) or salts thereof may form solvates or hydrates and the present disclosure includes all such solvates and hydrates. The terms "hydrates" and "solvates" simply mean that the compounds according to the present disclosure can be in the form of a hydrate or solvate, i.e. combined or associated with one or more water or solvent molecules. This is only a chemical characteristic of such compounds, which can be applied for all organic compounds of this type.

[0084] The compound of formula (I) can comprise one or more asymmetric carbon atoms. They can thus exist in the form of enantiomers or of diastereoisomers. These enantiomers, diastereoisomers and their mixtures, including the racemic mixtures, are encompassed within the scope of the present disclosure.

[0085] In the context of the present disclosure, the term:

[0086] - “halogen” is understood to mean chlorine, fluorine, bromine, or iodine, and in particular denotes chlorine, fluorine or bromine,

[0087] - a “hydroxyl group”: a “-OH” group,

[0088] - a “cyano group”: a “-ON” group or a CN group,

[0089] - “optionally substituted” as used herein means unsubstituted or substituted by one or more substituents as described herein,

[0090] - “(Ci-C5)alkyl” as used herein respectively refers to Ci-C5normal, secondary or tertiary saturated hydrocarbon. Examples are, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, butyl, pentyl,

[0091] “(C3-C6)cycloalkyl” as used herein refers to cyclic saturated hydrocarbon, in particular a monocyclic alkyl group, comprising, unless otherwise mentioned, from 3 to 6 carbon atoms, and being unsubstituted or substituted. Examples are, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like,.“(Ci-C4)alkoxy” as used herein respectively refers to O-(Ci-C4)alkyl moiety, wherein alkyl is as defined above. Examples are, but are not limited to, methoxy, ethoxy, 1 -propoxy, 2-propoxy, butoxy,

[0092] a “(C3-C6)cycloalkoxy” as used herein refers to a -O-(C3-C6)cycloalkyl group, where the (C3-Ce)cycloalkyl group is as previously defined. Examples are, but are not limited to cyclopropyloxy-, cyclobutyloxy-, cyclopentyloxy-, cyclohexyloxy-, and the like, a “(Ci-Cx)haloalkyl group” and a “(Ci-Cx)haloalkoxy” group as used herein refer respectively to an alkyl group and alkoxy group as above-defined and where the alkyl group and alkoxy group are substituted with at least one halogen atom, for example a fluorine atom. In other terms, at least one hydrogen atom of the alkyl group or of the alkoxy group is replaced by a halogen atom, for example a fluorine atom. By way of example, mention may be made of CF3, -CH2F, -CHF2, -CH2CH2F, -OCF3, -OCH2F, -OCHF2, -OCH2CH2F, and the like,

[0093] “fluoroalkyl group” and “fluoroalkoxy group” refers respectively to alkyl group and alkoxy group as above-defined, said groups being substituted by at least one fluorine atom. Examples are perfluoroalkyl groups, such as trifluoromethyl or perfluoropropyl,

[0094] - “saturated 5- or 6-membered heterocycle” as used herein respectively refers to a saturated cycle comprising at least one heteroatom. Examples are, but are not limited to, morpholine, piperazine, thiomorpholine, piperidine, pyrrolidine,

[0095] - - a 3- to 6-membered monocyclic heterocycloalkyl ring comprising from 2 to 5 carbon atoms and comprising 1 or 2 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atom as used herein refers to a monocyclic heterocycloalkyl ring, saturated or partially saturated but no aromatic, unsubstituted or substituted by the substituents disclosed in the present disclosure. Examples are, but are not limited to, oxirane, aziridine, oxetane, tetrahydrofuran, dioxane, morpholine, piperazine, thiomorpholine, piperidine, thietane, diazetidine, pyrrolidine and the like.

[0096] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ^

[0097]

[0098] C- or ^c.enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0099] As defined generally above, Z is C or N.

[0100] In some embodiments, Z is C. In some embodiments, Z is N.

[0101] In some embodiments, Z is selected from those depicted in Tables 1-3, below. As defined generally above, V is C or N.

[0102] In some embodiments, V is C. In some embodiments, V is N.

[0103] In some embodiments, V is selected from those depicted in Tables 1-3, below.

[0104] o

[0105]

[0106] As defined generally above, Z means an aromatic ring wherein V is C or N and when V is N, V is ortho, meta or para relative to Z.

[0107] In some embodiments,

[0108]

[0109] means an aromatic ring wherein V is C.

[0110] In some embodiments,

[0111]

[0112] c means an aromatic ring wherein V is N, and V is ortho, meta or para relative to Z.

[0113] In some embodiments, V is N, and V is ortho relative to Z. In some embodiments, V is N, and V is meta relative to Z. In some embodiments, V is N, and V is para relative to Z.

[0114]

[0115] In some embodiments, Z is phenyl.

[0116] In some embodiments,

[0117]

[0118] pyridine.In some embodiments,

[0119]

[0120] is pyridazine.

[0121] In some embodiments,

[0122]

[0123] is pyrimidine.

[0124] In some embodiments,

[0125]

[0126] is pyrazine.

[0127] In some embodiments,

[0128]

[0129] is selected from those depicted in Tables 1-3, below.

[0130] As described generally above, each R is independently hydrogen, halogen, -CN, hydroxyl, (Ci-C3)fluoroalkyl, (Ci-C3)fluoroalkoxy, (C3-C6)cycloalkyl, -NO2, -NRiR2, (Ci-C4)alkoxy, phenoxy, -NRI-SO2-NR1R2, -NRi-SO2-R1-NRi-C(=O)-Ri, -NRI. C(=O)-NR1R2, -SO2-NRIR2, -SO3H, -O-SO2-OR3, -O-P(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, said alkyl being optionally mono- or di-substituted by a hydroxyl group or a group of formula (Ila):

[0131]

[0132] , or a group of formula (Illa):

[0133] In some embodiments, R is hydrogen. In some embodiments, R is halogen. In some embodiments, R is -CN. In some embodiments, R is hydroxyl. In some embodiments, R is (Ci-C3)fluoroalkyl, said alkyl being optionally mono- or di- substituted by hydroxyl. In some embodiments, R is (Ci-C3)fluoroalkoxy. In some embodiments, R is (C3-C6)cycloalkyl. In some embodiments, R is -NO2. In some embodiments, R is -NR1R2. In some embodiments, R is (Ci-C4)alkoxy. In some embodiments, R is phenoxy. In some embodiments, R is -NRI-SO2-NR1R2. In some embodiments, R is -NRI-SO2-RI. In some embodiments, R is -NRi-C(=O)-Ri. In some embodiments, R is -NRI-C(=O)-NR1R2. In some embodiments, R is -SO2-NR1R2. In some embodiments, R is -SO3H. In some embodiments, R is -O-SO2-OR3. In some embodiments, R is -O-P(=O)-(OR3)(OR4). In some embodiments, R is -O-CH2-COOR3. In someembodiments, R is (C1-C3)alkyl, said alkyl being optionally mono- or di- substituted by hydroxyl.

[0134] In some embodiments, each R is independently halogen, (Ci-C3)fluoroalkyl, (Ci-C3)fluoroalkoxy, -NR1R2, (Ci-C4)alkoxy, or (C1-C3)alkyl.

[0135] In some embodiments, each R is independently hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, halogen, or -O-P(=O)-(OR3)(OR4). In some embodiments, R is methyl. In some embodiments, R is methoxy. In some embodiments, R is trifluoromethyl. In some embodiments, R is trifluoromethoxy. In some embodiments, R is amino. In some embodiments, R is -O-P(=O)-(OR3)(OR4).

[0136] In some embodiments, each R is independently methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy, or amino.

[0137] In some embodiments, R is selected from those depicted in Tables 1-3, below. As described generally above, Q is N or O, provided that R" does not exist when Q is O.

[0138] In some embodiments, Q is N. In some embodiments, Q is O, and R" does not exist.

[0139] In some embodiments, Q is selected from those depicted in Tables 1-3, below. As described generally above, each of R1 and R2 is independently hydrogen or (C1-C3)alkyl.

[0140] In some embodiments, Ri is hydrogen. In some embodiments, R1 is (C1-C3)alkyl. In some embodiments, R2 is hydrogen. In some embodiments, R2is (C1-C3)alkyl.

[0141] In some embodiments, each of Ri and R2is independently selected from those depicted in Tables 1-3, below.

[0142] As described generally above, each of R3and R4 is independently hydrogen, Li+, Na+, K+, N+(Ra)4or benzyl.

[0143] In some embodiments, R3is hydrogen. In some embodiments, R3is Li+. In some embodiments, R3is Na+. In some embodiments, R3is K+. In some embodiments, R3isN+(Ra)4. In some embodiments, R3is benzyl. In some embodiments, R4is hydrogen.In some embodiments, R4 is Li+. In some embodiments, R4is Na+. In some embodiments, R4is K+. In some embodiments, R4is N+(Ra)4. In some embodiments, R4 is benzyl.

[0144] In some embodiments, each of R3 and R4 is independently selected from those depicted in Tables 1-3, below.

[0145] As described generally above, n is 1, 2 or 3.

[0146] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0147] In some embodiments, n is selected from those depicted in Tables 1-3, below. As described generally above, n’ is 1, 2 or 3.

[0148] In some embodiments, n’ is 1 or 2. In some embodiments, n’ is 1. In some embodiments, n’ is 2. In some embodiments, n’ is 3.

[0149] In some embodiments, n’ is selected from those depicted in Tables 1-3, below. As described generally above, each R’ is independently hydrogen, (C1-C3)alkyl, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, Nmethylpiperazinyl-, (Ci-C3)fluoroalkyl, (Ci-C4)alkoxy, -O-P(=O)-(OR3)(OR4), -CN, a group of formula (Ila): / Ra

[0150] \xA< vB — N

[0151]

[0152] ' Ra' 'm Rb

[0153] / C / v°\

[0154] , or a group of formula (Illa): \°

[0155]

[0156] ' pRa

[0157] In some embodiments, R’ is hydrogen. In some embodiments, R’ is (C1-C3)alkyl. In some embodiments, R’ is Hydroxyl. In some embodiments, R’ is halogen. In some embodiments, R’ is -NO2. In some embodiments, R’ is -NR1R2. In some embodiments, R’ is morpholinyl. In some embodiments, R’ is morpholino. In some embodiments, R’ is N-methylpiperazinyl. In some embodiments, R’ is (Ci-C3)fluoroalkyl. In some embodiments, R’ is (Ci-C4)alkoxy. In some embodiments, R’ is -O-P(=O)-(OR3)(OR4). In some embodiments, R’ is -CN.

[0158] Ra / In some embodiments, R’ is a group of formula (Ila): \ / A B

[0159] Ra' 'm Rb

[0160] In some embodiments, R’ is a group of formula (Illa): A7

[0161] i O I Ra

[0162]

[0163] PIn some embodiments, R’ is amino. In some embodiments, R’ is methyl. In some embodiments, R’ is a group of formula I — A — (CH2)— N c-j

[0164] ’ m \ _ /

[0165] wherein A is O or NH, m is 2 or 3 and Xl is O, CH2or N-CH3, provided that when R’ is such a group, n’ is 1 or 2, and when n’ is 2, the other R’ group is different from said group.

[0166] I — N— (CH2)— N / \1In some embodiments, R’ is a group of formula

[0167]

[0168] 1 m\ /

[0169] wherein A is O or NH, m is 2 and Xi is O, CH2or N-CH3, provided that when R’ is such a group, n’ is 1 or 2, and when n’ is 2, the other R’ group is different from said group. > In some embodiments, R’ is a group of formula I

[0170]

[0171] N^CH^mN\ / Xlwherein A is O or NH, m is 3 and Xl is O, CH2or N-CH3, provided that when R’ is such a group, n’ is 1 or 2, and when n’ is 2, the other R’ group is different from said group.

[0172] In some embodiments, each R’ is independently hydrogen, halogen, amino, methyl, -O-P(=O)-(OR3)(OR4), or a group of formula | — N— (CH2)— r / wherein

[0173]

[0174] A is O or NH, m is 2 or 3 and Xl is O, CH2or N-CH3, provided that when R’ is such a group, n’ is 1 or 2, and when n’ is 2, the other R’ group is different from said group.

[0175] In some embodiments, each R’ is independently hydrogen, halogen, methyl, or a group of formula — N — (CH2)— N X, wherein A is O or NH, m is 2 and Xl °1’

[0176]

[0177] m \ _ /

[0178] is O, CH2or N-CH3, provided that when R’ is such a group, n’ is 1 or 2, and when n’ is 2, the other R’ group is different from said group.

[0179] In some embodiments, each R’ is independently halogen, (C1-C3)alkyl, hydroxyl, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (Ci-C3)fluoroalkyl, (Ci-C4)alkoxy, or a group of formulas (Ila) or (Illa) as described herein.

[0180] In some embodiments, R’ is halogen or methyl.

[0181] In some embodiments, each R’ is independently selected from those depicted in Tables 1-3, below.

[0182] As described generally above, A is a covalent bond, oxygen, or NH. In some embodiments, A is a covalent bond. In some embodiments, A is oxygen. In some embodiments, A is NH.

[0183] In some embodiments, A is selected from those depicted in Tables 1-3, below. As described generally above, B is a covalent bond orNH.In some embodiments, B is a covalent bond. In some embodiments, B is NH. In some embodiments, B is selected from those depicted in Tables 1-3, below. As described generally above, m is 1, 2, 3, 4 or 5.

[0184] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0185] In some embodiments, m is selected from those depicted in Tables 1-3, below. As described generally above, p is 1, 2 or 3.

[0186] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0187] In some embodiments, p is selected from those depicted in Tables 1-3, below. As described generally above, each of Ra and Rb is independently hydrogen, (Ci-C5)alkyl, or (C3-C6)cycloalkyl, or Ra and Rb form together with the nitrogen atom to which they are attached a saturated 5- or 6-membered heterocycle, said heterocycle being optionally substituted by one or more Ra, provided that when R’ is a group (Ila) or (Illa), n’ may be 2 or 3 only if other R’ groups are different from said group (Ila) or (Illa).

[0188] In some embodiments, Ra is hydrogen. In some embodiments, Ra is (Ci. C5)alkyl. In some embodiments, Ra is (C3-C6)cycloalkyl. In some embodiments, Rb is hydrogen. In some embodiments, Rb is (Ci-Cs)alkyl. In some embodiments, Rb is (C3. C6)cycloalkyl.

[0189] In some embodiments, Ra and Rb form together with the nitrogen atom to which they are attached a saturated 5- or 6- membered heterocycle, said heterocycle being optionally substituted by one or more Ra, provided that when R’ is a group of formulas (Ila) or (Illa), n’ may be 2 or 3 only if other R’ groups are different from said group of formulas (Ila) or (Illa). In some embodiments, a saturated 5- or 6- membered heterocycle formed by Ra and Rb together with the nitrogen atom to which they are attached, as described above, optionally has an additional heteroatom selected from N, O and S.

[0190] In some embodiments, Ra and Rb form together with the nitrogen atom to which they are attached a saturated 5- or 6- membered heterocycle having an additional heteroatom selected from N, O and S, said heterocycle being substituted by one or more Ra, provided that when R’ is a group of formulas (Ila) or (Illa), n’ may be 2 or 3 only if other R’ groups are different from said group of formulas (Ila) or (Illa).In some embodiments, Ra and Rb form together with the nitrogen atom to which they are attached a saturated 5-membered heterocycle, provided that when R’ is a group of formulas (Ila) or (Illa), n’ may be 2 or 3 only if other R’ groups are different from said group of formulas (Ila) or (Illa).

[0191] In some embodiments, Ra and Rb form together with the nitrogen atom to which they are attached a saturated 6-membered heterocycle, provided that when R’ is a group of formulas (Ila) or (Illa), n’ may be 2 or 3 only if other R’ groups are different from said group of formulas (Ila) or (Illa).

[0192] In some embodiments, Ra and Rb form together with the nitrogen atom to which they are attached a saturated 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N, O and S, said heterocycle being optionally substituted by one or more Ra, provided that when R’ is a group (Ila) or (Illa), n’ may be 2 only if the other R’ group is different from said group (Ila) or (Illa).

[0193] In some embodiments, each of Ra and Rb is independently selected from those depicted in Tables 1-3, below.

[0194] As described generally above, R” is hydrogen, (Ci-C4)alkyl, or a group of formula (Ila) as defined above.

[0195] In some embodiments, R” is hydrogen or (Ci-C4)alkyl. In some embodiments, R” is hydrogen. In some embodiments, R” is (Ci-C4)alkyl. In some embodiments, R” is a group of formula (Ila) as described herein.

[0196] In some embodiments, R” is a group of formula (CH2)— N X

[0197] I

[0198]

[0199] m \ _ / 1wherein m is 2 or 3, and Xxis O, CH2, or N-CH3.

[0200] In some embodiments, R” is selected from those depicted in Tables 1-3, below.

[0201] In some embodiments, n is 1; n’ is 1 or 2; R” is H; R is selected from methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy, and amino; and each R’ is independently halogen, methyl, or a group | — N — (CHJ — wherein A is O or

[0202]

[0203] NH, m is 2 or 3 and Xi is O, CH2or N-CH3, provided that when n’ is 2, the other R’ group is different from said group.

[0204] In some embodiments, n is 1; n’ is 1; R” is H; R is selected from methyl, methoxy, trifluoromethyl, halogen, and trifluoromethoxy; and R’ is halogen or methyl.

[0205] In some embodiments, the compound of formula (I) is a compound of formula (la):

[0206]

[0207] R" (la)

[0208] or a pharmaceutically acceptable salt thereof or prodrug thereof or a metabolite thereof, wherein each of variables R, R’, R”, n, and n’ is independently as defined above and described in embodiments

[0209] In some embodiments, the compound of formula (I) is a compound of formula

[0210]

[0211] R" (lb)

[0212] or a pharmaceutically acceptable salt thereof or prodrug thereof or a metabolite thereof, wherein each of variables R, R’, R”, n, and n’ is independently as defined above and described in embodiments herein, both singly and in combination.

[0213] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb):

[0214]

[0215] R" (lb)

[0216] or any one of its metabolites or a pharmaceutically acceptable salt thereof or prodrug thereof, wherein R, R’ and R” are as defined above.

[0217] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (Ic):

[0218]

[0219] or a pharmaceutically acceptable salt thereof or prodrug thereof or a metabolite thereof, wherein each of variables R, R’, R”, n, and n’ is independently as defined above and described in embodiments herein, both singly and in combination.

[0220] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (Id):

[0221]

[0222] or a pharmaceutically acceptable salt thereof or prodrug thereof or a metabolite thereof, wherein each of R and R’ is independently as defined above and described in embodiments herein, both singly and in combination, and R’” is hydrogen or a group

[0223] I _

[0224] |— A — (CH2)-N XT

[0225]

[0226] - wherein A is O or NH, m is 2 or 3, and Xl is O, CH2or N- CH3.

[0227] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (Id), or a pharmaceutically acceptable salt thereof or a prodrug or a metabolite thereof, wherein R is methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy, or amino; R’ is halogen I / \

[0228] |

[0229]

[0230] A — (CH2)— N XT

[0231] or methyl, and R’” is hydrogen or a group — wherein A is O or NH, m is 2 or 3, and Xi is O, CH2or N-CH3.

[0232] In some embodiments, R’” is hydrogen.

[0233] |_A-(ChH-N^x

[0234] In some embodiments, R’” is a group

[0235]

[0236] m x—zwherein A is O or NH, m is 2 or 3, and Xl is O, CH2or N-CH3. In some embodiments, R’” is a group I / \

[0237] | A — (CH2)— N X1

[0238]

[0239] ' — t, wherein A is O, m is 2 or 3, and Xxis O, CH2orN-CH3. In some |a_(CH2)_nv

[0240] embodiments, R’” is a group

[0241]

[0242] x' wherein A is NH, m is 2 or 3, and Xi is O, CH2orN-CH3.

[0243] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb’):

[0244] Rn-fi- J LT!r'

[0245] R' Cl (Ib’)

[0246] or a pharmaceutically acceptable salt thereof or prodrug thereof or a metabolite thereof, wherein each of variables R, R’, R”, and n is independently as defined above and described in embodiments herein, both singly and in combination.

[0247] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb), ora pharmaceutically acceptable salt thereof or a prodrug or a metabolite thereof, wherein: each R is independently halogen, (Ci-C3)fluoroalkyl, (Ci-C3)fluoroalkoxy, -NR1R2, (Ci-C4)alkoxy, or (C1-C3)alkyl, said alkyl being optionally mono- or di-substituted by a hydroxyl group; n is 1 or 2; n’ is 1 or 2;

[0248] each of R₁ and R₂ is independently hydrogen or (C₁-C₃)alkyl;

[0249] each of R’ is independently halogen, (C1-C3)alkyl, hydroxyl, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (Ci-C3)fluoroalkyl, (Ci-C4)alkoxy, or a group of formulas (Ila) or (Illa) as described herein;

[0250] A is a covalent bond, oxygen, or NH; B is a covalent bond or NH;

[0251] m is 1, 2, 3, 4 or 5;

[0252] p is 1, 2 or 3;

[0253] each of Ra and Rb is independently hydrogen, (Ci-C5)alkyl, or (C3-C6)cycloalkyl, or Ra and Rb form together with the nitrogen atom to which they are attached a saturated 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N, O and S, said heterocycle being optionally substituted by one or more Ra, provided that when R’ is a group (Ila) or (Illa), n’ may be 2 only if the other R’ group is different from said group (Ila) or (Illa); and R” is hydrogen or (Ci-C4)alkyl.

[0254] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb), or a pharmaceutically acceptable salt thereof prodrug thereof or a metabolite thereof, wherein each R’ is independently hydrogen, halogen, (C1-C3)alkyl, or a (Ci-C4)alkoxy group, said alkyl being optionally mono- or di-substituted by a hydroxyl group; R” is hydrogen or (C C4)alkyl; n is 1 or 2; n’ is 1 or 2; when n is 1, R is (C1-C3) fluoroalkoxy, NR1R2, or phenoxy, wherein each of R1and R2is independently (C1-C3)alkyl; and when n is 2, one of the two R groups is (Ci-C3) fluoroalkoxy and the other R group is (C1-C3)alkyl.

[0255] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb), or a pharmaceutically acceptable salt thereof prodrug thereof or a metabolite thereof, wherein each R is independently (Ci-C3)fluoroalkoxy; each R’ is independently hydrogen, halogen, (C1-C3)alkyl, or (Ci-C4)alkoxy; R” is hydrogen or (Ci-C4)alkyl; n is 1; and n’ is 1 or 2.In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb’), or a pharmaceutically acceptable salt thereof prodrug thereof or a metabolite thereof, wherein each R is independently hydrogen, halogen, (C1-C3)alkyl, -NR1R2, (Ci. C3)fluoroalkoxy, -NO2, phenoxy, or (Ci-C4)alkoxy, said alkyl being optionally mono-or di-substituted by a hydroxyl group; each of R1and R2is independently hydrogen or (C1-C3)alkyl; R’ is hydrogen, halogen, (C1-C3)alkyl, or (Ci-C4)alkoxy, with the proviso that R’ is different from a methyl group at position 4 of the quinoline group; R” is hydrogen or (Ci-C4)alkyl; n is 1, 2, or 3; and n’ is 1 or 2.

[0256] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb’) or any one of its metabolites or a pharmaceutically acceptable salt thereof, or a prodrug thereof for use as defined above, wherein:

[0257] R independently represent a halogen atom or a group chosen among a (Ci-C3)fluoroalkoxy group, a -NR1R2group, a (Ci-C4)alkoxy group, a -O-P(=O)(OR3)(OR4) group, a (C1-C3)alkyl group, a NO2group, a -A-(CH2)m-B-NRaRb group (formula Ila) and a -(O-CH2-CH2)P-O-Ra group (formula Illa),

[0258] n is 1 or 2,

[0259] R’ represents a hydrogen atom, a halogen atom or a group chosen among a -NR1R2group,a -O-P(=O)(OR3)(OR4) group, a -NH-SO2-N(CH3)2group, and a -A-(CH2)m-B-NRaRb group (Ila),

[0260] R” is a hydrogen atom, a (Ci-C4)alkyl group or a -A-(CH2)m-B-NRaRb group (formula Ila), Ri and R2are independently a hydrogen atom or a (C1-C3)alkyl group,

[0261] R3 and R4 are independently hydrogen, Li+, Na+, K+, N+(Ra)4or benzyl,

[0262] A is a covalent bond, an oxygen atom or NH,

[0263] B is a covalent bond,

[0264] m is 2, 3 or 4,

[0265] p is 1, 2 or 3,

[0266] Ra and Rb independently represent a hydrogen atom or a (Ci-C5)alkyl group, Ra and Rb can further form together with the nitrogen atom to which they are attached asaturated 5- or 6-membered heterocycle optionally containing a further heteroatom chosen among N, O and S, said heterocycle being optionally substituted by one or more Ra.

[0267] According to an even more particular embodiment, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound of formula (lb’) or any one of its metabolites or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for use as defined above, wherein:

[0268] R independently represent F, Cl, -NH2, -N(CH3)2, -OCH3, -O-(CH2)3-CH3, -OCF3, -CH3, -O-(CH2)2-OH, -O-(CH2)2-O-(CH2)2-OCH3, a -NO2group, a -O-P(=O)(OH)(OH) group, a -O-(CH2)2-morpholino group or a -O-(CH2)2-piperidino group,

[0269] n is 1 or 2,

[0270] R’ represents a hydrogen atom, Cl, -CH2-CH2-CH3, a -O-(CH2)2-morpholino group, a -O-(CH2)2-piperidino group, a -O-(CH2)3-piperidino group, a -N-(CH2)3-morpholino group, a -NH-SO2-N(CH3)2group, NH2, or a -O-P(=O)(OH)(OH) group, and

[0271] R” is a hydrogen atom, -CH3, a -(CH2)3-piperidino group, a -(CH2)2-morpholino group, a -(CH2)4-morpholino group or a -(CH2)2-pyrrolidino group.

[0272] In an embodiment, the present disclosure provides the compound of formula (lb’) or any one of its metabolites or a pharmaceutically acceptable salt thereof or a prodrug thereof for use as defined above, wherein said compound is chosen among: compounds 96, 98, 108, 109, 111, 115, 122, 125, 128, 129, 130, 132, 133, 135, 138 to 141, 143, and 145 to 164 as listed herein after.

[0273] The compound of the present disclosure may exist in the form of a free base or of pharmaceutically acceptable, namely of addition salts with pharmaceutically acceptable acids.

[0274] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, pantothenate, picrate, bitartrate, mandelate, edetate, gluceptate, salicylate, disalicylate, mucate, estolate, napsylate, esylate, napadisylate salts and the like.

[0275] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

[0276] According to a particular embodiment, suitable physiologically acceptable acid addition salts of compound of the present disclosure include sulfate, hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, maleate, formate, acetate, fumarate and sulfonate, in particular alkylsufonate or arylsulfonate, and more particularly mesylate, esylate, triflate, edisylate, besylate, tosylate and napadisylate.

[0277] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound selected from Table 1:Table 1 (compounds of formula la as defined above)

[0278] 1 0X9 Cl

[0279] 2

[0280] H

[0281] 3

[0282] ox o

[0283] H

[0284] 4

[0285] Cl

[0286] 5

[0287] H

[0288] 6 JC NXT '

[0289] H JOO

[0290] 7

[0291] Cl

[0292] 8

[0293] x io

[0294] H

[0295]

[0296] ox o

[0297] H

[0298] 1 XX XQ

[0299] XX XXO

[0300] H

[0301] 4 m ”

[0302] XX / X^XCX X X X X

[0303] H

[0304] ° TIJOO

[0305] Cl XXX

[0306] N 1O

[0307]

[0308] 2HX NO2XX CI1

[0309] N

[0310] fY HjOO

[0311] XU H ®

[0312] N

[0313] H

[0314] Ac® H »

[0315] Of H JOO I Cl

[0316] OX N" J^

[0317] H OO 1

[0318] Cl

[0319]

[0320] 1

[0321] ( Y XT J H

[0322] l+

[0323] ° XXXX)

[0324] N<^_

[0325] X p Q.. / n )^- Cl 3P \

[0326] F< X NX NX N

[0327] 1 H X^ F

[0328] T JL LT J

[0329] H 1 Cl

[0330] H

[0331]

[0332] \ 1 O )

[0333] 6x9

[0334] 6xp

[0335] 'xw

[0336] & X9

[0337]

[0338] (6x9Axp

[0339] 6x9

[0340] 6x9

[0341] / °

[0342] NH2

[0343] 6x6

[0344]

[0345] Stxp1

[0346] ( Y XX) H I

[0347] Cl

[0348] FXL N! N JO N

[0349] 1 H O I F Cl

[0350] Y x X X J H

[0351] JQL HOOO

[0352] Y x X X J H

[0353] Aixo H

[0354] a xp

[0355] Ox0 _

[0356] x x x x y 'X / ^NZXN^XN / X^

[0357] H

[0358]

[0359] [O L X T H

[0360] F^OL jeer

[0361] 6xo

[0362] XF

[0363] dcx$^

[0364] 6 / $

[0365] F> CFO'^'-'O

[0366]

[0367] x H 6 Cl°S z° F\ X / yCFHN N

[0368] 6x6 '

[0369] H Cl

[0370] ° S F\ / F ><F^XX H °N / \' x=0< 's / z Oz°—\

[0371] N / 6x H 5 zi 6 ^z~

[0372] FX p 6x6 Cl °X z° x / F x /

[0373] HN N

[0374] 6 Hx6 Cl '

[0375] ZO

[0376] 1 HN N 6X H 6 '

[0377] NH2AX NH2XX C> I

[0378]

[0379] °X z°

[0380] ^S' / I HN N

[0381] H Cl

[0382] 5x H 6

[0383] V

[0384] 6-X^ Cl

[0385] V p 6, Hxd

[0386] 5^x6

[0387] F^F6x< Cl)u

[0388] (Xup Cl

[0389] F$XQ

[0390]

[0391] '■l e? Cl

[0392] 'Sxp

[0393] J Cl °x / z'

[0394] J

[0395] J

[0396] Cl

[0397] sxv°^”0

[0398] Cl

[0399]

[0400]

[0401] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof.

[0402] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound selected from Table 2:

[0403] Table 2 (compounds of formula (lb) as defined above)

[0404]

[0405] XcCQ Cl

[0406] X X X X J

[0407] H

[0408] . 8

[0409] X

[0410] " oW CQ \ Cl

[0411] to fc H

[0412] oo H

[0413] 1

[0414] zN^^. \<5^sxzz<;ix X X X X J H

[0415] M ®

[0416] FXO^O^NJOO F H

[0417]

[0418] QXO

[0419] ° X1XO

[0420] &xo

[0421] 4. AX9

[0422] & XQ

[0423] rw

[0424] W Q

[0425] ■rVxo

[0426]

[0427] A FAX H O

[0428] COX

[0429] 'pw?

[0430] TOXO

[0431] ULXIJ

[0432] tixdo

[0433] VOXQ

[0434] tnx? F

[0435]

[0436] tw o?

[0437] au co

[0438] TU 0X?

[0439] TOX?

[0440] ^ T x £ X J

[0441]

[0442] -'A1??NH2CI

[0443] TUXX?

[0444] ^0 X X

[0445] NH2

[0446] t ax o 01

[0447] Ox zO F. / F / 2< Cl HN N

[0448] H Cl

[0449]

[0450] CK. O V Cl HN N ■‘O HXO

[0451] o> <0 2< Cl HN N M Hxb Cl

[0452] Cl

[0453] oxXi, X9 Cl vX W » Cl oxxoxo Cl

[0454] Ox / O HN

[0455] t» Hx6

[0456] NH2

[0457]

[0458] 'tax Cl’NH2

[0459] tccoi H

[0460] TU XI?

[0461] FK LF

[0462] xa^>

[0463] 2<

[0464] '■'cvtou

[0465] J

[0466] 'M

[0467] zlCl

[0468] ’v NH2A CI

[0469]

[0470] 1

[0471]

[0472] F'^ / F

[0473] 0 '•0 / 9

[0474] / ICl"w

[0475] 0

[0476] 0

[0477] '^X9

[0478]

[0479] 0

[0480]

[0481] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof.

[0482] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is a compound selected from Table 3:

[0483] Table 3 (compounds of formula (I) other that compounds (la) and (lb))

[0484] 165

[0485] ox a01

[0486] H

[0487]

[0488] cxxp Br

[0489] 0X9

[0490] Cl

[0491] Cxxo H

[0492] cx xSo H

[0493] ox o H

[0494] CXXQ

[0495] F

[0496] / °

[0497] oxx

[0498] Cl

[0499]

[0500] l

[0501] H JOO

[0502] iX Q H

[0503] OX Q

[0504] aZc

[0505] Sxp

[0506] XV ^O

[0507] ux9

[0508] ^

[0509] ax^

[0510]

[0511]

[0512] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof.

[0513] In some embodiments, a compound described herein is in a salt form selected from sulfate, hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, maleate, mesylate, formate, acetate, fumarate, and sulfonate. In some embodiments, a compound described herein is in salt form as alkylsufonate or arylsulfonate. In some embodiments, a compound described herein is in salt form as mesylate, triflate, edisylate, esylate, besylate, tosylate and napadisylate.

[0514] OBEFAZIMOD AND SALTS THEREOF

[0515] Obefazimod (INN) has the following formula and corresponds to compound 111 above (as in WO2020 / 127843) herein after:

[0516]

[0517] and is also called ABX464 or 8-Chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, which may in particular be implemented in the framework of the present disclosure.

[0518] Obefazimod and salts thereof can be prepared by any process known by the skilled person, such as the one disclosed in WO2010 / 143169.

[0519] Obefazimod is under a unique crystalline form which has a melting point of 120.5°C (±2°C) and shows the following main peaks expressed as degree 2-Theta angles by a XRPD analysis: 7.3, 14.6, 23.5, and 28.4 (each time ±0.2) and may further show the following additional peaks expressed as degree 2-Theta angles: 12.1, 17.3, 18.4, 23.0; 24.2, 24.9, 27.4 and 29.1 (each time ±0.2) and even optionally further the following additional peaks expressed as degree 2-Theta angles: 13.7, 16.3, 16.9, 18.1, 22.4, and 29.6 (each time ±0.2). In some embodiments, Obefazimod, or a pharmaceutically acceptable salt thereof or prodrug thereof or a metabolite thereof, is under an amorphous form. In someembodiments, Obefazimod, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, is under a crystallized form. In some embodiments, a crystallized form of Obefazimod, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, has a melting point at 120.5°C (± 2°C).

[0520] In some embodiments, a crystallized form of Obefazimod, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, shows peaks in an x-ray powder diffractogram (XRPD) at angles 7.3, 14.6, 18.4, and 24.9. In some embodiments, a crystallized form of Obefazimod, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, shows one or more XRPD peaks at angles selected from 18.0, 24.2, 28.3, and 29.5. In some embodiments, a crystallized form of Obefazimod, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, shows one or more XRPD peaks at angles selected from 18.6, 22.3, 23.0, and 23.5.

[0521] According to a particular embodiment, the crystalline polymorphic form of Obefazimod is characterized by the following main peaks expressed as degree 2-Theta angles by a XRPD analysis: 7.3, 14.6, 23.5, and 28.4 (each time ±0.2) and may further show the following additional peaks expressed as degree 2-Theta angles: 12.1, 17.3, 18.4, 23.0; 24.2, 24.9, 27.4 and 29.1 (each time ±0.2) and even optionally further the following additional peaks expressed as degree 2-Theta angles: 13.7, 16.3, 16.9, 18.1, 22.4, and 29.6 (each time ±0.2).

[0522] According to a particular embodiment, suitable physiologically acceptable acid addition salts of Obefazimod include sulfate, hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, maleate, formate, acetate, fumarate and sulfonate, in particular alkylsufonate or arylsulfonate, and more particularly mesylate, triflate, esylate, edisylate, besylate, tosylate, and napadisylate.

[0523] In one aspect, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) or metabolite thereof is under the form of a metabolite thereof. In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) is under the form of a N-glucuronide metabolite of compound of formula (I) as described herein.

[0524] In some embodiments, the present disclosure provides a combination,composition or kit wherein the compound of formula (I) or metabolite thereof is under the form of a compound of formula (IV):

[0525] Rn<VJL X X JlRri'

[0526] / L%sOH

[0527] 0I

[0528] x-L

[0529] TJH

[0530]

[0531] OH OH (IV)

[0532] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, wherein each of variables V, Z, R, R’, n, and n’ is as defined above and described in embodiments herein, both singly or in combination.

[0533] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) or metabolite thereof is under the form of a compound of formula (IVa):

[0534]

[0535] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, wherein each of variables R, R’, n, and n’ is independently as defined above and described in embodiments herein, both singly and in combination.

[0536] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) or metabolite thereof is under the form of a compound of formula (IVb):

[0537] A.'OH

[0538] o >■

[0539] K xk x^

[0540] OH

[0541]

[0542] OH OH (IVb)

[0543] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, wherein each of variables R, R’, n, and n’ is independently as defined above and described in embodiments herein, both singly and in combination.In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) or its metabolite is under their form of a compound of formula (IVc):

[0544] Rn-^ 1

[0545] tV ' N ' 1'1

[0546] / L,XOH

[0547] O >■

[0548] OH

[0549]

[0550] OH OH (IVc)

[0551] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, wherein each of variables R, R’, n, and n’ is independently as defined above and described in embodiments herein, both singly and in combination.

[0552] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) or its metabolite is under the form of a compound of formula (IVb’):

[0553]

[0554] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, wherein each of variables R, R’, and n is independently as defined above and described in embodiments herein, both singly and in combination.

[0555] In some embodiments, the present disclosure provides a combination, composition or kit wherein the compound of formula (I) or its metabolite is under the form of a compound of formula (IVd):

[0556]

[0557] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, wherein each of variables R, R’, R’” is independently as defined above and described in embodiments herein, both singly and in combination.According to one embodiment, the combination, composition or kit of the present disclosure comprises an Obefazimod metabolite and a a4p7 anti-integrin. Said metabolite may be a glucuronide metabolite, having the following formula:

[0558]

[0559] OH OH

[0560] In some embodiments, the metabolite of compound of formula (I) or salt thereof, as for the Obefazimod glucuronide metabolite as recited above is under amorphous form.

[0561] a4B7 anti-integrin

[0562] In one embodiment, the a4p7 anti-integrin is selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943.

[0563] In one embodiment, for the treatment of Ulcerative Colitis, the a4p7 anti-integrin is Vedolizumab.

[0564] In one embodiment, for the treatment of Ulcerative Colitis, the a4p7 anti-integrin is selected from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943.

[0565] Vedolizumab, in particular known under the tradename Entyvio, is a humanized monoclonal antibody that was developed to reduce lymphocyte trafficking to the intestine by specifically targeting the a4p7 heterodimer, which is expressed on the surface of gutspecific lymphocytes. It has been approved by the FDA and European Medicines Agency (EMA) for the treatment of UC and CD.

[0566] Natalizumab, in particular known under the tradename Tysabri, is a humanized monoclonal antibody that targets the a4 chain of the a4pi and a4p7 integrins expressed on the surface of leukocytes. Natalizumab was first used for the treatment of relapsing andremitting multiple sclerosis (MS). Natalizumab was also approved by the United States Food and Drug Administration (FDA) for treatment of CD, but market was discontinued due to high rate of Progressive Multifocal Leukoencephalopathy (PML), a lethal brain infection.

[0567] Etrolizumab is a humanized monoclonal antibody against the P7 subunit of integrins a4p7 and aEp7. Developments for induction and maintenance therapy in people with ulcerative colitis and Crohn's have been abandoned since February 2022.

[0568] Abrilumab (AMG-181, MEDI-7183) is a fully human IgG2K monoclonal antibody which selectively targets a4p7 integrin heterodimers that was developed by Medlmmune. It was designed for the treatment of inflammatory bowel diseases (ulcerative colitis, and Crohn's disease).

[0569] Ontamalimab (PF-00547659) is a fully human, IgG2, investigational monoclonal antibody targeting mucosal addressin cell adhesion molecule 1 (MADCAM1). It is being evaluated for clinical potential in inflammatory bowel diseases. PF-00547659 was granted FDA orphan drug designation for ulcerative colitis in November 2017. Carotegrast methyl, in particular known under the tradename Carogra, is a small molecule compound that was originated by EA Pharma (formerly known as Ajinomoto Pharmaceuticals Co., Ltd.) and co-developed with Kissei Pharmaceutical and is the first a4 integrin antagonist drug approved as an orally available dosage form. It acts on both a4pi and a4p7 integrins expressed on the surface of inflammatory cells to exert anti-inflammatory effects by suppressing excessive aggregation and invasion of inflammatory cells into the inflamed site of colonic mucosa in ulcerative colitis. It has the following structure

[0570]

[0571] ABBV-382 is a monoclonal antibody.

[0572] PR-026 or SPY 120 is a monoclonal antibody.

[0573] SPY130 or PR 022 is a monoclonal antibody.

[0574] Carotegrast (HCA2969) is the active metabolite of carotegrast methyl. It acts as an antagonist of a4 integrin-mediated transmigration of leukocytes to sites of inflammation. The chemical structure of carotegrast is claimed as example 108 in EA Pharma patentUS20110065918A1 which claims phenylalanine derivatives as a4 integrin antagonists for use as clinical therapeutics.

[0575] Firategrast (SB-683699) is an orally bioavailable, short-acting small molecule a4-integrin antagonist. It was designed to reduce a4pi / a4p7 integrin-mediated trafficking of lymphocytes into the central nervous system (CNS). Anti-a4-integrin natalizumab is currently approved to treat MS, but its long half-life is problematic, and it has to be administered by infusion. This short acting small molecule was developed as an alternative to antibody therapy. It has the following structure

[0576]

[0577] Zaurategrast (CDP-323) is a small molecule inhibitor of a4-containing integrin complexes that was developed by Celltech. It was intended as a new oral drug treatment for multiple sclerosis. Zaurategrast has the same mechanism of action as the approved MS therapeutic natalizumab. Zaurategrast is an ester prodrug whose active entity is CT7758. It has the following structure

[0578]

[0579] Valategrast (RO-0272441) is an orally available, small molecule a4 integrin inhibitor that was developed by Roche. It is active at a4pi and a4p7 integrins.Other a4p7 anti-integrins, all orally available, may be cited, that are now under development, i.e. Morf-057 or LY-4268989 (now owned by Lilly), NSHO-101 / EA1080 (owned by EA and out licensed to Ensho), GS-1427 from Gilead, ET3764 / ZP10000 (by Zealand pharma), unnamed candidate by Evotec and PTG-100 / PN-943 (by Protagonist Therapeutics).

[0580] EA-1080 (or NSHO-101) is in particular an oral agent for inflammatory bowel disease.

[0581] NSHO102, MT 101, AJM 347, TRK 170 are small molecule drugs.

[0582] GS-1427 is under development in the treatment of patients by oral route with moderate to severe ulcerative colitis.

[0583] PTG-100 or PN-943 is an oral a4p7 antagonist peptide showing a therapeutic potential with limited systemic exposure among patients with ulcerative colitis.

[0584] ET3764 / ZP10000 is a cyclic peptide orally administrable.

[0585] PN 10943 A is a synthetic peptide.

[0586] Evotec’ s candidate is a a4p7 antagonist reported to be useful for the treatment of ulcerative colitis and Crohn’s disease.

[0587] Other a4p7 antagonist may be cited:

[0588] • AJM-347, which is a small molecule, developed in the treatment of Inflammatory Bowel Disease,

[0589] • BIIB-107, which is monoclonal antibody, developed in the treatment of Multiple Sclerosis, and

[0590] • SPY001 or PR-011, which is monoclonal antibody, developed in the treatment of Inflammatory Bowel Disease and Ulcerative Colitis.

[0591] Pharmaceutical indications

[0592] The pharmaceutical composition or kit according to the present disclosure may be used in the treatment of a variety of inflammatory diseases, disorders of conditions.

[0593] An inflammatory disease can for example be selected in the list consisting of: an inflammatory disease associated with an autoimmune disease, a central nervous system (CNS) inflammatory disease, a joint inflammation disease, an inflammatory digestive tract disease, inflammatory skin and other inflammatory diseases related to epithelial cells,inflammation associated with cancer, inflammation associated with irritation, and inflammation associated with injury.

[0594] According to one embodiment, the inflammatory disease, disorder or condition is selected from:

[0595] (a) an inflammatory disease, disorder, or condition in the pancreas selected from diabetes type-1, diabetes type-2, acute and chronic pancreatitis;

[0596] (b) an inflammatory disease, disorder, or condition in the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger’s disease, Goodpasture’s syndrome, Wegener’s granulomatosis and kidney transplant acute or chronic rejection;

[0597] (c) an inflammatory disease, disorder, or condition in the liver selected from nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and liver transplant acute or chronic rejection;

[0598] (d) an inflammatory disease, disorder, or condition in the lung or heart selected from bronchitis, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and lung or heart transplant acute or chronic rejection, Coronaviridae infection and conditions related thereto, in particular wherein the Coronaviridae is a Sarbecovirus selected from Severe Acute Respiratory Syndrome-related coronaviruses, even more particularly wherein the Severe Acute Respiratory Syndrome (SARS)-related coronaviruses are selected from the group consisting of: SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2; including including strains responsible for COVID-19 and their mutants;

[0599] (e) an inflammatory disease, disorder, or condition in the skin selected from psoriasis, dermatitis, such as eczema, contact dermatitits, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acnea, keloid scar, and other inflammatory or allergic conditions of the skin;(f) an inflammatory disease, disorder, or condition in the vessel / blood selected from Behcet’s disease, vasculitis, sepsis, tumor angiogenesis, proliferative vascular disease and restenosis, atherosclerosis;

[0600] (g)an inflammatory disease, disorder, or condition in the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optical neuritis;

[0601] (h)an inflammatory disease, disorder, or condition in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, including chronic pain, traumatic brain injury, including stroke, neurodegenerative diseases such as Alzheimer’s disease, and Parkinson disease, Myelitis, Charcot-Mari e-Tooth disease type 1 (including CMT1A and CMT1B), Amyotrophic lateral sclerosis (ALS), Creutzfeldt–Jakob disease, demyelinating polyneuropathy and peripheral neuropathy;

[0602] (i) an autoimmune disease, disorder, or condition selected from Sjogren’s syndrome, Lupus, including in the skin and kidney, Guillain-Barre syndrome, Myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves disease, and Myocarditis;

[0603] (j) an inflammatory disease, disorder, or condition in the reproductive system selected from endometriosis, uterine fibroma, prostate dysplasia or growth, and cervix dysplasia;

[0604] (k) an inflammatory disease, disorder, or condition in the bone and / or joints selected from Rheumatoid arthritis (RA), osteoarthritis (OA); ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and hand, foot, ankle, knee, hip, shoulder, elbow or spine arthritis and / or demineralization;

[0605] (l) an inflammatory disease, disorder, or condition in the digestive tract selected from inflammation associated with colon carcinoma, Inflammatory Bowel Disease, including Crohn’s disease, Ulcerative Colitis and eosinophilic esophagitis; and (m)an inflammatory disease, disorder, or condition in the central nervous system selected from Multiple sclerosis (MS), relapsing-remitting multiple sclerosis (RRMS); relapsing forms of multiple sclerosis (RMS) and secondary progressive multiple sclerosis (SPMS).Inflammatory Diseases, Disorders or Conditions

[0606] Combinations as described herein are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. In some embodiments, an inflammatory disease, disorder, or condition is inflammatory or obstructive airways diseases including, but not limited to, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.

[0607] Combinations as described herein are useful in the treatment of heteroimmune diseases. In some embodiments, an inflammatory disease, disorder, or condition is heteroimmune diseases including, but not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0608] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". " Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.

[0609] In some embodiments, an inflammatory disease, disorder, or condition is selected from acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. In some embodiments, an inflammatory disease, disorder, or condition is bronchitis, wherein the bronchitis is of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. In some embodiments, an inflammatory disease, disorder, or condition is pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0610] In some embodiments, an inflammatory disease, disorder, or condition is an eosinophil related disorder, e.g. eosinophilia. In some embodiments, an eosinophil related disorder is an eosinophil related disorder of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and / or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg- Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.

[0611] Combinations as described herein are also useful in the treatment of inflammatory or allergic conditions of the skin. In some embodiments, an inflammatory or allergic condition of the skin is selected from psoriasis, dermatitis such as eczema, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0612] In some embodiments, an inflammatory disease, disorder, or condition is a disease or condition having an inflammatory component, for example, diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca,uveitis and vernal conjunctivitis, diseases and conditions affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca, uveitis, and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, intestinal failure, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, acute or chronic pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease,cystitis, dacryoadenitis, dermatitis such as asthma, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0613] In some embodiments, an inflammatory disease, disorder, or condition is acute or chronic graft rejection in kidney, liver, heart, pulmonary transplantation, or graft versus-host disease in bone marrow graft.

[0614] In some embodiments, an inflammatory disease, disorder, or condition is an inflammatory disease, disorder, or condition of the skin. In some embodiments, an inflammatory disease, disorder, or condition of the skin is selected from contact dermatitits, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.

[0615] In some embodiments, an inflammatory disease, disorder, or condition is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

[0616] In some embodiments, an inflammatory disease, disorder, or condition is a TH17 mediated disease. In some embodiments, a TH17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).

[0617] In some embodiments, an inflammatory disease, disorder, or condition is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis,and diseases affecting the nose such as allergic rhinitis.

[0618] In some embodiments, an inflammatory disease, disorder, or condition is associated with transplantation. In some embodiments, an inflammatory disease, disorder, or condition is associated with organ transplantation, organ transplant rejection, and / or graft versus host disease. In some embodiments, an inflammatory disease, disorder, or condition is an autoimmune disorder. In some embodiments an autoimmune disorder is type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behget's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, ankylosing spondylitis, axial spondyloarthritis, primary biliary cirrhosis, autoimmune hepatitis, or inflammatory bowel disease.

[0619] In some embodiments, an inflammatory disease, disorder, or condition is an inflammatory disorder. In some embodiments, an inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, ankylosing spondylitis, axial spondyloarthritis, primary biliary cirrhosis, polymyalgia rheumatica, giant cell arteritis, or inflammatory bowel disease.

[0620] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the pancreas. In some embodiments, an inflammatory disease, disorder, or condition in the pancreas is selected from diabetes type-1, diabetes type-2, acute and chronic pancreatitis.

[0621] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the kidney. In some embodiments, an inflammatory disease, disorder, or condition in the kidney is selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger’s disease, Goodpasture’s syndrome, Wegener’s granulomatosis, and kidney transplant acute or chronic rejection.

[0622] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the liver. In some embodiments, an inflammatory disease, disorder, or condition in the liver is selected from nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, and liver transplant acute or chronic rejection.

[0623] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the lung or heart. In someembodiments, an inflammatory disease, disorder, or condition in the lung is selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and lung or heart transplant acute or chronic rejection.

[0624] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the skin. In some embodiments, an inflammatory disease, disorder, or condition in the skin is selected from contact dermatitits, atopic dermatitis, psoriasis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acnea, keloid scar, and other inflammatory or allergic conditions of the skin.

[0625] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the vessel / blood. In some embodiments, an inflammatory disease, disorder, or condition in the vessel / blood is selected from Behcet’s disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative vascular disease, and restenosis.

[0626] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the eye. In some embodiments, an inflammatory disease, disorder, or condition in the eye is selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optical neuritis.

[0627] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the central or peripheral nervous system. In some embodiments, an inflammatory disease, disorder, or condition in the central or peripheral nervous system is selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, including chronic pain, traumatic brain injury, including stroke, Alzheimer disease, Parkinson disease, Myelitis, Charcot-Marie-Tooth disease type 1 (including CMT1A and CMT1B), Multiple sclerosis, Amyotrophic lateral sclerosis (ALS), Creutzfeldt–Jakob disease, demyelinating polyneuropathy and peripheral neuropathy.

[0628] In some embodiments, the present disclosure provides a method for treatingan autoimmune disease, disorder, or condition. In some embodiments, an autoimmune disease, disorder, or condition is selected from Lupus, including in the skin and kidney, Guillain-Barre syndrome, Myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves disease, and Myocarditis.

[0629] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the intestine. In some embodiments, an inflammatory disease, disorder, or condition in the intestine is selected from intestinal failure, Ulcerative colitis, and Crohn’s disease, eosinophilic esophagitis and inflammation associated with colon carcinoma.

[0630] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the reproductive system. In some embodiments, an inflammatory disease, disorder, or condition in the reproductive system is selected from endometriosis, uterine fibroma, prostate dysplasia or growth, and cervix dysplasia.

[0631] In some embodiments, the present disclosure provides a method for treating an inflammatory disease, disorder, or condition in the bone and / or joints. In some embodiments, an inflammatory disease, disorder, or condition in the bone and / or joints is selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and hand, foot, ankle, knee, hip, shoulder, elbow or spine arthritis and / or demineralization.

[0632] In some embodiment, the present disclosure provides a method for treating an inflammatory Coronaviridae infection and conditions related thereto, in particular wherein the Coronaviridae is a Sarbecovirus selected from Severe Acute Respiratory Syndrome-related coronaviruses, even more particularly wherein the Severe Acute Respiratory Syndrome (SARS)-related coronaviruses are selected from the group consisting of: SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2; including strains responsible for COVID-19 and their mutants.

[0633] Advantageously, the patients having, or being at risk of having a condition related to a Coronaviridae infection can also be considered.

[0634] According to particular embodiments, the condition related to a Coronaviridae infection which are particularly considered include: pulmonary fibrosis, vasculitis, Kawasaki disease and tissue damage or destruction, in particular lung tissue damage and destruction.As used herein, "repairing and remodeling tissue ” means promoting healing of tissues that have been damaged or destroyed by a disease, and namely lung tissue devastated by Coronaviridae infection or gastrointestinal tissue devasted by Coronaviridae infection, at least by not delaying the tissue repair, as usually stated in the framework of treatments with classical anti-inflammatory diseases, as for example corticosteroids which are the best representative of this class of drugs.

[0635] Unless instructed otherwise, all the disclosed combinations are specifically considered herein for the treatment or prevention of Coronaviridae, which may thus refer indifferently to any member of the said Coronaviridae family in the sense of the Baltimore convention.

[0636] As used herein, the term “ Coronaviridae ” refers to the corresponding family of RNA viruses belonging to the group IV of the Baltimore classification, which is it iself par of the Cornidovirineae suborder and of the Nidovirales Order. The Coronaviridae family includes both the Letovirinae and Orthocoronavirinae subfamilies.

[0637] As used herein, the term “Orthocoronavirinae” refers to the corresponding family of the Baltimore classification, which includes the Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus genus.

[0638] As used herein, the term “Alphacoronavirus” refers to the corresponding family of the Baltimore classification, which includes the Colacovirus, Decacovirus, Duvinacovirus, Luchacovirus, Minacovirus, Minunacovirus, Myotacovirus, Myctacovirus, Pedacovirus, Rhinacovirus, Setracovirus, and Tegacovirus subgenus. In a non-exhaustive manner, this includes the following species: Bat coronavirus CDPHE15, Bat coronavirus HKU10, Rhinolophus ferrumequinum alphacoronavirus HuB-2013, Human coronavirus 229E, Lucheng Rn rat coronavirus, Ferret coronavirus, Mink coronavirus 1, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Myotis ricketti alphacoronavirus Sax-2011, Nyctalus velutinus alphacoronavirus SC-2013, Porcine epidemic diarrhea virus, Scotophilus bat coronavirus 512, Rhinolophus bat coronavirus HKU2, Human coronavirus NL63, NL63-related bat coronavirus strain BtKYNL63-9b, Alphacoronavirus 1.

[0639] As used herein, the term “ elacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the Embecovirus, Hibecovirus, Merbecovirus, Nobecovirus, and Sarbecovirus subgenus. In a non-exhaustive manner, this includes the following species: Betacoronavirus 1, China Rattus coronavirus HKU24,Human coronavirus HKU1, Murine coronavirus, Bat Hp-betacoronavirus Zhejiang2013, Hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus, Pipistrellus bat coronavirus HKU5, Tylonycteris bat coronavirus HKU4, Hedgehog coronavirus 1, Middle East respiratory syndrome-related coronavirus, Pipistrellus bat coronavirus HKU5, Tylonycteris bat coronavirus HKU4, Rousettus bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome -related coronavirus.

[0640] As used herein, the term “Severe acute respiratory syndrome-related coronavirus", or SARS virus, includes, in a non-exhaustive manner, the SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, and SARS-CoV-2; including strains responsible for CO VID- 19 and their mutants.

[0641] As used herein, the term “ ellacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the Andecovirus, Buldecovirus, Herdecovirus, and Moor decovirus subgenus. In a non-exhaustive manner, this includes the following species: Wigeon coronavirus HKU20, Bulbul coronavirus HKU11, Coronavirus HKU15, Munia coronavirus HKU13, White-eye coronavirus HKU16, Night heron coronavirus HKU 19, Common moorhen coronavirus HKU21.

[0642] As used herein, the term “Gammacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the Cegacovirus and Igacovirus subgenus. In a non-exhaustive manner, this includes the following species: Beluga whale coronavirus SW1 and Avian coronavirus.

[0643] According to a particular embodiment, the pharmaceutical composition or kit according to the present disclosure may be used in the treatment of an inflammatory bowel disease (IBD), including Crohn’s disease or ulcerative colitis, dermatitis, psoriasis and rheumatoid arthritis.

[0644] According to a particular embodiment, the pharmaceutical composition or kit according to the present disclosure may be used in the treatment of ulcerative colitis, Crohn's disease and / or eosinophilic esophagitis.

[0645] The present disclosure further relates to a combination of a compound of formula (I) as defined herein after, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, with a α4β7 anti-integrin, for usein the treatment of inflammatory diseases, disorders or conditions as detailed above in a patient, wherein the α4β7 anti-integrin is administered in a daily dose reduced by at least 20%, at least 30%, or even at least 40% in comparison to a dose adapted to the treatment of the same inflammatory disease for the same patient, in absence of a compound of formula (I).

[0646] The inflammation modulating capacity of pharmaceutical combination according to the present disclosure can be assessed for Inflammatory bowel disease (IBD) and Rheumatoid Arthritis (RA). The Dextran Sulphate Sodium (DSS-) induced colitis mouse model can be used for studying Inflammatory Bowel Disease (see Perse & Cerar; “Dextran Sodium Sulphate Colitis Mouse Model: Traps and Tricks”; Journal of Biomedicine and Biotechnology (2012); 718617). The collagen-induced arthritis model can be used for studying Rheumatoid Arthritis, as shown in Brand et al. (“Collagen-induced arthritis”; Nature Protocols; (2007); 2(5): 1269-75).

[0647] Indeed, administration of a pharmaceutical combination as defined above leads to an in vivo improvement on colon length, weight loss and inflammation in the colon, in DSS- induced colitis mouse models with synergy observed when compared to administration of each of the compounds alone.

[0648] The administration of a pharmaceutical combination as defined above leads to a significant decreased joint swelling and lowered signs of inflammation based on a collagen-induced arthritis mouse model with synergy observed for the combination when compared to administration of each of the compounds of the combination alone.

[0649] Pharmaceutical composition or kit, method of treatment and administration scheme

[0650] According to another embodiment, the present disclosure provides a pharmaceutical composition or kit comprising a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite with a α4β7 anti-integrin and a pharmaceutically acceptable carrier, adjuvant, or vehicle.Herein is further provided a pharmaceutical kit, in particular intended for treating disorders or conditions as detailed herein above and in particular inflammatory bowel disease, including ulcerative colitis and Crohn’s disease rheumatoid arthritis, psoriasis and dermatitis, comprising:

[0651] (i) a first galenical formulation comprising a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod or one of its pharmaceutically acceptable salt or metabolite thereof, and particularly of its glucuronide metabolite, and

[0652] (ii) a second galenical formulation comprising a α4β7 anti-integrin.

[0653] According to a particular embodiment, a pharmaceutical composition or a kit according to the present disclosure comprises a compound of formula (I) as defined above being Obefazimod or one of its pharmaceutically acceptable salt.

[0654] According to a particular embodiment, a pharmaceutical composition or kit according to the present disclosure comprises a α4β7 anti-integrin selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, and is in particular Vedolizumab.

[0655] According to a particular embodiment, a pharmaceutical composition or a kit according to the present disclosure comprises Obefazimodor one of its pharmaceutically acceptable salt or metabolite thereof and Vedolizumab or a pharmaceutically acceptable salt thereof.

[0656] According to a particular embodiment, a pharmaceutical composition or a kit according to the present disclosure comprises Obefazimodand Vedolizumab.

[0657] In certain embodiments, a pharmaceutical composition or kit of this disclosure is formulated for administration to a patient in need of such a composition. In some embodiments, a composition or kit of this disclosure is formulated for oral administration to a patient, for intravenous or subcutaneous injection to a patient or for both.The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0658] Compositions or dosages forms of the kits of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, cutaneous patch or via an implanted reservoir or sustained release oral or parenteral dosage form. The term "parenteral" as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, subcutaneously or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0659] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0660] Pharmaceutical compositions or dosages forms of the kits of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0661] Alternatively, pharmaceutical compositions or dosages forms of the kits of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0662] Pharmaceutical compositions o r dosages forms of the kits of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0663] Topical application for the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.

[0664] For topical applications, provided pharmaceutical compositions or dosages forms of the kits may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration ofcombination of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.

[0665] Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0666] For ophthalmic use, provided pharmaceutical compositions or dosages forms of the kits may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0667] Pharmaceutical compositions o r dosages forms of the kits of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions or dosages forms of the kits are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0668] Most preferably, pharmaceutical compositions o r dosages forms of the kits of this disclosure are formulated for oral administration, in particular for administration of a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod. Such formulations may be administered with or without food.

[0669] In some embodiments, pharmaceutical compositions o r dosages forms of the kits of this disclosure are administered without food. In other embodiments, pharmaceutical compositions o r dosages forms of the kits of this disclosure are administered with food.

[0670] In one embodiment, both the compound of formula (I), a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and the a4p7 anti-integrin, such as Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347,TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A or PTG-100 / PN-943, are suitable for an oral administration.

[0671] Thus, herein is provided said specific combination that may be implemented in a unique dosage form or under the form of separate dosage forms, or under the form of a kit, in particular under the form of a unique dosage form for oral administration.

[0672] In one embodiment, pharmaceutical compositions o r dosages forms of the kits of this disclosure are formulated for intravenous or subcutaneous administration or for oral administration. Indeed, a4p7 anti-integrins_are often administered by intravenous injection or subcutaneously but can for some of them be administered orally.

[0673] According to some embodiments, the present disclosure further relates to a method for treating inflammatory diseases, disorders or conditions as detailed herein above and in particular inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, rheumatoid arthritis, psoriasis and dermatitis in a patient in need thereof, consisting of administering to a patient in need thereof an effective amount of a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod and an effective amount of a a4p7 anti-integrin, in particular Vedolizumab.

[0674] Doses and regimen

[0675] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, disease severity, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.

[0676] In one embodiment, the treatment is continuous with only one from the combination of a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and a a4p7 anti-integrin or with both or non continuous with only one from the combination of a compound of formula (I) as defined herein above, a pharmaceutically acceptable saltthereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and a a4p7 anti-integrin or with both.

[0677] In one embodiment, the treatment is continuous with both the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and for a4p7 anti-integrin, in particular Vedolizumab.

[0678] A “continuous treatment” means a long-term treatment, which can be implemented, including with various administration frequencies, in particular once per several weeks, for example once every 8 weeks or biweekly, twice a day or once a day.

[0679] The compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, may be administered twice a day or once a day, in particular once a day.

[0680] a4p7 anti-integrins_are often administered by intravenous or subcutaneous injection but also orally. They may typically be administered once per several weeks, for example once every 8 weeks, once every 6 weeks, once every three weeks or biweekly.

[0681] For all the description herein after, administration of the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and the a4p7 anti-integrin may be simultaneous, separate or spread out over time.

[0682] The expression “separate” is understood to mean the administration, at the same time, of the two compounds according to the invention, each contained in a distinct pharmaceutical dosage form.

[0683] The expression “spread out over time” is understood to mean the successive administration of one of the compounds according to the invention, contained in a pharmaceutical dosage form, and then of the second compound according to the invention, contained in a distinct pharmaceutical dosage form.

[0684] In the case of this use “spread out over time”, the time lapse between the administration of the first compound according to the invention and the administration of the second compound according to the invention generally may last more than several days or several weeks, in the same course of treatment such as in the case of a treatment comprising an induction sequence and a long term sequence, as described herein after.Also, in the case of a “separate use” and of a “use spread out over time”, two distinct pharmaceutical dosage forms may be intended for the same route of administration or for a different route of administration. In said embodiment, said administration takes place in the same course of treatment.

[0685] The combination can be administered repeatedly over the course of several sequences or cycles according to a protocol which depends on the nature of the disease and severity of the disease to be treated and also on the patient to be treated (age, weight, previous treatment(s), etc.). The protocol can be determined by any specialized practitioner.

[0686] In a particular embodiment, administration of the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and the a4p7 anti-integrin may be separate or spread out over time. In this particular embodiment, when the administration is spread out over time, it is meant within the same course of treatment or protocol so that earlier or later administration in another course of treatment or protocol is excluded.

[0687] Specifically, the pharmaceutical combination may comprise Obefazimod or a pharmaceutically acceptable salt, a prodrug thereof or a metabolite thereof and Vedolizumab for use in the treatment of an inflammatory bowel disease, wherein:

[0688] Obefazimod or a pharmaceutically acceptable salt, a prodrug thereof or a metabolite thereof, is administered to the patient in an amount in a range of 1 mg to 100 mg per day, and

[0689] Vedolizumab, is administered to the patient in an amount in a range of 15 mg and 330 mg per week,

[0690] wherein the administration of Obefazimod or a pharmaceutically acceptable salt, a prodrug thereof or a metabolite thereof and Vedolizumab is spread out over time but within the same course of treatment.

[0691] Various sequences or cycles of administration respectively of the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and the a4p7 anti-integrin_may be implemented within the framework of the present disclosure.

[0692] According to a particular embodiment, and to one of the possible sequences of administration, the compound of formula (I) as defined herein above, a pharmaceuticallyacceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, is administered to the patient during a first phase of treatment and the patient is then treated with the a4p7 anti-integrin_in a second phase of the treatment or inversely. Said both phases may overlap or not.

[0693] In one embodiment, the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod and the a4p7 anti-integrin_are administered simultaneously or coadministered.

[0694] Whatever the dose regimen, typically, the dose of the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, may range in human between 1 mg per day and 100 mg per day, in particular between 1 mg per day and 60 mg per day, more particularly between 1 mg per day and 50 mg per day, for example between 1 mg per day and 40 mg per day, still more particularly between 10 mg per day and 50 mg per day, even still more particularly between 10 mg per day and 25 mg per day, or more particularly between 2 mg per day and 30 mg per day.

[0695] Whatever the dose regimen, typically, the daily dose of the a4p7 anti-integrin, in particular Vedolizumab, may range between 15 mg per week and 330 mg per week, in particular between 30 mg per week and 300 mg per week or 40 mg per week and 200 mg per week, more particularly between 40 mg per week and 175 mg per week, for example between 30 and 60 mg per week, for example between 60 and 150 mg per week or between 150 and 300 mg per week.

[0696] Thus, herein is further provided a method as described above, wherein the compound of formula (I), in particular Obefazimod, the pharmaceutically acceptable salt thereof, the prodrug thereof, or the metabolite thereof is administered to the patient in an amount in a range of 1 mg to 100 mg per day, and

[0697] the a4p7 anti-integrin, in particular Vedolizumab, is administered to the patient in an amount in a range of 15 mg and 330 mg per week.

[0698] As an alternative of the regimen as described above, the administration of the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular, may be not continuouswhereas the administration of the a4p7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, is continuous or not.

[0699] As a further alternative of the regimen as described above, the administration of the a4p7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, may be not continuous whereas the administration of the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, is continuous or not.

[0700] As another alternative of the sequential administration as described above, the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and the a4p7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, may be administered in a unique dosage form or unit pharmaceutical preparation.

[0701] Accordingly, the present disclosure provides a single unit dosage form comprising the compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, and the a4β7 anti-integrin, in particular selected from Vedolizumab, Natalizumab,Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0702] In a particular embodiment the pharmaceutical composition according to the present disclosure, comprises an amount of compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod, ranging from 1 mg and 100 mg, in particular between 1 mg and 60 mg, more particularly between 1 mg and 50 mg, for example between 1 mg and 40 mg, still more particularly between 10 mg and 50 mg, even still more particularly between 10 mg and 25 mg, or more particularly between 2 mg and 30 mg and an amount of a4p7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, in particular, ranging 10 mg and 320 mg, in particular between 20 mg and 280 mg or 40 mg and 200 mg, more particularly between 40 mg and 160 mg, for example between 20 and 60 mg or for example between 60 and 100 mg or between 120 and 200 mg.

[0703] All combinations of doses, frequencies and treatment period are encompassed within the scope of the present disclosure.

[0704] In one embodiment, the treatment is a continuous treatment without induction phase.

[0705] In one embodiment, the treatment is a continuous treatment with an induction phase.

[0706] In one embodiment, at least one of the compound of formula (I), in particular Obefazimod, the pharmaceutically acceptable salt thereof, the prodrug thereof, or themetabolite thereof or of the a4p7 anti-integrin, in particular Vedolizumab, may be administered in each sequence.

[0707] In particular, an induction dose may be implemented during an induction sequence, which can last 4 to 16 weeks, followed by a long-term sequence of administration, which can be named maintenance phase, wherein the daily dose of at least one of the compounds of the pharmaceutical combination as defined above is reduced by 20% to 70% with respect to the induction daily dose for said compound of the combination, in particular reduced by 50% to 70%.

[0708] Herein is in particular provided a treatment regimen, wherein an induction dose may be implemented during an induction sequence, which can last 4 to 16 weeks, followed by a long-term sequence of administration, during which a different dosing is implemented, and wherein at least one of said sequences comprises the administration of both compounds of the combination according to the present invention.

[0709] In said embodiment, the daily dose of at least one of the compounds of the combination may be reduced during the long-term sequence with respect to the induction daily dose for said at least one of the compounds, for example by at least 20%, in particular by at least 30%, more particularly by 20 to 70%, and even more particularly by 50% to 70%.

[0710] By way of illustration, the daily dose of only one of the compounds of the pharmaceutical combination as defined above may be reduced by 20% to 70% with respect to the induction daily dose for said compound of the combination, in particular reduced by 50% to 70%.

[0711] Various dosing regimen may be implemented, respecting this scheme with an induction sequence followed by a long-term sequence of administration, that may be described herein after, and wherein all combinations of daily, weekly or biweekly doses or doses for several weeks, as described above with suitable dose ranges for each of the active ingredients, form part of the present invention.

[0712] In one embodiment, an induction dose is implemented, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod and a α4β7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrastmethyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, wherein said compounds are administered in first respective specific amounts, followed by a further sequence of administration, wherein the same compounds are administered in a second respective specific amount.

[0713] In one embodiment, an induction dose is implemented, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod and a a4p7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, wherein said compounds are administered in first respective specific amounts, followed by a further sequence of administration, wherein a a4p7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab is administered.

[0714] In one embodiment, an induction dose is implemented, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod and a a4p7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab, wherein said compounds areadministered in first respective specific amounts, followed by a further sequence of administration, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod is administered.

[0715] In one embodiment, an induction dose is implemented, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod is administered, followed by a further sequence of administration, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod and a α4β7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab are administered.

[0716] In one embodiment, an induction dose is implemented, wherein a α4β7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000 PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab is administered, followed by a further sequence of administration, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod and a α4β7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab are administered.In one embodiment, an induction dose is implemented, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod is administered, followed by a further sequence of administration, wherein a α4β7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP10000, PN 10943A, and PTG-100 / PN-943, more particularly Vedolizumab is administered.

[0717] In one embodiment, an induction dose is implemented, wherein a α4β7 anti-integrin, in particular selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP10000, PN 10943A and PTG-100 / PN-943, more particularly Vedolizumab is administered, followed by a further sequence of administration, wherein a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod is administered.

[0718] For both preceding scenarios, a bridging period of several weeks may be foreseen between the two periods wherein a combination of both compounds may be administered.

[0719] In the framework of treating an inflammatory bowel disease, i.e. ulcerative colitis, including moderately to severely active ulcerative colitis, or Crohn’s disease, Obefazimod may be used as a compound of formula (I) and Vedolizumab.

[0720] In this embodiment, an induction dose is implemented, wherein Vedolizumab and Obefazimod are administered, followed by a further long-term or maintenance sequence of administration, wherein Obefazimod alone is administered or wherein Vedolizumab and Obefazimod are administered.

[0721] In some embodiments, still for treating an inflammatory bowel disease, i.e. ulcerative colitis, including moderately to severely active ulcerative colitis, or Crohn’sdisease, an initial dose ranges from 30 to 60 mg, for example is 50 mg Obefazimod, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, once a day. In some embodiments, an initial period is between 3 and 12 weeks, for example 8 weeks. In some embodiments, a subsequent dose ranges from 2 to 30 mg, for example is 25 mg Obefazimod, or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof, once a day. In some embodiments, a subsequent period ranges from 40 to 60 weeks, and is for example 44 weeks.

[0722] In some embodiments, still for treating an inflammatory bowel disease, i.e. ulcerative colitis, including moderately to severely active ulcerative colitis, or Crohn’s disease, an initial dose of Vedolizumab, ranging from 250 to 350 mg, for example being 300 mg is intravenously injected to the patient. In some embodiments, a subsequent dose of Vedolizumab, ranging from 250 to 350 mg, for example being 300 mg, is intravenously administered two weeks later. In some embodiment, a subsequent dose is administered to the patient after the first and second injection once every 8 weeks by intravenous injection, wherein the dose ranges from 250 to 350 mg, for example being 300 mg, or once every 2 weeks by subcutaneous injection wherein the dose ranges from 80 to 120 mg, for example being 108 mg.

[0723] Of course, the physician may adapt the scheme of treatment depending on the patient’s response to each treatment.

[0724] In some embodiments, a patient has an inadequate response, no response, a loss of response, or an intolerance to conventional therapies and / or advanced therapies. In some embodiments, a conventional therapy is a corticosteroid or an immunosuppressant. In some embodiments, an immunosuppressant is selected from azathioprine, 6-mercaptopurine, and methotrexate. In some embodiments, an advanced therapy is a SIP receptor modulator or a JAK inhibitor.

[0725] For example, the effective amount of Obefazimod or a pharmaceutically acceptable salt thereof or a prodrug thereof or a metabolite thereof when administered in the combination may be lower than the effective amount of the compound of formula (I), such as Obefazimod, the pharmaceutically acceptable salt thereof, the prodrug thereof, or the metabolite thereof when administered individually as a single agent. Additionally or alternatively, the effective amount of Vedolizumab when administered in the combination may be lower than the effective amount of the α4β7 anti-integrin, such as Vedolizumab, orthe pharmaceutically acceptable salt thereof when administered individually as a single agent.

[0726] Because the combination can be administered in a lower effective amount, the side effects can be reduced or eliminated as compared to individual administration of one of: (i) the compound of formula (I), the pharmaceutically acceptable salt thereof, the prodrug thereof, or the metabolite thereof, and (ii) the α4β7 anti-integrin.

[0727] In an embodiment, herein is provided a pharmaceutical combination as defined above for use as defined above, for treating a patient, wherein a presence and / or expression level of miR-124 in a blood and / or tissue sample of the patient is measured prior to and during the use, in particular for adjusting the dosage of compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod.

[0728] In one embodiment, herein is further provided a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring a presence and / or level of a biomarker in a patient. In some embodiments, a presence and / or level of a biomarker is measured in a patient’s biological sample. In some embodiments, a patient’s biological sample is a blood sample. In some embodiments, a patient’s biological sample is a tissue sample. In some embodiments, a biomarker measured and / or monitored in a method of the present disclosure is miR-124, as described in WO 2014 / 111892, the entire content of which is incorporated herein by reference. In some embodiments, a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring a presence and / or expression level of miR-124 in a patient prior to administering a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod. In some embodiments, a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring a presence and / or expression level of miR-124 in a patient during the course of a treatment with a pharmaceutical combination as defined above.

[0729] In some embodiments, a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises adjusting (such asincreasing or decreasing) dosage regimen (such as dose amount and / or dose schedule) of a compound of formula (I) as defined herein above, a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof, in particular Obefazimod to be administered to a patient, by measuring and / or monitoring a presence and / or expression level of miR-124 in the patient.

[0730] In an embodiment, herein is provided a pharmaceutical combination as defined above for use as defined above, for treating a patient, wherein white blood cell counts and in particular T cells counts are measured prior to and during the use, in particular for adjusting the dosage of α4β7 anti-integrin, in particular Vedolizumab.

[0731] In one embodiment, herein is further provided a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring white blood cell counts in particular T-cells counts in a patient. In some embodiments, white blood cell counts, in particular T-cells counts is measured in a patient’s biological sample. In some embodiments, a patient’s biological sample is a blood sample. In some embodiments, a patient’s biological sample is a tissue sample. In some embodiments, a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises measuring white blood cell counts, in particular T-cells counts in a patient prior to administering a α4β7 anti-integrin, in particular Vedolizumab. In some embodiments, a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises measuring white blood cell counts, in particular T-cells counts in a patient during the course of a treatment with the pharmaceutical combination as defined above.

[0732] In some embodiments, a method of the present disclosure for treating an inflammatory disease, disorder or condition further comprises adjusting (such as increasing or decreasing) dosage regimen (such as dose amount and / or dose schedule) of a α4β7 anti-integrin, in particular Vedolizumab to be administered to a patient, by measuring white blood cell counts, in particular T-cells counts in the patient.

[0733] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a combination as described herein and one or more additional therapeutic agents.

[0734] Such additional therapeutic agents may be small molecules or recombinantbiologic agents and include, for example, acetaminophen, non-steroidal antiinflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®, Neoral®), tacrolimus, sirolimus, mycophenolate, leflunomide (Arava®), and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1 ” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), anti-T cell antibodies such as Thymoglobulin, IV Immunoglobulins (IVIg), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, upadacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HF A, Proventil® HF A), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleosidereverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), nonnucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron ®) in combination with lenalidomide (Revlimid ®), anti-IL36 agents such as BI655130, Dihydroorotate dehydrogenase inhibitors such as IMU-838, anti-OX40 agents such as KHK-4083, microbiome agents such as RBX2660, SER-287, Narrow spectrum kinase inhibitors such as TOP-1288, anti-CD40 agents such asBI-655064 and FFP-104, guanylate cyclase agonists such as dolcanatide, sphingosine kinase inhibitors such as opaganib, anti-IL-12 / IL-23 agents such as AK-101, Ubiquitin protein ligase complex inhibitors such as BBT- 401, sphingosine receptors modulators such as BMS-986166, P38MAPK / PDE4 inhibitors such as CBS-3595, CCR9 antagonists such as CCX-507, FimH antagonists such as EB-8018, HIF-PH inhibitors such as FG-6874, HIF-la stabilizer such as GB-004, MAP3K8 protein inhibitors such as GS-4875, LAG-3 antibdies such as GSK-2831781, RIP2 kinase inhibitors such as GSK- 2983559, Famesoid X receptor agonist such as MET -409, CCK2 antagonists such as PNB-001, IL-23 Receptor antagonists such as PTG-200, Purinergic P2X7 receptor antagonists such as SGM-1019, PDE4 inhibiotrs such as Apremilast, ICAM-1 inhibitors such as alicaforsen sodium, Anti- IL23 agents such as guselkumab, brazikumab and mirkizumab, ant-IL-15 agents such as AMG-714, TYK-2 inhibitors such as BMS-986165, NK Cells activators such as CNDO-201, RIP-1 kinase inhibitors such as GSK-2982772, anti-NKGD2 agents such as JNJ-4500, CXCL-10 antibodies such as JT-02, IL-22 receptor agonists such as RG-7880, GATA-3 antagonists such as SB-012 and Colony-stimulating factor-1 receptor inhibitors such asedicotinib or any combination(s) thereof.

[0735] Said additional therapeutic agents may alternately be selected from nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol and febuxostat (Uloric®), in particular for the treatment of gout.

[0736] In particular for the treatment of rheumatoid arthritis, said additional therapeutic agents may alternately be selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-l” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), “antiT-cell” agents such as abatacept (Orencia®) and “anti -IL-6” agents such as tocilizumab (Actemra®).

[0737] In particular for the treatment of osteoarthritis, said additional therapeutic agents may be selected from acetaminophen, non-steroidal anti- inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[0738] In particular for the treatment of lupus, said additional therapeutic agents may be selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®)and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0739] In particular for the treatment of Crohn’s disease, ulcerative colitis, or inflammatory bowel disease, the additional therapeutic agents may be selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0740] In particular of the treatment of asthma, the additional therapeutic agents may be selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HF A, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0741] In particular for the treatment of COPD, said additional therapeutic agents may be selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0742] In particular for the treatment of organ transplant rejection or graft vs. hostdisease, said additional therapeutic agents may be selected from a steroid, cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0743] In particular for the treatment of Coronaviridae infection and conditions related thereto, said additional therapeutic agents may be selected from a dynamin-2 inhibitor, such as Dynasore; an antibiotic, such as one selected from the group consisting of betalactams, fluoroquinolones, and macrolides, such as azythromicin; remdesivir; ribavirin; ritonavir; lopanivir; chloroquine or hydroxychloroquine; beta-interferon; an antiinflammatory compound, such as one selected from the group consisting of: anti-TNF, Jak inhibitors, anti-IL6 antibodies, IL6 receptor antagonists; and a calcium inhibitor such as diltiazem.

[0744] The combinations of the present disclosure may be the subject of pharmacological tests which demonstrate their relevance as active combination in therapy and in particular for preventing inflammatory disease.

[0745] For example 1, the combination of the present disclosure is a combination of Obefazimod and Vedolizumab, named “the combination”.

[0746] Example 1: Effect of the combination of the present disclosure on the (DSS-) induced colitis model

[0747] A. Material & Methods

[0748] Mouse models

[0749] DSS model

[0750] A commonly used mouse model of inflammatory bowel disease is the Dextran Sulphate Sodium (DSS-) induced colitis model. Typical histological changes of acute DSS-colitis are mucin depletion, epithelial degeneration and the eventual destruction of the mucosal barrier which leads to inflammation and colitis.

[0751] Five groups of C57Bl / 6J01aHsd mice (n=10 per group) males, 7 weeks old receive DSS administration in the drinking water (2%) for 7 days followed by 3 days of water only. Weight loss is measured every day and colon length and weight are measured at day 10. One group is treated with the vehicle of Obefazimod and the vehicle of vedoluzimab. One group of mice is treated orally with Obefazimod alone at doses comprised between 1and 40 mg / kg / day from the starting day of DSS administration. One group of mice is treated intraperitoneally with vedoluzimab at doses comprised between 0.1 and 10 mg / kg / day from seven days before the starting day of DSS administration and one group is treated with a combination of Obefazimod at doses comprised between 1 and 40 mg / kg / day from the starting day of DSS administration and vedoluzimab at doses between 0.1 to 10 mg / kg / day from seven days before the starting day of DSS administration.

[0752] B. Results

[0753] Results are established using the combination as described above. Combination treatment significantly prevents weight loss and colon weight / length ratio reduction after 10 days of treatment. Interestingly, when compared to the groups treated with each drug alone, the combination demonstrates a synergistic effect.

Claims

CLAIMS1. A pharmaceutical combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof with a a4p7 anti-integrin, wherein the compound of formula (I) has the following formula:R'n'(I)wherein:Z is C or N;V is C or N;means an aromatic ring wherein V is C or N, and when V is N, V is ortho,meta or para relative to Z;each R is independently hydrogen, halogen, -CN, hydroxyl, (Ci-C3)haloalkyl, (Ci-C3)haloalkoxy, -NO2, -NR1R2, (Ci-C4)alkoxy unsubstituted or substituted by a (C3-Ce)cycloalkyl group, said (C3-Ce)cycloalkyl group being unsubstituted or substituted by one or two halogen atoms, a (C3-Ce)cycloalkyl group unsubstituted or substituted by one substituent which is selected from a halogen atom, a (Ci-C4)haloalkyl group, a (Ci-C4)haloalkoxy group, a hydroxyl group, and a (Ci-C4)alkoxy group, a (C3-Ce)cycloalkoxy group unsubstituted or substituted by one or two halogen atoms, a 3- to 6-membered monocyclic heterocycloalkyl ring comprising from 2 to 5 carbon atoms and comprising 1 or 2 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atom, said 3- to 6-membered monocyclic heterocycloalkyl ring being unsubstituted or substituted by one substituent which is selected from a halogen atom, a (Ci-C4)haloalkyl group, a (Ci-C4)haloalkoxy group, a hydroxyl group, and a (Ci-C4)alkoxy group,phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-RI, -NRi-C(=O)-Ri, -NRI-C(=O)-NR1R2,SO2-NR1R2, -SO3H, -O-SO2-OR3, -O-P(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, said alkyl being optionally mono- or di-substituted by a hydroxyl group, a group of formula (Ila):or a group of formulaQ is N or O, provided that R” does not exist when Q is O;each of Ri and R2 is independently hydrogen or (C1-C3)alkyl;each of R3 and R4 is independently hydrogen, Li+, Na+, K+, N+(Ra)4 or benzyl; n is 1, 2 or 3;n’ is 1, 2 or 3;each R’ is independently hydrogen, (C1-C3)alkyl, hydroxyl, halogen, -NO2, - NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (Ci-C3)fluoroalkyl, (CiC4)alkoxy, OP(=O)-(OR3)(OR4), -CN, a group of formula (Ila):RaRa' 'm Rbor a group of formula (Illa):A is a covalent bond, oxygen, or NH;B is a covalent bond or NH;m is 1, 2, 3, 4 or 5;p is 1, 2 or 3; each of Ra and Rb is independently hydrogen, (C1-C5)alkyl, or (C3-C6)cycloalkyl, orRa and Rb form together with the nitrogen atom to which they are attached a saturated 5- or 6- membered heterocycle, said heterocycle being optionally substituted by one or more Ra, provided that when R’ is a group (Ila) or (Illa), n’ may be 2 or 3 only if other R’ groups are different from said group (Ila) or (Illa); andR” is hydrogen, (Ci-C4)alkyl, or a group of formula (Ila) as defined herein.

2. The pharmaceutical combination according to claim 1, wherein the compound of formula (I) is a compound of formula (lb):or a metabolite thereof, a pharmaceutically acceptable salt thereof, or prodrug thereof or a metabolite thereof, wherein R, R’ and R’ ’ are as defined in claim 1.

3. The pharmaceutical combination according to claim 1 or 2, wherein the compound of formula (I) is selected from Obefazimod or a pharmaceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein the a4p7 anti-integrin is selected from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943.

5. A pharmaceutical composition or kit, comprising the pharmaceutical combination according to any one of claims 1 to 4, and at least one pharmaceutically acceptable excipient.

6. The pharmaceutical composition or kit according to claim 5, wherein the pharmaceutical composition or kit comprises:Obefazimod or a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereofVedolizumab, andthe at least one pharmaceutically acceptable excipient.

7. The pharmaceutical composition or kit according to claim 5, wherein the pharmaceutical composition is for oral administration and comprises:Obefazimod or a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereofCarotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A or PTG-100 / PN-943, andthe at least one pharmaceutically acceptable excipient.

8. The pharmaceutical combination according to any one of claims 1 to 4 for use in the treatment of an inflammatory disease, disorder, or condition.

9. The pharmaceutical combination for use according to claim 8, wherein the inflammatory disease, disorder, or condition is selected from the group consisting of:(a) an inflammatory disease, disorder, or condition in the pancreas selected from diabetes type-1, diabetes type-2, acute and chronic pancreatitis;(b) an inflammatory disease, disorder, or condition in the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger’s disease, Goodpasture’s syndrome, Wegener’s granulomatosis and kidney transplant acute or chronic rejection;(c) an inflammatory disease, disorder, or condition in the liver selected from nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and liver transplant acute or chronic rejection;(d)an inflammatory disease, disorder, or condition in the lung or heart selected from bronchitis, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and lung or heart transplant acute or chronic rejection, Coronaviridae infection and conditions related thereto, in particular wherein the Coronaviridae is a Sarbecovirus selected from Severe Acute Respiratory Syndrome-related coronaviruses, even more particularly wherein the Severe Acute Respiratory Syndrome (SARS)-relatedcoronaviruses are selected from the group consisting of: SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2; including including strains responsible for COVID-19 and their mutants;(e) an inflammatory disease, disorder, or condition in the skin selected from psoriasis, dermatitis, eczema, contact dermatitits, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acnea, keloid scar, and other inflammatory or allergic conditions of the skin;(f) an inflammatory disease, disorder, or condition in the vessel / blood selected from Behcet’s disease, vasculitis, sepsis, tumor angiogenesis, proliferative vascular disease and restenosis, atherosclerosis;(g) an inflammatory disease, disorder, or condition in the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optical neuritis;(h) an inflammatory disease, disorder, or condition in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, including chronic pain, traumatic brain injury, including stroke, neurodegenerative diseases, Alzheimer’s disease, and Parkinson disease, Myelitis, Charcot-Marie-Tooth disease type 1 (including CMT1A and CMT1B), Amyotrophic lateral sclerosis (ALS), Creutzfeldt- Jakob disease, demyelinating polyneuropathy and peripheral neuropathy;(i) an autoimmune disease, disorder, or condition selected from Sjogren’s syndrome, Lupus, including in the skin and kidney, Guillain-Barre syndrome, Myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves disease, and Myocarditis;(j) an inflammatory disease, disorder, or condition in the reproductive system selected from endometriosis, uterine fibroma, prostate dysplasia or growth, and cervix dysplasia;(k) an inflammatory disease, disorder, or condition in the bone and / or joints selected from rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis,juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and hand, foot, ankle, knee, hip, shoulder, elbow or spine arthritis and / or demineralization;(l) an inflammatory disease, disorder, or condition in the digestive tract selected from inflammation associated with colon carcinoma, Inflammatory Bowel Disease, including Crohn’s disease, Ulcerative Colitis and eosinophilic esophagitis; and (m) an inflammatory disease, disorder, or condition in the central nervous system selected from Multiple sclerosis (MS), relapsing-remitting multiple sclerosis (RRMS); relapsing forms of multiple sclerosis (RMS) and secondary progressive multiple sclerosis (SPMS).

10. The pharmaceutical combination for use according to claim 8 or 9, wherein the inflammatory disease, disorder, or condition is selected from the group consisting of an inflammatory bowel disease, in particular ulcerative colitis or Crohn’s disease, rheumatoid arthritis, psoriasis and dermatitis.

11. The pharmaceutical combination for use according to any one of claims 8 to 10, wherein the compound of formula (I) is Obefazimod or a pharmaceutically acceptable salt, a prodrug thereof or a metabolite thereof.

12. The pharmaceutical combination for use according to any one of claims 8 to 11, wherein the a4p7 anti-integrin is selected from the group consisting of Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab ABBV-382, PR-026 and SPY 130, more particularly from Vedolizumab, Natalizumab, Etrolizumab, Abrilumab and Ontamalimab, as well as from Carotegrast methyl, Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A and PTG-100 / PN-943, in particular Vedolizumab.

13. The pharmaceutical combination for use according to any one of claims 8 to 12, wherein it comprises:an effective amount of Obefazimod or a pharmaceutically acceptable salt thereof, prodrug thereof or a metabolite thereof andan effective amount of Vedolizumab, Natalizumab, Etrolizumab, Abrilumab, Ontamalimab, ABBV-382, PR-026, SPY 130, Carotegrast methyl Carotegrast, Firategrast, Zaurategrast, Valategrast, Morf-057, NSHO-101 / EA1080, NSHO102, MT 101, AJM 347, TRK 170, GS-1427, ET3764 / ZP 10000, PN 10943A or PTG-100 / PN-943, in particular Vedolizumab.

14. The pharmaceutical combination for use according to any one of claims 8 to 13, whereinthe compound of formula (I), in particular Obefazimod, the pharmaceutically acceptable salt thereof, the prodrug thereof, or the metabolite thereof is administered to the patient in an amount in a range of 1 mg to 100 mg per day, andthe a4p7 anti-integrin, in particular Vedolizumab, is administered to the patient in an amount in a range of 15 mg and 330 mg per week.

15. The pharmaceutical combination for use according to any one of claims 8 to 14, wherein an induction dose is implemented during an induction sequence lasting between 4 to 16 weeks, followed by a long-term sequence of administration, wherein at least one of the compound of formula (I), in particular Obefazimod, the pharmaceutically acceptable salt thereof, the prodrug thereof, or the metabolite thereof or of the a4p7 anti-integrin, in particular Vedolizumab, is administered in each sequence.

16. The pharmaceutical combination for use according to claim 15, wherein the daily dose of the long-term dose of at least one of the compounds of the combination is reduced with respect to the induction daily dose for said at least one of the compounds, for example by at least 20%, in particular by at least 30%, more particularly by 20 to 70%, and even more particularly by 30% to 50%.

17. The pharmaceutical combination for use according to any one of claims 8 to 16, further comprising measuring and / or monitoring a presence and / or level of a biomarker in the patient, said biomarker being in particular miR-124.

18. The pharmaceutical combination for use according to claim 17, further comprising adjusting a dosage regimen of the compound of formula (I), the pharmaceutically acceptable salt thereof, the prodrug thereof, or the metabolite thereof based on the presence and / or expression level of miR-124 in the patient.

19. The pharmaceutical combination for use according to any one of claims 8 to 18, further comprising:measuring and / or monitoring T-cell counts in the patient, andoptionally adjusting a dosage regimen of the a4p7 anti-integrin based on the T-cell counts in the patient.

20. A pharmaceutical combination of a compound of formula (I) as defined in any one of claims 1 to 3, in particular Obefazimod or one of its pharmaceutically acceptable salt, prodrug or metabolite thereof and of a a4p7 anti-integrin, in particular Vedolizumab, for separate administration, administration spread out over time or simultaneous administration to patients suffering from inflammatory diseases, disorders or conditions, in particular as defined in claim 9.

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