Combination of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its derivatives with JAK inhibitors

Abstract

The present invention relates to a pharmaceutical combination of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, and a JAK inhibitor, or a pharma- ceutically acceptable salt thereof, wherein said compound of formula (I) has the formula: [Formula 1] JPEG2025503087000078.jpg40170The present invention further relates to pharmaceutical compositions comprising the above combinations, uses thereof, and pharmaceutical kits containing same.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, one of its prodrugs or derivatives, or a pharma- ceutically acceptable salt thereof, or one of its metabolites, and a JAK inhibitor or a pharma- ceutically acceptable salt thereof.

[0002] The present invention provides a combination of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, one of its prodrugs or derivatives, or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, with a JAK inhibitor or a pharma- ceutically acceptable salt thereof, which may be particularly useful in the treatment of inflammatory diseases, and more particularly in the treatment of inflammatory bowel diseases, such as those mentioned above, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis. [Background technology]

[0003] Some quinoline derivatives are described in International Publication Nos. WO2010 / 143169, WO2012 / 080953, WO2016 / 009065, WO2016 / 009066 and WO2020 / 127843, the contents of which are incorporated herein by reference in their entireties.

[0004] 8-Chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharma- ceutically acceptable salts, is one of the compounds disclosed in all such patent applications, as well as its use in the treatment of inflammatory diseases. Its glucuronide metabolite is in particular disclosed in International Publication No. WO2016 / 135052.

[0005] Janus kinase inhibitors, also known as JAK inhibitors or jakinibs (hereafter JAK inhibitors or JAKi), are a class of drugs that inhibit the JAK-STAT signaling pathway by inhibiting at least one of the Janus kinase enzymes JAKI, JAK2, JAK3, or TYK2. Some JAK inhibitors inhibit all of the above enzymes and are therefore called pan-JAK inhibitors.

[0006] JAK inhibitors have applications in the treatment of cancer and inflammatory diseases, such as rheumatoid arthritis. There is also interest in their use for various skin diseases. For example, JAK3 inhibitors are attractive as a possible treatment for various autoimmune diseases because their function is primarily restricted to lymphocytes.

[0007] Accordingly, several JAK inhibitors have been developed and marketed as treatments for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn's disease, myelofibrosis, and polycythemia vera.

[0008] Several side effects have been documented with JAK inhibitors, including upper respiratory tract infections (e.g., colds and sinusitis), bronchitis, headache, cough, high blood pressure, rash, nausea, shingles, increased risk of serious cardiac events, cancer, blood clots, and death.

[0009] None of the above cited documents discloses the synergistic activity of a combination of a compound of formula (I) as defined herein below, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharma- ceutically acceptable salts or metabolites thereof, with a JAK inhibitor, nor the advantage of this combination for reducing the above-mentioned side effects. Summary of the Invention [Problem to be solved by the invention]

[0010] Because the mechanism of action and side effects of JAK inhibitors differ from those of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, it would be of interest to evaluate synergistic effects on inflammation.

[0011] There remains a need for effective alternative or complementary therapies in the treatment of inflammatory diseases, disorders or conditions, such as inflammatory bowel disease.

[0012] Additionally, there remains a need for compounds that have no or limited side effects. [Means for solving the problem]

[0013] It has now been found that a compound of formula (I), a pharma- ceutically acceptable salt thereof, a prodrug or a metabolite thereof, in particular a combination of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine as defined hereinafter, and a JAK inhibitor, or a pharma- ceutically acceptable salt thereof, is useful for the treatment and / or prevention of various inflammatory diseases, disorders or conditions.

[0014] In particular, the present invention relates to compounds to be used to reduce the dose of a JAK inhibitor or a pharma- ceutically acceptable salt thereof, thereby limiting the side effects thereof while maintaining or increasing the efficacy and / or safety of said JAK inhibitor or a pharma- ceutically acceptable salt thereof for treating the various inflammatory diseases, disorders or conditions as defined hereinafter.

[0015] In particular, the present invention relates to compounds used to reduce the dose of one of the compounds of formula (I) as defined hereinafter, its pharma- ceutically acceptable salts, prodrugs or metabolites thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or its pharma- ceutically acceptable salts, prodrugs or metabolites thereof, in particular its glucuronide metabolite, thereby limiting the side effects thereof, while maintaining or increasing the efficacy and / or safety of the compound of formula (I) as detailed hereinafter, its pharma- ceutically acceptable salts, prodrugs or metabolites thereof for treating the various inflammatory diseases, disorders or conditions.

[0016] Provided herein are combination therapies for treating inflammatory diseases, disorders or conditions as detailed herein below, particularly inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, as mentioned above, including rheumatoid arthritis and dermatitis.

[0017] More particularly provided herein is a pharmaceutical combination of one of the compounds of formula (I) as defined hereinafter, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular a glucuronide metabolite thereof, and a JAK inhibitor or a pharma- ceutically acceptable salt thereof.

[0018] There is also provided a pharmaceutical combination of a compound of formula (I) as defined hereinafter, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, and a JAK inhibitor or a pharma- ceutically acceptable salt thereof, for use in the treatment of an inflammatory disease, disorder or condition as detailed hereinafter, in particular inflammatory bowel disease, such as inflammatory bowel disease as mentioned above, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

[0019] The compound of formula (I) as defined herein below, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, and the JAK inhibitor or a pharma- ceutically acceptable salt thereof, may be used simultaneously or separately, or may be used dispersed over time, preferably simultaneously.

[0020] Thus, there is provided herein a pharmaceutical combination of a compound of formula (I) as defined hereinafter, a pharma- ceutical acceptable salt thereof, a prodrug or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutical acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, and a JAK inhibitor or a pharma- ceutical acceptable salt thereof, for separate administration, administration spread out over time or simultaneous administration to a patient suffering from an inflammatory disease, disorder or condition as detailed hereinafter, in particular an inflammatory bowel disease, such as inflammatory bowel disease as described above, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

[0021] Further provided herein is a pharmaceutical composition comprising a compound of formula (I) as defined hereinafter, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, a JAK inhibitor or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient.

[0022] Further provided herein is a pharmaceutical composition comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharma- ceutically acceptable salts, upadacitinib, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0023] Further provided herein is a pharmaceutical composition comprising the 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine glucuronide metabolite, upadacitinib or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0024] The pharmaceutical combination comprises an effective amount as implemented in the combination herein of a compound of formula (I) as defined herein below, a pharma- ceutical acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharma- ceutical acceptable salts, or one of its metabolites, and an effective amount as implemented in the combination herein of a JAK inhibitor, or a pharma- ceutical acceptable salt thereof.

[0025] Further provided herein is a compound of formula (I) as defined hereinafter, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, for increasing the efficacy and / or safety of a JAK inhibitor or a pharma- ceutically acceptable salt thereof, in particular for its anti-inflammatory activity, thereby reducing the dose of said JAK inhibitor while maintaining its efficacy in patients in need of treatment suffering from an inflammatory disease, disorder or condition as detailed hereinafter, in particular an inflammatory bowel disease, such as the above-mentioned inflammatory bowel diseases including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

[0026] Further provided herein is a JAK inhibitor or a pharma- ceutically acceptable salt thereof for increasing the efficacy and / or safety of a compound of formula (I) as defined hereinafter, or a pharma- ceutically acceptable salt thereof, or a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, in particular for its anti-inflammatory activity, thereby reducing the dose of said compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a prodrug thereof or a metabolite thereof, while maintaining its efficacy, in patients in need of such treatment suffering from an inflammatory disease, disorder or condition as detailed hereinafter, in particular an inflammatory bowel disease, such as the above-mentioned inflammatory bowel diseases including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

[0027] A pharmaceutical kit, in particular intended for treating inflammatory diseases, disorders or conditions as detailed hereinbelow, in particular inflammatory bowel diseases as mentioned above, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis, comprising: (i) a first galenical formulation comprising a compound of formula (I) as defined hereinafter, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, and (ii) a second galenical formulation comprising a JAK inhibitor or a pharma- ceutical acceptable salt thereof; There is further provided a pharmaceutical kit as described above, comprising:

[0028] In the framework of the present invention, the following definitions can be given: Effective amount: the amount of a pharmaceutical compound that produces an effect against the disease being treated; Separate administration, simultaneous administration or distributed administration over time of a pharmaceutical combination means that the components of the combination can be administered simultaneously or at different moments each at once, or repeatedly or at different moments, in particular during a cycle. To do this, the components can be formulated as a mixture only if they are administered simultaneously, or else they can be formulated separately in the case of other administration schemes; As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is, 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, or the like, and is commensurate with a reasonable benefit / risk ratio; and The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human. As used herein, the term "side effects" has its ordinary meaning in the art and refers to unintended effects occurring at normal doses that are related to pharmacological properties.

[0029] In the framework of the present invention, for the sake of brevity, the term "combination according to the invention" or "pharmaceutical combination" means a pharmaceutical combination of a compound of formula (I) as defined hereinafter, a pharma- ceutical acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutical acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, and a JAK inhibitor, or one of its pharma- ceutical acceptable salts.

[0030] Synergy or synergism of a combination of drugs means that the combined effect is greater than that predicted by the individual potencies of the drugs. Synergistic interactions may allow for greater therapeutic efficacy and / or the use of lower doses of the drugs, e.g., at least one of the drugs, resulting in reduced adverse or side effects.

[0031] As an example, the evaluation of the synergy of drug combinations is described in Genes Cancer. 2011 Nov;2(11):1003-1008 (doi:10.1177 / 1947601912440575), in which it is stated that "If the combined effect observed is significantly greater than the expected (additive) effect, there is synergism". The above evaluation of the synergy of drug combinations in the framework of the present invention is not limited to the use of a unique method, but rather can be based on the use of any method known to the person skilled in the art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Compounds of formula (I) or their pharma- ceutically acceptable salts or prodrugs thereof that may be implemented within the framework of the present invention may be represented hereinbelow: [ka] Where: Z is C or N; V is C or N; [ka] means an aromatic ring, where V is C or N, and when V is N, V ​​is ortho, meta or para to Z; Each R is independently a hydrogen atom, a halogen atom, -CN, hydroxyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, (C3-C6)cycloalkyl, -NO2, -NR1R2, (C1-C4)alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1-C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -OP(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, where the alkyl is a hydroxyl group, a group of formula (IIa) below: [ka] or a group of formula (IIIa): [ka] optionally mono- or di-substituted by Q is N or O, with the proviso that when Q is O, then R″ is absent; Each of R1 and R2 is independently a hydrogen atom or a (C1-C3) alkyl; R3 and R4 each independently represent a hydrogen atom, Li + , Na + , K + , N + (Ra) 4 or benzyl; n is 1, 2 or 3; n' is 1, 2 or 3; Each R' is independently a hydrogen atom, a (C1-C3) alkyl, a hydroxyl, a halogen atom, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, a (C1-C3) fluoroalkyl, a (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, a group of formula (IIa): [ka] or a group of formula (IIIa): [ka] and A is a covalent bond, an oxygen atom, 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 a hydrogen atom, a (C1-C5) alkyl or a (C3-C6) cycloalkyl; or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, which is optionally substituted by one or more Ra, provided that, when R' is a group of (IIa) or (IIIa), n' may be 2 or 3 only if the other R' group is different from the group of (IIa) or (IIIa); and R″ is a hydrogen atom, a (C1-C4) alkyl, or a group of formula (IIa) as defined herein.

[0033] The compound of formula (I) or its salt may form a solvate or hydrate, and the present invention includes all such solvates and hydrates. The words "hydrate" and "solvate" simply mean that the compound according to the present invention can be in the form of a hydrate or solvate, i.e. in the form of a hydrate or solvate combined or associated with one or more water or solvent molecules. This is merely a chemical property of such compounds, which can be applied to all organic compounds of this type.

[0034] The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, are included within the scope of the present invention.

[0035] In the context of the present invention the following terms are defined as follows: "halogen atom" is understood to mean a chlorine, fluorine, bromine or iodine atom and in particular to denote a chlorine, fluorine or bromine atom; - As used herein, "(C1-C5) alkyl" refers to a C1-C5 linear, secondary or tertiary saturated hydrocarbon, respectively. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl. - As used herein, "(C3-C6)cycloalkyl" refers to each cyclic saturated hydrocarbon. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. - as used herein, "(C1-C4)alkoxy" refers to an O-(C1-C4)alkyl residue, respectively, where alkyl is as defined above. Examples are, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy. - "fluoroalkyl group" and "fluoroalkoxy group" refer respectively to alkyl and alkoxy groups as defined above, wherein the group is substituted with at least one fluorine atom. Examples are perfluoroalkyl groups, such as trifluoromethyl or perfluoropropyl. - "saturated 5- or 6-membered heterocycle" as used herein refers to a saturated ring containing at least one heteroatom. Examples include, but are not limited to, morpholine, piperazine, thiomorpholine, piperidine, and pyrrolidine.

[0036] Unless otherwise stated, structures depicted herein are also meant to encompass all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. 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, the replacement of a hydrogen atom by deuterium or tritium, or 13 C- or 14 Compounds having the present structures including the replacement of a carbon with a C-rich carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0037] Z is C or N, as generally defined above.

[0038] In some embodiments, Z is C. In some embodiments, Z is N.

[0039] In some embodiments, Z is selected from the compounds depicted in Tables 1-3 below.

[0040] V is C or N, as generally defined above.

[0041] In some embodiments, V is C. In some embodiments, V is N.

[0042] In some embodiments, V is selected from the compounds depicted in Tables 1-3 below.

[0043] As generally defined above, [ka] means an aromatic ring, where V is C or N, and when V is N, V ​​is ortho, meta, or para to Z.

[0044] In some embodiments, [ka] means an aromatic ring, where V is C.

[0045] In some embodiments, [ka] means an aromatic ring, where V is N and V is ortho, meta or para to Z.

[0046] In some embodiments, V is N and V is ortho to Z. In some embodiments, V is N and V is meta to Z. In some embodiments, V is N and V is para to Z.

[0047] In some embodiments, [ka] is phenyl.

[0048] In some embodiments, [ka] is pyridine.

[0049] In some embodiments, [ka] is a pyridazine.

[0050] In some embodiments, [ka] is a pyrimidine.

[0051] In some embodiments, [ka] is a pyrazine.

[0052] In some embodiments, [ka] is selected from the compounds illustrated in Tables 1 to 3 below.

[0053] As generally defined above, each R is independently a hydrogen atom, a halogen atom, -CN, hydroxyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, (C3-C6)cycloalkyl, -NO2, -NR1R2, (C1-C4)alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1-C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -OP(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, where the alkyl is a hydroxyl group, or a group of formula (IIa) below: [ka] or a group of formula (IIIa): [ka] It may be mono- or disubstituted by.

[0054] In some embodiments, R is a hydrogen atom. In some embodiments, R is a halogen atom. In some embodiments, R is -CN. In some embodiments, R is hydroxyl. In some embodiments, R is (C1-C3)fluoroalkyl, where the alkyl may be mono- or di-substituted with hydroxyl. In some embodiments, R is (C1-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 (C1-C4)alkoxy. In some embodiments, R is phenoxy. In some embodiments, R is -NR1-SO2-NR1R2. In some embodiments, R is -NR1-SO2-R1. In some embodiments, R is -NR1-C(=O)-R1. In some embodiments, R is -NR1-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 -OP(=O)-(OR3)(OR4). In some embodiments, R is -O-CH2-COOR3. In some embodiments, R is (C1-C3) alkyl, where the alkyl may be mono- or di-substituted by hydroxyl.

[0055] In some embodiments, each R is independently a halogen atom, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, -NR1R2, (C1-C4)alkoxy, or (C1-C3)alkyl.

[0056] In some embodiments, each R is independently a hydrogen atom, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, a halogen atom, or -OP(=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 -OP(=O)-(OR3)(OR4).

[0057] In some embodiments, each R is independently methyl, methoxy, trifluoromethyl, a halogen atom, trifluoromethoxy, or amino.

[0058] In some embodiments, R is selected from the compounds depicted in Tables 1-3 below.

[0059] As generally defined above, Q is N or O, with the proviso that when Q is O, R″ is absent.

[0060] In some embodiments, Q is N. In some embodiments, Q is O and R″ is absent.

[0061] In some embodiments, Q is selected from the compounds depicted in Tables 1-3 below.

[0062] As generally defined above, each of R1 and R2 is independently a hydrogen atom or a (C1-C3) alkyl.

[0063] In some embodiments, R1 is a hydrogen atom. In some embodiments, R1 is a (C1-C3) alkyl. In some embodiments, R2 is a hydrogen atom. In some embodiments, R2 is a (C1-C3) alkyl.

[0064] In some embodiments, each of R1 and R2 is independently selected from the compounds depicted in Tables 1-3 below.

[0065] As generally defined above, R3 and R4 each independently represent a hydrogen atom, Li + , Na + , K + , N + (Ra) 4 or benzyl.

[0066] In some embodiments, R3 is a hydrogen atom. In some embodiments, R3 is Li + In some embodiments, R3 is Na + In some embodiments, R3 is K + In some embodiments, R3 is N + (Ra)4. In some embodiments, R3 is benzyl. In some embodiments, R4 is a hydrogen atom. In some embodiments, R4 is Li + In some embodiments, R4 is Na + In some embodiments, R4 is K + In some embodiments, R4 is N + (Ra)4. In some embodiments, R4 is benzyl.

[0067] In some embodiments, each of R3 and R4 is independently selected from the compounds depicted in Tables 1-3 below.

[0068] As generally described above, n is 1, 2 or 3.

[0069] 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.

[0070] In some embodiments, n is selected from the compounds depicted in Tables 1-3 below.

[0071] As generally defined above, n' is 1, 2 or 3.

[0072] 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.

[0073] In some embodiments, n' is selected from the compounds depicted in Tables 1-3 below.

[0074] As generally defined above, each R' is independently a hydrogen atom, a (C1-C3) alkyl, a hydroxyl, a halogen atom, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, a (C1-C3) fluoroalkyl, a (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, a group of formula (IIa): [ka] or a group of formula (IIIa): [ka] It is.

[0075] In some embodiments, R' is a hydrogen atom. In some embodiments, R' is (C1-C3) alkyl. In some embodiments, R' is hydroxyl. In some embodiments, R' is a halogen atom. 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 (C1-C3) fluoroalkyl. In some embodiments, R' is (C1-C4) alkoxy. In some embodiments, R' is -OP(=O)-(OR3)(OR4). In some embodiments, R' is -CN.

[0076] In some embodiments, R' is a group of formula (IIa): [ka]

[0077] In some embodiments, R' is a group of formula (IIIa): [ka]

[0078] In some embodiments, R' is amino. In some embodiments, R' is methyl. In some embodiments, R' is a group of the formula: [ka] wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3, with the proviso that when R' is such a group, n' is 1 or 2, and when n' is 2, the other R' groups are different from the above groups.

[0079] In some embodiments, R' is a group of the formula: [ka] wherein A is O or NH, m is 2, and X1 is O, CH2 or N-CH3, with the proviso that when R' is such a group, n' is 1 or 2, and when n' is 2, the other R' groups are different from the above groups.

[0080] In some embodiments, R' is a group of the formula: [ka] wherein A is O or NH, m is 3, and X1 is O, CH2 or N-CH3, with the proviso that when R' is such a group, n' is 1 or 2, and when n' is 2, the other R' groups are different from the above groups.

[0081] In some embodiments, each R' is independently a hydrogen atom, a halogen atom, amino, methyl, -OP(=O)-(OR3)(OR4), or a group of the formula: [ka] wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3, with the proviso that when R' is such a group, n' is 1 or 2, and when n' is 2, the other R' groups are different from the above groups.

[0082] In some embodiments, each R' is independently a hydrogen atom, a halogen atom, methyl, or a group of the formula: [ka] wherein A is O or NH, m is 2, and X1 is O, CH2 or N-CH3, with the proviso that when R' is such a group, n' is 1 or 2, and when n' is 2, the other R' groups are different from the above groups.

[0083] In some embodiments, each R' is independently a halogen atom, a (C1-C3) alkyl, hydroxyl, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, a (C1-C3) fluoroalkyl, a (C1-C4) alkoxy, or a group of formula (IIa) or formula (IIIa) described herein.

[0084] In some embodiments, R' is a halogen atom or methyl.

[0085] In some embodiments, each R' is independently selected from the compounds depicted in Tables 1-3 below.

[0086] As generally defined above, A is a covalent bond, an oxygen atom, or NH.

[0087] In some embodiments, A is a covalent bond. In some embodiments, A is an oxygen atom. In some embodiments, A is NH.

[0088] In some embodiments, A is selected from the compounds depicted in Tables 1-3 below.

[0089] As generally defined above, B is a covalent bond or NH.

[0090] In some embodiments, B is a covalent bond. In some embodiments, B is NH.

[0091] In some embodiments, B is selected from the compounds depicted in Tables 1-3 below.

[0092] As generally defined above, m is 1, 2, 3, 4 or 5.

[0093] 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.

[0094] In some embodiments, m is selected from the compounds depicted in Tables 1-3 below.

[0095] As generally defined above, p is 1, 2 or 3.

[0096] 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.

[0097] In some embodiments, p is selected from the compounds depicted in Tables 1-3 below.

[0098] As generally defined above, each of Ra and Rb is independently a hydrogen atom, a (C1-C5) alkyl or a (C3-C6) cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, which may be substituted by one or more Ra, provided that, in the case where R' is a group of (IIa) or (IIIa), n' may be 2 or 3 only if the other R' group is different from the group of (IIa) or (IIIa).

[0099] In some embodiments, Ra is a hydrogen atom. In some embodiments, Ra is (C1-C5) alkyl. In some embodiments, Ra is (C3-C6) cycloalkyl. In some embodiments, Rb is a hydrogen atom. In some embodiments, Rb is (C1-C5) alkyl. In some embodiments, Rb is (C 3~ C6) Cycloalkyl.

[0100] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring, which may be substituted by one or more Ra, provided that, where R' is a group of formula (IIa) or formula (IIIa), n' may be 2 or 3 only if the other R' group is different from the group of formula (IIa) or formula (IIIa). In some embodiments, as described above, the saturated 5- or 6-membered heterocyclic ring formed by Ra and Rb together with the nitrogen atom to which they are attached may have an additional heteroatom selected from N, O, and S.

[0101] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N, O and S, which is optionally substituted with one or more Ra, provided that, when R' is a group of formula (IIa) or formula (IIIa), n' may be 2 or 3 only if the other R' group is different from the group of formula (IIa) or formula (IIIa).

[0102] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5-heterocycle, provided that, where R' is a group of formula (IIa) or formula (IIIa), n' may be 2 or 3 only if the other R' group is different from the group of formula (IIa) or formula (IIIa).

[0103] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 6-heterocycle, provided that, where R' is a group of formula (IIa) or formula (IIIa), n' may be 2 or 3 only if the other R' group is different from the group of formula (IIa) or formula (IIIa).

[0104] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N, O and S, wherein the heterocycle is optionally substituted by one or more Ra, provided that when R' is the (IIa) or (IIIa) group, n' may be 2 only if the other R' group is different from the (IIa) or (IIIa) group.

[0105] In some embodiments, each of Ra and Rb is independently selected from the compounds depicted in Tables 1-3 below.

[0106] As generally defined above, R″ is a hydrogen atom, a (C1-C4) alkyl, or a group of formula (IIa) as defined above.

[0107] In some embodiments, R" is a hydrogen atom or a (C1-C4) alkyl. In some embodiments, R" is a hydrogen atom. In some embodiments, R" is a (C1-C4) alkyl. In some embodiments, R" is a group of formula (IIa) as defined herein.

[0108] In some embodiments, R″ is a group of the formula: [ka] where m is 2 or 3, and X1 is O, CH2 or N-CH3.

[0109] In some embodiments, R″ is selected from the compounds depicted in Tables 1-3 below.

[0110] In some embodiments, n is 1; n' is 1 or 2; R" is H; R is selected from methyl, methoxy, trifluoromethyl, a halogen atom, trifluoromethoxy, and amino; and each R' is independently a halogen atom, methyl, or the following group: [ka] wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3, with the proviso that when n' is 2, the other R' groups are different from those above.

[0111] In some embodiments, n is 1; n' is 1; R" is H; R is selected from methyl, methoxy, trifluoromethyl, a halogen atom, and trifluoromethoxy; and R' is a halogen atom or methyl.

[0112] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia): or a pharma- ceutically acceptable salt or prodrug thereof: [ka] wherein each of the variables R, R', R'', n, and n' is independently as defined above and as described in the embodiments.

[0113] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib) below, or a pharma- ceutically acceptable salt or prodrug thereof: [ka] wherein the variables R, R', R", n, and n' are each independently as defined above and as described in the embodiments, both alone and in combination.

[0114] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound of formula (Ib), or a metabolite thereof, or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, any one of: [ka] where R, R' and R" are as defined above.

[0115] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound of formula (Ic), or a pharma- ceutically acceptable salt or prodrug thereof: [ka] wherein the variables R, R', R", n, and n' are each independently as defined above and as described in the embodiments, both alone and in combination.

[0116] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound of formula (Id) or a pharma- ceutically acceptable salt or prodrug thereof: [ka] wherein R and R' are each independently as defined above and as described in the embodiments, both alone and in combination, and R'" is a hydrogen atom or the following group: [ka] where A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3.

[0117] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound of formula (Id), or a pharma- ceutically acceptable salt thereof, wherein R is methyl, methoxy, trifluoromethyl, a halogen atom, trifluoromethoxy, or amino; R' is a halogen atom or methyl, and R'" is a hydrogen atom or the following group: [ka] where A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3.

[0118] In some embodiments, R''' is a hydrogen atom.

[0119] In some embodiments, R'" is the following group: [ka] wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3. In some embodiments, R'" is the following group: [ka] wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3. In some embodiments, R'" is the following group: [ka] where A is NH, m is 2 or 3, and X1 is O, CH2 or N-CH3.

[0120] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound of formula (Ib'), or a pharma- ceutically acceptable salt or prodrug thereof: [ka] wherein the variables R, R', R", n, and n' are each independently as defined above and as described in the embodiments, both alone and in combination.

[0121] In some embodiments, the present invention provides a combination, composition, or kit wherein the compound of formula (I) is a compound of formula (Ib) or a pharma- ceutically acceptable salt thereof, wherein each R is independently a halogen atom, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, -NR1R2, (C1-C4)alkoxy, or (C1-C3)alkyl, wherein the alkyl is optionally mono- or di-substituted with hydroxyl groups; n is 1 or 2; n' is 1 or 2; Each of R1 and R2 is independently a hydrogen atom or a (C1-C3) alkyl; each R' is independently a halogen atom, (C1-C3)alkyl, hydroxyl, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, or a group of formula (IIa) or formula (IIIa) described herein; A is a covalent bond, an oxygen atom, 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 a hydrogen atom, a (C1-C5) alkyl or a (C3-C6) cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N, O and S, wherein the heterocycle is optionally substituted by one or more Ra, provided that, in the case where R' is the group of (IIa) or (IIIa), n' may be 2 only if the other R' group is different from the group of (IIa) or (IIIa); and R" is a hydrogen atom or a (C1-C4) alkyl.

[0122] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound of formula (Ib), or a pharma- ceutically acceptable salt thereof, wherein each R' is independently a hydrogen atom, a halogen atom, a (C1-C3) alkyl, or a (C1-C4) alkoxy group, wherein the alkyl may be mono- or di-substituted by a hydroxyl group; R" is a hydrogen atom or a (C1-C4) alkyl; n is 1 or 2; n' is 1 or 2; when n is 1, R is a (C1-C3) fluoroalkoxy, -NR1R2, or a phenoxy, wherein each of R1 and R2 is independently a (C1-C3) alkyl; and wherein n is 2, and one of the two R groups is a (C1-C3) fluoroalkoxy, and the other R group is a (C1-C3) alkyl.

[0123] In some embodiments, the present invention provides a combination, composition, or kit wherein the compound of Formula (I) is a compound of Formula (Ib), or a pharma- ceutically acceptable salt thereof, wherein each R is independently (C1-C3)fluoroalkoxy; each R' is independently hydrogen, halogen, (C1-C3)alkyl, or (C1-C4)alkoxy; R" is hydrogen or (C1-C4)alkyl; n is 1; and n' is 1 or 2.

[0124] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound of formula (Ib'), or a pharma- ceutically acceptable salt thereof, wherein each R is independently a hydrogen atom, a halogen atom, a (C1-C3) alkyl, -NR1R2, a (C1-C3) fluoroalkoxy, -NO2, a phenoxy, or a (C1-C4) alkoxy, wherein the alkyl may be mono- or di-substituted with a hydroxyl group; each of R1 and R2 is independently a hydrogen atom or a (C1-C3) alkyl; R' is a hydrogen atom, a halogen atom, a (C1-C3) alkyl, or a (C1-C4) alkoxy, with the proviso that R' is different from a methyl group at the 4-position of the quinoline group; R" is a hydrogen atom or a (C1-C4) alkyl; n is 1, 2, or 3; and n' is 1 or 2.

[0125] In some embodiments, the present invention provides a combination, composition or kit, wherein the compound of formula (I) is any one of the compounds of formula (Ib'), or metabolites thereof or pharma- ceutically acceptable salts thereof, for use as defined above, wherein: R is independently a halogen atom, a (C1-C3) fluoroalkoxy group, a -NR1R2 group, a (C1-C4) alkoxy group, a -OP(=O)(OR3)(OR4) group, a (C1-C3) alkyl group, a NO2 group, or -A-(CH2) m -B-NRaRb group (Formula IIa) and -(O-CH2-CH2) p represents a group selected from the -O-Ra group (formula IIIa), n is 1 or 2; R' is a hydrogen atom, a halogen atom, or a -NR1R2 group, a -OP(=O)(OR3)(OR4) group, a -NH-SO2-N(CH3)2 group, or a -A-(CH2) m -B-NRaRb radicals (formula IIa), R″ is a hydrogen atom, a (C1-C4) alkyl group, or -A-(CH2) m -B-NRaRb group (formula IIa), R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group; R3 and R4 are independently a hydrogen atom, Li + , Na + , K + , N + (Ra) 4 or benzyl, A is a covalent bond, an oxygen atom or NH; B is a covalent bond; m is 2, 3 or 4; p is 1, 2 or 3; Ra and Rb each independently represent a hydrogen atom or a (C1-C5) alkyl group, and Ra and Rb may further combine with the nitrogen atom to which they are bonded to form a saturated 5- or 6-membered heterocycle which may further contain a heteroatom selected from N, O and S, and the heterocycle may be substituted by one or more Ra.

[0126] According to an even more particular embodiment, the present invention provides a combination, composition or kit, wherein said compound of formula (I) is a compound of formula (Ib'), or any one of its metabolites or its pharma- ceutically acceptable salts, for use as defined above, Where: R independently represents F, Cl, -NH2, -N(CH3)2, -OCH3, -O-(CH2)3-CH3, -OCF3, -CH3, -O-(CH2)2-OH, -O-(CH2)2-O-(CH2)2-OCH3, -NO2 group, -OP(=O)(OH)(OH) group, -O-(CH2)2-morpholino group or -O-(CH2)2-piperidino group; n is 1 or 2; R' represents a hydrogen atom, Cl, -CH2-CH2-CH3, -O-(CH2)2-morpholino group, -O-(CH2)2-piperidino group, -O-(CH2)3-piperidino group, -N-(CH2)3-morpholino group, -NH-SO2-N(CH3)2 group, NH2, or -OP(=O)(OH)(OH) group, and 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.

[0127] In one embodiment, the present invention provides any one of the compounds of formula (Ib'), or its metabolites or pharma- ceutically acceptable salts thereof, for use as defined above, wherein the compound is selected from compounds 96, 98, 108, 109, 111, 115, 122, 125, 128, 129, 130, 132, 133, 135, 138-141, 143 and 145-164 listed hereinbelow.

[0128] 8-Chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine has the formula: [ka] Also called ABX464, it may in particular be implemented within the framework of the present invention.

[0129] In some embodiments, the compound ABX464 or its pharma- ceutically acceptable salt is in amorphous form.In some embodiments, the compound ABX464 or its pharma- ceutically acceptable salt is in crystalline form.In some embodiments, the crystalline form of the compound ABX464 or its pharma- ceutically acceptable salt has a melting point of 120.5°C (±2°C).

[0130] In some embodiments, the crystalline form of the compound ABX464 or a pharma- ceutically acceptable salt thereof exhibits peaks in an X-ray powder diffraction diagram (XRPD) at angles 7.3, 14.6, 18.4, and 24.9. In some embodiments, the crystalline form of the compound ABX464 or a pharma- ceutically acceptable salt thereof exhibits one or more XRPD peaks at angles selected from 18.0, 24.2, 28.3, and 29.5. In some embodiments, the crystalline form of the compound ABX464 or a pharma- ceutically acceptable salt thereof exhibits one or more XRPD peaks at angles selected from 18.6, 22.3, 23.0, and 23.5.

[0131] According to a particular embodiment, the crystalline polymorph of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine is characterized by XRPD analysis by the following major peaks expressed as order 2-theta angles: 7.3, 14.6, 23.5 and 28.4 (each time ±0.2), and may further exhibit the following additional peaks expressed as order 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 may optionally further exhibit the following additional peaks expressed as order 2-theta angles: 13.7, 16.3, 16.9, 18.1, 22.4 and 29.6 (each time ±0.2).

[0132] The compounds of the present invention may exist in the form of a free base or in a pharma- ceutically acceptable form, ie, in the form of an addition salt with a pharma- ceutically acceptable acid.

[0133] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutical acceptable salts, which are detailed in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is 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.

[0134] Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharma-ceutically acceptable, non-toxic acid addition salts are salts of amino groups 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Salts include, but are not limited to, 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, and the like.

[0135] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharma- ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0136] According to a particular embodiment, suitable physiologically acceptable acid addition salts of the compounds of the invention include sulfates, hydrobromides, citrates, trifluoroacetates, ascorbates, hydrochlorides, tartrates, triflates, maleates, mesylates, formates, acetates, fumarates and sulfonates, in particular alkylsulfonates or arylsulfonates, more in particular mesylates, triflates, edisylate, besylate and tosylate.

[0137] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound selected from Table 1 below, or a pharma- ceutically acceptable salt or prodrug thereof.

[0138] [Table 1] JPEG2025503087000043.jpg236170JPEG2025503087000044.jpg254170JPEG2025503087000045.jpg255168JPEG2025503087000046.jpg252170 JPEG2025503087000047.jpg255165JPEG2025503087000048.jpg248170JPEG2025503087000049.jpg255164JPEG2025503087000050.jpg255168

[0139] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound selected from Table 2 below, or a pharma- ceutically acceptable salt or prodrug thereof.

[0140] [Table 2] JPEG2025503087000052.jpg255163JPEG2025503087000053.jpg255170JPEG2025503087000054.jpg255163JPEG2025503087 000055.jpg255170JPEG2025503087000056.jpg255168JPEG2025503087000057.jpg255165JPEG2025503087000058.jpg56170

[0141] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) is a compound selected from Table 3 below, or a pharma- ceutically acceptable salt or prodrug thereof.

[0142] [Table 3] JPEG2025503087000060.jpg251170JPEG2025503087000061.jpg28170

[0143] In some embodiments, the compounds described herein are in the form of a salt selected from sulfate, hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate, fumarate and sulfonate. In some embodiments, the compounds described herein are in the form of a salt as an alkylsulfonate or arylsulfonate. In some embodiments, the compounds described herein are in the form of a salt as a mesylate, triflate, edisylate, besylate and tosylate.

[0144] In one aspect, the present invention provides a combination, composition or kit, wherein the compound of formula (I) or its metabolite is in the form of its metabolite. In some embodiments, the present invention provides a combination, composition or kit, wherein the compound of formula (I) is in the form of the N-glucuronide metabolite of the compound of formula (I) described herein.

[0145] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) or a metabolite thereof is in the form of a compound of formula (IV) below or a pharma- ceutically acceptable salt thereof: [ka] wherein each of the variables V, Z, R, R', n, and n' are as defined above and as described in the embodiments, both alone or in combination.

[0146] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) or a metabolite thereof is in the form of a compound of formula (IVa) or a pharma- ceutically acceptable salt thereof or a pharma- ceutically acceptable salt thereof: [ka] wherein the variables R, R', n, and n' are each independently as defined above and as described in the embodiments, both alone and in combination.

[0147] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) or a metabolite thereof is in the form of a compound of formula (IVb) or a pharma- ceutically acceptable salt thereof: [ka] wherein the variables R, R', n, and n' are each independently as defined above and as described in the embodiments, both alone and in combination.

[0148] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) or a metabolite thereof is in the form of a compound of formula (IVc) or a pharma- ceutically acceptable salt thereof: [ka] wherein the variables R, R', n, and n' are each independently as defined above and as described in the embodiments, both alone and in combination.

[0149] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) or a metabolite thereof is in the form of a compound of formula (IVb') or a pharma- ceutically acceptable salt thereof: [ka] wherein the variables R, R', and n are each independently as defined above and as described in the embodiments, both alone and in combination.

[0150] In some embodiments, the present invention provides a combination, composition, or kit, wherein the compound of formula (I) or a metabolite thereof is in the form of a compound of formula (IVd) or a pharma- ceutically acceptable salt thereof: [ka] wherein the variables R, R', and R'" are each independently as defined above and as described in the embodiments, both alone and in combination.

[0151] According to one embodiment, the combination, composition or kit of the invention comprises a metabolite of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and a JAK inhibitor or a pharma- ceutically acceptable salt thereof. The metabolite may be a glucuronide metabolite having the formula: [ka]

[0152] In some embodiments, the metabolite of the compound of Formula (I) or a salt thereof is in amorphous form, such as the metabolite of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine glucuronide described above.

[0153] JAK inhibitors

[0154] In some embodiments of the method, the JAK inhibitor is a small molecule. According to certain embodiments, the JAK inhibitor is selected from the group consisting of abrocitinib, baricitinib, BMS-986165, decernotinib (VX509), filgotinib, itacitinib, oclacitinib, peficitinib, fedratinib, deucravacitinib, PF In some embodiments, the JAK inhibitor is selected from the group consisting of upadacitinib or a pharmaceutically acceptable salt thereof.

[0155] Further JAK inhibitors include cerdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, CHZ868, cucurbitacin I (JSI-124).

[0156] Further JAK inhibitors include AZD1480 (Astra Zeneca), a JAK2 FL3 kinase inhibitor, LY3009104 / INCB28050 (Eli Lilly, Incyte), a JAK2 inhibitor, Pacritinib / SB1518 (S*BIO), a JAK1 / 2 inhibitor, GLPG0634 (Galapagos), a JAK3 inhibitor, INC424 (Novartis), a JAK1 inhibitor, R-348 (Rigel), a JAK3 inhibitor, CYT387 (YM Bioscience), a JAK1 / 2 inhibitor, TG 10138, a JAK1 / 2 inhibitor, AEG 3482 (Axon), a JAK2 inhibitor, and pharma- ceutical acceptable salts and prodrugs thereof.

[0157] During the past decade, various classes of JAK inhibitors have been developed, some of which, e.g., tofacitinib, peficitinib, filgotinib, upadacitinib, SHR-0302, PF-06700841, BMS986165, PF-06651600 and izencitinib (TD-1473), have been approved or registered in various phases of human clinical trials focused on the treatment of inflammatory bowel diseases (IBD), i.e., Crohn's disease treatment and ulcerative colitis treatment.

[0158] As for upadacitinib, it is approved in the U.S. It is a JAK1 selective inhibitor being studied to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, psoriatic arthritis, axial SpA giant cell arteritis, and Takayasu's arteritis.

[0159] Upadacitinib, also called (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, known as ABT-494, has the following formula: [ka]

[0160] Upadacitinib is disclosed in International Publication No. WO2011 / 068881. Various solid forms of the free base of upadacitinib, as well as different acid addition salts of upadacitinib, are disclosed in International Publication No. WO2017 / 066775, all of which form part of the present invention.

[0161] The present invention extends to pharma- ceutically acceptable acid or base addition salts of all the JAK inhibitors mentioned above, as well as to their pro-drugs.

[0162] Drug Indications

[0163] The pharmaceutical compositions according to the present invention may be used in the treatment of a variety of inflammatory diseases, disorders or conditions.

[0164] The inflammatory disease may be selected from the list consisting of, for example, inflammatory diseases associated with autoimmune diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory gastrointestinal diseases, inflammatory skin diseases, and other inflammatory diseases associated with epithelial cells, inflammation associated with cancer, inflammation associated with irritation, and inflammation associated with injury.

[0165] According to one embodiment, the inflammatory disease, disorder or condition is selected from: (a) an inflammatory disease, disorder or condition of the pancreas selected from type 1 diabetes, type 2 diabetes, acute pancreatitis and chronic pancreatitis; (b) an inflammatory disease, disorder or condition of the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis, and acute or chronic rejection of a kidney transplant; (c) an inflammatory disease, disorder or condition of the liver selected from nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, and acute or chronic rejection of a liver transplant; (d) an inflammatory disease, disorder or condition in the lungs or heart selected from bronchitis, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of a lung or heart transplant, Coronaviridae infections and conditions associated therewith, particularly wherein the Coronaviridae is a Sarbecovirus selected from Severe Acute Respiratory Syndrome-associated Coronaviruses, and even more particularly wherein the Severe Acute Respiratory Syndrome (SARS)-associated Coronaviruses are selected from the group consisting of SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2, including the strain causing COVID-19 and variants thereof; (e) an inflammatory disease, disorder or condition of the skin selected from psoriasis, dermatitis, e.g., eczema, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, rosacea, flexural / inverse psoriasis, lichen planus, seborrheic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne, keloid scars, and other inflammatory or allergic conditions of the skin; (e) an inflammatory disease, disorder or condition in the blood / vessels selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, proliferative vascular disease and restenosis, atherosclerosis, axial spondyloarthritis, such as those listed above including axial SpA giant cell arteritis, and Takayasu's arteritis; (f) an inflammatory disease, disorder or condition of the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease and optic neuritis; (g) inflammatory diseases, disorders or conditions in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, e.g. neuropathic pain as described above including chronic pain, traumatic brain injury, e.g. traumatic brain injury as described above including stroke, neurodegenerative diseases, e.g. Alzheimer's disease, and Parkinson's 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 lupus of the skin and kidney, Guillain-Barre syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves disease and myocarditis; (k) an inflammatory disease, disorder or condition of the reproductive system selected from endometriosis, uterine fibroids, prostatic dysplasia or hyperplasia, and cervical dysplasia; (l) an inflammatory disease, disorder or condition of the bones and / or joints selected from rheumatoid arthritis (RA), osteoarthritis (OA); ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hand, foot, ankle, knee, hip, shoulder, elbow or spine; (m) an inflammatory disease, disorder or condition in the digestive tract selected from inflammation associated with colon cancer, inflammatory bowel disease, such as the inflammatory bowel diseases listed above, including Crohn's disease and ulcerative colitis, and eosinophilic esophagitis; and (n) 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).

[0166] Inflammatory diseases, disorders or conditions

[0167] The combinations described herein are useful in the treatment of inflammatory or obstructive airway diseases, for example resulting in a reduction in tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression. In some embodiments, the inflammatory disease, disorder or condition is an inflammatory or obstructive airway disease, for example asthma of any type or origin, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, including mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Treatment of asthma should also be understood to include treatment of subjects, for example subjects under the age of 4 or 5, who exhibit wheezing symptoms and are diagnosed or diagnosable as "wheezy infants," an established patient category of major medical concern and currently often identified as early or early stage asthma patients.

[0168] The combinations described herein are useful for treating heteroimmune diseases. In some embodiments, the inflammatory disease, disorder or condition is a heteroimmune disease, including but not limited to graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy (e.g., allergy to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, mite dust or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0169] The prophylactic effect in the treatment of asthma will be evidenced by a reduced frequency or severity of symptomatic attacks, for example, a reduced frequency or severity of attacks of acute asthma or bronchoconstrictors, an improvement in lung function, or improved airway hyperresponsiveness. It may further be evidenced by a reduced need for other symptomatic therapies, such as anti-inflammatory drugs or bronchodilators, to limit or stop symptomatic attacks, or treatments intended to limit or stop symptomatic attacks, if they occur. The prophylactic effect in asthma may be seen especially in subjects prone to "morning dipping." "Morning dip" is a recognized asthma syndrome common to a significant proportion of asthmatics and characterized by asthma attacks between about 4:00 a.m. and about 6:00 a.m., i.e., a time usually substantially removed from previously administered symptomatic asthma therapy.

[0170] In some embodiments, the inflammatory disease, disorder, or condition is selected from acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), chronic obstructive airways disease (COAD) or chronic obstructive lung disease (COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, and airway hyperresponsiveness due to other medications, particularly other inhaled medications. In some embodiments, the inflammatory disease, disorder, or condition is bronchitis, where the bronchitis is bronchitis of any type or origin, including, but not limited to, acute bronchitis, arachidic acid bronchitis, catarrhal bronchitis, croup bronchitis, chronic bronchitis, or tuberculous bronchitis. In some embodiments, the inflammatory disease, disorder or condition is pneumoconiosis of any kind or origin (an inflammatory, generally occupational, lung disease, whether chronic or acute, frequently associated with airway obstruction and caused by repeated inhalation of dust), such as the pneumoconiosis described above, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacco poisoning, and byssinosis.

[0171] In some embodiments, the inflammatory disease, disorder, or condition is an eosinophil-associated disorder, e.g., eosinophilia. In some embodiments, the eosinophil-associated disorder is an eosinophil-associated disorder of the airways (including, e.g., pathological eosinophil infiltration of lung tissue), e.g., hypereosinophilia affecting the airways and / or lungs, and eosinophil-associated disorders of the airways, e.g., caused by or associated with Loeffler's syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas, and eosinophil-associated disorders affecting the airways caused by drug reactions.

[0172] The combinations described herein are also useful in treating inflammatory or allergic conditions of the skin.In some embodiments, the inflammatory or allergic conditions of the skin are selected from psoriasis, dermatitis, such as eczema, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, rosacea, flexural psoriasis / inverse psoriasis, lichen planus, seborrheic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, 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.

[0173] In some embodiments, the 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 allergies, conjunctivitis, keratoconjunctivitis sicca, uveitis and vernal conjunctivitis, diseases and conditions affecting the nose (including allergic rhinitis), inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology (including autoimmune blood diseases (e.g., hemolytic anemia, aplastic anemia, true erythrocytic anemia, and idiopathic thrombocytopenia)), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, sprue), autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca, uveitis, and vernal conjunctivitis. keratoconjunctivitis), interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minor change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, myocardial infarction, myopathy, chronic granulomatous disease, chronic pulmonary fibrosis ... wasting, dysphagia, obesity, fetal growth retardation, intestinal failure, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, acute or chronic pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, anaphylaxis, nasal sinusitis, eye allergies, silica induced diseasediseases), COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression), pulmonary diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, diabetes mellitus type 1 or type 2, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, e.g. asthma , dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein 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, interstitial pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0174] In some embodiments, the inflammatory disease, disorder or condition is acute or chronic graft rejection in kidney, liver, heart, lung transplants, or graft-versus-host disease in bone marrow transplants.

[0175] In some embodiments, the inflammatory disease, disorder or condition is an inflammatory disease, disorder or condition of the skin, hi some embodiments, the inflammatory disease, disorder or condition of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, rosacea, flexural / inverse psoriasis, lichen planus, seborrheic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.

[0176] In some embodiments, the 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.

[0177] In some embodiments, the inflammatory disease, disorder or condition is a T17-mediated disease. In some embodiments, the T17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0178] In some embodiments, the inflammatory disease, disorder or condition is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye conditions such as eye allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose, such as allergic rhinitis.

[0179] In some embodiments, the inflammatory disease, disorder or condition is associated with transplantation. In some embodiments, the inflammatory disease, disorder or condition is associated with organ transplantation, organ transplant rejection and / or graft-versus-host disease. In some embodiments, the inflammatory disease, disorder or condition is an autoimmune disorder. In some embodiments, the autoimmune disorder is type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, ankylosing spondylitis, axial spondyloarthritis (axSpA), primary biliary cirrhosis, autoimmune hepatitis, or inflammatory bowel disease.

[0180] In some embodiments, the inflammatory disease, disorder or condition is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, ankylosing spondylitis, axial spondyloarthritis, such as axial spondyloarthritis as described above, including axial SpA giant cell arteritis, primary biliary cirrhosis, polymyalgia rheumatica, giant cell arteritis, or inflammatory bowel disease.

[0181] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition of the pancreas, hi some embodiments, the inflammatory disease, disorder, or condition of the pancreas is selected from type 1 diabetes, type 2 diabetes, acute pancreatitis, and chronic pancreatitis.

[0182] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition of the kidney, hi some embodiments, the inflammatory disease, disorder, or condition of the kidney is selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis, and acute or chronic rejection of a kidney transplant.

[0183] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition in the liver, hi some embodiments, the inflammatory disease, disorder, or condition is selected from nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, and acute or chronic rejection of a liver transplant.

[0184] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition in the lungs or heart, hi some embodiments, the inflammatory disease, disorder, or condition in the lungs is selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis, and acute or chronic rejection of a lung or heart transplant.

[0185] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition of the skin, in some embodiments, the inflammatory disease, disorder or condition of the skin is selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, dermatitis herpetiformis, rosacea, flexural / inverse psoriasis, lichen planus, seborrheic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne, keloid scars, and other inflammatory or allergic conditions of the skin.

[0186] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition of the blood vessels / blood, hi some embodiments, the inflammatory disease, disorder, or condition of the blood vessels / blood is selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, axial SpA giant cell arteritis and Takayasu's arteritis, proliferative vascular diseases, and restenosis.

[0187] In some embodiments, the present invention provides a method for treating an ophthalmic inflammatory disease, disorder, or condition, in which the ophthalmic inflammatory disease, disorder, or condition is selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis.

[0188] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition in the central or peripheral nervous system, in some embodiments, the 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's disease, Parkinson's disease, myelitis, Charcot-Marie-Tooth type 1 (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathy.

[0189] In some embodiments, the present invention provides a method for treating an autoimmune disease, disorder, or condition, hi some embodiments, the autoimmune disease, disorder, or condition is selected from lupus, e.g., lupus of the skin and kidney, Guillain-Barre syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis.

[0190] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition of the intestine, hi some embodiments, the inflammatory disease, disorder or condition of the intestine is selected from inflammation associated with intestinal failure, ulcerative colitis, and Crohn's disease, eosinophilic esophagitis, and colon cancer.

[0191] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition in the reproductive system, hi some embodiments, the inflammatory disease, disorder or condition in the reproductive system is selected from endometriosis, uterine fibroids, prostatic dysplasia or hyperplasia, and cervical dysplasia.

[0192] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition of bone and / or joints, hi some embodiments, the inflammatory disease, disorder or condition of bone and / or joints is selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hand, foot, ankle, knee, hip, shoulder, elbow, or spine.

[0193] In some embodiments, the present invention provides methods for treating inflammatory Coronaviridae infections and conditions associated therewith, particularly wherein the Coronaviridae is a Sarbecovirus selected from Severe Acute Respiratory Syndrome-associated coronaviruses, and more particularly wherein the Severe Acute Respiratory Syndrome (SARS)-associated coronaviruses are selected from the group consisting of SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2; including the causative strain of COVID-19 and variants thereof.

[0194] Advantageously, patients having or at risk of having a pathology associated with a Coronaviridae infection may also be considered.

[0195] According to certain embodiments, conditions associated with Coronaviridae infection that are particularly contemplated include pulmonary fibrosis, vasculitis, Kawasaki disease, and tissue damage or destruction, particularly lung tissue damage and destruction.

[0196] As used herein, "tissue repair and remodeling" means promoting the healing of tissue damaged or destroyed by disease, i.e., lung tissue destroyed by a coronavirus infection or gastrointestinal tissue destroyed by a coronavirus infection, as usually described in the context of treatment with classical anti-inflammatory diseases, e.g., corticosteroids, the most representative of this class of drugs, at least without slowing down the repair of the tissue.

[0197] Unless otherwise indicated, all disclosed combinations are specifically contemplated herein for the treatment or prophylaxis of coronaviruses and may therefore refer indiscriminately to any member of said coronaviruses within the meaning of the Baltimore convention.

[0198] As used herein, the term "Coronavirus family" refers to the corresponding family of RNA viruses belonging to Group IV of the Baltimore Classification, which is itself equivalent to part of the suborder Cornidovirineae and the order Nidovirale. The Coronavirus family includes both the subfamilies Letovirinae and Orthocoronavirinae.

[0199] As used herein, the term "Orthocoronavirus" refers to the corresponding family in the Baltimore classification, which includes the genera Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus.

[0200] As used herein, the term "alphacoronavirus genus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Colacovirus, Decacovirus, Duvinacovirus, Luchacovirus, Minacovirus, Minunacovirus, Myotacovirus, Myctacovirus, Pedacovirus, Rhinacovirus, Setracovirus, and Tegacovirus. Although not exhaustive, 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, long-fingered 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.

[0201] As used herein, the term "Betacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Embecovirus, Hibecovirus, Merbecovirus, Nobecovirus and Sarbecovirus. Although not exhaustive, this includes the following species: Betacoronavirus 1, China Rattus coronavirus HKU24, Human coronavirus HKU1, Murine coronavirus, Bat Hp-Betacoronavirus Zhejiang 2013, 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 bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus.

[0202] As used herein, the term "severe acute respiratory syndrome associated coronavirus", i.e., SARS virus, includes, but is not exhaustive, SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, and SARS-CoV-2, including the strain that causes COVID-19 and variants thereof.

[0203] As used herein, the term "Deltacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Andecovirus, Buldecovirus, Herdecovirus, and Moordecovirus. Although not exhaustive, this includes the following species: Wigeon coronavirus HKU20, Bulbul coronavirus HKU11, coronavirus HKU15, Munia coronavirus HKU13, White-eye coronavirus HKU16, Night heron coronavirus HKU19, and Common moorhen coronavirus HKU21.

[0204] As used herein, the term "Gammacoronavirus" refers to the corresponding family of the Baltimore classification, which includes the subgenera Cegacovirus and Igacovirus, which includes, but is not limited to, the following species: Beluga whale coronavirus SW1 and Avian coronavirus.

[0205] According to a particular embodiment, the pharmaceutical compositions according to the invention may be used in the treatment of inflammatory bowel diseases (IBD), such as those mentioned above including Crohn's disease or ulcerative colitis, dermatitis and rheumatoid arthritis.

[0206] According to a particular embodiment, the pharmaceutical compositions according to the invention may be used in the treatment of ulcerative colitis, Crohn's disease and / or eosinophilic esophagitis.

[0207] The present invention further relates to a combination of a compound of formula (I) as defined hereinafter, a pharma- ceutical or pharmaceutical acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, and a JAK inhibitor or a pharma- ceutical or pharmaceutical acceptable salt thereof, for use in the treatment of an inflammatory disease, disorder or condition as detailed above in a patient, in which the JAK inhibitor is administered at a daily dose that is reduced by at least 20%, at least 30%, or even at least 40% compared to the dose indicated for the treatment of the same inflammatory disease for the same patient in the absence of the compound of formula (I).

[0208] The inflammation modulating capacity of the pharmaceutical combination according to the present invention can be evaluated for inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). The Dextran Sulphate Sodium (DSS-) induced colitis mouse model can be used to study 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 to study rheumatoid arthritis, as shown in Brand et al. ("Collagen-induced arthritis"; Nature Protocols; (2007); 2(5): 1269-75).

[0209] Indeed, administration of the pharmaceutical combination defined above led to an in vivo improvement in colon length, weight loss, and inflammation in the colon in a DSS-induced colitis mouse model, with a synergistic effect being observed when compared to the administration of each compound alone.

[0210] Administration of the pharmaceutical combination defined above resulted in a significant reduction in joint swelling and a decrease in signs of inflammation based on a collagen-induced arthritis mouse model, and a synergistic effect was observed for the combination when compared to the administration of each compound of the combination alone.

[0211] Pharmaceutical compositions, methods of treatment and administration schemes

[0212] According to another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma- ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, and a JAK inhibitor or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, adjuvant or vehicle.

[0213] The present invention relates to a pharmaceutical kit, in particular intended to treat the disorders or conditions detailed herein above, in particular inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis, comprising: (i) a first galenical formulation comprising a compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or a pharma-ceutically acceptable salt thereof or one of its metabolites, in particular one of its glucuronide metabolites, and (ii) a second galenical formulation comprising a JAK inhibitor or a pharma- ceutical acceptable salt thereof; The present invention relates to a pharmaceutical kit comprising:

[0214] According to a particular embodiment, the pharmaceutical composition or kit according to the invention comprises a compound of formula (I) as defined above, which is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharma- ceutically acceptable salts.

[0215] According to a particular embodiment, the pharmaceutical composition or kit according to the invention comprises abrocitinib, baricitinib, BMS-986165, decernotinib (VX509), filgotinib, itacitinib, oclacitinib, peficitinib, fedratinib, deucravacitinib, P F-06651600, PF-06700841, SHR-0302, R333 (R932333), R348 (R932348), ruxolitinib, solcitinib, delgocitinib, Izencitinib (TD-1473), TD-3504, tofacitinib, and upadacitinib or a pharma- ceutically acceptable salt thereof, in particular upadacitinib.

[0216] According to a specific embodiment, the pharmaceutical composition or kit according to the present invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharma- ceutically acceptable salts or its metabolites, and upadacitinib or a pharma- ceutically acceptable salt thereof.

[0217] According to a particular embodiment, the pharmaceutical composition or kit according to the invention comprises 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and upadacitinib.

[0218] In certain embodiments, the pharmaceutical compositions of the invention are formulated for administration to a patient in need of such a composition, hi some embodiments, the compositions of the invention are formulated for oral administration to a patient.

[0219] The term "pharmaceutical acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound in which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, 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, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0220] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, intravaginally, via a skin patch or an implanted reservoir, or via sustained release oral or parenteral dosage forms. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. 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.

[0221] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, and its glyceride derivatives, especially in their polyoxyethylated versions, are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils, such as olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, that are commonly used in the preparation of pharma- ceutical acceptable dosage forms, including emulsions and suspensions. Commonly used surfactants, such as Tweens, Spans, and other emulsifiers, or bioavailability enhancers that are also commonly used in the manufacture of pharma- ceutical acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0222] The pharmaceutical composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants, such as magnesium stearate, are also typically added.For oral administration in 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 sweeteners, flavors or colorants can also be added.

[0223] Alternatively, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0224] The pharmaceutical compositions of this invention may also be administered topically, especially when the subject of treatment includes areas or organs readily accessible by topical application, including disorders of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0225] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0226] For topical application, the prepared pharmaceutical composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical application of the combination of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the prepared pharmaceutical composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers.

[0227] 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.

[0228] For ophthalmic use, the prepared pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0229] The pharmaceutical compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents. Most preferably, the pharmaceutical compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food.

[0230] In some embodiments, the pharmaceutical compositions of the invention are administered without food, hi other embodiments, the pharmaceutical compositions of the invention are administered with food.

[0231] According to some embodiments, the present invention further relates to a method for treating an inflammatory disease, disorder or condition as detailed herein above, in particular inflammatory bowel diseases, such as inflammatory bowel diseases as described above, including ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis, in a patient in need of such treatment, comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I), a pharma- ceutical acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, as defined herein above, and an effective amount of a JAK inhibitor or a pharma-ceutical acceptable salt thereof, in particular upadacitinib or a pharma-ceutical acceptable salt thereof.

[0232] Dosage and Regimen

[0233] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including, for example, the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of a compound of the invention in the composition will also depend on the particular compound in the composition.

[0234] In one embodiment, the treatment is continuous with respect to either one or both of the compound of formula (I) as defined herein above, its pharma- ceutically acceptable salts, its prodrugs or its metabolites, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and the JAK inhibitor or its pharma- ceutically acceptable salts, or is non ... ceutical acceptable salts.

[0235] In one embodiment, the treatment is sequential for both the compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, and the JAK inhibitor or a pharma- ceutically acceptable salt thereof.

[0236] "Continuous treatment" means long-term treatment, which can be carried out including various dosing frequencies, preferably twice daily, more preferably once daily.

[0237] The administration of the compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, and the JAK inhibitor or a pharma- ceutically acceptable salt thereof, may be carried out simultaneously, separately or dispersed over time.

[0238] The combination can be administered repeatedly during several sequences or cycles, according to a protocol that depends on the nature of the disease and the intensity of the disease to be treated, and also on the patient to be treated (age, weight, previous one or more treatments, etc.), which can be determined by a specialist physician.

[0239] Various sequences or cycles of administration of the compound of formula (I) as defined herein above, its pharma- ceutically acceptable salts, its prodrugs or metabolites, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, and the JAK inhibitor or its pharma-ceutically acceptable salts, respectively, may be carried out within the framework of the present invention.

[0240] According to a particular embodiment and one of the possible administration sequences, a compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, is administered to the patient during a first phase of treatment, and then, in a second phase of treatment or in the reverse order, the patient is treated with said JAK inhibitor or a pharma- ceutically acceptable salt thereof. Both phases may or may not overlap.

[0241] Whatever the dosage regimen, typically the dose of the compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, in humans, may be in the range of 1 mg to 50 mg per day, in particular 5 mg to 25 mg per day, more in particular 10 mg to 25 mg per day.

[0242] Whatever the dosing regimen, typically the daily dose of the JAK inhibitor or a pharma- ceutical acceptable salt thereof, particularly upadacitinib, may be in the range of from 1 mg to 30 mg per day, particularly from 1 mg to 25 mg per day, more particularly from 1 mg to 20 mg per day, for example from 1 mg to 15 mg per day.

[0243] As an alternative to the above mentioned regimen, the administration of the compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, may be discontinuous, while the administration of the JAK inhibitor or a pharma- ceutically acceptable salt thereof, in particular upadacitinib, may be continuous or discontinuous.

[0244] As another alternative to the above described sequence of administration, the compound of formula (I) as defined herein above, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, and the JAK inhibitor or a pharma- ceutically acceptable salt thereof, in particular upadacitinib, may be administered in unique dosage forms or unit pharmaceutical formulations.

[0245] Accordingly, the present invention provides a unit dosage form comprising a compound of formula (I) as defined hereinabove, a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, and the JAK inhibitor or a pharma- ceutically acceptable salt thereof, in particular upadacitinib, and a pharma- ceutically acceptable carrier, adjuvant or vehicle.

[0246] In a particular embodiment, the pharmaceutical composition according to the invention comprises a compound of formula (I) as defined herein above, a pharma- ceutical acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, in an amount ranging from 1 mg to 50 mg, in particular from 5 mg to 25 mg, more in particular from 10 mg to 25 mg, and a JAK inhibitor or a pharma- ceutical acceptable salt thereof, in particular upadacitinib, in an amount ranging from 1 to 30 mg, in particular from 1 to 25 mg, more in particular from 1 to 20 mg, and even more in particular from 1 to 15 mg.

[0247] All combinations of dosage, frequency and duration of treatment are within the scope of the present invention.

[0248] In one embodiment, the treatment is continuous treatment without an induction phase.

[0249] In one embodiment, the induction dose is carried out during an induction sequence which may last from 4 to 16 weeks, followed by a further administration sequence in which the daily dose of only one of the compounds of the pharmaceutical combination defined above is reduced by 20% to 60%, in particular by 30% to 50%, relative to the induction daily dose for said compound of said combination.

[0250] In one embodiment, there is provided herein a pharmaceutical combination as defined above for the use as defined above for treating a patient, wherein the presence and / or expression level of miR-124 in a blood sample and / or a tissue sample of the patient is measured before and during use, in particular for adjusting the dosage of the compound of formula (I), a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, as defined herein above.

[0251] In one embodiment, further provided herein is a method of the present invention for treating an inflammatory disease, disorder or condition, further comprising measuring and / or monitoring the presence and / or level of a biomarker in a patient. In some embodiments, the presence and / or level of a biomarker is measured in a biological sample of a patient. In some embodiments, the biological sample of a patient is a blood sample. In some embodiments, the biological sample of a patient is a tissue sample. In some embodiments, the biomarker measured and / or monitored in the method of the present invention is miR-124, as described in International Publication No. WO2014 / 111892 (the entire contents of which are incorporated herein by reference). In some embodiments, the method of the invention for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in the patient prior to administering a compound of formula (I), a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, as defined hereinabove. In some embodiments, the method of the invention for treating an inflammatory disease, disorder or condition further comprises measuring and / or monitoring the presence and / or expression level of miR-124 in the patient during the course of treatment with the pharmaceutical combination as defined hereinabove.

[0252] In some embodiments, the methods of the invention for treating an inflammatory disease, disorder or condition further comprise adjusting (e.g., increasing or decreasing) the dosing regimen (e.g., dosage and / or dosing schedule) of a compound of formula (I), a pharma- ceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, as defined hereinabove, to be administered to the patient by measuring and / or monitoring the presence and / or expression level of miR-124 in the patient.

[0253] In one embodiment, there is provided herein a pharmaceutical combination as defined above for the use as defined above for treating a patient, wherein relevant proteins, metabolites or receptors, such as H3K122Ac, C1M, C2M, C3M or C4M, are measured before and during use, in particular to adjust the dosage of the JAK inhibitor or a pharma- ceutical acceptable salt thereof, in particular upadacitinib.

[0254] Further provided herein is a method for treating an inflammatory disease, disorder or condition of the present invention, further comprising measuring and / or monitoring in a patient an associated protein, metabolite or receptor, such as H3K122Ac, C1M, C2M, C3M or C4M. In some embodiments, the associated protein, metabolite or receptor, such as H3K122Ac, C1M, C2M, C3M or C4M, is measured in a patient's biological sample. In some embodiments, the patient's biological sample is a blood sample. In some embodiments, the patient's biological sample is a tissue sample. In some embodiments, the method for treating an inflammatory disease, disorder or condition of the present invention further comprises measuring in a patient an associated protein, metabolite or receptor, such as H3K122Ac, C1M, C2M, C3M or C4M, before administering a JAK inhibitor or a pharma- ceutically acceptable salt thereof, particularly upadacitinib. In some embodiments, the method of the present invention for treating an inflammatory disease, disorder or condition further comprises measuring associated proteins, metabolites or receptors, such as H3K122Ac, C1M, C2M, C3M or C4M, in the patient during the course of treatment with the pharmaceutical combination defined above.

[0255] In some embodiments, the methods of the invention for treating an inflammatory disease, disorder or condition further include adjusting (e.g., increasing or decreasing) the dosing regimen (e.g., dosage and / or dosing schedule) of a JAK inhibitor or a pharma- ceutical acceptable salt thereof, particularly upadacitinib, to be administered to a patient by measuring an associated protein, metabolite or receptor, e.g., H3K122Ac, C1M, C2M, C3M or C4M, in the patient.

[0256] In some embodiments, the present invention provides a pharmaceutical composition comprising a combination described herein and one or more additional therapeutic agents.

[0257] Such additional therapeutic agents may be small molecules or recombinant biologics, such as, for example, acetaminophen; non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine); 登録商標 ) and celecoxib; colchicine (Colcrys 登録商標 ;corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; probenecid, allopurinol, febuxostat (Uloric 登録商標 ), Sulfasalazine (Azulfidine 登録商標 ; antimalarials, e.g., hydroxychloroquine (Plaquenil) 登録商標 ) and chloroquine (Aralen 登録商標 );Methotrexate (Rheumatrex 登録商標 ; gold salts, e.g., gold thioglucose (Solganal 登録商標 ), Gold Thiomalate (Myochrysine 登録商標 ) and auranofin (Ridaura 登録商標 );D-Penicillamine (Depen 登録商標 or Cuprimine 登録商標 ), azathioprine (Imuran 登録商標 ), cyclophosphamide (Cytoxan 登録商標), chlorambucil (Leukeran 登録商標 ), cyclosporine (Sandimmune 登録商標 , Neoral 登録商標 ), tacrolimus, sirolimus, mycophenolate, leflunomide (Arava 登録商標 ; and "anti-TNF" agents, such as etanercept (Enbrel 登録商標 ), infliximab (Remicade 登録商標 ), golimumab (Simponi 登録商標 ), certolizumab pegol (Cimzia 登録商標 ) and adalimumab (Humira 登録商標 ); "anti-IL-1" agents, such as anakinra (Kineret 登録商標 ) and rilonacept (Arcalyst 登録商標 anti-T cell antibodies, e.g., thymoglobulin, intravenous (IV) immunoglobulin (IVIG), canakinumab (Ilaris 登録商標 ; antibodies, such as rituximab (Rituxan 登録商標 ); "anti-T cell" agents, such as abatacept (Orencia 登録商標 ); "anti-IL-6" agents, such as tocilizumab (Actemra) 登録商標 );Diclofenac, Cortisone, Hyaluronic Acid (Synvisc 登録商標 or Hyalgan 登録商標 ; monoclonal antibodies, e.g., tanezumab; anticoagulants, e.g., heparin 登録商標 Or Liquaemin 登録商標 ) and warfarin (Coumadin 登録商標 ;Antidiarrheal drugs, such as diphenoxylate (Lomotil) 登録商標 ) and loperamide (Imodium 登録商標 ; bile acid binding drugs, such as cholestyramine; alosetron (Lotronex 登録商標 ), lubiprostone (Amitiza登録商標 ); Laxatives, e.g., Milk of Magnesia, Polyethylene Glycol (MiraLax 登録商標 ), Dulcolax 登録商標 ), Correctol 登録商標 ) and Senokot 登録商標 ; anticholinergics or antispasmodics, such as dicyclomine (Bentyl 登録商標 ), Singulair 登録商標 ; beta-2 (β2) agonists, e.g., albuterol (Ventolin 登録商標 HFA, Proventil 登録商標 HFA), levalbuterol (Xopenex 登録商標 ), metaproterenol (Alupent 登録商標 ), Pirbuterol Acetate (Maxair 登録商標 ), terbutaline sulfate (Brethaire 登録商標 ), salmeterol xinafoate (Serevent 登録商標 ) and formoterol (Foradil 登録商標 ; anticholinergics, such as ipratropium bromide (Atrovent 登録商標 ) and tiotropium (Spiriva 登録商標 inhaled corticosteroids, such as beclomethasone dipropionate (Beclovent 登録商標 , Qvar 登録商標 and Vanceril 登録商標 ), triamcinolone acetonide (Azmacort 登録商標 ), mometasone (Asthmanex 登録商標 ), budesonide (Pulmocort 登録商標 ) and flunisolide (Aerobid 登録商標 ); Mometasone (Asthmanex 登録商標 ), budesonide (Pulmocort 登録商標 ) and flunisolide (Aerobid 登録商標 ), Afviar 登録商標 ), Symbicort 登録商標 ) and Dulera登録商標 ); Cromolyn sodium (Intal 登録商標 ; methylxanthines, e.g. theophylline (Theo-Dur 登録商標 , Theolair 登録商標 , Slo-bid 登録商標 , Uniphyl 登録商標 , Theo-24 登録商標 ) and aminophylline; IgE antibodies, such as omalizumab (Xolair) 登録商標 ; nucleoside reverse transcriptase inhibitors, such as zidovudine (Retrovir 登録商標 ), abacavir (Ziagen 登録商標 ), abacavir / lamivudine (Epzicom 登録商標 ), Abacavir / Lamivudine / Zidovudine (Trizivir 登録商標 ), didanosine (Videx 登録商標 ), emtricitabine (Emtriva 登録商標 ), Lamivudine (Epivir 登録商標 ), Lamivudine / Zidovudine (Combivir 登録商標 ), Stavudine (Zerit 登録商標 ) and zalcitabine (Hivid 登録商標 ; non-nucleoside reverse transcriptase inhibitors, such as delavirdine (Rescriptor 登録商標 ), Efavirenz (Sustiva 登録商標 ), nevirapine (Viramune 登録商標 ) and etravirine (Intelence 登録商標 nucleotide reverse transcriptase inhibitors, such as tenofovir (Viread 登録商標 ; protease inhibitors, e.g., amprenavir (Agenerase 登録商標 ), atazanavir (Reyataz 登録商標 ), darunavir (Prezista 登録商標 ), fosamprenavir (Lexiva 登録商標 ), Indinaville (Crixivan 登録商標 ), lopinavir-ritonavir (Kaletra 登録商標 ), Nelfinavir (Viracept 登録商標 ), ritonavir (Norvir 登録商標), saquinavir (Fortovase 登録商標 or Invirase 登録商標 ), and tipranavir (Aptivus 登録商標 Entry inhibitors, such as enfuvirtide (Fuzeon 登録商標 ) and Maraviroc (Selzentry 登録商標 integrase inhibitors, such as raltegravir (Isentress 登録商標 ), doxorubicin (Hydrodaunorubicin 登録商標 ), vincristine (Oncovin 登録商標 ), bortezomib (Velcade 登録商標 ), and lenalidomide (Revlimid 登録商標 ) and combination dexamethasone (Decadron 登録商標); 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 as BI-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; ubiquinone protein ligase complex inhibitors, such as BBT- 401;sphingosine receptor modulators, e.g. BMS-986166;P38MAPK / PDE4 inhibitors, e.g. CBS-3595;CCR9 antagonists, e.g. CCX-507;FimH antagonists, e.g. EB-8018;HIF-PH inhibitors, e.g. FG-6874;HIF-1α stabilizers, e.g. GB-004; MAP3K8 protein inhibitors, e.g., GS-4875; LAG-3 antibodies, e.g., GSK-2831781; RIP2 kinase inhibitors, e.g., GSK-2983559; farnesoid X receptor agonists, e.g., MET-409; CCK2 antagonists, e.g., PNB-001; IL-23 receptor antagonists, e.g., PTG-200; purinergic P2X7 receptor antagonists, e.g., SGM-1019; PDE4 inhibitors, e.g., apremilast; ICAM-1 inhibitors, e.g., alicaforsen sodium; anti-IL23 agents, e.g., guselkumab, bradykinin, erythropoietin ... brazikumab and mirkizumab; anti-IL-15 agents such as AMG-714; TYK-2 inhibitors such as BMS-986165; NK cell 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 as edicotinib;Or any combination of one or more thereof.

[0258] The additional therapeutic agent may alternatively be non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine), and the like, particularly for the treatment of gout. 登録商標 ) and celecoxib; colchicine (Colcrys 登録商標 ;corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; probenecid, allopurinol, febuxostat (Uloric 登録商標 ) may be selected from.

[0259] In particular, for the treatment of rheumatoid arthritis, the additional therapeutic agent may alternatively be a non-steroidal anti-inflammatory drug (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine 登録商標 ) and celecoxib; corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; sulfasalazine (Azulfidine 登録商標 ; antimalarials, e.g., hydroxychloroquine (Plaquenil) 登録商標 ) and chloroquine (Aralen 登録商標 );Methotrexate (Rheumatrex 登録商標 ; gold salts, e.g., gold thioglucose (Solganal 登録商標 ), Gold Thiomalate (Myochrysine 登録商標 ) and auranofin (Ridaura 登録商標 );D-Penicillamine (Depen 登録商標 or Cuprimine 登録商標 ), azathioprine (Imuran 登録商標 ), cyclophosphamide (Cytoxan 登録商標 ), chlorambucil (Leukeran 登録商標 ), cyclosporine (Sandimmune登録商標 ), leflunomide (Arava 登録商標 ; and "anti-TNF" agents, such as etanercept (Enbrel 登録商標 ), infliximab (Remicade 登録商標 ), golimumab (Simponi 登録商標 ), certolizumab pegol (Cimzia 登録商標 ) and adalimumab (Humira 登録商標 ); "anti-IL-1" agents, such as anakinra (Kineret 登録商標 ) and rilonacept (Arcalyst 登録商標 ; antibodies, such as rituximab (Rituxan 登録商標 ); "anti-T cell" agents, such as abatacept (Orencia 登録商標 ); "anti-IL-6" agents, such as tocilizumab (Actemra) 登録商標 ) may be selected from.

[0260] In particular, in the case of the treatment of osteoarthritis, the additional therapeutic agent may be acetaminophen; non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib; diclofenac, cortisone, hyaluronic acid (Synvisc®), 登録商標 or Hyalgan 登録商標 ); and monoclonal antibodies, such as tanezumab.

[0261] In particular, for the treatment of lupus, the additional therapeutic agent may be acetaminophen; non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine); 登録商標) and celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; antimalarials such as hydroxychloroquine (Plaquenil 登録商標 ) and chloroquine (Aralen 登録商標 );Cyclophosphamide (Cytoxan 登録商標 ), methotrexate (Rheumatrex 登録商標 ), azathioprine (Imuran 登録商標 ), as well as anticoagulants such as heparin (Calcinparine 登録商標 Or Liquaemin 登録商標 ) and warfarin (Coumadin 登録商標 ) may be selected from.

[0262] In particular, for the treatment of Crohn's disease, ulcerative colitis or inflammatory bowel disease, the additional therapeutic agent may be mesalamine (Asacol). 登録商標 ), Sulfasalazine (Azulfidine 登録商標 ;Antidiarrheal drugs, such as diphenoxylate (Lomotil) 登録商標 ) and loperamide (Imodium 登録商標 ; bile acid binding drugs, such as cholestyramine; alosetron (Lotronex 登録商標 ), lubiprostone (Amitiza 登録商標 ); Laxatives, e.g., Milk of Magnesia, Polyethylene Glycol (MiraLax 登録商標 ), Dulcolax 登録商標 ), Correctol 登録商標 ) and Senokot 登録商標 ; and anticholinergic or antispasmodic drugs such as dicyclomine (Bentyl 登録商標 ); anti-TNF therapy; steroids; and antibiotics, such as Flagyl or ciprofloxacin.

[0263] In particular, in the case of the treatment of asthma, the additional therapeutic agent is Singulair. 登録商標 ; beta-2 (β2) agonists, e.g., albuterol (Ventolin登録商標 HFA, Proventil 登録商標 HFA), levalbuterol (Xopenex 登録商標 ), metaproterenol (Alupent 登録商標 ), Pirbuterol Acetate (Maxair 登録商標 ), terbutaline sulfate (Brethaire 登録商標 ), salmeterol xinafoate (Serevent 登録商標 ) and formoterol (Foradil 登録商標 ; anticholinergics, such as ipratropium bromide (Atrovent 登録商標 ) and tiotropium (Spiriva 登録商標 ; inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent 登録商標 , Qvar 登録商標 and Vanceril 登録商標 ), triamcinolone acetonide (Azmacort 登録商標 ), mometasone (Asthmanex 登録商標 ), budesonide (Pulmocort 登録商標 ) and flunisolide (Aerobid 登録商標 ); Mometasone (Asthmanex 登録商標 ), budesonide (Pulmocort 登録商標 ) and flunisolide (Aerobid 登録商標 ), Afviar 登録商標 ), Symbicort 登録商標 ) and Dulera 登録商標 ); Cromolyn sodium (Intal 登録商標 ; methylxanthines, e.g. theophylline (Theo-Dur 登録商標 , Theolair 登録商標 , Slo-bid 登録商標 , Uniphyl 登録商標 , Theo-24 登録商標 ) and aminophylline; and IgE antibodies, such as omalizumab (Xolair 登録商標 ), may be selected from.

[0264] In particular, in the case of the treatment of COPD, the additional therapeutic agent may alternatively be a beta-2 (β2) agonist, such as albuterol (Ventolin). 登録商標 HFA, Proventil 登録商標 HFA), levalbuterol (Xopenex 登録商標 ), metaproterenol (Alupent 登録商標 ), Pirbuterol Acetate (Maxair 登録商標 ), terbutaline sulfate (Brethaire 登録商標 ), salmeterol xinafoate (Serevent 登録商標 ) and formoterol (Foradil 登録商標 ; anticholinergics, such as ipratropium bromide (Atrovent 登録商標 ) and tiotropium (Spiriva 登録商標 ; methylxanthines, e.g. theophylline (Theo-Dur 登録商標 , Theolair 登録商標 , Slo-bid 登録商標 , Uniphyl 登録商標 , Theo-24 登録商標 ) and aminophylline; inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent 登録商標 , Qvar 登録商標 and Vanceril 登録商標 ), triamcinolone acetonide (Azmacort 登録商標 ), mometasone (Asthmanex 登録商標 ), budesonide (Pulmocort 登録商標 ), flunisolide (Aerobid 登録商標 ), Afviar 登録商標 ), Symbicort 登録商標 ) and Dulera 登録商標 ) may be selected from.

[0265] In particular, in the case of treatment of organ transplant rejection or graft-versus-host disease, the additional therapeutic agent may be selected from steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0266] In particular, in the case of treating Coronaviridae infections and conditions associated therewith, the additional therapeutic agent may be selected from dynamin-2 inhibitors, such as Dynasore; antibiotics, such as antibiotics selected from the group consisting of beta-lactams, fluoroquinolones, and macrolides, such as azythromicin; Remdesivir; Ribavirin; Ritonavir; lopanivir; chloroquine or hydroxychloroquine; beta-interferon; anti-inflammatory compounds, such as anti-TNF, Jak inhibitors, anti-IL6 antibodies, IL6 receptor antagonists; and calcium inhibitors, such as diltiazem.

[0267] The combinations of the invention may be the subject of pharmacological tests which demonstrate their suitability as active combinations in therapy, in particular in therapy for the prevention of inflammatory diseases.

[0268] In both examples below, the combination of the invention is a combination of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and upadacitinib, and is named "the combination."

[0269] Example 1: Effect of the combination of the present invention on (DSS-) induced colitis model

[0270] A. Materials and Methods

[0271] Mouse model

[0272] DSS Model

[0273] A commonly used mouse model of inflammatory bowel disease is the Dextran Sulphate Sodium (DSS-) induced colitis model. Typical histological changes in acute DSS-colitis are mucin depletion, epithelial degeneration, and ultimately disruption of the mucosal barrier leading to inflammation and colitis.

[0274] Five groups (n=10 per group) of 9-week-old female C57Bl / 6JOlaHsd mice are administered DSS in drinking water (2.5%) for 7 days followed by water only for 3 days. Weight loss is measured daily, clinical scores are calculated every 2-3 days, and colon length is measured on day 10. One group is treated with 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine. One group is treated with upadacitinib vehicle. One group of mice is treated with 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine alone at doses ranging from 1 to 40 mg / kg / day. One group of mice is treated with upadacitinib at a dose of 1 to 10 mg / kg / day, and one group is treated with a combination of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine at a dose of 1 to 40 mg / kg / day and upadacitinib at a dose of 1 to 10 mg / kg / day.

[0275] B. Results

[0276] Results are established using the combinations described above.

[0277] The combination treatment significantly inhibits weight loss, clinical scores, and colon length loss after 10 days of treatment. Interestingly, the combination treatment demonstrates synergistic effects when compared to groups treated with each agent alone.

[0278] Example 2: Effect of the combination of the present invention on collagen-induced arthritis model

[0279] A. Materials and Methods

[0280] Mouse model

[0281] Collagen-induced arthritis model:

[0282] Groups of 9-10 week old DBA / 1 mice are immunized intradermally with bovine collagen type II emulsified 1:1 with complete Freund's adjuvant. Mice are challenged 21 days after the first immunization and the phenotypic appearance of arthritis is assessed by monitoring the thickness of the ankle joints of each hind limb every 2 days using a dial caliper (0-10 mm) test gauge.

[0283] One group is treated with 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine vehicle for two weeks. One group is treated with upadacitinib vehicle for two weeks. One group of mice is treated with 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine alone at a dose of 1-40 mg / kg / day for two weeks. One group of mice is treated with upadacitinib at a dose of 1-10 mg / kg / day, and one group is treated with a combination of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine at a dose of 1-40 mg / kg / day and upadacitinib at a dose of 1-10 mg / day.

[0284] B. Results

[0285] Treatment with the combination significantly prevents paw swelling after 2 weeks of treatment. Interestingly, the combination demonstrates synergistic effects when compared to groups treated with each agent alone.

[0286] Therefore, the results of the studies carried out on the combination of the present invention indicate that said combination may be useful for treating and / or preventing inflammatory diseases, as further described above.

Claims

1. A pharmaceutical combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a metabolite thereof, and a JAK inhibitor, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) has the formula: 【Chemistry 1】 where: Z is C or N; V is C or N; 【Chemistry 2】 means an aromatic ring, wherein V is C or N, and when V is N, V ​​is ortho, meta or para to Z; Each R is independently a hydrogen atom, a halogen atom, -CN, hydroxyl, (C 1 ~C 3 ) fluoroalkyl, (C 1 ~C 3 ) fluoroalkoxy, (C 3 ~C 6 ) cycloalkyl, -NO 2 , -NR 1 R 2 , (C 1 ~C 4 )Alkoxy, Phenoxy, -NR 1 -SO 2 -NR 1 R 2 , -NR 1 -SO 2 -R1, -NR 1 -C(=O)-R 1 , -NR 1 -C(=O)-NR 1 R 2 , -SO 2 -NR 1 R 2 , -SO 3 H, -O-SO 2 -OR 3 ,-OP(=O)-(OR 3 )(OR 4 ), -O-CH 2 -COOR 3 , (C 1 ~C 3 ) alkyl, wherein the alkyl is selected from the group consisting of a hydroxyl group, a group of formula (IIa): 【Transformation 3】 or a group of formula (IIIa): 【Chemistry 4】 optionally mono- or disubstituted by Q is N or O, with the proviso that when Q is O, R″ is absent; R 1 and R 2 Each of the groups independently represents a hydrogen atom or (C 1 ~C 3 ) alkyl; R 3 and R 4 each independently represents a hydrogen atom, Li + , Na + , K. + , N + (Ra) 4 or benzyl; n is 1, 2 or 3; n' is 1, 2 or 3; Each R' is independently a hydrogen atom, (C 1 ~C 3 ) Alkyl, hydroxyl, halogen atom, -NO 2 , -NR 1 R 2 , morpholinyl, morpholino, N-methylpiperazinyl, (C 1 ~C 3 ) fluoroalkyl, (C 1 ~C 4 )alkoxy, -OP(=O)-(OR 3 )(OR 4 ), —CN, a group of formula (IIa): 【Transformation 5】 or a group of formula (IIIa): 【Transformation 6】 and A is a covalent bond, an oxygen atom, 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 independently represents a hydrogen atom, (C 1 ~C 5 ) alkyl or (C 3～ C 6 ) cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, wherein the heterocycle may be substituted with one or more Ra, provided that when R' is a group of (IIa) or (IIIa), n' may be 2 or 3 only when the other R' group is different from the group of (IIa) or (IIIa); and R" is a hydrogen atom, (C 1 ~C 4 ) alkyl, or a group of formula (IIa) as defined above.

2. The compound of formula (I) is any one of the compounds of formula (Ib) below, or metabolites thereof, pharmaceutically acceptable salts thereof, or prodrugs thereof: 【Transformation 7】 wherein R, R' and R" are as defined in claim 1. The pharmaceutical combination according to claim 1.

3. 3. The pharmaceutical combination according to claim 1 or 2, wherein the compound of formula (I) is selected from 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharmaceutically acceptable salts or metabolites.

4. 2. A pharmaceutical combination according to claim 1, comprising a metabolite of the compound of formula (I), in particular a glucuronide metabolite thereof.

5. 5. The pharmaceutical combination of claim 4, comprising a glucuronide metabolite of the formula: 【Transformation 8】

6. 2. The pharmaceutical combination of claim 1, wherein the JAK inhibitor is selected from abrocitinib, baricitinib, BMS-986165, decernotinib (VX509), filgotinib, itacitinib, oclacitinib, peficitinib, fedratinib, deuclavatinib, PF-06651600, PF-06700841, SHR-0302, R333 (R932333), R348 (R932348), ruxolitinib, solcitinib, delgocitinib, izencitinib (TD-1473), TD-3504, tofacitinib and upadacitinib; in particular upadacitinib, and pharmaceutically acceptable salts thereof.

7. 2. The pharmaceutical combination of claim 1, wherein the compound of formula (I) is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and the JAK inhibitor is upadacitinib.

8. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, a pharmaceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, and a JAK inhibitor or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

9. 9. The pharmaceutical composition of claim 8, wherein the compound of formula (I) and the JAK inhibitor are as defined in claim 2.

10. 9. The pharmaceutical composition of claim 8, comprising 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharmaceutically acceptable salts, and upadacitinib or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

11. A combination as defined in claim 1 for use in the treatment of an inflammatory disease, disorder or condition as defined below: (a) an inflammatory disease, disorder, or condition of the pancreas selected from type 1 diabetes, type 2 diabetes, acute pancreatitis, and chronic pancreatitis; (b) an inflammatory disease, disorder, or condition of the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis, and acute or chronic rejection of a kidney transplant; (c) an inflammatory disease, disorder, or condition of the liver selected from nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, and acute or chronic rejection of a liver transplant; (d) inflammatory diseases, disorders, or conditions of the lungs or heart selected from bronchitis, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis, and acute or chronic rejection of lung or heart transplants, Coronaviridae infections and conditions related thereto, particularly wherein the Coronaviridae is a Sarbecovirus selected from severe acute respiratory syndrome-associated coronaviruses, and even more particularly wherein the severe acute respiratory syndrome (SARS)-associated coronavirus is selected from the group consisting of SARS-CoV, SARSr-CoV WIV1, SARSr-CoV HKU3, SARSr-CoV RP3, SARS-CoV-2; including the strains that cause COVID-19 and their variants; (e) inflammatory diseases, disorders or conditions of the skin selected from psoriasis, dermatitis, e.g., eczema, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, rosacea, flexural / inverse psoriasis, lichen planus, seborrheic dermatitis, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne, keloid scars, and other inflammatory or allergic conditions of the skin; (f) an inflammatory disease, disorder, or condition of the blood vessels / blood selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, proliferative vascular disease and restenosis, atherosclerosis, axial spondyloarthritis, including, for example, axial SpA giant cell arteritis, and Takayasu's arteritis; (g) an inflammatory disease, disorder, or condition of the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis; (h) inflammatory diseases, disorders, or conditions of the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, including, for example, chronic pain, traumatic brain injury, including, for example, stroke, neurodegenerative diseases, including, for example, Alzheimer's disease, and Parkinson's 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 lupus of the skin and kidney, Guillain-Barré syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease and myocarditis; (j) an inflammatory disease, disorder, or condition of the reproductive system selected from endometriosis, uterine fibroids, prostatic dysplasia or hyperplasia, and cervical dysplasia; (k) an inflammatory disease, disorder or condition of the bones and / or joints selected from rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hand, foot, ankle, knee, hip, shoulder, elbow or spine; (l) an inflammatory disease, disorder, or condition of the digestive tract selected from inflammation associated with colon cancer, inflammatory bowel disease, including, for example, Crohn's disease and ulcerative colitis, and eosinophilic esophagitis; and (m) An inflammatory disease, disorder or condition of 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).

12. 12. The combination for use according to claim 11, wherein the inflammatory disease is inflammatory bowel disease, including for example ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

13. 12. A pharmaceutical combination of a compound of formula (I) as defined in claim 1, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharmaceutically acceptable salts, prodrugs or metabolites, with a JAK inhibitor or a pharmaceutically acceptable salt thereof, for separate administration, distributed administration over time or simultaneous administration to a patient suffering from an inflammatory disease, disorder or condition, in particular a disease, disorder or condition as defined in claim 11.

14. 14. A pharmaceutical combination for separate administration, separate administration over time or simultaneous administration to a patient suffering from an inflammatory disease, disorder or condition according to claim 13, wherein the inflammatory disease, disorder or condition is inflammatory bowel disease, including, for example, ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis.

15. A pharmaceutical kit, in particular intended for treating inflammatory diseases, disorders or conditions, in particular inflammatory bowel diseases, including for example ulcerative colitis and Crohn's disease, rheumatoid arthritis and dermatitis, according to claim 11, comprising: (i) a first galenical formulation comprising a compound of formula (I) as defined in claim 1, in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine, or one of its pharmaceutically acceptable salts, its prodrugs or its metabolites, in particular its glucuronide metabolite as defined in claim 5, and (ii) a second galenical formulation comprising a JAK inhibitor or a pharmaceutically acceptable salt thereof, in particular upadacitinib or a pharmaceutically acceptable salt thereof. The pharmaceutical kit comprising:

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