Quinoline derivatives for treatment of inflammatory diseases

Abstract

The present disclosure relates to quinoline derivatives useful in the treatment of inflammatory diseases. The present disclosure relates to any of a compound of formula (I) or a metabolite thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of an inflammatory disease, disorder or condition. The present invention also relates to compounds of formula (IV) or pharmaceutically acceptable salts thereof for use in the treatment and / or prevention of inflammatory diseases, disorders or conditions. # imgabs0 #

Description

[0001] This application is a divisional application of the parent case, Chinese invention patent application 201980088825.4. Technical Field

[0002] The present invention relates to quinoline derivatives for use in the treatment of inflammatory diseases. Background Art

[0003] Inflammation is the immune system's protective response to tissue damage and infection. However, the inflammatory response can harm the body under certain circumstances. In the acute stage, inflammation is characterized by pain, fever, redness, swelling, and loss of function.

[0004] Inflammatory diseases encompass a wide range of conditions including inflammatory diseases associated with autoimmune diseases, inflammatory diseases of the central nervous system (CNS), inflammatory diseases of the joints, inflammatory digestive tract diseases, and inflammatory skin.

[0005] Some quinoline derivatives have been described in WO2010 / 143169, WO2012 / 080953, WO2016 / 009065 and WO2016 / 009066, the entire contents of which are incorporated herein by reference. Summary of the invention

[0006] SUMMARY OF THE INVENTION

[0007] It has been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof can be used to treat and / or prevent various inflammatory diseases, disorders or conditions. In one aspect, the present invention provides a method for treating an inflammatory disease, disorder or condition, comprising administering to a patient in need thereof a compound of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 Describing the NAFLD Activity Score in the STAM Model of Nonalcoholic Steatohepatitis (NASH Study)

[0011] Figure 2 The sebaceous gland disease score in the STAM model of nonalcoholic steatohepatitis (NASH study) was described for ABX464 and its glucuronide metabolites (Example 2).

[0012] Figure 3 The inflammation score in the STAM model of non-alcoholic steatohepatitis (NASH study) was described for ABX464 and its glucuronide metabolites (Example 2).

[0013] Figure 4 Ballooning analysis in the STAM model of nonalcoholic steatohepatitis (NASH study) was described for ABX464 and its glucuronide metabolite (Example 2).

[0014] Figure 5 The fibrosis area in the histological analysis in the STAM model of non-alcoholic steatohepatitis (NASH study) was described for ABX464 and its glucuronide metabolites (Example 2). DETAILED DESCRIPTION

[0015] General Description of Certain Embodiments of the Invention:

[0016] The compounds of the invention and pharmaceutical compositions thereof are useful for treating inflammatory diseases, disorders or conditions such as those described herein.

[0017] In one aspect, the present invention provides a method for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of formula (I):

[0018]

[0019] or a pharmaceutically acceptable salt thereof, wherein: Z is C or N;

[0020] V is C or N;

[0021] means an aromatic ring wherein V is C or N, and in the case where V is N, V ​​is in the ortho, meta or para position relative to Z;

[0022] Each R is independently hydrogen, halogen, -CN, hydroxy, (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, -SO 2- NR1R2, -SO3H, -O-SO2-OR3, -OP(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3) alkyl, the alkyl group is optionally substituted by one or two of the following: hydroxyl, a group of formula (IIa):

[0023] Or the following group

[0024]

[0025] Q is N or O, provided that R" does not exist when Q is O;

[0026] Each R1 and R2 is independently hydrogen or (C1-C3) alkyl;

[0027] Each R3 and R4 is independently hydrogen, Li + , Na + , K + , N + (Ra) 4 or benzyl; n is 1, 2 or 3;

[0028] n' is 1, 2 or 3;

[0029] Each R' is independently hydrogen, (C1-C3) alkyl, hydroxy, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3) fluoroalkyl, (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN,

[0030] Group of formula (IIa):

[0031] or a group of formula (IIIa):

[0032] A is a covalent bond, oxygen or NH;

[0033] B is a covalent bond or NH;

[0034] m is 1, 2, 3, 4 or 5;

[0035] p is 1, 2 or 3; each Ra and Rb is independently hydrogen, (C1-C5) alkyl or (C 3- C6) cycloalkyl, or

[0036] Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring, said heterocyclic ring being optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' may be 2 or 3 only if the other R' group is different from said group (IIa) or (IIIa); and

[0037] R" is hydrogen, (C1-C4)alkyl or a group of formula (IIa) as defined herein.

[0038] According to yet another embodiment, the present invention relates to compounds of formula (I):

[0039]

[0040] or any of its metabolites or pharmaceutically acceptable salts thereof for use in treating and / or preventing inflammatory diseases, disorders or conditions

[0041] in:

[0042] Z is C or N;

[0043] V is C or N;

[0044] means an aromatic ring wherein V is C or N, and in the case where V is N, V ​​is in the ortho, meta or para position relative to Z;

[0045] Each R is independently hydrogen, halogen, -CN, hydroxy, (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, which is optionally mono- or di-substituted by the following groups: hydroxy, a group of formula (IIa):

[0046]

[0047] or a group of formula (IIIa):

[0048]

[0049] Q is N or O, provided that in the case where Q is O, R" is absent; each R1 and R2 is independently hydrogen or (C1-C3)alkyl;

[0050] Each R3 and R4 is independently hydrogen, Li + , Na + , K + , N + (Ra)4 or benzyl;

[0051] n is 1, 2 or 3;

[0052] n' is 1, 2 or 3;

[0053] Each R' is independently hydrogen, (C1-C3) alkyl, hydroxy, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3) fluoroalkyl, (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, -NH-SO2-N(CH3)2 group, group of formula (IIa):

[0054]

[0055] or a group of formula (IIIa):

[0056]

[0057] A is a covalent bond, oxygen or NH; B is a covalent bond or NH;

[0058] m is 1, 2, 3, 4 or 5;

[0059] p is 1, 2 or 3;

[0060] Each Ra and Rb is independently hydrogen, (C1-C5)alkyl or (C3-C6)cycloalkyl, or

[0061] Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring optionally containing further heteroatoms selected from N, O and S, said heterocyclic ring being optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' may be 2 or 3 provided only that the other R' groups are different from said groups (IIa) or (IIIa); and

[0062] R" is hydrogen, (C1-C4)alkyl or a group of formula (IIa) as defined herein,

[0063] Wherein the inflammatory disease, disorder or condition is selected from:

[0064] (a) an inflammatory disease, disorder or condition in the pancreas selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis;

[0065] (b) an inflammatory disease, disorder or condition in the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis and acute or chronic rejection of a renal transplant;

[0066] (c) an inflammatory disease, disorder or condition in the liver selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and acute or chronic rejection of a liver transplant;

[0067] (d) an inflammatory disease, disorder or condition in the lung or heart selected from chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of a lung or heart transplant;

[0068] (e) an inflammatory disease, disorder or condition in the skin selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloid, and other inflammatory or allergic conditions of the skin;

[0069] (f) an inflammatory disease, disorder or condition in the blood vessels / blood selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, proliferative vascular disease and restenosis;

[0070] (g) an inflammatory disease, disorder or condition in the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis;

[0071] (h) an inflammatory disease, disorder or condition in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain including chronic pain, traumatic brain injury including stroke, Parkinson's disease, myelitis, type 1 Shiller-Marinus syndrome Figure 3 disease (including CMT1A and CMT1B), amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathies;

[0072] (i) an autoimmune disease, disorder or condition selected from lupus including in the skin and kidney, Guillain-Barre syndrome, myasthenia gravis, Jobben's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis;

[0073] (k) an inflammatory disease, disorder or condition of the reproductive system selected from the group consisting of endometriosis, uterine fibroids, prostate dysplasia or growth, and cervical dysplasia; and

[0074] (l) an inflammatory disease, disorder or condition in bones and / or joints selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hands, feet, ankles, knees, hips, shoulders, elbows or spine.

[0075] The present invention further relates to a method for preventing, inhibiting or treating an inflammatory disease as defined above, comprising at least one of the following steps: administering to a patient suffering from the disease an effective amount of a compound as defined in the following formula (I), (Ib), (Ib'), (IV), (IVb) or (IVb') or a pharmaceutically acceptable salt thereof.

[0076] Compounds and Definitions

[0077] In the framework of the present invention, the following definitions can be provided:

[0078] ·Effective amount: the amount of the drug compound that produces an effect on the treated tumor and / or the amount of the compound of the present invention that effectively prevents, reduces, eliminates, treats or controls the symptoms of the diseases and conditions described herein. The term "effective amount" includes "preventively effective amount" and "therapeutically effective amount"; the term "preventively effective amount" refers to the concentration of the compound of the present invention that effectively inhibits, prevents, and reduces the possibility of inflammatory diseases;

[0079] The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human;

[0080] • In the context of the present invention, the term "treat" or "treatment" as used herein means reversing, alleviating, inhibiting the progression of or preventing an inflammatory disease.

[0081] - The term "control" is intended to refer to the overall process wherein there may be a slowing, interruption, quiescence or cessation of progression of the diseases and conditions described herein, but does not necessarily refer to the complete elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.

[0082] • The term "prevention" as used herein means reducing the risk of onset or delaying the occurrence of a given phenomenon, i.e. an inflammatory disease in the present invention. "Prevention" as used herein also encompasses "reducing the likelihood of existence" or "reducing the likelihood of recurrence".

[0083] The compounds of the present invention may exist in the form of free alkali or with a pharmaceutically acceptable acid addition salt. Suitable physiologically acceptable acid addition salts of the compounds of the present invention include sulfates, hydrobromides, citrates, trifluoroacetates, ascorbates, hydrochlorides, trifluoromethanesulfonates, tartrates, maleates, methanesulfonates, formates, acetates, fumarates and sulfonates, especially alkylsulfonates or arylsulfonates, and more particularly methanesulfonates, trifluoromethanesulfonates, edisylate, benzenesulfonates and toluenesulfonates.

[0084] The compounds of the present invention and / or their salts may form solvates or hydrates, and the present invention includes all such solvates and hydrates. The terms "hydrate" and "solvate" simply mean that the compounds according to the present invention can be in the form of a hydrate or solvate, i.e., combined or bound with one or more water or solvent molecules. This is only a chemical feature of such compounds, which can be applied to all organic compounds of this type.

[0085] The compounds of the present invention can contain one or more asymmetric carbon atoms. Thus, they can exist in the form of enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof (including racemic mixtures) belong to the scope of the present invention.

[0086] In the context of the present invention, the terms:

[0087] - "halogen" is understood to mean chlorine, fluorine, bromine or iodine, in particular chlorine, fluorine or bromine,

[0088] - "(C1-C5) alkyl" as used herein refers to C1-C5 primary, secondary or tertiary saturated hydrocarbons, respectively. Examples are but are not limited to methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,

[0089] - "(C3-C6)cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon.

[0090] Examples are but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0091] - "(C1-C4) alkoxy" as used herein refers to an O-(C1-C4) alkyl moiety, wherein alkyl is as defined above. Examples are, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy,

[0092] - "Fluoroalkyl" and "fluoroalkoxy" refer to alkyl and alkoxy groups, respectively, as defined above, which are substituted with at least one fluorine atom. Examples are perfluoroalkyl groups such as trifluoromethyl or perfluoropropyl,

[0093] - "Saturated 5- or 6-membered heterocycle" as used herein refers to a saturated ring containing at least one heteroatom, respectively. Examples are, but are not limited to, morpholine, piperazine, thiomorpholine, piperidine, pyrrolidine.

[0094] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of reasonable medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which are 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.

[0095] Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group 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 salts formed by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, bigluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0096] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts appropriately include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonate anions.

[0097] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (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 intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the scope of the invention includes compounds having the structures of the invention by replacement of hydrogen by deuterium or tritium, or by replacement of hydrogen by deuterium or tritium. 13 C or 14 The compounds are useful, for example, as analytical tools, probes in biological tests or therapeutic agents according to the invention.

[0098] Description of exemplary embodiments:

[0099] In one aspect, the present invention provides a method for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of formula (I):

[0100]

[0101] or a pharmaceutically acceptable salt thereof, wherein:

[0102] Z is C or N;

[0103] V is C or N

[0104] means an aromatic ring wherein V is C or N, and in the case where V is N, V ​​is in the ortho, meta or para position relative to Z;

[0105] Each R is independently hydrogen, halogen, -CN, hydroxy, (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, which is optionally mono- or di-substituted by the following groups: hydroxy, a group of formula (IIa):

[0106] or a group of formula (IIIa)

[0107] Q is N or O, provided that R" does not exist when Q is O;

[0108] Each R1 and R2 is independently hydrogen or (C1-C3) alkyl;

[0109] Each R3 and R4 is independently hydrogen, Li + , Na + , K + , N + (Ra)4 or benzyl;

[0110] n is 1, 2 or 3;

[0111] n' is 1, 2 or 3;

[0112] Each R' is independently hydrogen, (C1-C3) alkyl, hydroxy, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3) fluoroalkyl, (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, a group of formula (IIa):

[0113] or a group of formula (IIIa):

[0114] A is a covalent bond, oxygen or NH;

[0115] B is a covalent bond or NH;

[0116] m is 1, 2, 3, 4 or 5;

[0117] p is 1, 2 or 3;

[0118] Each Ra and Rb is independently hydrogen, (C1-C5)alkyl or (C3-C6)cycloalkyl, or

[0119] Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring, said heterocyclic ring being optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' may be 2 or 3 only if the other R' group is different from said group (IIa) or (IIIa); and

[0120] R" is hydrogen, (C1-C4)alkyl or a group of formula (IIa) as defined above.

[0121] Z is C or N as generally defined above.

[0122] In certain embodiments, Z is C. In certain embodiments, Z is N.

[0123] In certain embodiments, Z is selected from those described in Tables 1-3 below.

[0124] V is C or N as generally defined above.

[0125] In certain embodiments, V is C. In certain embodiments, V is N.

[0126] In certain embodiments, V is selected from those described in Tables 1-3 below.

[0127] As generally defined above, It refers to an aromatic ring wherein V is C or N, and in the case where V is N, V ​​is in the ortho, meta or para position relative to Z.

[0128] In certain embodiments, It refers to an aromatic ring wherein V is C.

[0129] In certain embodiments, It refers to an aromatic ring wherein V is N, and V is in the ortho, meta or para position relative to Z.

[0130] In certain embodiments, V is N, and V is in the ortho position relative to Z. In certain embodiments, V is N, and V is in the meta position relative to Z. In certain embodiments, V is N, and V is in the para position relative to Z.

[0131] In certain embodiments, It is phenyl.

[0132] In certain embodiments, It's pyridine.

[0133] In certain embodiments, It's pyridazine.

[0134] In certain embodiments, It is pyrimidine.

[0135] In certain embodiments, It's pyrazine.

[0136] In certain embodiments, Select from those described in Tables 1-3 below.

[0137] As generally described above, each R is independently hydrogen, halogen, -CN, hydroxy, (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, which is optionally mono- or di-substituted by hydroxy or a group of formula (IIa): or a group of formula (IIIa):

[0138] In certain embodiments, R is hydrogen. In certain embodiments, R is halogen. In certain embodiments, R is -CN. In certain embodiments, R is hydroxy. In certain embodiments, R is (C1-C3)fluoroalkyl, the alkyl being optionally substituted mono- or di-substituted by hydroxy. In certain embodiments, R is (C1-C3)fluoroalkoxy. In certain embodiments, R is (C3-C6)cycloalkyl. In certain embodiments, R is -NO2. In certain embodiments, R is -NR1R2. In certain embodiments, R is (C1-C4)alkoxy. In certain embodiments, R is phenoxy. In certain embodiments, R is -NR1-SO2-NR1R2. In certain embodiments, R is -NR1-SO2-R1. In certain embodiments, R is -NR1-C(=O)-R1. In certain embodiments, R is -NR1-C(=O)-NR1R2. In certain embodiments, R is -SO2-NR1R2. In certain embodiments, R is -SO3H. In certain embodiments, R is -O-SO2-OR3. In certain embodiments, R is -OP(=O)-(OR3)(OR4). In certain embodiments, R is -O-CH2-COOR3. In certain embodiments, R is (C1-C3)alkyl, which is optionally mono- or di-substituted with hydroxyl.

[0139] In certain embodiments, each R is independently halogen, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, -NR1R2, (C1-C4)alkoxy, or (C1-C3)alkyl.

[0140] In certain embodiments, each R is independently hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, halogen, or -OP(=O)-(OR3)(OR4). In certain embodiments, R is methyl. In certain embodiments, R is methoxy. In certain embodiments, R is trifluoromethyl. In certain embodiments, R is trifluoromethoxy. In certain embodiments, R is amino. In certain embodiments, R is -OP(=O)-(OR3)(OR4).

[0141] In certain embodiments, each R is independently methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy, or amino.

[0142] In certain embodiments, R is selected from those described in Tables 1-3 below.

[0143] As generally described above, Q is N or O, with the proviso that in the case where Q is O R" is absent.

[0144] In certain embodiments, Q is N. In certain embodiments, Q is O, and R" is absent.

[0145] In certain embodiments, Q is selected from those described in Tables 1-3 below.

[0146] As generally described above, each R1 and R2 is independently hydrogen or (C1-C3)alkyl.

[0147] In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is (C1-C3) alkyl. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is (C1-C3) alkyl.

[0148] In certain embodiments, each of R1 and R2 is independently selected from those described in Tables 1-3 below.

[0149] As generally described above, each R3 and R4 are independently hydrogen, Li + , Na + , K + , N + (Ra)4 or benzyl.

[0150] In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is Li + In certain embodiments, R3 is Na + In certain embodiments, R3 is K + In certain embodiments, R3 is N + (Ra)4. In certain embodiments, R3 is benzyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is Li + In certain embodiments, R4 is Na + In certain embodiments, R4 is K + In certain embodiments, R4 is N + (Ra) 4. In certain embodiments, R4 is benzyl.

[0151] In certain embodiments, each R3 and R4 is independently selected from those described in Tables 1-3 below.

[0152] As generally described above, n is 1, 2 or 3.

[0153] In certain embodiments, n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0154] In certain embodiments, n is selected from those described in Tables 1-3 below.

[0155] As generally described above, n' is 1, 2 or 3.

[0156] In certain embodiments, n' is 1 or 2. In certain embodiments, n' is 1. In certain embodiments, n' is 2. In certain embodiments, n' is 3.

[0157] In certain embodiments, n' is selected from those described in Tables 1-3 below.

[0158] As generally described above, each R' is independently hydrogen, (C1-C3) alkyl, hydroxy, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3) fluoroalkyl, (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, a group of formula (IIa): or a group of formula (IIIa):

[0159] In certain embodiments, R' is hydrogen. In certain embodiments, R' is (C1-C3) alkyl. In certain embodiments, R' is hydroxy. In certain embodiments, R' is halogen. In certain embodiments, R' is -NO2. In certain embodiments, R' is -NR1R2. In certain embodiments, R' is morpholinyl. In certain embodiments, R' is morpholino. In certain embodiments, R' is N-methylpiperazinyl. In certain embodiments, R' is (C1-C3) fluoroalkyl. In certain embodiments, R' is (C1-C4) alkoxy. In certain embodiments, R' is -OP(=O)-(OR3)(OR4). In certain embodiments, R' is -CN.

[0160] In certain embodiments, R' is a group of formula (IIa):

[0161] In certain embodiments, R' is a group of formula (IIIa):

[0162] In certain embodiments, R' is amino. In certain embodiments, R' is methyl. In certain embodiments, R' is a group of the formula

[0163] wherein A is O or NH, m is 2 or 3 and X1 is O, CH2 or N-CH3, provided that in the case where R' is a group as described above, n' is 1 or 2, and in the case where n' is 2, the other R' groups are different from the groups described.

[0164] In certain embodiments, R' is a group of the formula

[0165] wherein A is O or NH, m is 2 and X1 is O, CH2 or N-CH3, provided that in the case where R' is a group as described above, n' is 1 or 2, and in the case where n' is 2, the other R' groups are different from the groups described.

[0166] In certain embodiments, R' is a group of the formula

[0167] wherein A is O or NH, m is 3 and X1 is O, CH2 or N-CH3, provided that in the case where R' is a group as described above, n' is 1 or 2, and in the case where n' is 2, the other R' groups are different from the groups described.

[0168] In certain embodiments, each R' is independently hydrogen, halogen, amino, methyl, -OP(=O)-(OR3)(OR4), or a group of the formula

[0169]

[0170] wherein A is O or NH, m is 2 or 3 and X1 is O, CH2 or N-CH3, provided that in the case where R' is a group as described above, n' is 1 or 2, and in the case where n' is 2, the other R' groups are different from the groups described.

[0171] In certain embodiments, each R' is independently hydrogen, halogen, methyl, or a group of the formula

[0172] wherein A is O or NH, m is 2 and X1 is O, CH2 or N-CH3, provided that in the case where R' is a group as described above, n' is 1 or 2, and in the case where n' is 2, the other R' groups are different from the groups described.

[0173] In certain embodiments, each R' is independently halogen, (C1-C3)alkyl, hydroxy, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, or a group of formula (IIa) or (IIIa) as described herein.

[0174] In certain embodiments, R' is halogen or methyl.

[0175] In certain embodiments, each R' is independently selected from those described in Tables 1-3 below.

[0176] As generally described above, A is a covalent bond, oxygen or NH.

[0177] In certain embodiments, A is a covalent bond. In certain embodiments, A is oxygen. In certain embodiments, A is NH.

[0178] In certain embodiments, A is selected from those described in Tables 1-3 below.

[0179] As generally described above, B is a covalent bond or NH.

[0180] In certain embodiments, B is a covalent bond. In certain embodiments, B is NH.

[0181] In certain embodiments, B is selected from those described in Tables 1-3 below.

[0182] As generally described above, m is 1, 2, 3, 4 or 5.

[0183] In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.

[0184] In certain embodiments, m is selected from those described in Tables 1-3 below.

[0185] As generally described above, p is 1, 2 or 3.

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

[0187] In certain embodiments, p is selected from those described in Tables 1-3 below.

[0188] As generally described above, each Ra and Rb are independently hydrogen, (C1-C5)alkyl or (C3-C6)cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5-membered or 6-membered heterocyclic ring optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' may be 2 or 3 only when the other R' group is different from said group (IIa) or (IIIa).

[0189] In certain embodiments, Ra is hydrogen. In certain embodiments, Ra is (C1-C5)alkyl. In certain embodiments, Ra is (C3-C6)cycloalkyl. In certain embodiments, Rb is hydrogen. In certain embodiments, Rb is (C1-C5)alkyl. In certain embodiments, Rb is (C3-C6)cycloalkyl.

[0190] In certain embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring optionally substituted by one or more Ra, provided that in the case where R' is a group of formula (IIa) or (IIIa), n' can be 2 or 3 only when the other R' group is different from the group of formula (IIa) or (IIIa). In certain embodiments, the saturated 5- or 6-membered heterocyclic ring formed by Ra and Rb together with the nitrogen atom to which they are attached as described above optionally has an additional heteroatom selected from N, O and S.

[0191] In certain embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring having an additional heteroatom selected from N, O and S, which is substituted with one or more Ra, provided that in the case where R' is a group of formula (IIa) or (IIIa), n' can be 2 or 3 only when the other R' group is different from the group of formula (IIa) or (IIIa).

[0192] In certain embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5-membered heterocyclic ring, provided that in the case where R' is a group of formula (IIa) or (IIIa), n' can be 2 or 3 only when the other R' group is different from the group of formula (IIa) or (IIIa).

[0193] In certain embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 6-membered heterocyclic ring, provided that in the case where R' is a group of formula (IIa) or (IIIa), n' can be 2 or 3 only when the other R' group is different from the group of formula (IIa) or (IIIa).

[0194] In certain embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5-membered or 6-membered heterocyclic ring optionally with additional heteroatoms selected from N, O and S, which is optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' can be 2 only when the other R' group is different from the group (IIa) or (IIIa).

[0195] In certain embodiments, each of Ra and Rb is independently selected from those described in Tables 1-3 below.

[0196] As generally described above, R" is hydrogen, (C1-C4)alkyl or a group of formula (IIa) as defined above.

[0197] In certain embodiments, R" is hydrogen or (C1-C4)alkyl. In certain embodiments, R" is hydrogen. In certain embodiments, R" is (C1-C4)alkyl. In certain embodiments, R" is a group of formula (IIa) as described herein.

[0198] In certain embodiments, R" is a group of the formula

[0199] wherein m is 2 or 3, and X1 is O, CH2 or N-CH3.

[0200] In certain embodiments, R" is selected from those described in Tables 1-3 below.

[0201] In certain embodiments, n is 1; n' is 1 or 2; R" is H; R is selected from methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy and amino; and each R' is independently halogen, methyl, or a group

[0202] wherein A is O or NH, m is 2 or 3 and X1 is O, CH2 or N-CH3, provided that in the case where n' is 2, the other R' groups are different from those stated.

[0203] In certain embodiments, n is 1; n' is 1; R" is H; R is selected from methyl, methoxy, trifluoromethyl, halogen and trifluoromethoxy; and R' is halogen or methyl.

[0204] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of formula (Ia):

[0205]

[0206] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', R", n and n' is independently as defined above and described in the embodiments.

[0207] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of formula (Ib):

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', R", n and n' is independently as defined above and described in the embodiments herein, both alone and in combination.

[0210] In certain embodiments, the present invention provides a compound for use as defined above, wherein the compound has formula (Ib):

[0211]

[0212] or any one of its metabolites, or a pharmaceutically acceptable salt thereof, wherein R, R' and R" are as defined above.

[0213] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of formula (Ic):

[0214]

[0215] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', R", n and n' is independently as defined above and described in the embodiments herein, both alone and in combination.

[0216] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of formula (Id):

[0217]

[0218] or a pharmaceutically acceptable salt thereof, wherein each R and R' is independently as defined above and described in the embodiments herein, both alone and in combination, and R'" is hydrogen or a group

[0219] wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3.

[0220] In certain embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition, comprising administering to a patient in need thereof a compound of formula (Id) or a pharmaceutically acceptable salt thereof, wherein R is methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy or amino; R' is halogen or methyl, and R'" is hydrogen or a group

[0221] wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3.

[0222] In certain embodiments, R'" is hydrogen.

[0223] In certain embodiments, R'" is a group

[0224] Wherein A is O or NH, m is 2 or 3, and X1 is O, CH2 or N-CH3. In certain embodiments, R'" is a group Wherein A is O, m is 2 or 3, and X1 is O, CH2 or N-CH3. In certain embodiments, R'" is a group

[0225] wherein A is NH, m is 2 or 3, and X1 is O, CH2 or N-CH3. In certain embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of formula (Ib'):

[0226]

[0227] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', R" and n is independently as defined above and described in the embodiments herein, both alone and in combination. In certain embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition, comprising administering to a patient in need thereof a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein: each R is independently halogen, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, -NR1R2, (C1-C4)alkoxy or (C1-C3)alkyl, the alkyl being optionally mono- or di-substituted with hydroxyl; n is 1 or 2; n' is 1 or 2;

[0228] Each R1 and R2 is independently hydrogen or (C1-C3) alkyl;

[0229] each R' is independently halogen, (C1-C3)alkyl, hydroxy, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, or a group of formula (IIa) or (IIIa) as described herein;

[0230] A is a covalent bond, oxygen or NH; B is a covalent bond or NH;

[0231] m is 1, 2, 3, 4 or 5;

[0232] p is 1, 2 or 3;

[0233] Each Ra and Rb is independently hydrogen, (C1-C5)alkyl or (C3-C6)cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring optionally having additional heteroatoms selected from N, O and S, which is optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' may be 2 only when the other R' group is different from said group (IIa) or (IIIa); and R" is hydrogen or (C1-C4)alkyl.

[0234] In certain embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition, comprising administering to a patient in need thereof a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each R' is independently hydrogen, halogen, (C1-C3)alkyl or (C1-C4)alkoxy, wherein the alkyl is optionally mono- or di-substituted with hydroxy; R" is hydrogen or (C1-C4)alkyl; n is 1 or 2; n' is 1 or 2; in the case where n is 1, R is (C1-C3)fluoroalkoxy, NR1R2 or phenoxy, wherein each R1 and R2 are independently (C1-C3)alkyl; and in the case where n is 2, one of the two R groups is (C1-C3)fluoroalkoxy and the other R group is (C1-C3)alkyl.

[0235] In certain embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition, comprising administering to a patient in need thereof a compound of formula (Ib) or a pharmaceutically 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.

[0236] In certain embodiments, the present invention provides a method for treating an inflammatory disease, disorder or condition, comprising administering to a patient in need thereof a compound of formula (Ib') or a pharmaceutically acceptable salt thereof, wherein each R is independently hydrogen, halogen, (C1-C3) alkyl, -NR1R2, (C 1- C3) fluoroalkoxy, -NO2, phenoxy or (C1-C4) alkoxy, the alkyl group being optionally mono- or di-substituted with hydroxyl groups; each R1 and R2 are independently hydrogen or (C1-C3) alkyl; R' is hydrogen, halogen, (C1-C3) alkyl, or (C1-C4) alkoxy, provided that R' is different from the methyl group at the 4-position of the quinoline group; R" is hydrogen or (C1-C4) alkyl; n is 1, 2 or 3; and n' is 1 or 2.

[0237] In certain embodiments, the present invention provides a compound for use as defined above, wherein the compound has formula (Ib'):

[0238]

[0239] or any one of its metabolites, or a pharmaceutically acceptable salt thereof, wherein R, R' and R" are as defined above.

[0240] In certain embodiments, the present invention provides any one of the compounds of formula (Ib') or its metabolites or a pharmaceutically acceptable salt thereof for use as defined above, wherein:

[0241] R independently represents a halogen atom or a group selected from the following: (C1-C3) fluoroalkoxy, -NR1R2 group, (C1-C4) alkoxy, -OP(=O)(OR3)(OR4) group, (C1-C3) alkyl, NO2 group, -A-(CH2) m -B-NRaRb group (Formula IIa) and -(O-CH2-CH2) p- O-Ra group (Formula IIIa),

[0242] n is 1 or 2,

[0243] R' represents a hydrogen atom, a halogen atom or a group selected from the group consisting of: -NR1R2 group, -OP(=O)(OR3)(OR4) group, -NH-SO2-N(CH3)2 group, and -A-(CH2) m -B-NRaRb group (IIa),

[0244] R" is a hydrogen atom, (C1-C4) alkyl or -A-(CH2) m -B-NRaRb group (Formula IIa),

[0245] R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group,

[0246] R3 and R4 are independently hydrogen, Li + , Na + , K + , N + (Ra)4 or benzyl,

[0247] A is a covalent bond, an oxygen atom or NH,

[0248] B is a covalent bond,

[0249] m is 2, 3 or 4,

[0250] p is 1, 2 or 3,

[0251] Ra and Rb independently represent a hydrogen atom or a (C1-C5) alkyl group, and Ra and Rb can further form together with the nitrogen atom to which they are attached a saturated 5-membered or 6-membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S, which is optionally substituted by one or more Ra.

[0252] According to an even more specific embodiment, the present invention provides any one of the compounds of formula (Ib') or its metabolites or a pharmaceutically acceptable salt thereof for use as defined above, wherein:

[0253] 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,

[0254] n is 1 or 2,

[0255] R' represents a hydrogen atom, Cl, -CH2-CH2-CH3, -O-(CH2)2-morpholino, -O-(CH2)2-piperidino, -O-(CH2)3-piperidino, -N-(CH2)3-morpholino, -NH-SO2-N(CH3)2 group, NH2, or -OP(=O)(OH)(OH) group, and

[0256] R" is a hydrogen atom, -CH3, -(CH2)3-piperidino, -(CH2)2-morpholino, -(CH2)4-morpholino or -(CH2)2-pyrrolidino.

[0257] In an embodiment, the present invention provides any one of the compounds of formula (Ib') or their metabolites for use as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: compounds 96, 98, 108, 109, 111, 115, 122, 125, 128, 129, 130, 132, 133, 135, 138 to 141, 143 and 145 to 164 as listed below.

[0258] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of the formula: ("ABX464") or a pharmaceutically acceptable salt thereof.

[0259] In certain embodiments, the present invention provides a compound of formula (Ib') or any one of its metabolites or a pharmaceutically acceptable salt thereof for use as defined above, wherein the compound is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine.

[0260] In certain embodiments, compound ABX464 or a pharmaceutically acceptable salt thereof is in amorphous form. In certain embodiments, compound ABX464 or a pharmaceutically acceptable salt thereof is in crystalline form. In certain embodiments, the crystalline form of compound ABX464 or a pharmaceutically acceptable salt thereof has a melting point at 120.5° C. (±2° C.).

[0261] In certain embodiments, the crystalline form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits peaks at angles 7.3, 14.6, 18.4 and 24.9 in an X-ray powder diffraction pattern (XRPD). In certain embodiments, the crystalline form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits one or more XRPD peaks at angles selected from 18.0, 24.2, 28.3 and 29.5. In certain embodiments, the crystalline form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits one or more XRPD peaks at angles selected from 18.6, 22.3, 23.0 and 23.5.

[0262] According to a specific embodiment, the crystalline polymorphic form of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine is characterized by the following major peaks expressed in 2-θ angles as expressed by XRPD analysis: 7.3, 14.6, 23.5 and 28.4 (each ± ​​0.2) and may further show the following additional peaks expressed in 2-θ angles: 12.1, 17.3, 18.4, 23.0; 24.2, 24.9, 27.4 and 29.1 (each ± ​​0.2) and even optionally the following additional peaks expressed in 2-θ angles: 13.7, 16.3, 16.9, 18.1, 22.4 and 29.6 (each ± ​​0.2).

[0263] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound selected from Table 1:

[0264] Table 1 (Compounds of formula Ia as defined above)

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] or a pharmaceutically acceptable salt thereof.

[0274] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound selected from Table 2:

[0275] Table 2 (Compounds of formula (Ib) as defined above)

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] or a pharmaceutically acceptable salt thereof.

[0283] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound selected from Table 3:

[0284] Table 3 (Compounds of formula (I) different from compounds (Ia) and (Ib))

[0285]

[0286]

[0287] or a pharmaceutically acceptable salt thereof.

[0288] In certain embodiments, the compounds described herein are in the form of salts selected from sulfates, hydrobromides, citrates, trifluoroacetates, ascorbates, hydrochlorides, tartrates, trifluoromethanesulfonates, maleates, methanesulfonates, formates, acetates, fumarates, and sulfonates. In certain embodiments, the compounds described herein are in the form of salts of alkylsulfonates or arylsulfonates. In certain embodiments, the compounds described herein are in the form of salts of methanesulfonates, trifluoromethanesulfonates, edisylate, benzenesulfonates, and toluenesulfonates.

[0289] In one aspect, the present invention provides metabolites of compounds described herein. In certain embodiments, the present invention provides N-glucuronide metabolites of compounds described herein. In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions comprising administering to a patient in need thereof an N-glucuronide metabolite of a compound described herein.

[0290] In certain embodiments, the present invention provides a compound of formula (IV):

[0291]

[0292] or a pharmaceutically acceptable salt thereof, wherein each variable V, Z, R, R', n and n' is as defined above and described in the embodiments herein, alone or in combination, provided that the compound is not

[0293]

[0294] In certain embodiments, the present invention provides a compound of formula IVa:

[0295]

[0296] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', n and n' is independently as defined above and described in the embodiments herein, alone and in combination.

[0297] In certain embodiments, the present invention provides a compound of formula (IVb):

[0298]

[0299] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', n and n' is independently as defined above and described in the embodiments herein, alone and in combination, provided that the compound is not

[0300]

[0301] In certain embodiments, the present invention provides a compound of formula (IVc):

[0302]

[0303] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', n and n' is independently as defined above and described in the embodiments herein, alone and in combination.

[0304] In certain embodiments, the present invention provides a compound of formula (IVb'):

[0305]

[0306] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', and n is independently as defined above and described in the embodiments herein, alone and in combination, provided that the compound is not

[0307]

[0308] In certain embodiments, the present invention provides a compound of formula (IVd):

[0309]

[0310] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', R'" is independently as defined above and described in the embodiments herein, alone and in combination, provided that the compound is not

[0311]

[0312] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions comprising administering to a patient in need thereof a compound of any one of Formula (IV), (IVa), (IVb), (IVc), (IVb') and (IVd) or a pharmaceutically acceptable salt thereof.

[0313] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of the formula:

[0314]

[0315] or a pharmaceutically acceptable salt thereof.

[0316] In certain embodiments, the present invention provides a compound of formula (IV):

[0317]

[0318] or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of an inflammatory disease, disorder or condition as defined hereinbefore, wherein V, Z, R, R', n and n' are as defined hereinbefore.

[0319] The present invention also provides compounds of formula (IV) for use in the treatment and / or prevention of an inflammatory disease, disorder or condition as defined hereinbefore, wherein the compound has formula (IVb):

[0320]

[0321] or a pharmaceutically acceptable salt thereof, wherein R, n, R', n' are as defined above.

[0322] Also provided herein are compounds of formula (IVb) for use in the treatment and / or prevention of an inflammatory disease, disorder or condition as defined hereinbefore, wherein the compound has formula (IVb'):

[0323]

[0324] or a pharmaceutically acceptable salt thereof, wherein R, n, R', n' are as defined above.

[0325] Also provided herein are compounds of formula (IVb') for use in the treatment and / or prevention of an inflammatory disease, disorder or condition as defined hereinbefore, wherein the compound is

[0326]

[0327] or a pharmaceutically acceptable salt thereof.

[0328] In certain embodiments, the methods of the invention for treating inflammatory diseases, disorders or conditions further comprise measuring the level of a compound as described herein or a pharmaceutically acceptable salt thereof or a metabolite thereof in a patient. In certain embodiments, the level of a compound as described herein or a pharmaceutically acceptable salt thereof or a metabolite thereof is measured in a biological sample of a patient. In certain embodiments, the biological sample of a patient is a blood, plasma, tissue, saliva and / or serum sample.

[0329] In a further embodiment, the present invention provides a compound (I), (Ib), (Ib'), (IV), (IVb) or (IVb') for use as defined hereinbefore for treating a patient, wherein during use the level of a compound of formula (I), (Ib), (Ib'), (IV), (IVb) or (IVb') as defined hereinbefore is measured in a blood, plasma, tissue, saliva and / or serum sample of the patient.

[0330] In certain embodiments, the methods of the present invention for treating an inflammatory disease, disorder, or condition further comprise measuring the level of a compound of formula (I), (Ia), (Ib), (Ib'), (Ic) and (Id), or a pharmaceutically acceptable salt thereof, in a patient. In certain embodiments, the methods of the present invention for treating an inflammatory disease, disorder, or condition further comprise measuring the level of a compound of formula (IV), (IVa), (IVb), (IVb'), (IVc) and (IVd), or a pharmaceutically acceptable salt thereof, in a patient. In certain embodiments, the methods of the present invention for treating an inflammatory disease, disorder, or condition further comprise measuring the total level of a compound of formula (I) and (IV), or a pharmaceutically acceptable salt thereof, in a patient. In certain embodiments, the methods of the present invention for treating an inflammatory disease, disorder, or condition further comprise measuring the total level of a compound of formula (I) and (IV), or a pharmaceutically acceptable salt thereof, in a patient. In certain embodiments, the methods of the present invention for treating an inflammatory disease, disorder, or condition further comprise measuring the total level of a compound of formula (I) and (IV), or a pharmaceutically acceptable salt thereof, in a patient. In certain embodiments, the methods of the present invention for treating an inflammatory disease, disorder, or condition further comprise measuring the total level of a compound of formula (I) and (IVa), or a pharmaceutically acceptable salt thereof, in a patient. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders, or conditions further include measuring the total level of compounds of formula (Ib) and (IVb) or pharmaceutically acceptable salts thereof in patients. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders, or conditions further include measuring the total level of compounds of formula (Ib') and (IVb') or pharmaceutically acceptable salts thereof in patients. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders, or conditions further include measuring the total level of compounds of formula (Ic) and (IVc) or pharmaceutically acceptable salts thereof in patients. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders, or conditions further include measuring the total level of compounds of formula (Id) and (IVd) or pharmaceutically acceptable salts thereof in patients.

[0331] In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders or conditions also include measuring and / or monitoring the presence and / or level of biomarkers in patients. In certain embodiments, the presence and / or level of biomarkers in biological samples of patients is measured. In certain embodiments, the biological sample of the patient is a blood sample. In certain embodiments, the biological sample of the patient is a tissue sample. In certain embodiments, the biomarker measured and / or monitored in the methods of the present invention is miR-124, as described in WO 2014 / 111892, which is incorporated herein by reference in its entirety. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders or conditions also include measuring and / or monitoring the presence and / or expression level of miR-124 in patients before administering a compound as described herein or a pharmaceutically acceptable salt or composition thereof. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders or conditions also include measuring and / or monitoring the presence and / or expression level of miR-124 in patients during the course of treatment with a compound as described herein or a pharmaceutically acceptable salt or composition thereof. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders or conditions also include selecting patients treated with compounds as described herein or pharmaceutically acceptable salts thereof or compositions by measuring and / or monitoring the presence and / or expression level of miR-124 in patients. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders or conditions also include excluding patients from treatment with compounds as described herein or pharmaceutically acceptable salts thereof or compositions by measuring and / or monitoring the presence and / or expression level of miR-124 in patients. In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders or conditions also include regulating (such as increasing or decreasing) the dosing regimen (such as dosage and / or dosing schedule) of the compound as described herein or its pharmaceutically acceptable salt or composition to be administered to the patient by measuring and / or monitoring the presence and / or expression level of miR-124 in patients.

[0332] In certain embodiments, the methods of the present invention for treating inflammatory diseases, disorders or conditions include comparing the measured expression level of miR-124 in a patient with a control reference value. The control reference value for comparing the measured expression level of miR-124 in a patient is derived from a control sample. The control sample can be obtained from various sources. In certain embodiments, the control sample is obtained from a patient (such as an archived blood sample or tissue sample) before treatment or before the disease exists. In certain embodiments, the control sample is obtained from a group of normal, non-diseased members of a population. In certain embodiments, the control sample is obtained from a patient before treatment with a compound as described herein or a pharmaceutically acceptable salt thereof or a composition. In certain embodiments, cell testing can be performed on a biological sample.

[0333] In certain embodiments, the presence and / or expression level of miR-124 regulated in a patient compared to a control reference value indicates an inflammatory disease, disorder or condition. In certain embodiments, the presence and / or expression level of miR-124 regulated in a patient compared to a control reference value indicates the efficacy of treatment with a compound as described herein or a pharmaceutically acceptable salt or composition thereof given to a patient. The term "regulation" or "regulated presence and / or expression level" means that the presence or expression level of a biomarker is induced or increased, or alternatively inhibited or reduced.

[0334] In some embodiments, the presence or reduced expression level of miR-124 reduction or inhibition measured relative to the control reference value indicates an inflammatory disease, disorder or condition. In some embodiments, the miR-124 measured relative to the control reference value has an induction or increase or an increase in expression level indicating the effectiveness of a compound as described herein or its pharmaceutically acceptable salt or composition. In some embodiments, the expression level of miR-124 measured in a patient treated with a compound as described herein or its pharmaceutically acceptable salt or composition is 2 times, 4 times, 6 times, 8 times or 10 times the control reference value.

[0335] Thus, according to a specific embodiment, the present invention also provides a compound of formula (I), (Ib), (Ib'), (IV), (IVb) or (IVb') or a pharmaceutically acceptable salt thereof for the use as defined above, for treating a patient, wherein the presence and / or expression level of miR-124 in the patient's blood and / or tissue samples is measured before and during use.

[0336] In certain embodiments, the present invention provides an algorithm for monitoring the severity of a disease, disorder or condition and / or monitoring the efficacy of a treatment (including but not limited to the treatments described herein) that combines miR-124 levels and the levels of a cytokine or another biomarker, or the levels of a compound of formula (I) or (IV) or a pharmaceutically acceptable salt thereof. In certain embodiments, the treatment methods as described herein comprise monitoring the severity of a disease, disorder or condition and / or monitoring the efficacy of a treatment with an algorithm that combines miR-124 levels and the levels of a cytokine or another biomarker, or the levels of a compound of formula (I) or (IV) or a pharmaceutically acceptable salt thereof.

[0337] Also provided herein are compounds for use according to the invention, wherein an algorithm is used to monitor the severity of the disease, disorder or condition and / or to monitor the efficacy of the use or treatment, said algorithm combining the levels of miR-124 and the levels of a cytokine or another biomarker, or the levels of a compound of formula (I) or (IV) as defined herein, or a pharmaceutically acceptable salt thereof.

[0338] Also provided herein are compounds for use according to the invention, wherein an algorithm is used to select patients for use or treatment, the algorithm combining the levels of miR-124 and the levels of a cytokine or another biomarker, or the levels of a compound of formula (I) or (IV) as defined herein, or a pharmaceutically acceptable salt thereof.

[0339] Also provided herein are algorithms for monitoring the severity of a disease, disorder or condition and / or monitoring the efficacy of a treatment that combine miR-124 levels with the level of a cytokine or another biomarker, or the level of a compound of Formula (I) or (IV) as defined above, or a pharmaceutically acceptable salt thereof.

[0340] Thus, according to a specific embodiment, the present invention also provides a compound of formula (I), (Ib), (Ib'), (IV), (IVb) or (IVb') for use as defined above, wherein an algorithm is used to monitor the severity of the disease, disorder or condition and / or to monitor the efficacy of the use, said algorithm combining the level of miR-124 and the level of a cytokine or another biomarker, or the level of a compound of formula (I), (Ib), (Ib'), (IV), (IVb) or (IVb') or a pharmaceutically acceptable salt thereof.

[0341] Use, formulation and administration

[0342] Pharmaceutically acceptable compositions

[0343] According to another embodiment, the present invention provides compositions comprising the compounds of the present invention or pharmaceutically acceptable derivatives thereof and pharmaceutically acceptable carriers, adjuvants or vehicles. In certain embodiments, the compositions of the present invention are formulated for administration to patients in need of the compositions. In certain embodiments, the compositions of the present invention are formulated for oral administration to patients.

[0344] The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[0345] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. 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 phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acids, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0346] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an active metabolite or residue thereof.

[0347] A "biological sample" suitable for the present invention can be a biological fluid, such as blood, plasma or serum, saliva, interstitial fluid or urine sample; a cell sample, such as a cell culture, cell line or PBMC sample, a biopsy such as oral tissue, gastrointestinal tissue, skin, oral mucosal samples or a variety of samples from clinical trials.

[0348] Biological samples can be crude samples or can be purified to various degrees before storage, processing or measurement. In certain embodiments, the biological sample is selected from biological tissue samples, whole blood samples, swab samples, plasma samples, serum samples, saliva samples, vaginal fluid samples, semen samples, pharyngeal fluid samples, synovial samples, bronchial or pleural fluid samples, fecal fluid samples, cerebrospinal fluid samples, tear samples and tissue culture supernatant samples.

[0349] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated with suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be non-toxic sterile injectable solutions or suspensions in parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media.

[0350] For this purpose, any gentle non-volatile oil can be used to include synthetic glycerol mono- or di-esters. Fatty acids such as oleic acid and glyceride derivatives thereof can be used to prepare injectables, such as natural pharmaceutically acceptable oils such as olive oil or castor oil, particularly its polyoxyethylated form. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants such as carboxymethyl cellulose or include similar dispersants generally used in emulsions and suspensions in the preparation of pharmaceutically acceptable dosage forms. Other generally used surfactants such as Tweens, Spans and other emulsifiers or the bioavailability enhancers generally used to prepare pharmaceutically acceptable solids, liquids or other dosage forms can also be used to prepare intentions.

[0351] Pharmaceutically acceptable compositions 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. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also generally added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. In the case of oral use requiring an aqueous suspension, the active ingredient is combined with an emulsifying and suspending agent. If desired, certain sweeteners, flavorings or coloring agents may also be added.

[0352] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of rectal suppositories. These can be prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

[0353] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly where the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or the small intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0354] 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.

[0355] For topical administration, the pharmaceutically acceptable compositions provided can be formulated in suitable ointments containing active components suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in suitable lotions or creams containing active components suspended or dissolved in one or more pharmaceutically acceptable carriers.

[0356] 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.

[0357] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated in ointments such as petrolatum.

[0358] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the field of pharmaceutical preparations and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters that enhance bioavailability, fluorocarbons and / or other conventional solvating or dispersing agents. Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. The formulations can be administered with or without food.

[0359] In certain embodiments, the pharmaceutically acceptable compositions of the invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the invention are administered with food.

[0360] The amount of the compound of the invention that can be combined with a carrier material to produce a single dosage composition will vary depending on the host being treated, the particular mode of administration. Preferably, the provided compositions should be formulated so that the patient can receive these compositions at a dosage of 0.01-100 mg / kg body weight / day of the inhibitor.

[0361] It is also understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the invention in the composition also depends on the specific compound in the composition.

[0362] Uses of compounds and pharmaceutically acceptable compositions

[0363] The compounds and compositions described herein are generally useful for treating inflammatory diseases, disorders or conditions.

[0364] As used herein, the terms "treat", "treat" and "manage" refer to reversing, alleviating, delaying the onset of a disease or disorder as described herein or one or more symptoms thereof, or inhibiting its progression. In certain embodiments, treatment can be given after one or more symptoms have developed. In other embodiments, treatment can be given in the absence of symptoms. For example, treatment can be given to a susceptible individual before the onset of symptoms (e.g., taking into account symptom history and / or genetic or other susceptibility factors). Treatment can also continue after symptoms subside, for example, to prevent or delay their recurrence.

[0365] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound or composition as described herein.

[0366] Inflammatory diseases, disorders or conditions

[0367] Compounds as described herein are useful for treating inflammatory or obstructive airway diseases, such as to reduce tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. In certain embodiments, the inflammatory disease, disorder, or condition is an inflammatory or obstructive airway disease, including but not limited to asthma of any type or origin, including internal (non-allergic) asthma and external (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma-induced secondary bacterial infections. Asthma treatment is also understood to include treatment of subjects, such as those less than 4 or 5 years of age, who display symptoms of wheezing and are diagnosed or can be diagnosed as "asthmatic infants," which is an established patient category of medical importance and is currently often identified as incipient or early asthma.

[0368] The compounds as described herein are useful for treating heteroimmune diseases. In certain embodiments, the inflammatory disease, disorder or condition is a heteroimmune disease, including but not limited to graft-versus-host disease, transplantation, infusion, anaphylaxis, allergy (e.g., to pollen, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites or cockroach shells), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0369] The preventive efficacy of treating asthma will be shown as a reduced frequency or severity of symptomatic attacks (e.g., acute asthma or bronchoconstriction attacks), improved lung function, or improved airway hyperresponsiveness. It can also be shown as a reduced need for other symptomatic treatments (such as treatments for or intended to limit or interrupt the occurrence of symptomatic attacks, such as anti-inflammatory or bronchodilator treatments). The preventive benefit of asthma can be particularly evident in subjects prone to "early deterioration." Early deterioration" is a known asthma syndrome, common in substantial percentages of asthma and characterized by asthma attacks, the time of which is, for example, between about 4 and 6 am, that is, usually substantially away from the time of any symptomatic asthma treatment given in advance.

[0370] In certain embodiments, the inflammatory disease, disorder or condition is selected from acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, and exacerbation of airway hyperresponsiveness caused by other drug treatments (especially other inhaled drug treatments). In certain embodiments, the inflammatory disease, disorder or condition is bronchitis, wherein the bronchitis is of any type or origin, including but not limited to acute, arachidonic, catarrhal, croup, chronic or tuberculous bronchitis. In certain embodiments, the inflammatory disease, disorder or condition is pneumoconiosis (inflammatory, general occupational lung disease, frequently associated with chronic or acute airway obstruction, and caused by repeated inhalation of powders) of any type or origin, including, for example, alum lung, anthracis, asbestosis, lithostomy, eyelash loss, siderosis, silicosis, tobacco poisoning and byssinosis.

[0371] In certain embodiments, the inflammatory disease, disorder or condition is an eosinophil-related disorder, such as eosinophilia. In certain embodiments, the eosinophil-related disorder is an eosinophil-related disorder of the respiratory tract (e.g., involving pathological eosinophilic infiltration of lung tissue), including eosinophilia (which affects the respiratory tract and / or lungs), and, for example, respiratory eosinophil-related disorders secondary to or accompanying Loffler syndrome, eosinophilic pneumonia, parasitic (especially metazoan) invasion (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas, and eosinophil-related disorders affecting the respiratory tract caused by drug reactions.

[0372] The compounds as described herein are also useful for treating inflammatory or allergic conditions of the skin. In certain embodiments, the inflammatory or allergic condition of the skin is selected from psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquired, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0373] In certain embodiments, the inflammatory disease, disorder or condition is a disease or condition with an inflammatory component, such as ocular diseases and conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, uveitis and vernal conjunctivitis, diseases and conditions affecting the nose, including allergic rhinitis, and inflammatory diseases involving an autoimmune reaction or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammation intestinal diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca, uveitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold agglutinin-associated periodic syndromes, Muckle-Wells syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g., including Nephrotic syndrome or minimal change disease), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscular dystrophy, dyscrasia, obesity, fetal growth retardation, intestinal failure, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinence pigmenti, Paget's disease, acute or chronic pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergy, dioxide Silicon-induced diseases, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or decreased disease progression), lung disease, cystic fibrosis, acid-induced lung damage, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type I or type II diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,Fibritis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonitis, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis. ,

[0374] In certain embodiments, the inflammatory disease, disorder or condition is acute or chronic transplant rejection in a kidney, liver, heart, lung transplant or graft-versus-host disease in a bone marrow transplant.

[0375] In certain embodiments, the inflammatory disease, disorder or condition is an inflammatory disease, disorder or condition of the skin. In certain embodiments, the inflammatory disease, disorder or condition of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, and other inflammatory or allergic conditions of the skin.

[0376] In certain 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 juvenile idiopathic arthritis (SJIA), cold agglutinin-associated periodic syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

[0377] In certain embodiments, the inflammatory disease, disorder or condition is a TH17-mediated disease. In certain embodiments, the TH17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0378] In certain embodiments, the inflammatory disease, disorder or condition is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye diseases such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0379] In certain embodiments, the inflammatory disease, disorder or condition is associated with transplantation. In certain embodiments, the inflammatory disease, disorder or condition is associated with organ transplantation, organ transplant rejection and / or graft-versus-host disease. In certain embodiments, the inflammatory disease, disorder or condition is an autoimmune disorder. In certain embodiments, the autoimmune disorder is type I diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, disease, POEMS syndrome, Crohn's disease, ulcerative colitis, ankylosing spondylitis, orthopaedic spondylitis, primary biliary cirrhosis, autoimmune hepatitis, or inflammatory bowel disease.

[0380] In certain embodiments, the inflammatory disease, disorder or condition is an inflammatory disorder. In certain embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, ankylosing spondylitis, orthopaedic spondylitis, primary biliary cirrhosis, polymyalgia rheumatica, giant cell arteritis, or inflammatory bowel disease.

[0381] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in the pancreas. In certain embodiments, the inflammatory diseases, disorders or conditions in the pancreas are selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis.

[0382] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition in the kidney. In certain embodiments, the inflammatory disease, disorder or condition in the kidney is selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis, and acute or chronic rejection of a renal transplant.

[0383] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition in the liver. In certain embodiments, the inflammatory disease, disorder or condition in the liver is selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, and acute or chronic rejection of a liver transplant.

[0384] Also provided herein is a compound of formula (I), (Ib) or (Ib') as defined hereinbefore for use as defined hereinbefore, wherein the inflammatory disease, disorder or condition in the liver is selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and acute or chronic rejection of liver transplantation.

[0385] Non-alcoholic fatty liver disease (NAFLD) actually covers a wide range of diseases from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). Diagnosis of the disease currently means invasive liver biopsy. In addition, there is a need to have appropriate therapies.

[0386] NAFLD is characterized by predominantly macrovesicular steatosis and the presence of visible sebaceous glands on >5% of hepatocytes, which is generally considered a valid definition of fatty liver. The NAFLD activity score (NAS) is generally used to define and quantify disease activity by evaluating the severity of ongoing liver damage observed on liver biopsy. NAS is thus one of the clinical endpoints for evaluating NASH activity (Sanyal AJ. et al., Hepatology, 2011; 54:344). The score is based on the evaluation of the severity of sebaceous glands (0-3), inflammation (0-3), and hepatocyte ballooning (0-2).

[0387] As can be seen from Example 2 below, the following formula 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its metabolites

[0388]

[0389] Tested in the STAM model of non-alcoholic steatohepatitis, which is a well-established model for evaluating the activity of compounds in treating NASH. The compounds showed a trend toward a reduction in NAS compared to the vehicle group, and their use in the treatment of cholestatic liver disease, sclerosing cholangitis, and NAFLD, including NAFL and NASH, is expected.

[0390] In addition, as shown in Example 2, points 4.3 and 4.4 below, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine decreased Α-SMA and decreased the F4 / 80-positive area in the liver.

[0391] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in the lungs or heart. In certain embodiments, the inflammatory diseases, disorders or conditions in the lungs are selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of lung or heart transplantation.

[0392] Also provided herein are compounds of formula (I), (Ib) or (Ib') as defined hereinbefore for use as defined hereinbefore, wherein the inflammatory disease, disorder or condition is selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of lung or heart transplantation.

[0393] As can be seen in Example 3 below, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine showed a tendency to reduce mean pulmonary artery pressure at 70 mg / kg when tested in the Sugen hypoxia model.

[0394] As can be seen from Example 4 below, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine significantly reduces the pulmonary pressure in female rats in which pulmonary hypertension has been induced by monocrotaline.

[0395] All of these results anticipate its use in the treatment of pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis and pericarditis.

[0396] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in the skin. In certain embodiments, the inflammatory diseases, disorders or conditions in the skin are selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquired, acne, keloid, and other inflammatory or allergic conditions of the skin.

[0397] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in blood vessels / blood. In certain embodiments, inflammatory diseases, disorders or conditions in blood vessels / blood are selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative vascular disease, and restenosis.

[0398] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder or condition in the eye. In certain embodiments, the inflammatory disease, disorder or condition in the eye is selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis.

[0399] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in the central or peripheral nervous system. In certain embodiments, the inflammatory diseases, disorders or conditions in the central or peripheral nervous system are 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, type 1 Shiller-Marinus syndrome, Figure 3 disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathies.

[0400] In certain embodiments, the present invention provides methods for treating an autoimmune disease, disorder or condition. In certain embodiments, the autoimmune disease, disorder or condition is selected from lupus including in the skin and kidney, Guillain-Barre syndrome, myasthenia gravis, Jobben's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis.

[0401] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in the intestine. In certain embodiments, the inflammatory diseases, disorders or conditions in the intestine are selected from intestinal failure, ulcerative colitis and Crohn's disease.

[0402] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in a reproductive system. In certain embodiments, the inflammatory diseases, disorders or conditions in a reproductive system are selected from endometriosis, uterine fibroids, prostate dysplasia or growth, and cervical dysplasia.

[0403] In certain embodiments, the present invention provides methods for treating inflammatory diseases, disorders or conditions in bones and / or joints. In certain embodiments, the inflammatory diseases, disorders or conditions in bones and / or joints are selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hands, feet, ankles, knees, hips, shoulders, elbows or spine.

[0404] Combination therapy

[0405] Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions as described herein. As used herein, additional therapeutic agents that are normally administered to treat a specific disease or condition are referred to as "appropriate for the disease or condition being treated."

[0406] In certain embodiments, the present invention provides methods for treating an inflammatory disease, disorder, or condition comprising administering to a patient in need thereof a compound or composition as described herein in combination with a further therapeutic agent.

[0407] Those additional agents may be administered separately from the provided combination therapy, serving as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within a time period spaced from each other (usually within five hours).

[0408] As used herein, the terms "combination", "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combination of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0409] The amount of the additional therapeutic agent in the compositions of the invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure is about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0410] The combination may result in an additive or synergistic effect, wherein lower doses of one or both compounds may be used to obtain similar efficacy, or wherein the same doses may result in significantly improved efficacy.

[0411] In certain embodiments, the present invention provides compositions comprising a compound as described herein and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound as described herein, or can be administered before or after administration of the compound as described herein. Suitable therapeutic agents are further described in detail as follows. In certain embodiments, the compound as described herein can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours before the therapeutic agent. In certain embodiments, the compound as described herein can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours after the therapeutic agent.

[0412] In certain embodiments, the present invention provides methods of treating inflammatory diseases, disorders or conditions by administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents. The additional therapeutic agent can be a small molecule or a recombinant biological agent and includes, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat Sulfasalazine Antimalarials such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as gold thioglucosinolate gold thiomalate Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Tacrolimus, sirolimus, mycophenolate mofetil, leflunomide and "anti-TNF" agents such as etanercept Infliximab Golimumab Pecilizumab Adalimumab "Anti-IL-1" agents such as anakinra Rinascept Anti-T cell antibodies such as thymoglobulin, IV immune globulin (IVIg), canakinumab Anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab "Anti-T-cell" agents such as Abatacept "Anti-IL-6" agents such as tocilizumab Diclofenac, cortisone, hyaluronic acid ( or ), monoclonal antibodies such as tanezumab, anticoagulants such as heparin ( or ) and warfarin Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine, alosetron Lubiprostone Laxatives such as emulsion of magnesia, polyethylene glycol and Anticholinergics or anticonvulsants such as dicyclomine Beta-2 agonists such as albuterol ( HFA, HFA), levosalbutamol Ocenetrin Pirbuterol acetate Terbutaline sulfate Salmeterol Xinafoate and formoterol Anticholinergics such as ipratropium and tiotropium Inhaled corticosteroids such as beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide Disodium cromoglycate Methylxanthines such as theophylline and aminophylline, IgE antibodies such as omalizumab Nucleoside reverse transcriptase inhibitors such as zidovudine Abacavir Abacavir / Lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors such as delavirdine Efavirenz nevairapine and etravirine Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as amprenavir Atazanavir Darunavir Fusamprenavir Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir ( or ), and tipranavir Entry inhibitors such as enfuvirtide and Maravero Integrase inhibitors such as raltegravir Doxorubicin Vincristine Bortezomib and dexamethasone Lenalidomide combinations of, 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, ubiquitin protein ligase complex inhibitors such as BBT-401, sphingosine receptor modulators such as BMS- 986166, P38MAPK / PDE4 inhibitors such as CBS-3595, CCR9 antagonists such as CCX-507, FimH antagonists such as EB-8018, HIF-PH inhibitors such as FG-6874, HIF-1α stabilizers such as GB-004, MAP3K8 protein inhibitors such as GS-4875, LAG-3 antibodies such as GSK-2831781, RIP2 kinase inhibitors such as GSK-2983559, farnesoid X receptor agonists such as MET-409, CCK2 antagonists such as PNB-001, IL-23 receptor antagonists such as PTG-200, Purinergic P2X7 receptor antagonists such as SGM-1019, PDE4 inhibitors such as Apremilast, ICAM-1 inhibitors such as alicaforsen sodium, anti-IL23 agents such as guselkumab, 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 thereof.

[0413] In another embodiment, the present invention provides a method of treating gout comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and febuxostat

[0414] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine Antimalarials such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as gold thioglucosinolate gold thiomalate Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents such as etanercept Infliximab Golimumab Pecilizumab Adalimumab "Anti-IL-1" agents such as anakinra Rinascept Antibodies such as rituximab "Anti-T-cell" agents such as Abatacept and "anti-IL-6" agents such as tocilizumab

[0415] In certain embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, diclofenac, cortisone, hyaluronic acid ( or ) and monoclonal antibodies such as tanezumab.

[0416] In certain embodiments, the present invention provides a method of treating lupus comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarials such as hydroxychloroquine and chloroquine Cyclophosphamide Methotrexate Azathioprine and anticoagulants such as heparin ( or ) and warfarin

[0417] In certain embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis or inflammatory bowel disease comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from mesalamine Sulfasalazine Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine, alosetron Lubiprostone Laxatives such as emulsion of magnesia, polyethylene glycol and and anticholinergic or anticonvulsant drugs such as dicyclomine Anti-TNF therapy, steroids, and antibiotics such as Flagyl or Ciprofloxacin.

[0418] In certain embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from Beta-2 agonists such as albuterol ( HFA, HFA), levosalbutamol Ocenetrin Pirbuterol acetate Terbutaline sulfate Salmeterol Xinafoate and formoterol Anticholinergics such as ipratropium and tiotropium Inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide and Disodium cromoglycate Methylxanthines such as theophylline and aminophylline, and IgE antibodies such as omalizumab

[0419] In certain embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol ( HFA, HFA), levosalbutamol Osinaline Pirbuterol acetate Terbutaline sulfate Salmeterol Xinafoate and formoterol Anticholinergics such as ipratropium and tiotropium Methylxanthines such as theophylline and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide and

[0420] In certain embodiments, the present invention provides a method of treating HIV comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine Abacavir Abacavir / Lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors such as delavirdine Efavirenz nevairapine and etravirine Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as amprenavir Atazanavir Darunavir Fusamprenavir Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir ( or ), and tipranavir Entry inhibitors such as enfuvirtide and Maravero Integrase inhibitors such as raltegravir and combinations thereof.

[0421] In certain embodiments, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, comprising administering to a patient in need thereof a compound as described herein and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0422] The compounds and compositions according to the methods of the present invention can be administered in any amount and any route of administration that is effective in treating an inflammatory disease, disorder or condition or reducing its severity. The exact amount required varies between subjects, depending on the species, age and general condition of the subject, the severity of the disease or condition, the specific agent, its mode of administration, etc. The compounds as described herein are preferably formulated in dosage unit form for ease of administration and dosage uniformity. The phrase "dosage unit form" as used herein refers to physically discrete reagent units suitable for patients to be treated. However, it should be understood that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the time of administration, the route of administration, and the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination or simultaneously with the specific compound used, and other factors well known in the medical field. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[0423] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccally, as oral or nasal sprays, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, once or more per day to obtain the desired therapeutic effect.

[0424] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and aromatics.

[0425] Injectable preparations such as sterile injectable aqueous or oily suspensions can be prepared according to known in the art with suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be nontoxic sterile injectable solutions, suspensions or emulsions in parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are especially water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. Any mild non-volatile oil can be used for this purpose, including synthetic monoglycerides or diesters. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0426] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0427] In order to prolong the effect of the compounds of the present invention, it is often desirable to delay the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, the delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot dosage forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-type injectable formulations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

[0428] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0429] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dibasic calcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0430] Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms of tablets, lozenges, capsules, pills and granules can be prepared with coatings and shells such as other coatings known in the field of enteric coatings and pharmaceutical preparations. They can optionally contain opacifiers and can also be compositions that release active ingredients only or preferentially in some parts of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used include polymeric substances and waxes. Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0431] The active compound can also be in microencapsulated form, containing one or more of the above excipients. Solid dosage forms of tablets, lozenges, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. In the solid dosage form, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch.

[0432] In common practice, the dosage form may also include additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. They may optionally contain an opacifier and may also be a composition that releases the active ingredient only or preferentially in certain parts of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0433] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.

[0434] The active ingredient is mixed as required with a pharmaceutically acceptable carrier and any required preservative or buffer under aseptic conditions. Eye formulations, ear drops and eye drops are also expected to belong to the scope of the invention. Additionally, the present invention is expected to use a transdermal patch, which has the additional advantage of providing a controlled delivery of the compound to the body. The dosage form can be prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or a gel.

[0435] The compounds of the present invention are also used as co-therapeutic compounds in combination with other drug substances (such as anti-inflammatory, bronchodilator or antihistamine drug substances), in particular for the treatment of obstructive or inflammatory respiratory diseases such as those mentioned above, for example as a synergist of the therapeutic activity of the drug or as a means of reducing the required dose or potential side effects of the drug. The compounds of the present invention can be mixed with other drug substances in a fixed pharmaceutical composition, or they can be administered separately before, at the same time or after the other drug substances. Accordingly, the present invention includes the combination of the compounds of the present invention described above with anti-inflammatory, bronchodilator, antihistamine or antitussive drug substances, wherein the compounds of the present invention and the drug substances are located in the same or different pharmaceutical compositions.

[0436] Suitable anti-inflammatory drugs include steroids, especially glucocorticoids such as budesonide, beclomethasone dipropionate, fluticasone propylacetate, ciclesonide or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast ( GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-5 351591 (Schering-Plough), arofylline (Almirall Prodesfarma), PD189659 / PD168787 (ParkeDavis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID TM CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenergic receptor agonists such as salbutamol (salbutamol), metaprenaline, terbutaline, salmeterol fenoterol, procaterol, and especially formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium bromide salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0437] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, nitrogen ebastine, epinastine, mizolastine, and tefenadine.

[0438] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR 10 , CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and particularly CCR-5 antagonists such as the Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0439] The active compound structure is identified by a coded number, the generic or trade name may be taken from a physical version of the standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0440] The compounds of the invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapies being in the form of a fixed combination, or administration of the compounds of the invention and one or more other therapeutic compounds being staggered or provided independently of one another, or a fixed combination and one or more other therapeutic compounds being administered in combination.

[0441] Those additional agents may be administered separately from the composition containing the compounds of the invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within separate time periods (usually within five hours).

[0442] As used herein, the terms "combination", "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0443] The amount of a compound as described herein and an additional therapeutic agent (in those compositions comprising such additional therapeutic agents) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dose of 0.01-100 mg / kg body weight / day of a compound of the invention can be administered.

[0444] In those compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compounds of the invention may act synergistically. Thus, the amount of the additional therapeutic agent in the composition will be less than that required in a monotherapy using only that therapeutic agent. In the composition, the additional therapeutic agent can be administered at a dose of 0.01-1,000 μg / kg body weight / day.

[0445] The amount of additional therapeutic agent in the compositions of the invention will not exceed the amount that would normally be administered in a composition comprising the therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure is about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0446] The compounds of the present invention or their pharmaceutical compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices have the risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the present invention.

[0447] In addition to the above-mentioned prevention and / or treatment methods, the present invention also provides the corresponding use of the disease, disorder or condition as described herein for prevention and / or treatment. In certain embodiments, the present invention provides a compound as described herein or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of an inflammatory disease, disorder or condition as described herein. In certain embodiments, the prevention and / or treatment of an inflammatory disease, disorder or condition provided by the present invention is desired for a patient, and the presence and / or expression level of miR-124 is measured and / or monitored by a method as described herein.

[0448] Also provided herein is a compound of formula (I), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa), (IVb), (IVb'), (IVc), or (IVd) as defined above, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an inflammatory disease, disorder or condition in a patient in need thereof, wherein the inflammatory disease, disorder or condition is selected from:

[0449] (a) an inflammatory disease, disorder or condition in the pancreas selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis;

[0450] (b) an inflammatory disease, disorder or condition in the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis and acute or chronic rejection of a renal transplant;

[0451] (c) an inflammatory disease, disorder or condition in the liver selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and acute or chronic rejection of a liver transplant;

[0452] (d) an inflammatory disease, disorder or condition in the lung or heart 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;

[0453] (e) an inflammatory disease, disorder or condition in the skin selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloid, and other inflammatory or allergic conditions of the skin;

[0454] (f) an inflammatory disease, disorder or condition in the blood vessels / blood selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative vascular disease and restenosis;

[0455] (g) an inflammatory disease, disorder or condition in the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis;

[0456] (h) an inflammatory disease, disorder or condition in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, including chronic pain, traumatic brain injury, including stroke, Alzheimer's disease, Parkinson's disease, myelitis, type 1 Shiller-Jackson syndrome, Figure 3 disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathies;

[0457] (i) an autoimmune disease, disorder or condition selected from lupus, including in the skin and kidney, Guillain-Barre syndrome, myasthenia gravis, Jobben's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis;

[0458] (j) an inflammatory disease, disorder or condition in the intestine selected from intestinal failure, ulcerative colitis and Crohn's disease;

[0459] (k) an inflammatory disease, disorder or condition of the reproductive system selected from the group consisting of endometriosis, uterine fibroids, prostate dysplasia or growth, and cervical dysplasia; and

[0460] (l) an inflammatory disease, disorder or condition in the bones and / or joints selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hands, feet, ankles, knees, hips, shoulders, elbows or spine.

[0461] Also provided herein is a compound of Formula (I), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa), (IVb), (IVb'), (IVc), or (IVd) as defined above, or a pharmaceutically acceptable salt thereof, for use as an anti-inflammatory agent intended for use in a patient, wherein the presence and / or expression level of miR-124 in the patient's blood and / or tissue sample is monitored before and / or during the course of use of the anti-inflammatory agent.

[0462] Animal preclinical models can be used to evaluate the anti-inflammatory activity of any form of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine and its metabolites or one of its pharmaceutically acceptable salts.

[0463] Example 1

[0464] For example, in a mouse IMQ-induced psoriasis model. Psoriasis can be induced by, for example, daily dosing of IMQ on days 0 to 9, and treatment can be given daily, for example, on days 0 to 9. Anti-inflammatory activity can be evaluated, for example, by measuring psoriasis scores.

[0465] For example, in an MPTP-induced Parkinson's disease mouse model, mice can receive, for example, 4 intraperitoneal (IP) injections of 20 mg / ml MPTP at 2 hour intervals on day 0. Treatment can be given daily, for example, from day 0 to day 7. Anti-inflammatory activity can be evaluated, for example, by TH immunoreactivity analysis at the substantia nigra pars compacta (SNpc) level.

[0466] For example, in the experimental autoimmune encephalomyelitis (EAE) rodent model of MOG-induction, carry out.EAE can be induced, for example, by injecting MOG / CFA inoculation in the paravertebral region at the 0th day of the study.And in order to increase blood-brain barrier (BBB) ​​penetration, all animals can be by intraperitoneal injection of pertussis toxin (PT) at the 0th day and the 2nd day of the study for example to carry out supplementary immunostimulation.Treatment can be given daily, for example, from the 0th day, the 3rd day or the 10th day, and anti-inflammatory activity can be measured, for example, by clinical score or / and evaluation of cell infiltration and demyelination, by H&E staining, histological evaluation and / or CNS / pain parameter evaluation of the spinal cord.For example, in the NOD idiopathic model of mouse diabetes, carry out.Treatment can be given daily, and anti-inflammatory activity can be evaluated, for example, by blood sugar level and / or oral glucose tolerance test.

[0467] In the following examples, Compound A is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or ABX464 and Compound B is a metabolite thereof of the formula

[0468]

[0469] Example 2: In vivo efficacy study of compounds in the STAM model of non-alcoholic steatohepatitis (NASH study)

[0470] A. Materials and Methods

[0471] 1. Test substances

[0472] To prepare the dosing solution, compounds A and B were weighed and suspended in a vehicle consisting of 20% vehicle-A1 and 80% vehicle-A2. The composition of vehicle-A1 is 0.5% (w / v) carboxymethylcellulose (CMC) (400-800 centipoise in water for injection) + 2.5% (w / v) Tween 80. The composition of vehicle-A2 is 0.5% (w / v) carboxymethylcellulose (CMC) (400-800 centipoise in water for injection). Telmisartan It was purchased from Boehringer Ingelheim GmbH (Germany) and dissolved in purified water.

[0473] 2. Induction of NASH

[0474] NASH was induced in 48 male mice: a single subcutaneous injection of 200 μg of streptozotocin (STZ, Sigma-Aldrich, USA) solution was given 2 days after birth and they were fed a high fat diet (HFD, 57 kcal% fat, Cat#HFD32, CLEA Japan, Inc., Japan) after 4 weeks of age.

[0475] 3. Drug administration route

[0476] Compounds A and B and telmisartan were orally administered in a volume of 10 mL / kg.

[0477] 4. Therapeutic dose

[0478] From 6 to 9 weeks of age, Compound A was administered at 3 dose levels of 10, 20 and 40 mg / kg once daily. From 6 to 9 weeks of age, Compound B was administered at a dose of 40 mg / kg once daily. From 6 to 9 weeks of age, Telmisartan was administered at a dose of 10 mg / kg once daily.

[0479] 5. Animals

[0480] C 57 BL / 6 mice (14-day-pregnant females) were obtained from Japan SLC, Inc. (Japan). All animals used in the studies were housed and cared for in accordance with the guidelines for animal use of the Japanese Pharmacological Society.

[0481] The animals were kept in an SPF facility under controlled conditions with respect to temperature (23±3°C), humidity (50±20%), lighting (12-hour artificial light and light-avoidance cycle; light on from 8:00 to 20:00), and air exchange. High pressure was maintained in the laboratory to prevent facility contamination.

[0482] Animals were housed in TPX cages (CLEA Japan) with a maximum of 4 mice per cage. Sterile Palmas-μ (Material Research Center, Japan) was used for bedding and replaced once a week.

[0483] Sterile solid HFD was provided ad libitum, which was placed on the metal cover on the top of the cage. Purified water was provided ad libitum from a water bottle equipped with a rubber stopper and a straw. The water bottle was replaced once a week, cleaned and sterilized in an autoclave and reused.

[0484] Mice were identified by ear punching. Each cage was labeled with a specific identification code.

[0485] 6. Measurement of Plasma Biochemistry

[0486] For plasma biochemistry, non-fasting blood was collected in polypropylene tubes containing anticoagulant (Novo-Heparin, Mochida Pharmaceutical Co. Ltd., Japan) and centrifuged at 1,000 x g for 15 minutes at 4°C. The supernatant was collected and stored at -80°C until use. Plasma ALT was measured by FUJIDRI-CHEM 7000 (Fujifilm, Japan).

[0487] 7. Measurement of Hepatic Triglyceride Content

[0488] Liver total lipid extracts were obtained by the Folch method (Folch J. et al., J. Biol. Chem. 1957; 226: 497). Liver samples were homogenized in chloroform-methanol (2: 1, v / v) and incubated overnight at room temperature. After washing with chloroform-methanol-water (8: 4: 3, v / v / v), the extract was evaporated to dryness and dissolved in isopropanol. Liver triglyceride content was measured by triglyceride E-test (FUJIFILM Wako Pure Chemical Corporation, Japan).

[0489] 8. Histological Analysis

[0490] For HE staining, sections were cut from paraffin blocks of liver tissue prefixed in Bouin's solution and stained with Lillie-Mayer hematoxylin (Muto Pure Chemical Co., Ltd., Japan) and eosin solution (FUJIFILM Wako PureChemical Corporation). NAFLD activity score (NAS) was calculated according to the criteria of Kleiner (Kleiner DE. et al., Hepatology, 2005; 41: 1313). To visualize collagen deposition, Bouin's fixed liver sections were stained with picro-Sirius red solution (Waldeck, Germany). For quantitative analysis of fibrosis area, the fibrosis area was analyzed using a digital camera (DFC 295 ; Leica, Germany) captured bright-field images of Sirius red-stained sections around the central vein at 200-fold magnification, and the positive area in 5 fields / section was measured using ImageJ software (National Institute of Health, USA).

[0491] 9. Sample Collection

[0492] For plasma samples, non-fasting blood was collected in polypropylene tubes containing anticoagulant (Novo-Heparin) and centrifuged at 1,000xg for 15 minutes at 4°C. 20 μL of supernatant was collected and stored at -80°C for biochemical analysis. The remaining plasma was collected and stored at -80°C for transportation. For frozen liver samples, the left lateral lobe was collected and cut into 6 pieces. 2 pieces in the left lateral lobe, left and right middle lobe, and tail lobe were quickly frozen in liquid nitrogen and stored at -80°C for transportation. The other 2 pieces of the left lateral lobe were fixed in Bouin solution and then embedded in paraffin. Paraffin blocks were stored at room temperature for histological analysis. The remaining pieces of the left lateral lobe were embedded in OCT compound and quickly frozen in liquid nitrogen. The samples were stored at -80°C. The right lobe was quickly frozen in liquid nitrogen and stored at -80°C for liver biochemistry.

[0493] 10. Statistical tests

[0494] Statistical analysis was performed using the Bonferroni multiple comparison test on GraphPad Prism 6 (GraphPad Software Inc., USA). P values ​​< 0.05 were considered statistically significant. The condition for showing a trend or tendency was that a one-tailed T test returned a P value < 0.1. The results are expressed as mean ± SD.

[0495] B. Experimental Design and Treatment

[0496] 1. Research Group

[0497] Group 1: Vehicle

[0498] Vehicle [20% of Vehicle-A1 and 80% of Vehicle-A2] was orally administered to 8 NASH mice at a volume of 10 mL / kg once daily from 6 to 9 weeks of age.

[0499] Group 2: Compound A Low

[0500] Vehicle supplemented with Compound A was orally administered to 8 NASH mice once daily from 6 to 9 weeks of age at a dose of 10 mg / kg.

[0501] Group 3: Compound A

[0502] Vehicle supplemented with Compound A was orally administered to 8 NASH mice once daily from 6 to 9 weeks of age at a dose of 20 mg / kg.

[0503] Group 4: Compound A High

[0504] Vehicle supplemented with Compound A was orally administered to 8 NASH mice once daily from 6 to 9 weeks of age at a dose of 40 mg / kg.

[0505] Group 5: Compound B

[0506] Vehicle supplemented with Compound B was orally administered to 8 NASH mice once daily from 6 to 9 weeks of age at a dose of 40 mg / kg.

[0507] Group 6: Telmisartan

[0508] Purified water supplemented with telmisartan was orally administered to 8 NASH mice once daily from 6 to 9 weeks of age at a dose of 10 mg / kg.

[0509] Table 4 below summarizes the treatment plan:

[0510] Table 4

[0511]

[0512] 2. Animal Monitoring and Sacrifice

[0513] Survival rate, clinical signs and behavior were monitored daily. Body weight was recorded before treatment. Approximately 60 minutes after each administration, mice were observed for significant clinical signs of poisoning, moribundity and death. Animals were sacrificed by direct cardiac puncture exsanguination under isoflurane anesthesia (Pfizer Inc.) at 9 weeks of age.

[0514] C. Results

[0515] 1. Weight changes and general condition

[0516] The mean body weight of the telmisartan group was significantly lower than that of the vehicle group from day 9 to day 21. There was no significant change in mean body weight between the vehicle group and the other treatment groups on any day during the treatment period.

[0517] There were no deaths of animals in all groups during the treatment period. In this study, no animal showed deterioration in general condition.

[0518] 2. Body and liver weight on the day of sacrifice

[0519] 2.1. Body weight on the day of sacrifice (Table 5)

[0520] On the day of sacrifice, the telmisartan group showed a significant decrease in mean body weight compared to the vehicle group. On the day of sacrifice, there was no significant difference in mean body weight between the vehicle group and the other treatment groups.

[0521] 2.2. Liver weight and liver weight to body weight ratio (Table 5)

[0522] The telmisartan group showed a significant decrease in mean liver weight compared to the vehicle group. The compound A low group showed a significant increase in mean liver weight compared to the vehicle group. The mean liver weights of the compound A high and compound B groups tended to increase compared to the vehicle group. There was no significant difference in mean liver weight between the vehicle group and the compound A medium group.

[0523] The mean liver weight to body weight ratio of the telmisartan group tended to decrease compared with the vehicle group. The mean liver weight to body weight ratio in the Compound A low, medium and high groups and the Compound B group tended to increase compared with the vehicle group.

[0524] Table 5: Body weight and liver weight

[0525]

[0526] 3. Biochemistry

[0527] 3.1. Plasma ALT

[0528] The compound A high group showed a significant increase in plasma ALT levels compared to the vehicle group. The plasma ALT levels of the compound A low and medium groups and the compound B group tended to increase compared to the vehicle group. There was no significant difference in plasma ALT levels between the vehicle group and the telmisartan group.

[0529] 3.2. Hepatic triglycerides

[0530] The hepatic triglyceride content in the telmisartan group tended to decrease compared with the vehicle group. The hepatic triglyceride content in the compound B group tended to increase compared with the vehicle group. There was no significant difference in hepatic triglyceride content between the vehicle group and the other treatment groups.

[0531] Table 6: Biochemistry

[0532]

[0533] 4. Histological Analysis

[0534] 4.1. HE staining and NAFLD activity score (Table 7 and Figure 1 , 2 , 3 and 4)

[0535] Representative photomicrographs of HE-stained liver sections were analyzed. Figure 1 represents the NAFLD activity score, Figure 2 represents the sebaceous gland disease score, Figure 3 represents the inflammation score and Figure 4 Represents balloon-like changes.

[0536] Liver sections of the vehicle group showed microvesicular and macrovesicular fat deposition, hepatocyte ballooning and inflammatory cell infiltration. The telmisartan group showed a significant decrease in NAS compared with the vehicle group. The NAS of the compound A low, medium and high groups and the compound B group tended to decrease compared with the vehicle group.

[0537] Table 7: NAFLD activity scores

[0538]

[0539] Definition of NAS components

[0540]

[0541] 4.2. Sirius red staining and fibrosis area (Table 8 and Figure 5 )

[0542] Representative photomicrographs of Sirius red-stained liver sections were analyzed. Figure 5 Represents the fibrosis area.

[0543] Liver sections from the vehicle group showed increased collagen deposition in the pericentral region of the liver lobule. The fibrosis area (Sirius red-positive area) of the compound A group tended to decrease compared with the vehicle group. The fibrosis area of ​​the compound B group tended to increase compared with the vehicle group. There was no significant difference in fibrosis area between the vehicle group and the other treatment groups.

[0544] Table 8: Fibrosis area

[0545]

[0546] 4.3α-SMA Immunostaining and α-SMA-Positive Area

[0547] α-SMA immunostaining of liver sections of the vehicle group showed that α-SMA-positive cells were mainly accumulated in zone 3. The α-SMA-positive area of ​​the compound A high and telmisartan groups tended to be reduced compared with the vehicle group. (Table 9 below)

[0548] 4.4F4 / 80 Immunostaining

[0549] F4 / 80 immunostaining of liver sections of the vehicle group showed that F4 / 80-positive cells were mainly accumulated in zone 3.

[0550] The compound A high group showed a significant decrease in the F4 / 80-positive area compared to the vehicle group. The F4 / 80-positive area of ​​the compound A neutral and compound B groups tended to decrease compared to the vehicle group. (Table 9)

[0551] Table 9:

[0552]

[0553] in conclusion

[0554] Telmisartan

[0555] Treatment with telmisartan showed a significant decrease in NAS compared to the vehicle group, indicating that the drug successfully functioned as a positive control in this study. Treatment with telmisartan showed a trend toward a decrease in hepatic triglyceride levels compared to the vehicle group.

[0556] Compound A

[0557] Treatment with Compound A at a low dose showed a decreasing trend of NAS compared to the vehicle group. Treatment with Compound A at a low dose showed an increasing trend of plasma ALT level compared to the vehicle group.

[0558] Treatment with Compound A at a medium dose showed a trend of decrease in NAS and fibrosis area compared to the vehicle group. Treatment with Compound A at a medium dose showed a trend of increase in plasma ALT levels compared to the vehicle group. Treatment with Compound A at a high dose showed a significant increase in plasma ALT levels compared to the vehicle group. Treatment with Compound A at a high dose showed a trend of decrease in NAS compared to the vehicle group.

[0559] Compound B

[0560] Treatment with Compound B showed a decreasing trend in NAS compared to the vehicle group.

[0561] Treatment with Compound B showed an increasing trend in plasma ALT levels, liver triglyceride content, and fibrosis area compared with the vehicle group.

[0562] In this study, compounds A and B showed a trend of reduction in NAS compared to the vehicle group. In addition, compound A showed a trend of reduction in collagen pathological deposition in the liver, as shown by Sirius red staining. In summary, compound A showed effective anti-NAS and anti-fibrotic effects in this NASH model, while compound B showed effective anti-NAS effects.

[0563] Example 3: In vivo efficacy study of compounds in the Sugen hypoxia model of pulmonary arterial hypertension (PAH) in rats

[0564] Experimental Procedure

[0565] Study Design

[0566] Induced PAH

[0567] Animals were randomized between treatment groups by study instructions based on their body weight and the results of transthoracic echocardiography (on day 21). Animals in the same treatment group were housed in pairs.

[0568] On day 0, animals in groups 2 to 5 (see Table 10) received a single subcutaneous injection of sugen (20 mg / kg, 2 mL / kg volume) solution (10 mg / mL) and were returned to their cages. On day 0, animals in group 1 received a single subcutaneous injection of 2 mL / kg of DMSO (sugen vehicle) and were returned to their respective cages.

[0569] Groups 2-5 were placed in cages with controlled atmosphere adjusted to receive an FiO2 equivalent to 0.10 (10%) using a mixture of nitrogen and ambient air controlled by a ventilation cage system. They were kept in these hypoxic conditions for 21 days. Cages were cleaned and changed once a week under hypoxia, exposing the animals to ambient oxygen levels for less than 10 minutes. They were exposed to ambient oxygen levels from day 22 to day 56. Group 1 animals were kept in cages exposed to ambient oxygen (normoxia) levels for 56 days. The animals were observed daily for any changes in behavior and general health status.

[0570] deal with

[0571] On day 22 (groups 2-5), treatment with compound A, sildenafil or vehicle was administered as planned and described in Table 10. Groups 2-4 received a single dose per day. Reference group 5 received sildenafil twice per day. Food and water were provided ad libitum. Daily observations of the animals' behavior and general health were completed. Weekly body weights were recorded.

[0572] Echocardiography

[0573] All animals were monitored for disease progression by echocardiography on Day 0, Day 21 and on the day of surgery (Day 56).

[0574] Blood sampling

[0575] Venous blood (0.5 ml, anticoagulated with EDTA) was sampled from all animals (including normoxic controls) on Day 0, on Day 22, and on Day 56, just after the first dose. EDTA-anticoagulated whole blood was centrifuged to produce plasma, which was decanted into clean tubes labeled with at least the animal number, group ID, and time point, and stored frozen at -80°C until transfer to the sponsor.

[0576] Table 10. Treatment group assignment and treatment information

[0577]

[0578] * Groups of n=10, 12 animals were started to compensate for the approximately 10-20% mortality rate in this model.

[0579] Surgical Instrumentation and Measurement of Hemodynamic and Functional Parameters in Efficacy Study Animals

[0580] 1. On the selected surgical day, rats were anesthetized with a mixture of 2 to 2.5% isoflurane USP (Abbot Laboratories, Montreal, Canada) / oxygen and placed on a heating pad to maintain body temperature.

[0581] 2. The rat's trachea was cut and ventilated immediately via a positive pressure rodent respirator set at ≈10 ml / kg body weight at a rate of 65-70 pulses / min.

[0582] 3. Lead II ECG contact electrodes were placed on the rat to continuously monitor the ECG during the surgical procedure.

[0583] 4. A cannula connected to a pressure transducer was inserted into the left femoral artery to measure arterial blood pressure.

[0584] 5. A cannula connected to a pressure transducer was inserted into the right atrium through the right jugular vein to measure right atrial pressure.

[0585] 6. The heart was exposed through sternotomy, a 20 GA 1.16 / Insyte was introduced into the right ventricle and quickly hooked to a saline-filled PE-50 catheter connected to the transducer.

[0586] 7. After recording the right ventricular pressure for a few seconds, push the Insyte further into the pulmonary artery to record PAP for an additional 60 seconds.

[0587] 8. Record hemodynamic parameters continuously for the duration of the procedure or until the PAP signal is lost.

[0588] 9. After hemodynamic monitoring, the chest cavity was further opened to expose the lungs. The muscles over the trachea were dissected to remove the lungs and heart. The harvested tissue was rinsed with PBS to remove any excess blood before weighing.

[0589] 10. For lung histology and casting, the procedure was as follows: 1) eight (8) rats per group were retained for evaluation of left lung histology and were processed accordingly as described in point 12 of section 8.2 of this article; 2) two (2) rats per group allowed for quantitative characterization of the three-dimensional vascular structure of the left lung and were processed accordingly for left lung casting as described in section 8.3.

[0590] 11. For histology, the left lobe was inflated with a 10 mL syringe filled with fixative (10% NBF) and attached with a blunt tip needle (23 g). The needle tip was inserted into the trachea and the position was fixed with a tying suture while another syringe was tied to the pulmonary artery. The lungs were gently inflated at physiological pressure (20-25 mmHg) until all lobes were fully, evenly and uniformly expanded (fixative was not allowed to seep through the lung surface). This provided optimal vascular and airway expansion without causing excessive tissue disruption. The needle was then removed, sutures were tied around the trachea, and immersed in 10% NBF at a 1:20 tissue: fixative ratio. The tissues were kept in formalin for 24-48 hours. They were then cut into three parts (upper, middle and lower). Sections were sent to the Institute for Research in Immunology and Cancer (IRIC) in Montreal (Quebec, Canada) for embedding, sectioning, and staining for endothelial cells with hematoxylin and eosin (H&E) or von Willebrand factor (VWF).

[0591] 12. As part of the Fulton index, the heart is dissected and the right ventricle is separated from the left ventricle with its septum and weighed separately.

[0592] Pulmonary artery casting procedure

[0593] 1. After the hemodynamic parameters were recorded, the lungs and hearts of 2 of the 10 rats were harvested and processed for pulmonary artery casts of the left lung.

[0594] 2. Polyethylene (PE190) tubing was cut to a length of 40 cm, one end was connected to an 18-G needle and the other end, which was heat-passivated, was used as a catheter to enter the right ventricle (RV). The catheter was pushed to the level of the main pulmonary artery (MPA) and fixed there. For right lung casting, the catheter was pushed into the pulmonary artery (PA) of the right lung and fixed there to avoid perfusion of the left lung.

[0595] 3. Flush the blood from the PA by pumping 2 ml of diluted sodium heparin (5 units / ml) (APP Pharmaceuticals, Inc., Schaumburg, IL, USA) using a continuous syringe pump set at 2 ml / min. A small incision was made in the left atrial appendage of the left ventricle to allow the solution to flow out of the pulmonary arterial circulation.

[0596] 4. To ensure uniform filling, especially in the lower lung segments, the lungs are kept in an upright position.

[0597] 5. The silicone polymer casting compound, MV-yellow Microfil with a viscosity of 25 centipoise (cP; 0.01 g per cm-second), was mixed with a medium viscosity (MV) diluent at a volume ratio of 5:4 (diluent: compound) and added to 5% (volume) curing agent. The freshly mixed silicone polymer casting material was then pumped through the catheter at 2 ml / min until the polymer reached the RV. The flow rate was reduced to 0.05 ml / min as the polymer entered the pulmonary circulation.

[0598] 6. Stop pumping when polymer is evenly visible on the lung surface. Ligate the PA of the irrigated left lung before resection from the cardio-pulmonary segment.

[0599] 7. The PA-ligated left lung was then transferred into a small container and stored at 4°C for 24 hours to allow the silicone polymer to fully polymerize. In the case of the right lung cast, the right PA was ligated.

[0600] 8. Once polymerized, add 10% formalin to the container to submerge the left lung (or right lung lobe) with formalin and store at 4°C for an additional 48 hours.

[0601] 9. The left lung (or right lobe) was then transported to the Department of Engineering at the University of Sherbrooke (Quebec, Canada) for micro-CT imaging using a Skyscan from Bruker (Manning Park, MA, USA). The images were then transferred to Fluidda Inc. for analysis.

[0602] result:

[0603] Mean lung pressure in females

[0604] deal with Mean lung pressure (mmHg) SEM Normoxia control 14.7 0.60 SuHx+ Vehicle 33.5 3.42 SuHx + Compound A, 70 mg / kg QD 24.1 3.35 SuHx + Compound A, 120 mg / kg QD 34.4 4.22 SuHx + sildenafil, 50 mg / kg BID 22.5 1.85

[0605] Average lung pressure in males

[0606] deal with Mean lung pressure (mmHg) SEM Normoxia control 15.8 0.73 SuHx+ Vehicle 41.7 3.29 SuHx + Compound A, 70 mg / kg QD 26.8 2.87 SuHx + Compound A, 120 mg / kg QD 33.6 6.71 SuHx + sildenafil, 50 mg / kg BID 30.1 3.04

[0607] In conclusion, treatment of rats with Compound A in the Sugen hypoxia model showed a tendency to reduce mean pulmonary artery pressure at 70 mg / kg.

[0608] Example 4: In vivo efficacy study of compounds in the monocrotaline model of pulmonary hypertension in rats

[0609] Experimental system

[0610] Acquisition system

[0611] Data acquisition was performed using a networked personal computer running Microsoft Windows XP Professional 2007. The acquisition software was AxoScope 10.2 using the Axon Instrument interface Digidata. AxoScope 10.2 has been fully validated in the environment in which it was used.

[0612] Analysis system

[0613] The analysis software was Clampfit 10.2.0.14 from Axon Instrument, installed on a networked PC running Microsoft Windows XP Professional 2016. Clampfit 10.2.0.14 has been fully validated in the environment in which it was used. The image analysis software was Microsoft Office Excel 2016, installed on a networked PC running Microsoft Windows 10 Family.

[0614] Compiling experimental data

[0615] 1. Open the experimental trace to be analyzed in Clampfit.

[0616] 2. Record right atrial pressure for 1 minute.

[0617] 3. Extract mean, diastolic, and systolic pulmonary pressures using PAP recorded continuously for at least 1 min or until loss of signal.

[0618] 4. The mean, diastolic and systolic arterial pressures were extracted using the continuously recorded systemic arterial pressure (SAP).

[0619] 5. At the end point of the hemodynamic parameter recording, the right and left ventricles including the diaphragm and lobes were removed to determine the wet weight.

[0620] 6. Compile each parameter for each group and present it in a bar graph and perform appropriate statistical analysis.

[0621]

[0622] Experimental Procedure:

[0623] Preparation of monocrotaline solution

[0624] Weigh the appropriate amount of monocrotaline and add 1 / 3 correct volume of 1.0N HCl, mix to ensure monocrotaline solvation. The solution is then neutralized with 1 / 3 correct volume of 1.0N NaOH. The pH of the solution is checked with pH test paper / strips or an electronic pH meter and adjusted to neutral as necessary; the final volume is made up with water for injection to obtain a 20 mg / mL solution. The monocrotaline solution is injected subcutaneously into the loose skin on the neck at 3 mL / kg body weight (dose is 60 mg / kg) to the shoulder of each rat.

[0625] Preparation of Compound A solution

[0626] Compound A was administered as a suspension in the vehicle. To achieve the desired concentration, Compound A was ground to a fine powder using a mortar and pestle and then mixed with 20% (final volume) of Vehicle A1 until a suspension was obtained. 80% of Vehicle A2 was then added to the suspension under magnetic stirring.

[0627] Vehicle A1: 0.5% (w / v) carboxymethylcellulose (CMC) (400-800 cps in water for injection) + 2.5% (w / v) Tween 80

[0628] Vehicle A2: 0.5% (w / v) carboxymethylcellulose (CMC) (400-800 cps in water for injection)

[0629] Vehicle for dosing: 20% Vehicle A1 + 80% Vehicle A2

[0630] Control and Compound A dose formulations were stirred for at least 15 minutes prior to dosing and maintained under continuous magnetic stirring throughout the dosing procedure.

[0631] Table 11. Concentration solutions and dosing volumes of Compound A

[0632]

[0633] Preparation of sildenafil

[0634] Weigh an appropriate amount of sildenafil and add an appropriate volume of distilled water to obtain a suspension at 5 mg / mL. Mix the suspension with a stirrer for 30-60 minutes until a uniform suspension is obtained. Carefully maintain a uniform suspension (continuous stirring) while aspirating the dose into the gavage syringe. Fill one gavage syringe at a time and give before filling the next syringe. The solution is stored frozen at 2 to 8°C and protected from light. The expiration date is set at 7 days after preparation.

[0635] Table 12. Concentration solutions and dosing volumes of sildenafil

[0636]

[0637] Experimental Procedure

[0638] Study Design

[0639] Induced PAH

[0640] Animals were randomized between treatment groups based on their body weight and the results of transthoracic echocardiography (Day 7) by study supervisor. Animals in the same treatment group were housed in pairs.

[0641] Animals in groups 2 to 5 (see Table 13) received a single subcutaneous injection of monocrotaline (60 mg / kg) solution and were returned to their cages on day 0. Animals in group 1 received a single subcutaneous injection of MCT vehicle on day 0 and were returned to their respective cages.

[0642] deal with

[0643] On day 7 (groups 2-5), Compound A, sildenafil or vehicle treatment was administered as scheduled and described in Table 13. Groups 2-4 received a single dose per day. Reference group 5 received sildenafil twice per day. Food and water were provided ad libitum. Daily observations of the animals' behavior and general health were completed. Body weights were recorded weekly.

[0644] Echocardiography

[0645] Echocardiographic monitoring of disease progression was performed on all animals on days 0, 7, and on the day of surgery (day 28).

[0646] Blood sampling

[0647] Venous blood (0.5 ml, anticoagulated with EDTA) was collected from all animals (including normoxic controls) on day 0, just after the first dose on day 7. On the end of surgery day (day 28), after hemodynamic measurements, rats underwent cardiac puncture to collect 3 ml of blood. EDTA-anticoagulated whole blood was centrifuged to produce plasma, which was decanted into clean tubes labeled with at least the animal number, group ID, and time point, and stored frozen at -80°C until transfer to the sponsor.

[0648] Table 13: Treatment group assignment and treatment information

[0649]

[0650] *Start with groups of n=10, 12 animals to compensate for the approximately 10-20% mortality in this model. Measurement of Hemodynamic and Functional Parameters in Efficacy Study Animals and Surgical Instrumentation 1. On the chosen day of surgery, rats were anesthetized with a 2 to 2.5% isoflurane USP (Abbot Laboratories, Montreal, Canada) / oxygen mixture and placed on a heating pad to maintain body temperature.

[0651] 2. The rats were tracheotomized and immediately ventilated via a positive pressure rodent respirator set at ≈10 ml / kg body weight, 65-70 pulses / min.

[0652] 3. Lead II ECG contact electrodes were placed on the rat to continuously monitor the ECG during the surgical procedure.

[0653] 4. A cannula connected to a pressure transducer was inserted into the left femoral artery to measure arterial blood pressure.

[0654] 5. A cannula connected to a pressure transducer was inserted into the right atrium through the right jugular vein to measure right atrial pressure.

[0655] 6. The heart was exposed through sternotomy and a 20 GA 1.16 / Insyte was introduced into the right ventricle and quickly hooked to a saline filled PE-50 catheter connected to the transducer.

[0656] 7. After a few seconds of right ventricular pressure recording, advance the Insyte further into the pulmonary artery to record an additional 60 seconds of PAP.

[0657] 8. Hemodynamic parameters were continuously recorded for the duration of the surgery or until the PAP signal was lost.

[0658] 9. After hemodynamic monitoring, the chest cavity was opened to expose the lungs. The muscles over the trachea were dissected to remove the lungs and heart. The harvested tissue was rinsed with PBS to remove any excess blood before weighing.

[0659] 10. The chest cavity was further opened to expose the lungs. The muscles over the trachea were dissected to remove the lungs and heart. The harvested tissue was rinsed with PBS to remove any excess blood before weighing.

[0660] 11. For lung histology and casting, the procedure was as follows: 1) eight (8) rats per group were retained for evaluation of left lung histology and were therefore processed as described in point 12 of this section 8.2; 2) two (2) rats per group allowed for quantitative characterization of the three-dimensional vascular structure of the left lung and were therefore processed for left lung casting as described in section 8.3.

[0661] 12. For histology, the left lobe was inflated with a 10 mL syringe filled with fixative (10% NBF) and attached with a blunt tip needle (23 g). The needle tip was inserted into the trachea and the position was fixed with a tying suture while another syringe was tied to the pulmonary artery. The lungs were gently inflated at physiological pressure (20-25 mmHg) until all lobes were fully, evenly and uniformly expanded (fixative was not allowed to seep through the lung surface). This provided optimal vascular and airway expansion without causing excessive tissue disruption. The needle was then removed, sutures were tied around the trachea, and immersed in 10% NBF at a 1:20 tissue: fixative ratio. The tissues were kept in formalin for 24-48 hours. They were then cut into three parts (upper, middle and lower). Sections were sent to the Institute for Research in Immunology and Cancer (IRIC) in Montreal (Quebec, Canada) to be embedded, sectioned, and stained with hematoxylin and eosin (H&E) and von Willebrand factor (VWF) for endothelial cell staining.

[0662] 13. As part of the Fulton index, the heart is dissected and the right ventricle is separated from the left ventricle with its septum and weighed separately.

[0663] Pulmonary artery casting procedure

[0664] 1. After the hemodynamic parameters were recorded, the lungs and hearts of 2 of the 10 rats were harvested and processed for pulmonary artery casts of the left lung.

[0665] 2. Polyethylene (PE190) tubing was cut to a length of 40 cm, one end was connected to an 18-G needle and the other end, which was heat-passivated, was used as a catheter to enter the right ventricle (RV). The catheter was pushed to the level of the main pulmonary artery (MPA) and fixed there. For right lung casting, the catheter was pushed into the pulmonary artery (PA) of the right lung and fixed there to avoid perfusion of the left lung.

[0666] 3. Flush the blood from the PA by pumping 2 ml of diluted sodium heparin (5 units / ml) (APP Pharmaceuticals, Inc., Schaumburg, IL, USA) using a continuous syringe pump set at 2 ml / min. A small incision was made in the left atrial appendage of the left ventricle to allow the solution to flow out of the pulmonary arterial circulation.

[0667] 4. To ensure uniform filling, especially in the lower lung segments, the lungs are kept in an upright position.

[0668] 5. The silicone polymer casting compound, MV-yellow Microfil with a viscosity of 25 centipoise (cP; 0.01 g per cm-second), was mixed with a medium viscosity (MV) diluent at a volume ratio of 5:4 (diluent: compound) and added to 5% (volume) curing agent. The freshly mixed silicone polymer casting material was then pumped through the catheter at 2 ml / min until the polymer reached the RV. The flow rate was reduced to 0.05 ml / min as the polymer entered the pulmonary circulation.

[0669] 6. Stop pumping when polymer is evenly visible on the lung surface. Ligate the PA of the irrigated left lung before resection from the cardio-pulmonary segment.

[0670] 7. The PA-ligated left lung was then transferred into a small container and stored at 4°C for 24 hours to allow the silicone polymer to fully polymerize. In the case of the right lung cast, the right PA was ligated.

[0671] 8. Once polymerized, add 10% formalin to the container to submerge the left lung (or right lung lobe) with formalin and store at 4°C for an additional 48 hours.

[0672] 9. The left lung (or right lobe) was then transported to the Department of Engineering at the University of Sherbrooke (Quebec, Canada) for micro-CT imaging using a Skyscan from Bruker (Manning Park, MA, USA). The images were then transferred to Fluidda Inc. for analysis.

[0673] result:

[0674] Mean lung pressure:

[0675] Mean lung pressure in female rats

[0676]

[0677] in conclusion

[0678] In the present study, treatment with Compound A significantly reduced lung pressure in female rats in which pulmonary hypertension had been induced by monocrotaline, whereas there was no effect in male rats.

[0679] Other exemplary embodiments:

[0680] 1. A method for treating an inflammatory disease, disorder or condition in a patient in need thereof, wherein the inflammatory disease, disorder or condition is selected from:

[0681] a. an inflammatory disease, disorder or condition in the pancreas selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis;

[0682] b. an inflammatory disease, disorder or condition in the kidney selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, Goodpasture's syndrome, Wegener's granulomatosis, and acute or chronic rejection of a renal transplant;

[0683] c. an inflammatory disease, disorder or condition in the liver selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and acute or chronic rejection of a liver transplant;

[0684] d. an inflammatory disease, disorder or condition in the lung or heart 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;

[0685] e. an inflammatory disease, disorder or condition in the skin selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquired, acne, keloid, and other inflammatory or allergic conditions of the skin;

[0686] f. an inflammatory disease, disorder or condition in the blood vessels / blood selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative vascular disease and restenosis;

[0687] g. an inflammatory disease, disorder or condition in the eye selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis;

[0688] h. Inflammatory diseases, disorders or conditions in the central or peripheral nervous system selected from non-viral and viral encephalitis and meningitis, depression, neuropathic pain, including chronic pain, traumatic brain injury, including stroke, Alzheimer's disease, Parkinson's disease, myelitis, type 1 Shiller-Jackson syndrome, Figure 3 disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathies;

[0689] i. an autoimmune disease, disorder or condition selected from lupus, including in the skin and kidney, Guillain-Barre syndrome, myasthenia gravis, Jobben's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis;

[0690] j. an inflammatory disease, disorder or condition in the intestine selected from the group consisting of intestinal failure, ulcerative colitis and Crohn's disease;

[0691] k. an inflammatory disease, disorder or condition in the reproductive system selected from the group consisting of endometriosis, uterine fibroids, prostate dysplasia or growth, and cervical dysplasia; and

[0692] 1. An inflammatory disease, disorder or condition in bones and / or joints selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hands, feet, ankles, knees, hips, shoulders, elbows or spine; comprising the step of administering to a patient a compound of formula (I):

[0693]

[0694] or a pharmaceutically acceptable salt thereof, wherein: Z is C or N;

[0695] V is C or N;

[0696] means an aromatic ring wherein V is C or N, and in the case where V is N, V ​​is in the ortho, meta or para position relative to Z;

[0697] Each R is independently hydrogen, halogen, -CN, hydroxy, (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, which is optionally mono- or di-substituted by the following groups: hydroxy, a group of formula (IIa):

[0698] or a group of formula (IIIa):

[0699] Q is N or O, provided that R" does not exist when Q is O;

[0700] Each R1 and R2 is independently hydrogen or (C1-C3) alkyl;

[0701] Each R3 and R4 is independently hydrogen, Li + , Na + , K + , N + (Ra)4 or benzyl;

[0702] n is 1, 2 or 3;

[0703] n' is 1, 2 or 3;

[0704] Each R' is independently hydrogen, (C1-C3) alkyl, hydroxy, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3) fluoroalkyl, (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, a group of formula (IIa):

[0705] or a group of formula (IIIa):

[0706] A is a covalent bond, oxygen or NH; B is a covalent bond or NH;

[0707] m is 1, 2, 3, 4 or 5;

[0708] p is 1, 2 or 3;

[0709] Each Ra and Rb is independently hydrogen, (C1-C5)alkyl or (C3-C6)cycloalkyl, or

[0710] Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring, said heterocyclic ring being optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' may be 2 or 3 only if the other R' group is different from said group (IIa) or (IIIa); and

[0711] R" is hydrogen, (C1-C4)alkyl or a group of formula (IIa) as defined herein.

[0712] 2. The method of embodiment 1, wherein the compound has the following formula (Ia):

[0713]

[0714] or a pharmaceutically acceptable salt thereof.

[0715] 3. The method of embodiment 1, wherein the compound has the following formula (Ib):

[0716]

[0717] or a pharmaceutically acceptable salt thereof.

[0718] 4. The method of embodiment 1, wherein the compound has the following formula (Ic):

[0719] or a pharmaceutically acceptable salt thereof.

[0720] 5. The method of embodiment 1, wherein the compound has the following formula (Ib'):

[0721] or a pharmaceutically acceptable salt thereof.

[0722] 6. The method of embodiment 1, wherein the compound has the following formula (Id):

[0723] or a pharmaceutically acceptable salt thereof.

[0724] 7. Compounds of formula (IV):

[0725]

[0726] or a pharmaceutically acceptable salt thereof, wherein each variable V, Z, R, R', n and n' is as described in Embodiment 1, provided that the compound is not

[0727]

[0728] 8. The compound of embodiment 7, wherein the compound has the following formula (IVa):

[0729]

[0730] or a pharmaceutically acceptable salt thereof.

[0731] 9. The compound of embodiment 7, wherein the compound has the following formula (IVb):

[0732]

[0733] or a pharmaceutically acceptable salt thereof.

[0734] 10. The compound of embodiment 7, wherein the compound has the following formula (IVc):

[0735]

[0736] or a pharmaceutically acceptable salt thereof.

[0737] 11. The compound of embodiment 7, wherein the compound has the following formula (IVb'):

[0738]

[0739] or a pharmaceutically acceptable salt thereof.

[0740] 12. The compound of embodiment 7, wherein the compound has the following formula (IVd):

[0741]

[0742] or a pharmaceutically acceptable salt thereof.

[0743] 13. A pharmaceutical composition comprising a compound according to any one of embodiments 7 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0744] 14. A method for treating an inflammatory disease, disorder or condition comprising administering to a patient in need thereof a compound of any one of Embodiments 7-12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 13.

[0745] 15. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the pancreas and is selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis.

[0746] 16. The method of any of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the kidney and 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 renal transplant.

[0747] 17. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the liver and is selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis and acute or chronic rejection of a liver transplant.

[0748] 18. The method of any of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the lung or heart and is selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis and acute or chronic rejection of lung or heart transplantation.

[0749] 19. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the skin and is selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquired, acne, keloid, and other inflammatory or allergic conditions of the skin.

[0750] 20. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the blood vessels / blood and is selected from Behcet's disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative vascular disease and restenosis.

[0751] 21. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the eye and is selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, neuroretinitis, uveitis, orbital inflammatory disease, and optic neuritis.

[0752] 22. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the central or peripheral nervous system and 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, type 1 Shiller-Jackson syndrome, Figure 3 disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease, demyelinating polyneuropathy, and peripheral neuropathies.

[0753] 23. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is an autoimmune disease, disorder or condition selected from lupus, including in the skin and kidney, Guillain-Barre syndrome, myasthenia gravis, Jobben's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis.

[0754] 24. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the intestine and is selected from the group consisting of intestinal failure, ulcerative colitis and Crohn's disease.

[0755] 25. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in a reproductive system selected from the group consisting of endometriosis, uterine fibroids, prostate dysplasia or growth, and cervical dysplasia.

[0756] 26. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the bones / skeleton and / or joints selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hands, feet, ankles, knees, hips, shoulders, elbows or spine.

[0757] 27. The method of any one of embodiments 1-6 and 14-26, further comprising measuring the level of the compound of formula (I) or a pharmaceutically acceptable salt thereof in a patient's blood, plasma, tissue, saliva and / or serum sample.

[0758] 28. The method of any one of embodiments 1-6 and 14-27, further comprising measuring the level of the compound of formula (IV) or a pharmaceutically acceptable salt thereof in a patient's blood, plasma, tissue, saliva and / or serum sample.

[0759] 29. The method of any one of embodiments 1-6 and 14-28, further comprising measuring the total level of the compound of formula (I) and (IV) or a pharmaceutically acceptable salt thereof in a patient's blood, plasma, tissue, saliva and / or serum sample.

[0760] 30. The method of any one of embodiments 1-6 and 14-29, further comprising measuring the presence and / or expression level of miR-124 in the patient's blood and / or tissue samples before and during the treatment course.

[0761] 31. The method of any one of embodiments 1-6 and 14-30, further comprising selecting a patient by measuring the presence and / or expression level of miR-124 in the patient's blood and / or tissue samples.

[0762] 32. The method of any one of embodiments 1-6 and 14-31, further comprising monitoring the severity of the disease, disorder or condition and / or monitoring the effectiveness of treatment using an algorithm that combines the level of miR-124 and the level of a cytokine or another biomarker, or the level of a compound of formula (I) or (IV) or a pharmaceutically acceptable salt thereof.

[0763] 33. The method of any one of embodiments 1-6 and 14-31, further comprising selecting patients for treatment using an algorithm that combines miR-124 levels with levels of cytokines or another biomarker, or levels of a compound of formula (I) or (IV) or a pharmaceutically acceptable salt thereof.

[0764] 34. An algorithm for monitoring the severity of a disease, disorder or condition and / or monitoring the efficacy of a treatment that combines the levels of miR-124 and a selected cytokine or another biomarker, or the levels of a compound of formula (I) or (IV) or a pharmaceutically acceptable salt thereof.

Claims

1. Use of the compound of formula (IV) or its pharmaceutically acceptable salt for preparing a drug: The medicament is used to treat and / or prevent inflammatory diseases, disorders or conditions in: Z is C or N; V is C or N; means an aromatic ring wherein V is C or N, and in the case where V is N, V ​​is in the ortho, meta or para position relative to Z; Each R is independently hydrogen, halogen, -CN, hydroxy, (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, which is optionally mono- or di-substituted by the following groups: hydroxy, a group of formula (IIa): or a group of formula (IIIa): Q is N or O, provided that in the case where Q is O, R" is absent; each R1 and R2 is independently hydrogen or (C1-C3)alkyl; Each R3 and R4 is independently hydrogen, Li + , Na + , K + , N + (Ra)4 or benzyl; n is 1, 2 or 3; n' is 1, 2 or 3; Each R' is independently hydrogen, (C1-C3) alkyl, hydroxy, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3) fluoroalkyl, (C1-C4) alkoxy, -OP(=O)-(OR3)(OR4), -CN, -NH-SO2-N(CH3)2 group, group of formula (IIa): or a group of formula (IIIa): A is a covalent bond, oxygen or NH; B is a covalent bond or NH; m is 1, 2, 3, 4 or 5; p is 1, 2 or 3; Each Ra and Rb is independently hydrogen, (C1-C5)alkyl or (C3-C6)cycloalkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic ring optionally containing further heteroatoms selected from N, O and S, said heterocyclic ring being optionally substituted by one or more Ra, provided that in the case where R' is a group (IIa) or (IIIa), n' may be 2 or 3 provided only that the other R' groups are different from said groups (IIa) or (IIIa); and R" is hydrogen, (C1-C4)alkyl or a group of formula (IIa) as defined herein, wherein the inflammatory disease, disorder or condition is selected from: (a) an inflammatory disease, disorder or condition selected from the group consisting of intestinal failure, ulcerative colitis and Crohn's disease; and (b) an inflammatory disease, disorder or condition selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cold agglutinin-associated periodic syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

2. The use according to claim 1, wherein the inflammatory disease, disorder or condition is selected from the group consisting of intestinal failure, ulcerative colitis and Crohn's disease.

3. The method of claim 1, wherein the inflammatory disease, disorder or condition is selected from the group consisting of acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cold agglutinin-associated periodic syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

4. The use according to claim 1, wherein the compound of formula (IV) is formula (IVb): or a pharmaceutically acceptable salt thereof, wherein R, n, R′, n′ are as defined in claim 1.

5. Use according to claim 4, wherein the inflammatory disease, disorder or condition is selected from the group consisting of intestinal failure, ulcerative colitis and Crohn's disease.

6. The method of claim 4, wherein the inflammatory disease, disorder or condition is selected from the group consisting of acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cold agglutinin-associated periodic syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

7. The use according to claim 1, wherein the compound of formula (IV) is formula (IVb'): or a pharmaceutically acceptable salt thereof, wherein R, n, and R′ are as defined in claim 1.

8. Use according to claim 7, wherein the inflammatory disease, disorder or condition is selected from the group consisting of intestinal failure, ulcerative colitis and Crohn's disease.

9. The method of claim 7, wherein the inflammatory disease, disorder or condition is selected from the group consisting of acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cold agglutinin-associated periodic syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

10. The use according to claim 1, wherein the compound of formula (IV) is or a pharmaceutically acceptable salt thereof.

11. Use according to claim 10, wherein the inflammatory disease, disorder or condition is selected from the group consisting of intestinal failure, ulcerative colitis and Crohn's disease.

12. The method of claim 10, wherein the inflammatory disease, disorder or condition is selected from the group consisting of acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cold agglutinin-associated periodic syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

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