Quinoline derivatives for use in the treatment of inflammation diseases

Abstract

The present disclosure relates to quinoline derivatives useful in the treatment of inflammatory diseases. Specifically, the present invention relates to any one of compounds of formula (I) or metabolites thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of inflammatory diseases, disorders or conditions. 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.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511811792.5 (22) Application Date 2019.12.19 (30) Priority Data 18306782.6 2018.12.20 EP (62) Divisional Application Data 201980088825.4 2019.12.19 (71) Applicant ABIVAX Company Address French Applicant Curie Institute Montpellier University National Center for Scientific Research (72) Inventors P. Borreti H. Ehrlich D. Chere J. Tazé (74) Patent Agency China Council for the Promotion of International Trade Patent & Trademark Office Co., Ltd. 11038 Patent Attorney Xu Da (51) Int.Cl. A61K 31 / 706 (2006.01) A61P 29 / 00 (2006.01) A61P 1 / 16 (2006.01) A61P 11 / 00 (2006.01) A61P 9 / 12 (2006.01) (54) Invention Title: Quinoline Derivatives for Treating Inflammatory Diseases (57) Abstract: This disclosure relates to quinoline derivatives for treating inflammatory diseases. Specifically, it relates to any one of the compounds of formula (I) or its metabolites or pharmaceutically acceptable salts thereof for treating and / or preventing inflammatory diseases, disorders or conditions. The invention also relates to compounds of formula (IV) or their pharmaceutically acceptable salts for treating and / or preventing inflammatory diseases, disorders or conditions. Claims 1 page, Description 68 pages, Drawings 3 pages, CN 121846117 A 2026.04.14 CN 1 21 84 61 17 A 1. Use of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prevention of an inflammatory disease, disorder or condition, wherein the inflammatory disease, disorder or condition is selected from: (c) an inflammatory disease, disorder or condition of the liver, selected from non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD); (d) an inflammatory disease, disorder or condition of the lungs or heart, wherein pulmonary hypertension is present. 2. Use of the following compounds or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prevention of an inflammatory disease, disorder or condition as defined in claim 1. 3. The use according to claim 1 or 2, wherein the inflammatory disease, disorder, or condition is in the liver, selected from non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). 4. The use according to claim 1 or 2, wherein the inflammatory disease, disorder, or condition is in the lungs, specifically pulmonary hypertension. 5. The use according to claim 1 or 2, wherein the drug is used to treat a patient,The level of the compound as defined in claim 1 or the compound as defined in claim 2 or a pharmaceutically acceptable salt thereof in a patient's blood, plasma, tissue, saliva, and / or serum samples is measured during use. 6. The use according to claim 1 or 2, wherein the drug is used to treat a patient, wherein the presence and / or expression level of miR-124 in a patient's blood and / or tissue samples is measured before and during use. 7. The use according to claim 1 or 2, wherein an algorithm is used to monitor the severity of a disease, disorder, or condition and / or the effectiveness of the monitoring purpose, said algorithm combining miR-124 levels with the levels of cytokines or another biomarker, or the levels of the compound as defined in claim 1 or the compound as defined in claim 2 or a pharmaceutically acceptable salt thereof. Claims 1 / 1 page 2 CN 121846117 A Quinoline derivative for treating inflammatory diseases

[0001] This application is a divisional application of Chinese Invention Patent Application 201980088825.4. Technical Field

[0002] This disclosure relates to quinoline derivatives for treating inflammatory diseases. Background Art

[0003] Inflammation is a protective response of the immune system to tissue damage and infection. However, inflammatory responses can harm the body under certain circumstances. In the acute phase, 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), joint inflammation, inflammatory digestive tract diseases, and inflammatory skin conditions.

[0005] Several 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] The compounds of the present invention and pharmaceutically acceptable compositions thereof have been found to be useful for the treatment and / or prevention of a variety of inflammatory diseases, disorders, or conditions. In one aspect, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound of formula (I) to a patient in need:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined and described herein. Brief Description of the Drawings

[0009] Figure 1 illustrates the NAFLD activity score in a non-alcoholic steatohepatitis (NASH study) STAM model.

[0010] Figure 2 illustrates the sebaceous gland disease score in a non-alcoholic steatohepatitis (NASH study) STAM model, which is based on ABX464 and its glucuronide metabolites (Example 2).

[0011] Figure 3 illustrates the inflammation score in a non-alcoholic steatohepatitis (NASH study) STAM model.The analysis of ABX464 and its glucuronide metabolites was performed (Example 2).

[0012] Figure 4 illustrates the ballooning fibrosis component in a non-alcoholic steatohepatitis (NASH study) STAM model, which was analyzed for ABX464 and its glucuronide metabolites (Example 2).

[0013] Figure 5 illustrates the fibrosis area in a histological analysis of a non-alcoholic steatohepatitis (NASH study) STAM model, which was analyzed for ABX464 and its glucuronide metabolites (Example 2). Detailed Description

[0014] General description of certain embodiments of the present invention:

[0015] The compounds of the present invention and their pharmaceutical compositions may be used to treat inflammatory diseases, disorders or conditions such as those described herein. Instructions for Use, Page 1 / 68, CN 121846117 A

[0016] In one aspect, the present invention provides a method for treating an inflammatory disease, disorder, or condition, comprising administering to a patient in need a compound of formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein: Z is C or N;

[0019] V is C or N;

[0020] meaning 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;

[0021] Each R is independently hydrogen, halogen, -CN, hydroxyl, (C1-C3) fluoroalkyl, (C1-C3) fluoroalkoxy, (C3-C6) cycloalkyl, -NO2, -NR1R2, (C1-C4) alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1-C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -O-P(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3) alkyl, wherein the alkyl group is optionally substituted by one or two of the following: hydroxyl, group of formula (IIa): ,

[0022] or group of the following formula

[0023]

[0024] (IIIa),

[0025] Q is N or O, provided that R' is not present 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, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, -O-P(=O)-(OR3)(OR4), -CN,

[0030] Formula (IIa) group: ,

[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 (C3-C6) cycloalkyl, or

[0036] Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, said heterocycle optionally substituted by one or more Ra, provided that n' is a group (IIa) or (IIIa) and n' can be 2 or 3 only when the other R' groups are 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): Specification 2 / 68 pages 4 CN 121846117 A

[0039]

[0040] or any of its metabolites or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of inflammatory diseases, disorders or conditions

[0041] wherein:

[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 of V being N, V ​​is in the ortho, meta or para position relative to Z;

[0045] each R is independently hydrogen, halogen, -CN, hydroxyl, (C1-C3) fluoroalkyl, (C1-C3) fluoroalkoxy, (C3-C6) cycloalkyl, -NO2, -NR1R2, (C1-C4) alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1- C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -O-P(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, wherein the alkyl group is optionally substituted by one or two of the following groups: hydroxyl, group of formula (IIa):

[0046]

[0047] or group of formula (IIIa):

[0048]

[0049] Q is N or O, provided that R" is absent when Q is O; 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, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, -O-P(=O)-(OR3)(OR4),-CN, -NH-SO2-N(CH3)2 group, group of formula (IIa):

[0054]

[0055] or 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 heterocycle optionally containing other heteroatoms selected from N, O and S, said heterocycle optionally substituted by one or more Ra, provided that R' is group (IIa) or (IIIa), n' can be 2 or 3 only if the other R' groups are different from said group (IIa) or (IIIa); and specification 3 / 68 Page 5 CN 121846117 A

[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 of the pancreas, selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis;

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

[0066] (c) an inflammatory disease, disorder or condition of 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 liver transplantation;

[0067] (d) Inflammatory diseases, disorders, or conditions of the lungs or heart, selected from chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcomatoid disease, myocarditis, pericarditis, and acute or chronic rejection of lung or heart transplants;

[0068] (e) Inflammatory diseases, disorders, or conditions of the skin, selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloids, and other inflammatory or allergic conditions of the skin;

[0069] (f) Inflammatory diseases, disorders, or conditions of the blood vessels / blood, selected from Behcet disease, vasculitis, sepsis, tumor angiogenesis, proliferative angiopathy, and restenosis;

[0070] (g) An inflammatory disease, disorder, or condition of the eye, selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, choroidoretinitis, optic nerve retinitis, uveitis.Orbital inflammatory diseases and optic neuritis;

[0071] (h) Inflammatory diseases, disorders, or conditions of the central or peripheral nervous system, selected from nonviral and viral encephalitis and meningitis, depression, neuropathic pain including chronic pain, traumatic brain injury including stroke, Parkinson's disease, myelitis, type I Shayma-Tussan disease (including CMT1A and CMT1B), amyotrophic lateral sclerosis (ALS), Kreutzfeldt-Jacob disease, demyelinating polyneuropathy, and peripheral neuropathy;

[0072] (i) Autoimmune diseases, disorders, or conditions, selected from lupus including cutaneous and renal lupus, Graves' syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis;

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

[0074] (l) an inflammatory disease, disorder, or condition of 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 invention further relates to a method of preventing, inhibiting, or treating an inflammatory disease as defined above, comprising at least one step of administering to a patient suffering from said disease an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in formula (I), (Ib), (Ib'), (IV), (IVb), or (IVb').

[0076] Compounds and Definitions

[0077] Within the framework of this invention, the following definitions may be provided:

[0078] • Effective amount: The amount of a pharmaceutical compound that has an effect on the treated tumor and / or the amount of a compound of the invention that effectively prevents, reduces, eliminates, treats, or controls the symptoms of the diseases and conditions described herein. The term "effective amount" includes both "preventive effective amount" and "therapeutic effective amount"; the term "preventive effective amount" refers to the concentration of a compound of the invention that effectively inhibits, prevents, or reduces the likelihood 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 this invention, the term "treatment" or "treatment" as used herein means reversing, alleviating, or inhibiting the progression of inflammatory diseases or preventing inflammatory diseases.

[0081] ● The term "control" is expected to refer to the entire process, which may include the slowing, interruption, quiescence, or cessation of the progression of the disease and condition described herein, but does not necessarily mean the complete elimination of all symptoms of the disease and condition, and is expected to include preventive 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. As used herein,"Prevention" also encompasses "reducing the likelihood of presence" or "reducing the likelihood of recurrence."

[0083] The compounds of the present invention can exist as free bases or as addition salts of pharmaceutically acceptable acids. Suitable physiologically acceptable acid addition salts of the compounds of the present invention include sulfates, hydrobroms, citrates, trifluoroacetates, ascorbic acid salts, hydrochlorides, trifluoromethanesulfonates, tartrates, maleates, methanesulfonates, formates, acetates, fumarates, and sulfonates, especially alkyl sulfonates or aryl sulfonates, and more particularly methanesulfonates, trifluoromethanesulfonates, ethanedisulfonates, benzenesulfonates, and toluenesulfonates.

[0084] The compounds of the present invention and / or their salts can form solvates or hydrates, and the present invention includes all of the aforementioned solvates and hydrates. The terms "hydrate" and "solvent" simply refer to the ability of the compounds according to the present invention to be in hydrate or solvate form, i.e., combined or combined with one or more water or solvent molecules. This is merely a chemical characteristic 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 enantiomeric or diastereomeric forms. These enantiomers, diastereomerics, and mixtures thereof (including racemic mixtures) are within the scope of the present invention.

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

[0087] - "halogen" should be understood to mean chlorine, fluorine, bromine, or iodine, especially 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 cyclic saturated hydrocarbons, respectively.

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

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

[0092] - "fluoroalkyl" and "fluoroalkoxy" refer to the alkyl and alkoxy groups as defined above, respectively, wherein the group is substituted with at least one fluorine atom. Examples are perfluoroalkyl 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. Examples are, but are not limited to, morpholine, piperazine, thiomorpholine, piperidine, pyrrolidine.

[0094] As used herein, the term "pharmaceutically acceptable salt" means that, within reasonable medical judgment, it is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc.And in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S. M. Berge et al. 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 present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups 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 adipic acid salts, ascorbic acid salts, aspartate salts, benzenesulfonate salts, benzoate salts, hydrogen sulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentane propionate salts, gluconate salts, dodecyl sulfate salts, ethanesulfonate salts, and formate salts. Fumarate, glucono-p-ethyl, glycerol phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0096] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-4 alkyl)4 salts. Representative base or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Other pharmaceutically acceptable salts suitably 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, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformations)) of the structures; for example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformations), are within the scope of the present invention. Unless otherwise stated, all tautomer forms of the compounds of the present invention are within the scope of the present invention. Additionally, unless otherwise stated,The structures described herein are also intended to include compounds, the only difference being the presence of one or more isotopically enriched atoms. For example, the scope of this invention includes compounds having the structures of this invention, wherein hydrogen is replaced by deuterium or tritium, or carbon is replaced by carbon enriched in 13C or 14C. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to this 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 a compound of formula (I) to a patient in need:

[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 that V is N, V ​​is in the ortho, meta, or para position relative to Z;

[0105] each R is independently hydrogen, halogen, -CN, hydroxyl, (C1-C3) fluoroalkyl, (C1-C3) fluoroalkoxy, (C3-C6) cycloalkyl, -NO2, -NR1R2, (C1-C4) alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1- C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -O-P(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, wherein the alkyl group is optionally substituted by one or two of the following groups: hydroxyl, group of formula (IIa):

[0106] or group of formula (IIIa);

[0107] Q is N or O, provided that R" is absent when Q is O;

[0108] Each R1 and R2 is independently hydrogen or (C1-C3)alkyl; Specification 6 / 68 pages 8 CN 121846117 A

[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, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, -O-P(=O)-(OR3) (OR4), -CN, group of formula (IIa):

[0113] or group of formula (IIIa):

[0114] A is covalent, oxygen or NH;

[0115] B is covalent 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,Alternatively,

[0119] Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, which is optionally substituted with one or more Ra, provided that R' is a group (IIa) or (IIIa), and n' can be 2 or 3 only if the other R' groups are 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] As generally defined above, Z is C or N.

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

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

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

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

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

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

[0128] In some embodiments, this refers to an aromatic ring in which V is C.

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

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

[0131] In some embodiments, this is phenyl.

[0132] In some embodiments, this is pyridine. Specification 7 / 68 pages 9 CN 121846117 A

[0133] In some embodiments, this is pyridazine.

[0134] In some embodiments, this is pyrimidine.

[0135] In some embodiments, this is pyrazine.

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

[0137] As generally described above, each R is independently hydrogen, halogen, -CN, hydroxyl, (C1-C3) fluoroalkyl, (C1-C3) fluoroalkoxy, (C3-C6) cycloalkyl, -NO2, -NR1R2, (C1-C4) alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1-C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3, -O-P(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3) alkyl, wherein the alkyl group is optionally substituted by one or two of the following groups: hydroxyl or group of formula (IIa): ,Or formula (IIIa) group: ;

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

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

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

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

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

[0143] As generally described above, Q is N or O, provided that R″ is absent when Q is O.

[0144] In some embodiments, Q is N. In some embodiments, Q is O, and R″ is absent.

[0145] In some 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. Specification 8 / 68 pages 10 CN 121846117 A

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

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

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

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

[0151] In some 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 some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0154] In some 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 some embodiments, n' is 1 or 2. In some embodiments, n' is 1. In some embodiments, n' is 2. In some embodiments, n' is 3.

[0157] In some 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, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, -O-P(=O)-(OR3)(OR4), -CN, formula (IIa) group: , or formula (IIIa) group: .

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

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

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

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

[0163] wherein A is O or NH, m is 2 or 3 and X1 is O, CH2 or N-CH3, provided that when R' is one of the above groups, n' is 1 or 2, and when n' is 2, the other R' groups are different from the groups described above.

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

[0165] wherein A is O or NH, m is 2 and X1 is O, CH2 or N-CH3, provided that when R' is one of the above groups, n' is 1 or 2, and when n' is 2, the other R' groups are different from the stated groups.

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

[0167] wherein A is O or NH, m is 3 and X1 is O, CH2 or N-CH3, provided that when R' is one of the above groups, n' is 1 or 2, and when n' is 2, the other R' groups are different from the stated groups.

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

[0169]

[0170] wherein A is O or NH, m is 2 or 3 and X1 is O, CH2 or N-CH3, provided that when R' is one of the above groups, n' is 1 or 2, and when n' is 2, the other R' groups are different from the groups described above.

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

[0172] wherein A is O or NH, m is 2 and X1 is O, CH2 or N-CH3, provided that when R' is one of the above groups, n' is 1 or 2, and when n' is 2, the other R' groups are different from the groups described above.

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

[0174] In some embodiments,R' is a halogen or a methyl group.

[0175] In some 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 some embodiments, A is a covalent bond. In some embodiments, A is oxygen. In some embodiments, A is NH.

[0178] In some 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 some embodiments, B is a covalent bond. In some embodiments, B is NH.

[0181] In some 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 some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

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

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

[0188] As generally described above, 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 heterocycle, said heterocycle optionally substituted with one or more Ra, provided that R' is a group (IIa) or (IIIa), n' can be 2 or 3 only when the other R' groups are different from said group (IIa) or (IIIa).

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

[0190] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, which is optionally substituted with one or more Ra groups, provided that R' is a group of formula (IIa) or (IIIa), and n' can be 2 or 3 only if the other R' groups are different from those of formula (IIa) or (IIIa). In some embodiments,As described above, the saturated 5- or 6-membered heterocycles formed by Ra and Rb together with the nitrogen atoms to which they are attached optionally have additional heteroatoms selected from N, O, and S.

[0191] In some embodiments, the saturated 5- or 6-membered heterocycles formed by Ra and Rb together with the nitrogen atoms to which they are attached have additional heteroatoms selected from N, O, and S, said heterocycle being substituted by one or more Ra, provided that R' is a group of formula (IIa) or (IIIa), n' can be 2 or 3 only when the other R' groups are different from said formula (IIa) or (IIIa).

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

[0193] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 6-membered heterocycle, provided that n' can be 2 or 3 only if the other R' groups are different from those of formula (IIa) or (IIIa).

[0194] In some embodiments, Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle optionally having additional heteroatoms selected from N, O, and S, wherein the heterocycle is optionally substituted by one or more Ra, provided that n' can be 2 only if the other R' groups are different from those of formula (IIa) or (IIIa).

[0195] In some embodiments, each 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 some embodiments, R" is hydrogen or (C1-C4)alkyl. In some embodiments, R" is hydrogen. In some embodiments, R" is (C1-C4)alkyl. In some embodiments, R" is a group of formula (IIa) as described herein.

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

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

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

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

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

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

[0204] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders or conditions, comprising administering a compound of formula (Ia) to a patient in need:

[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. In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound of formula (Ib) to a patient in need:

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein the variables R, R', R'", n, and n' are present individually and in combination as defined above and described in the embodiments herein.

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

[0211]

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

[0213] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound of formula (Ic) to a patient in need:

[0214]

[0215] Or a pharmaceutically acceptable salt thereof, wherein the variables R, R', R", n and n' are independently present, individually and in combination, as defined above and described in the embodiments herein.

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

[0217]

[0218] or a pharmaceutically acceptable salt thereof, wherein each R and R' is present individually and in combination as defined above and described herein, 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 some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition, comprising administering a compound of formula (Id) or a pharmaceutically acceptable salt thereof to a patient in need, 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 some embodiments, R'" is hydrogen.

[0223] In some embodiments,R'" is a group specified on page 12 / 68 of the specification, CN 121846117 A

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

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

[0226]

[0227] or a pharmaceutically acceptable salt thereof, wherein the variables R, R', R" and n are present individually and in combination as defined above and described in the embodiments herein. In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound of formula (Ib) or a pharmaceutically acceptable salt thereof to a patient in need, wherein: each R is independently a halogen, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, -NR1R2, (C1-C4)alkoxy, or (C1-C3)alkyl, said alkyl being optionally mono- or di-substituted with a hydroxyl group; 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 a halogen, (C1-C3)alkyl, hydroxyl, -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 heterocycle optionally having additional heteroatoms selected from N, O, and S, said heterocycle optionally substituted by one or more Ra, provided that R' is a group (IIa) or (IIIa), n' can be 2 only if the other R' groups are different from said group (IIa) or (IIIa); and R" is hydrogen or (C1-C4) alkyl.

[0234] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound of formula (Ib) or a pharmaceutically acceptable salt thereof to a patient in need, wherein each R' is independently hydrogen, halogen, (C1-C3) alkyl, or (C1-C4) alkoxy, said alkyl being optionally mono- or di-substituted with a hydroxyl group; 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 is 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 some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound of formula (Ib) or a pharmaceutically acceptable salt thereof to a patient in need, 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 some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound of formula (Ib') or a pharmaceutically acceptable salt thereof to a patient in need, wherein each R is independently hydrogen, halogen, or (C1-C3)alkyl. Alkyl, -NR1R2, (C1-C3)fluoroalkoxy, -NO2, phenoxy, or (C1-C4)alkoxy, wherein the alkyl group is optionally mono- or di-substituted with a hydroxyl group; each R1 and R2 is independently hydrogen or (C1-C3)alkyl; R' is hydrogen, halogen, (C1-C3)alkyl, or (C1-C4)alkoxy, provided that R' is different from a methyl group at the 4-position of a quinoline group; R" is hydrogen or (C1-C4)alkyl; n is 1, 2, or 3; and n' is 1 or 2. Specification 13 / 68 pages 15 CN 121846117 A

[0237] In some embodiments, the present invention provides compounds for use as defined above, wherein the compounds have the formula (Ib'):

[0238]

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

[0240] In some embodiments, the present invention provides any of the compounds of formula (Ib') or their metabolites or their pharmaceutically acceptable salts as defined above, wherein:

[0241] R independently represents a halogen atom or a group selected from: (C1-C3) fluoroalkoxy, -NR1R2 group, (C1-C4) alkoxy, -O-P(=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 following: -NR1R2 group, -O-P(=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 hydrogen atoms or (C1-C3)alkyl,

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

[0247] A is a covalent bond, 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 hydrogen atoms or (C1-C5)alkyl, Ra and Rb are capable of further forming, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle optionally containing additional heteroatoms selected from N, O and S, said heterocycle optionally substituted by one or more Ra.

[0252] According to even more specific embodiments, the present invention provides any of the compounds of formula (Ib') or their metabolites or their pharmaceutically acceptable salts 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, -O-P(=O)(OH)(OH) group, -O-(CH2)2-morpholino group or -O-(CH2)2-piperidinyl group,

[0254] n is 1 or 2,

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

[0256] R'' is a hydrogen atom, -CH3, -(CH2)3-piperidinyl, -(CH2)2-morpholinoyl, -(CH2)4-morpholinoyl or -(CH2)2-pyrrolidineyl.

[0257] In embodiments, the present invention provides any one of the compounds of formula (Ib') or their metabolites or their pharmaceutically acceptable salts as defined above, wherein the compounds are 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 listed below.

[0258] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders or conditions.This includes administering the following compound ("ABX464") or a pharmaceutically acceptable salt thereof to a patient requiring treatment, as specified on page 14 / 68 of CN 121846117 A.

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

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

[0261] In some embodiments, the crystalline form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits peaks at angles of 7.3, 14.6, 18.4, and 24.9 in an X-ray powder diffraction (XRPD) pattern. In some embodiments, the crystalline form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits one or more XRPD peaks selected from angles of 18.0, 24.2, 28.3, and 29.5. In some embodiments, the crystalline form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits one or more XRPD peaks selected from angles of 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)quinoline-2-amine is characterized by the following major peaks at a 2-Θ angle 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 at a 2-Θ angle: 12.1, 17.3, 18.4, 23.0; 24.2, 24.9, 27.4, and 29.1 (each ± ​​0.2) and even optionally expressed at a 2-Θ angle: 13.7, 16.3, 16.9, 18.1, 22.4, and 29.6 (each ± ​​0.2).

[0263] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions.This includes administering to patients in need the compounds selected from Table 1:

[0264] Table 1 (compounds of formula Ia as defined above) Product description 15 / 68 pages 17 CN 121846117 A Product description 16 / 68 pages 18 CN 121846117 A Product description 17 / 68 pages 19 CN 121846117 A Product description 18 / 68 pages 20 CN 121846117 A Product description 19 / 68 pages 21 CN 121846117 A Product description 20 / 68 pages 22 CN 121846117 A Product description 21 / 68 pages 23 CN 121846117 A Product description 22 / 68 pages 24 CN 121846117 A

[0265] or pharmaceutically acceptable salts thereof.

[0266] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering to a patient in need a compound selected from Table 2:

[0267] Table 2 (Compounds of formula (Ib) as defined above) Specification 23 / 68 pages 25 CN 121846117 A Specification 24 / 68 pages 26 CN 121846117 A Specification 25 / 68 pages 27 CN 121846117 A Specification 26 / 68 pages 28 CN 121846117 A Specification 27 / 68 pages 29 CN 121846117 A

[0268] or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering to a patient in need a compound selected from Table 3:

[0270] Table 3 (Compounds of Formula (I) different from compounds (Ia) and (Ib)) Specification 28 / 68 pages 30 CN 121846117 A Specification 29 / 68 pages 31 CN 121846117 A

[0271] or pharmaceutically acceptable salts thereof.

[0272] In some embodiments, the compounds described herein are in salt form and are selected from sulfates, hydrobromide salts, citrates, trifluoroacetates, ascorbic acid salts, hydrochlorides, tartrates, trifluoromethanesulfonates, maleates, methanesulfonates, formates, acetates, fumarates, and sulfonates. In some embodiments, the compounds described herein are in the form of alkyl sulfonates or aryl sulfonates. In some embodiments, the compounds described herein are in the form of methanesulfonates, trifluoromethanesulfonates, ethanedisulfonates, benzenesulfonates, and toluenesulfonates.

[0273] In one aspect, the present invention provides metabolites of the compounds described herein. In some embodiments,This invention provides N-glucuronide metabolites of the compounds described herein. In some embodiments, this invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering to a patient in need an N-glucuronide metabolite of the compounds described herein.

[0274] In some embodiments, this invention provides compounds of formula (IV):

[0275]

[0276] or pharmaceutically acceptable salts thereof, wherein the variables V, Z, R, R', n, and n' are present individually or in combination as defined above and described in the embodiments herein, provided that the compound is not

[0277]

[0278] In some embodiments, this invention provides compounds of formula IVa:

[0279]

[0280] or pharmaceutically acceptable salts thereof, wherein the variables R, R', n, and n' are present individually and in combination independently as defined above and described in the embodiments herein, on pages 30 / 68 of CN 121846117 A.

[0281] In some embodiments, the present invention provides a compound of formula (IVb):

[0282]

[0283] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', n and n' is present independently, alone and in combination, as defined above and described in the embodiments herein, provided that the compound is not

[0284]

[0285] In some embodiments, the present invention provides a compound of formula (IVc):

[0286]

[0287] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', n and n' is present independently, alone and in combination, as defined above and described in the embodiments herein.

[0288] In some embodiments, the present invention provides a compound of formula (IVb'):

[0289]

[0290] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', and n is independently present, alone and in combination, as defined above and described herein, provided that the compound is not

[0291]

[0292] In some embodiments, the present invention provides a compound of formula (IVd):

[0293]

[0294] or a pharmaceutically acceptable salt thereof, wherein each variable R, R', R'" is independently present, alone and in combination, as defined above and described herein, provided that the compound is not

[0295]

[0296] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering to a patient in need a compound of any one of formulas (IV), (IVa), (IVb), (IVc), (IVb'), and (IVd) or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions.This includes administering a compound of the following formula to a patient in need:

[0298]

[0299] or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the present invention provides a compound of formula (IV):

[0301]

[0302] or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of inflammatory diseases, disorders or conditions as defined above, wherein V, Z, R, R', n and n' are as defined above.

[0303] The present invention also provides a compound of formula (IV) for the treatment and / or prevention of inflammatory diseases, disorders or conditions as defined above, wherein the compound has formula (IVb):

[0304]

[0305] or a pharmaceutically acceptable salt thereof, wherein R, n, R', n' are as defined above.

[0306] This document also provides compounds of formula (IVb) for the treatment and / or prevention of inflammatory diseases, disorders, or conditions as defined above, wherein the compound has formula (IVb'):

[0307]

[0308] or a pharmaceutically acceptable salt thereof, wherein R, n, R', n' are as defined above.

[0309] This document also provides compounds of formula (IVb') for the treatment and / or prevention of inflammatory diseases, disorders, or conditions as defined above, wherein the compound is

[0310]

[0311] or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the level of the compound as described herein or a pharmaceutically acceptable salt thereof or a metabolite thereof in a patient. In some embodiments, the level of the compound as described herein or a pharmaceutically acceptable salt thereof or a metabolite thereof is measured in a biological sample of a patient. In some embodiments, the biological sample of the patient is a blood, plasma, tissue, saliva, and / or serum sample.

[0313] In a further embodiment, the present invention provides compounds (I), (Ib), (Ib'), (IV), (IVb), or (IVb') as defined above for use in treating a patient, wherein during use, the levels of the compound of formula (I), (Ib), (Ib'), (IV), (IVb), or (IVb') or a pharmaceutically acceptable salt thereof, as defined above, are measured in the patient's blood, plasma, tissue, saliva, and / or serum sample.

[0314] In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the levels of compounds of formulas (I), (Ia), (Ib), (Ib'), (Ic), and (Id) or a pharmaceutically acceptable salt thereof in the patient. In some embodiments,The method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the levels of compounds of formulas (IV), (IVa), (IVb), (IVb'), (IVc), and (IVd), or pharmaceutically acceptable salts thereof, in a patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the total levels of compounds of formulas (I) and (IV), or pharmaceutically acceptable salts thereof, in a patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the total levels of compounds of formulas (I) and (IV), or pharmaceutically acceptable salts thereof, in a patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the total levels of compounds of formulas (Ia) and (IVa), or pharmaceutically acceptable salts thereof, in a patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the total levels of compounds of formulas (Ib) and (IVb), or pharmaceutically acceptable salts thereof, in a patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the total level of compounds of formula (Ib') and (IVb') or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the total level of compounds of formula (Ic) and (IVc) or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring the total level of compounds of formula (Id) and (IVd) or pharmaceutically acceptable salts thereof in a patient.

[0315] In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring and / or monitoring the presence and / or level of biomarkers in a patient. In some embodiments, the presence and / or level of biomarkers in a biological sample of the patient is measured. In some embodiments, the biological sample of the patient is a blood sample. In some embodiments, the biological sample of the patient is a tissue sample. In some embodiments, the biomarker measured and / or monitored in the method of the present invention is miR-124, as described in WO 2014 / 111892, the entire contents of which are incorporated herein by reference. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring and / or monitoring the presence and / or expression level of miR-124 in a patient prior to administration of a compound as described herein or a pharmaceutically acceptable salt or composition thereof. In some embodiments,The method of the present invention for treating inflammatory diseases, disorders, or conditions further includes measuring and / or monitoring the presence and / or expression level of miR-124 in a patient during treatment with a compound as described herein or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes selecting patients to be treated with a compound as described herein or a pharmaceutically acceptable salt or composition thereof by measuring and / or monitoring the presence and / or expression level of miR-124 in the patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes excluding patients from treatment with a compound as described herein or a pharmaceutically acceptable salt or composition thereof by measuring and / or monitoring the presence and / or expression level of miR-124 in the patient. In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions further includes adjusting (e.g., increasing or decreasing) the dosing regimen (e.g., dosage and / or dosing schedule) of the compound, as described herein, or a pharmaceutically acceptable salt or composition thereof, to be administered to the patient by measuring and / or monitoring the presence and / or expression level of miR-124 in the patient.

[0316] In some embodiments, the method of the present invention for treating inflammatory diseases, disorders, or conditions includes comparing a measured expression level of miR-124 in the patient with a control reference value. The control reference value used to compare the measured expression level of miR-124 in the patient is obtained from a control sample. The control sample can be obtained from a variety of sources. In some embodiments, the control sample is obtained from the patient (e.g., archived blood or tissue samples) before treatment or before the presence of disease. In some embodiments, the control sample is obtained from a group of normal, non-disease-prone members of a population. In some embodiments, the control sample is obtained from the patient before treatment with a compound, as described herein, or a pharmaceutically acceptable salt or composition thereof. In some embodiments, cell testing can be performed on a biological sample.

[0317] In some embodiments, the regulated presence and / or expression level of miR-124 in a patient, compared to a control reference value, indicates an inflammatory disease, disorder, or condition. In some embodiments, the regulated presence and / or expression level of miR-124 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, administered to the patient. The terms "regulated" or "regulated presence and / or expression level" mean that the presence or expression level of the biomarker is induced or increased, or alternatively inhibited or reduced.

[0318] In some embodiments, the presence or reduced expression level of miR-124 measured relative to a control reference value indicates an inflammatory disease, disorder, or condition. In some embodiments,The presence or increase of miR-124 as measured relative to a control reference value indicates the potency of the compound or its pharmaceutically acceptable salt or composition as described herein. In some embodiments, the miR-124 expression level measured in patients treated with the compound or its pharmaceutically acceptable salt or composition as described herein is 2, 4, 6, 8, or 10 times the control reference value.

[0319] Thus, according to specific embodiments, the present invention also provides compounds of formula (I), (Ib), (Ib'), (IV), (IVb), or (IVb') as defined above for use in treating patients, wherein the presence and / or expression level of miR-124 in patient blood and / or tissue samples is measured before and during use.

[0320] In some embodiments, the present invention provides algorithms for monitoring the severity of a disease, disorder, or condition and / or monitoring the efficacy of treatments (including, but not limited to, treatments as described herein), which combine miR-124 levels with levels of cytokines or another biomarker, or levels of compounds of formula (I) or (IV) or pharmaceutically acceptable salts thereof. In some embodiments, treatment methods as described herein include using algorithms to monitor the severity of a disease, disorder, or condition and / or monitoring the efficacy of treatments, said algorithms combining miR-124 levels with levels of cytokines or another biomarker, or levels of compounds of formula (I) or (IV) or pharmaceutically acceptable salts thereof.

[0321] This document also provides compounds for use according to the invention, wherein algorithms are used to monitor the severity of a disease, disorder, or condition and / or monitor the efficacy of use or treatment, said algorithms combining miR-124 levels with levels of cytokines or another biomarker, or levels of compounds of formula (I) or (IV) or pharmaceutically acceptable salts thereof as defined herein.

[0322] This document also provides compounds for use according to the invention, wherein an algorithm is used to select patients for use or treatment, the algorithm described in CN 121846117 A (pages 34 / 68) combines miR-124 levels with levels of cytokines or another biomarker, or levels of compounds of formula (I) or (IV) as defined herein, or pharmaceutically acceptable salts thereof.

[0323] This document also provides algorithms for monitoring the severity of a disease, disorder, or condition and / or monitoring the efficacy of treatment, which combine miR-124 levels with levels of cytokines or another biomarker, or levels of compounds of formula (I) or (IV) as defined above, or pharmaceutically acceptable salts thereof.

[0324] Thus, according to specific embodiments, the invention also provides compounds of formula (I), (Ib), (Ib'), (IV), (IVb), or (IVb') as defined above, wherein an algorithm is used to monitor the severity of a disease, disorder, or condition and / or monitor the efficacy of the use,The algorithm combines miR-124 levels with the levels of cytokines or another biomarker, or the levels of compounds of formula (I), (Ib), (Ib'), (IV), (IVb), or (IVb') or their pharmaceutically acceptable salts.

[0325] Uses, Formulations, and Administration

[0326] Pharmaceutically Acceptable Compositions

[0327] According to another embodiment, the present invention provides compositions comprising the compounds of the present invention or their pharmaceutically acceptable derivatives and pharmaceutically acceptable carriers, adjuvants, or mediators. In some embodiments, the compositions of the present invention are formulated for administration to a patient in need of the compositions. In some embodiments, the compositions of the present invention are formulated for oral administration to a patient.

[0328] The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[0329] The term "pharmaceutically acceptable carrier, adjuvant, or mediator" refers to a nontoxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or mediators that may 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, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylic acids, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0330] "Pharmaceutically acceptable derivatives" means any non-toxic salt, ester, salt of ester, or other derivative of the compounds of the present invention that, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their active metabolites or residues.

[0331] The “biological sample” suitable for use in this invention can be a biological fluid, such as blood, plasma or serum, saliva, interstitial fluid or urine; a cell sample, such as a cell culture, cell line or PBMC sample; a biopsy sample, such as oral tissue, gastrointestinal tissue, skin, oral mucosa sample or a variety of samples from clinical trials.

[0332] The biological sample can be a crude sample or can be purified to various degrees before storage, processing or measurement. In some 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 samples, cerebrospinal fluid samples, tear samples and tissue culture supernatant samples.

[0333] The compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via implanted reservoir. The term “parenterally” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular,Intrasynovial, intrasternal, intrasheath, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention can be an aqueous or oil-containing suspension. These suspensions can be formulated with suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are routinely used as solvents or suspension media, according to the specification on pages 35 / 68, CN 121846117 A.

[0334] For this purpose, any mild non-volatile oil, including synthetic mono- or diglycerides of glycerol, can be used. Fatty acids, such as oleic acid and its glycerol derivatives, can be used to prepare injectable formulations, such as pharmaceutically acceptable natural oils, such as olive oil or castor oil, particularly in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose, or similar dispersants commonly used in pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers, or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solids, liquids, or other dosage forms, may also be used in the formulation.

[0335] Pharmaceutically acceptable compositions of the present invention can be administered orally 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 commonly added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. In cases where an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0336] 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 reagent 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. The substances include cocoa butter, beeswax, and polyethylene glycol.

[0337] The pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly where the therapeutic target includes areas or organs easily accessible for topical application, including eye, skin, or small bowel diseases. Suitable topical formulations can be readily prepared for each of these areas or organs.

[0338] Topical application to the small bowel can be performed in rectal suppository formulations (see above) or in suitable enema formulations. Topical transdermal patches can also be used.

[0339] For topical application,The pharmaceutically acceptable compositions provided can be formulated in suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in suitable lotions or creams containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.

[0340] Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0341] For ophthalmic use, the pharmaceutically acceptable compositions provided 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 benzyl ammonium chloride. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions may be formulated in ointments such as petrolatum.

[0342] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the field of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and / or other conventional solubilizers or dispersants. Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. The formulation may be administered with or without food.

[0343] In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0344] The amount of the compounds of the present invention that can be combined with a carrier substance to produce a single dosage form composition will vary depending on the host being treated and the specific administration modality. Preferably, the provided compositions are formulated as inhibitors that enable patients to receive these compositions at a dose of 0.01-100 mg / kg body weight / day. Instructions for Use, pages 36 / 68, CN 121846117 A

[0345] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, weight, general health, sex, diet, time of administration, excretion rate, 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 present invention in the composition also depends on the specific compound in the composition.

[0346] Use of the compounds and pharmaceutically acceptable compositions

[0347] The compounds and compositions described herein are generally used to treat inflammatory diseases, disorders or conditions.

[0348] As used herein, the terms “treatment,” “management,” and “curing” mean reversing, alleviating, or delaying the onset of a disease or disorder or one or more of its symptoms as described herein.Or inhibit its progression. In some embodiments, treatment may be given after one or more symptoms have developed. In other embodiments, treatment may be given in the absence of symptoms. For example, treatment may be given to a susceptible individual before the onset of symptoms (e.g., considering a history of symptoms and / or genetic or other susceptibility factors). Treatment may also continue after the symptoms have subsided, thereby, for example, preventing or delaying their recurrence.

[0349] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions, comprising administering a compound or composition as described herein to a patient in need.

[0350] Inflammatory diseases, disorders, or conditions

[0351] The compounds described herein are used to treat inflammatory or obstructive airway diseases such as reducing, for example, tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. In some embodiments, the inflammatory disease, disorder, or condition is an inflammatory or obstructive airway disease, 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, for example, of subjects under 4 or 5 years of age who present with wheezing symptoms and are diagnosed or can be diagnosed as "asthmatic infants," which is an established patient category of significant medical importance and is currently often identified as having initial or early-stage asthma.

[0352] The compounds described herein are used to treat xenoimmune diseases. In some embodiments, the inflammatory disease, disorder, or condition is a xenoimmune disease, including but not limited to graft-versus-host disease, transplantation, infusion, allergic reactions, hypersensitivity (e.g., allergic reactions to pollen, latex, drugs, food, insect toxins, animal hair, animal dander, dust mites, or cockroach shells), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0353] The preventive efficacy of treating asthma will be demonstrated as a reduction in the frequency or severity of symptom attacks (e.g., acute asthma or bronchoconstriction attacks), improvement in lung function, or improvement in airway hyperresponsiveness. It may also be demonstrated as a reduced need for other symptomatic treatments (e.g., treatments intended to limit or interrupt symptomatic attacks during occurrence, such as anti-inflammatory or bronchodilator therapy). The preventive benefits of asthma can be particularly evident in subjects prone to “early deterioration.” "Early deterioration" is a known asthma syndrome that is common in a substantial percentage of asthma cases and is characterized by an asthma attack, occurring, for example, between 4 and 6 am, which is generally substantially outside the time frame of any pre-administered symptomatic asthma treatment.

[0354] In some embodiments, the inflammatory disease, disorder, or condition is selected from acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, respiratory, or lung disease (COPD, COAD, or COLD).This includes chronic bronchitis or related dyspnea, emphysema, and exacerbations of airway hyperresponsiveness resulting from other drug treatments (especially other inhaled drug treatments). In some embodiments, the inflammatory disease, disorder, or condition is bronchitis, wherein the bronchitis has any type or origin, including but not limited to acute, peanut inhalation, catarrhal, gravid, chronic, or tuberculous bronchitis. In some embodiments, the inflammatory disease, disorder, or condition is pneumoconiosis of any type or origin (inflammatory, general occupational lung disease, frequently accompanied by chronic or acute airway obstruction and caused by repeated inhalation of powders), including, for example, alumina pneumoconiosis, carbon deposit disease, asbestosis, stone deposit disease, eyelash loss, iron pneumoconiosis, silicosis, tobacco poisoning, and cotton dust pneumoconiosis. Specification 37 / 68 pages 39 CN 121846117 A

[0355] In some embodiments, the inflammatory disease, disorder, or condition is an eosinophil-related disorder, such as eosinophilia. In some embodiments, eosinophilic disorders are eosinophilic disorders of the respiratory tract (e.g., morbid eosinophilic infiltration involving lung tissue), including eosinophilia (which affects the respiratory tract and / or lungs), and, for example, respiratory eosinophilic disorders secondary to or associated with Loffler syndrome, eosinophilic pneumonia, parasitic (especially metazoan) invasion (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas, and eosinophilic disorders of the respiratory tract caused by drug reactions.

[0356] The compounds described herein are also used to treat inflammatory or allergic conditions of the skin. In some embodiments, the inflammatory or allergic condition of the skin is selected from psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoderma, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0357] In some embodiments, the inflammatory disease, disorder, or condition is a disease or condition having an inflammatory component, such as eye diseases and conditions like ocular allergies, conjunctivitis, keratoconjunctivitis sicca, uveitis, and vernal conjunctivitis; diseases and conditions affecting the nose, including allergic rhinitis; and inflammatory diseases involving or having an autoimmune component or etiology, including autoimmune hematologic disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic hepatitis, myasthenia gravis, Stevens-Johnson syndrome, and idiopathic stomatitis diarrhea.Autoimmune inflammatory bowel 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 ophthalmopathy, Graves' disease, sarcomatoid disease, alveolitis, chronic hypersensitivity pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior uveitis), Sjögren's syndrome, keratoconjunctivitis sicca, uveitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cold agglutinin-related periodic syndrome, Muckle-Wells syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndromes, including idiopathic nephritis). Minimal change disease (or nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscular atrophy, catastrophic disorders, obesity, fetal growth restriction, intestinal failure, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, pigmentary disorders, Paget's disease, acute or chronic pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, allergic reactions, sinusitis, ocular allergies, silica-induced diseases, COPD. (Injury, respiratory tract inflammation, bronchial hyperresponsiveness, reduced remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis. Inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type I or type II diabetes, appendicitis, atopic dermatitis, asthma, allergic reactions, 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, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease. Laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis. (Instructions 38 / 68, 40 pages, CN 121846117 A)Vasculitis, or vulvitis.

[0358] In some embodiments, the inflammatory disease, disorder, or condition is acute or chronic transplant rejection in kidney, liver, heart, or lung grafts, or graft-versus-host disease in bone marrow transplants.

[0359] In some embodiments, the inflammatory disease, disorder, or condition is an inflammatory disease, disorder, or condition of the skin. In some embodiments, the inflammatory disease, disorder, or condition of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired bullous epidermolysis bullosa, and other inflammatory or allergic conditions of the skin.

[0360] In some embodiments, the inflammatory disease, disorder, or condition is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cold agglutinin-related cycle syndrome (CAPS), Muckle-Wells syndrome, and osteoarthritis.

[0361] In some embodiments, the inflammatory disease, disorder, or condition is a TH17-mediated disease. In some embodiments, TH17-mediated diseases are selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0362] In some embodiments, the inflammatory disease, disorder, or condition is selected from Sjögren'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.

[0363] In some embodiments, the inflammatory disease, disorder, or condition is related to transplantation. In some embodiments, the inflammatory disease, disorder, or condition is related to organ transplantation, organ transplant rejection, and / or graft-versus-host disease. In some embodiments, the inflammatory disease, disorder, or condition is an autoimmune disorder. In some embodiments, the autoimmune disorder is type 1 diabetes mellitus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, ankylosing spondylitis, orthostatic spondylitis, primary biliary cirrhosis, autoimmune hepatitis, or inflammatory bowel disease.

[0364] In some embodiments, the inflammatory disease, disorder, or condition is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, ankylosing spondylitis, orthostatic spondylitis, primary biliary cirrhosis, polymyalgia rheumatica, giant cell arteritis, or inflammatory bowel disease.

[0365] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition in the pancreas. In some embodiments, the inflammatory disease, disorder, or condition in the pancreas is selected from type 1 diabetes.Type 2 diabetes, acute and chronic pancreatitis.

[0366] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions in the kidneys. In some embodiments, the inflammatory diseases, disorders, or conditions in the kidneys are selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, pulmonary hemorrhage nephritis syndrome, Wegener's granulomatosis, and acute or chronic rejection of kidney transplantation.

[0367] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions in the liver. In some embodiments, the inflammatory diseases, disorders, or conditions in the liver are 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.

[0368] This document also provides compounds of formula (I), (Ib), or (Ib') as defined above for the purposes defined above, wherein the inflammatory disease, disorder, or condition in the liver is selected from non-alcoholic steatohepatitis (NAFLD), non-alcoholic fatty liver disease specification 39 / 68 pages 41 CN 121846117 A (NAFLD), cholestatic liver disease, sclerosing cholangitis, and acute or chronic rejection of liver transplantation.

[0369] Non-alcoholic fatty liver disease (NAFLD) practically encompasses a variety of diseases ranging from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NAFLD). The diagnosis of said disease now means invasive liver biopsy. In addition, appropriate treatment is required.

[0370] NAFLD characterized by predominantly macrovesicular steatosis and the presence of visible sebaceous glands on >5% of hepatocytes is generally considered an effective 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 injury observed in a 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 severity of sebaceous gland disease (0-3), inflammation (0-3), and hepatocellular ballooning degeneration (0-2).

[0371] As can be seen from Example 2 below, the following formula 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine and its metabolites

[0372]

[0373] were tested in a non-alcoholic steatohepatitis STAM model, which is a well-established model for evaluating the therapeutic activity of the compound for NASH. The compound showed a decreasing trend in NAS compared to the mediator group, and its application is anticipated in the treatment of cholestatic liver disease, sclerosing cholangitis, and NAFLD, including NAFLD and NASH.

[0374] Furthermore, as shown in points 4.3 and 4.4 of Embodiment 2 below,8-Chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine reduces A-SMA and reduces F4 / 80-positive area in the liver.

[0375] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions in the lungs or heart. In some embodiments, the inflammatory diseases, disorders, or conditions in the lungs are selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcomatoid disease, myocarditis, pericarditis, and acute or chronic rejection of lung or heart transplantation.

[0376] This document also provides compounds of formula (I), (Ib), or (Ib') as defined above for use as defined above, wherein the inflammatory diseases, disorders, or conditions are selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcomatoid disease, myocarditis, pericarditis, and acute or chronic rejection of lung or heart transplantation.

[0377] As can be seen from Example 3 below, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine showed a tendency to reduce mean pulmonary artery pressure to 70 mg / kg when tested in the Sugen hypoxia model.

[0378] As can be seen from Example 4 below, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine significantly reduced lung pressure in female rats with pulmonary hypertension induced by limonene in rats with pulmonary hypertension.

[0379] All of the results indicate its potential use in the treatment of pulmonary fibrosis, pulmonary hypertension, sarcomatoid disease, myocarditis, and pericarditis.

[0380] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions of the skin. In some embodiments, the inflammatory disease, disorder, or condition of the skin is selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloids, and other inflammatory or allergic conditions of the skin.

[0381] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions in the blood vessels / blood. In some embodiments, the inflammatory disease, disorder, or condition of the blood vessels / blood is selected from Behcet disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative angiopathy, and restenosis.

[0382] In some embodiments, the present invention provides a method for treating inflammatory diseases, disorders, or conditions in the eye. In some embodiments, the inflammatory disease, disorder, or condition of the eye is selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, choroidoretinitis, optic nerve retinitis, uveitis, and orbital inflammatory disease.And optic neuritis.

[0383] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition of the central or peripheral nervous system. In some embodiments, the inflammatory disease, disorder, or condition of the central or peripheral nervous system is selected from nonviral 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 Shah-Ma-Tu-San disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Kreutzfeld-Jacob disease, demyelinating polyneuropathy, and peripheral neuropathy.

[0384] In some embodiments, the present invention provides a method for treating an autoimmune disease, disorder, or condition. In some embodiments, the autoimmune disease, disorder, or condition is selected from lupus including skin and kidney, Graves-Barré syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis.

[0385] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition in the intestine. In some embodiments, the inflammatory disease, disorder, or condition in the intestine is selected from intestinal failure, ulcerative colitis, and Crohn's disease.

[0386] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition in the reproductive system. In some embodiments, the inflammatory disease, disorder, or condition in the reproductive system is selected from endometriosis, uterine fibroids, prostatic dysplasia or growth, and cervical dysplasia.

[0387] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition in the bone and / or joint. In some embodiments, the inflammatory disease, disorder, or condition in the bone and / or joint is selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis, and arthritis and / or demineralization of the hand, foot, ankle, knee, hip, shoulder, elbow, or spine.

[0388] Combination Therapy

[0389] Depending on the specific condition or disease to be treated, additional therapeutic agents normally given to treat the condition may be given in combination with compounds and compositions as described herein. As used herein, additional therapeutic agents normally given to treat a specific disease or condition are referred to as "applicable to the disease or condition being treated".

[0390] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition, comprising administering to a patient in need a compound or composition as described herein and another therapeutic agent in combination therewith.

[0391] Those additional agents may be given separately from the provided combination therapy 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 present invention in a single composition. If given as part of a multiple dosing regimen,The two active agents can be administered simultaneously, sequentially, or at intervals (usually within five hours).

[0392] As used herein, the terms "combination," "synthesis," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, the combination of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0393] The amount of the additional therapeutic agent in the composition of the invention will not exceed the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the composition disclosed herein is about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutic active agent.

[0394] Combinations can produce additive or synergistic effects, wherein similar potency can be obtained with a lower dose of one or both of the compounds, or wherein the same dose can produce significantly improved potency. Specification 41 / 68 pages 43 CN 121846117 A

[0395] In some embodiments, the invention provides compositions comprising compounds as described herein and one or more additional therapeutic agents. The therapeutic agent may be administered together with the compound described herein, or may be administered before or after the administration of the compound described herein. Suitable therapeutic agents are further described in detail below. In some embodiments, the compound described herein may 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 some embodiments, the compound described herein may 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.

[0396] In some embodiments, the present invention provides a method for treating an inflammatory disease, disorder, or condition by administering to a patient in need a compound as described herein and one or more additional therapeutic agents. The additional therapeutic agents may be small molecule or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), etc.Antimalarial agents such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as thioglucosinolate (Solganal®), gold thiomalate (Myochrysine®) and auronoxine (Ridaura®), D-penicillamine (Depen® or Cuprinine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®, Neoral®), tacrolimus, sirolimus, mycophenolate mofetil, leflunomide (Arava®), and anti-TNF agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), peseziazumab (Cimzia®), and adalimumab (Humira®). Anti-IL-1 agents include anaerobicin (Kineret®) and linacicept (Acalyst®); anti-T cell antibodies include thymoglobulin; IV immunoglobulin (IVIg); cananumumab (Ilaris®); anti-Jak inhibitors include tofacitinib; antibodies include rituximab (Rituxan®); anti-T cell agents include abatacept (Orencia®); anti-IL-6 agents include tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®); monoclonal antibodies include tanizumab; and anticoagulants include heparin (Calcinparine® or Liquaemin®). And warfarin (Coumadin®), antidiarrheal medications such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, allosetron (Lotronex®), rubiprostone (Amitiza®), laxatives such as magnesium oxide emulsion, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergic or antispasmodic agents such as betyl® and Singulair®, β-2 agonists such as salbutamol (Ventolin® HFA, Proventil® HFA), Levosalbutamol (Xopenex®), Osinaline (Alupent®), Pirbuterol Acetate (Maxair®), Terbutaline Sulfate (Brethaire®), Salmeterol Sinate (Serevent®), and Formoterol (Foradil®), anticholinergic agents such as Ipratropium Bromide (Atrovent®) and Tiotropium Bromide (Spiriva®),Inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone furoate (Asthmanex®), budesonide (Pulmocort®), and flunisolone (Aerobid®), Afviar®, Symbicort®, Dulera®, disodium cromoglycate (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), and nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®) are also considered. Abacavir (Ziagen®), Abacavir / lamivudine (Epzicom®), Abacavir / lamivudine / zidovudine (Trizivir®), Doxine (Videx®), Emtricitabine (Emtriva®), Lamivudine (Epivir®), Lamivudine / zidovudine (Combivir®), Stavudine (Zerit®), and Zacitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors, such as Rescriptor®, Sustiva®, and nevairapine, are available in the product manual (page 42 / 68, CN 121846117 A). Viramune® and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as ampravir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), furazonavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and telanavir (Aptivus®), entry inhibitors such as entofiviride (Fuzeon®) and maravirovir (Selzentry®), and integrase inhibitors such as retegvir (Isentress®). Combinations of doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) and lenalidomide (Revlimid®), anti-IL36 reagents such as BI655130, dihydroorotate dehydrogenase inhibitors such as IMU-838, anti-OX40 reagents such as KHK-4083, and microbiome reagents such as RBX2660 and 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, and 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 gusekumab, 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 community-stimulating factor-1 receptor inhibitors such as edicotinib or any combination thereof.

[0397] In another embodiment, the present invention provides a method of treating gout, comprising administering to a patient in need a compound as described herein and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, lodine® and celecoxib, colchicine®, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol and febuxostat (Uloric®).

[0398] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need a compound as described herein and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, lodine® and celecoxib,Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; sulfasalazine (Azulfidine®); antimalarial agents such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®); methotrexate (Rheumatrex®); gold salts such as thioglucosinolate (Solganal®), gold thiomalate (Myochrysine®), and auronoxine (Ridaura®); D-penicillamine (Depen® or Cuprex) Imine®, azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents such as etanercept (Enbrel®), indiximab (Remicade®), golimumab (Simponi®), pescizumab (Cimzia®), and adalimumab (Humira®), "anti-IL-1" agents such as anaerobicin (Kineret®) and linacicept (Acalyst®), antibodies such as rituximab (Rituxan®), "anti-T-cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

[0399] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need 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, etodoxacin (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanizumab.

[0400] In some embodiments, the present invention provides a method of treating lupus, comprising administering to a patient in need 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, etodoxacin (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarial agents such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0401] In some embodiments,This invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to a patient in need a compound as described herein and one or more additional therapeutic agents selected from asarazin (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, allosetron (Lotronex®), rubiprostone (Amitiza®), laxatives such as magnesium oxide emulsion, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, and anticholinergic or antispasmodic agents such as betyl®, anti-TNF therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0402] In some embodiments, the present invention provides a method of treating asthma, comprising administering to a patient in need a compound as described herein and one or more additional therapeutic agents selected from Singulair®, β-2 agonists such as salbutamol (Ventolin® HFA, Proventil® HFA), levosalbutamol (Xopenex®), orsinol (Alupent®), pibuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol sinemetidine (... Serevent® and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium bromide (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolone (Aerobid®), Afviar®, Symbicort®, and Dulera®, disodium cromoglycate (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0403] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need a compound as described herein and one or more additional therapeutic agents selected from β-2 agonists such as salbutamol (Ventolin® HFA, Proventil® HFA), levosalbutamol (Xopenex®), orsinol (Alupent®), pibuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),Salmeterol benzoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium bromide (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolone (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0404] In some embodiments, the present invention provides a method of treating HIV, comprising administering to a patient in need a compound as described herein and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), doxorinosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), and non-nucleoside reverse transcriptase inhibitors such as deraviridine (Rescriptor®), efavirenz (Sustiva®), and nevairapine. (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as ampravir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), furazonavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and telanavir (Aptivus®), entry inhibitors such as entvaviride (Fuzeon®) and maravirovir (Selzentry®), integrase inhibitors such as retegvir (Isentress®), and combinations thereof.

[0405] In some embodiments, the present invention provides a method for treating organ transplant rejection or graft-versus-host disease.This includes administering to patients in need the compounds described herein and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, hedgehog signal transduction inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0406] The compounds and compositions according to the method of the invention can be administered in any amount and via any route of administration for the effective treatment of an inflammatory disease, disorder, or condition or to reduce its severity. The precise amount required varies among subjects and depends on the type of subject, age and general condition, severity of the disease or condition, specific reagent, mode of administration, etc. The compounds described herein are preferably formulated in unit dosage form for ease of administration and dose uniformity. The term "unit dosage form" as used herein refers to physically discrete units of reagent suitable for the patient to be treated. However, it should be understood that the total daily use of the compounds and compositions of the invention will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and its severity; 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, route of administration, and the rate of excretion of the specific compound used; the duration of treatment; the drugs used in combination with or concurrently with the specific compound used; and other factors well known in the medical field. The term "patient" as used herein means animal, preferably mammal, and most preferably human.

[0407] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intravenously, vaginally, intraperitoneally, topically (as a powder, ointment, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention may be administered orally or parenterally once or more daily at dose levels of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight to achieve the desired therapeutic effect.

[0408] 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, liquid dosage forms may also contain inert diluents generally 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-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitol, and mixtures thereof. Besides inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, etc.Flavoring agents and aromatics.

[0409] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated with suitable dispersants or wetting agents and suspending agents as known in the art. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are, in particular, water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile non-volatile oils, as per specification 45 / 68 pages 47 CN 121846117 A, are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic mono- or diesters of glycerol. In addition, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0410] Injectable formulations can be sterilized, for example by filtration through a bacterial trap, or by incorporating sterile reagents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0411] To prolong the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystals or amorphous substances with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of the compound in parenteral administration is achieved by dissolving or suspending the compound in an oil medium. Injectable reservoir formulations are prepared by forming microcapsule matrices of the compound in a biodegradable polymer such as polylactide-polyglycolic acid lactide. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir-type injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0412] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound.

[0413] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In the solid dosage form, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or calcium hydrogen phosphate, and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerin; and d) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate.e) dissolution retarders 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 glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0414] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, which use excipients such as lactose or lactose and high molecular weight polyethylene glycol, etc. Solid dosage forms of tablets, lozenges, capsules, pills, and granules can be prepared using coatings and shells such as casings and other coatings known in the pharmaceutical formulation field. They may optionally contain light-blocking agents and may also be compositions that optionally release the active ingredient in a delayed manner only or preferably in certain parts of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol, etc.

[0415] 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 using coatings and shells such as casings, controlled-release coatings and other coatings well known in the pharmaceutical formulation field. In said solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch.

[0416] In common practice, said dosage forms may also contain 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 forms may also contain buffers. They may optionally contain light-blocking agents and may also be compositions that release the active ingredient only or preferably in certain parts of the intestine in a delayed manner. Examples of encapsulation compositions that can be used include polymers and waxes.

[0417] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches.

[0418] The active ingredient is mixed aseptically with a pharmaceutically acceptable carrier and any desired preservatives or buffers as needed. Ophthalmic preparations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches.It has the added advantage of providing controlled delivery of the compound to the body. The dosage form can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0419] The compounds of the present invention are also used as co-therapeutic compounds in combination with other pharmaceutical substances (such as anti-inflammatory, bronchodilator, or antihistamine pharmaceutical substances), particularly for the treatment of obstructive or inflammatory respiratory diseases such as those mentioned above, for example as an enhancer 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 pharmaceutical substances in a fixed pharmaceutical composition, or they can be administered separately before, simultaneously with, or after other pharmaceutical substances. Accordingly, the present invention includes combinations of the compounds of the present invention described above with anti-inflammatory, bronchodilator, antihistamine, or antitussive pharmaceutical substances, wherein the compounds of the present invention and the pharmaceutical substances are in the same or different pharmaceutical compositions.

[0420] Suitable anti-inflammatory drugs include steroids, especially glucocorticoids such as budesonide, beclomethasone dipropionate, fluticasone propionate, cicosone, 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 sillosterol (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-5 351591 (Schering-Plough), and almirallium. Prodesfarma, PD189659 / PD168787 (ParkeDavis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists such as salbutamol, orsenafil, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and its pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergics or antimuscarinic compounds, especially ipratropium bromide, oxotrol, and oxotrol.Tiotropium bromide and CHF 4226 (Chiesi), and glycopyrronium bromide.

[0421] Suitable antihistamines include cetirizine hydrochloride, acetaminophen, chlormastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azithromycin, ebastine, epinastine, mizolastine and tefenadine.

[0422] Other useful combinations of the compounds of the present 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 CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists such as 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-cycloheptene-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0423] The structure of the active compound is identified by a coded number, and the generic or trade name may be derived from the physical standard compilation "The Merck Index" or databases such as Patents International (e.g., IMS World Publications).

[0424] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies are in fixed combination form, or the administration of the compounds of the present invention and one or more other therapeutic compounds is staggered or provided independently of each other, or a fixed combination and one or more other therapeutic compounds are administered together. Specification 47 / 68 pages 49 CN 121846117 A

[0425] Those additional agents may be administered separately from the composition containing the compounds of the present invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form and mixed together with the compounds of the present invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or at intervals (typically within five hours).

[0426] As used herein, the terms "combination," "in combination," and related terms refer to therapeutic agents administered simultaneously or sequentially according to the present invention. For example, the compounds 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. Accordingly, the present invention provides a single unit dosage form.The composition comprises the compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0427] The amount of the compound as described herein and the additional therapeutic agent (in those compositions comprising the above-described additional therapeutic agent) that can be combined with the carrier substance to produce a single dosage form will depend on the host being treated and the specific dosing pattern. Preferably, the compositions of the present invention are formulated such that a dose of 0.01–100 mg / kg body weight / day of the compound of the present invention can be administered.

[0428] In those compositions comprising the additional therapeutic agent, the additional therapeutic agent and the compound of the present invention can act synergistically. Therefore, the amount of the additional therapeutic agent in the composition will be less than that required in a single therapy using only the therapeutic agent. In the composition, a dose of 0.01–1,000 μg / kg body weight / day of the additional therapeutic agent can be administered.

[0429] The amount of the additional therapeutic agent in the compositions of the present invention will not exceed the amount that would normally be administered in a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the composition disclosed herein is about 50% to 100% of the amount normally present in a composition containing the agent as the sole therapeutic active agent.

[0430] The compounds of the present invention or pharmaceutical compositions thereof may also be incorporated into the composition 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 (the narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at 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 containing a kinase inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the invention.

[0431] In addition to the above-described preventive and / or therapeutic methods, the present invention also provides corresponding uses for the prevention and / or treatment of diseases, disorders, or conditions as described herein. In some embodiments, the present invention provides uses of compounds as described herein or pharmaceutically acceptable salts thereof for the prevention and / or treatment of inflammatory diseases, disorders, or conditions as described herein. In some embodiments, the prevention and / or treatment of inflammatory diseases, disorders, or conditions provided by the present invention are intended for use in patients whose miR-124 presence and / or expression levels are measured and / or monitored by methods as described herein.

[0432] This document also provides compounds of formulas (I), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa), (IVb), (IVb'), (IVc), or (IVd) as defined above, or pharmaceutically acceptable salts thereof, for the treatment or prevention of inflammatory diseases, disorders, or conditions in patients in need, wherein the inflammatory disease, disorder, or condition is selected from:

[0433] (a) an inflammatory disease, disorder, or condition in the pancreas, selected from type 1 diabetes, type 2 diabetes,

[0434] (b) Inflammatory diseases, disorders, or conditions in the kidneys, selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, pulmonary hemorrhage nephritis syndrome, Wegener's granulomatosis, and acute or chronic rejection of kidney transplantation;

[0435] (c) Inflammatory diseases, disorders, or conditions 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 liver transplantation;

[0436] (d) Inflammatory diseases, disorders, or conditions in the lungs or heart, selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcomatoid disease, myocarditis, pericarditis, and acute or chronic rejection of lung or heart transplantation;

[0437] (e) Inflammatory diseases, disorders, or conditions in the skin, selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, Instruction manual, pages 48 / 68, 50 CN 121846117 A: Erythema multiforme, dermatitis herpetiformis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloids, and other inflammatory or allergic conditions of the skin;

[0438] (f) Inflammatory diseases, disorders, or conditions in the blood vessels / bloodstream, selected from Behcet disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative angiopathy, and restenosis;

[0439] (g) Inflammatory diseases, disorders, or conditions in the eye, selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, choroidoretinitis, optic nerve retinitis, uveitis, orbital inflammatory diseases, and optic neuritis;

[0440] (h) Inflammatory diseases, disorders, or conditions of the central or peripheral nervous system, selected from nonviral 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 Shah-Ma-Tu3 disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Crout-Felter-Jacob disease, demyelinating polyneuropathy, and peripheral neuropathy;

[0441] (i) Autoimmune diseases, disorders, or conditions, selected from lupus, including cutaneous and renal lupus, Graves' syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis;

[0442] (j) Inflammatory diseases, disorders, or conditions of the intestine, selected from intestinal failure, ulcerative colitis, and Crohn's disease;

[0443] (k) Inflammatory diseases, disorders, or conditions of the reproductive system, selected from endometriosis, uterine fibroids, prostatic dysplasia or growth.and cervical dysplasia; and

[0444] (l) inflammatory diseases, disorders or conditions 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.

[0445] This document also provides compounds of formula (I), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa), (IVb), (IVb'), (IVc), or (IVd) as defined above, or pharmaceutically acceptable salts thereof, as anti-inflammatory agents intended for use in patients, wherein the presence and / or expression level of miR-124 in said patient blood and / or tissue samples are monitored before and / or during said use of the anti-inflammatory agent.

[0446] The anti-inflammatory activity of any form of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine and its metabolites or pharmaceutically acceptable salts thereof can be evaluated using animal preclinical models.

[0447] Example 1

[0448] For example, in a mouse IMQ-induced psoriasis model. Psoriasis can be induced, for example, by administering IMQ at daily doses from day 0 to day 9, and treatment can be given daily, for example, from day 0 to day 9. Anti-inflammatory activity can be evaluated, for example, by measuring psoriasis scores.

[0449] For example, in an MPTP-induced Parkinson's disease mouse model, mice can receive, for example, four 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 assays at the substantia nigra pars compacta (SNpc) level.

[0450] For example, in a MOG-induced experimental autoimmune encephalomyelitis (EAE) mouse model. EAE can be induced, for example, by injecting MOG / CFA into the paravertebral region on day 0 of the study. Furthermore, to increase blood-brain barrier (BBB) ​​penetration, all animals could be subjected to supplemental immunostimulation, for example, by intraperitoneal injection of pertussis toxin (PT) on study days 0 and 2. Treatment could be administered daily, for example, from day 0, day 3, or day 10, and anti-inflammatory activity could be measured, for example, by clinical scores and / or histological evaluation of the spinal cord via H&E staining and / or CNS / pain parameters, assessing cell infiltration and demyelination. For example, this was performed in a mouse model of NOD idiopathic diabetes. Treatment could be administered daily, and anti-inflammatory activity could be assessed, for example, by blood glucose levels and / or an oral glucose tolerance test.

[0451] In the following examples,Compound A is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine or ABX464, page 49 / 68, CN 121846117 A, and compound B is its metabolite

[0452] .

[0453] Example 2: In vivo efficacy study of compounds in a non-alcoholic steatohepatitis (NASH study) STAM model

[0454] A. Substances and methods

[0455] 1. Test substances

[0456] To prepare a dose-controlled solution, compounds A and B were weighed and suspended in a medium consisting of 20% medium-A1 and 80% medium-A2. The medium-A1 consisted of 0.5% (w / v) carboxymethyl cellulose (CMC) (400-800 centipoise, in water for injection) + 2.5% (w / v) Tween 80. The mediator A2 consisted of 0.5% (w / v) carboxymethyl cellulose (CMC) (400-800 centipoise, in water for injection). Telmisartan (Micardis®) was purchased from Boehringer Ingelheim GmbH (Germany) and dissolved in pure water.

[0457] 2. Induction of NASH

[0458] NASH was induced in 48 male mice: a single subcutaneous injection of 200 µg streptozotocin (STZ, Sigma-Aldrich, USA) solution was given 2 days after birth, followed by feeding a high-fat diet (HFD, 57 kcal% fat, Cat# HFD32, CLEA Japan, Inc., Japan) after 4 weeks of age.

[0459] 3. Route of administration

[0460] Compounds A and B and telmisartan were administered orally at a volume of 10 mL / kg.

[0461] 4. Treatment Dosage

[0462] From 6 to 9 weeks of age, compound A was administered once daily at three dose levels of 10, 20, and 40 mg / kg. From 6 to 9 weeks of age, compound B was administered once daily at a dose of 40 mg / kg. From 6 to 9 weeks of age, telmisartan was administered once daily at a dose of 10 mg / kg.

[0463] 5. Animals

[0464] C57BL / 6 mice (14-day-pregnant females) were obtained from Japan SLC, Inc. (Japan). All animals used in the study were housed and cared for in accordance with the Animal Use Guidelines of the Japanese Pharmacological Society.

[0465] Animals were kept in an SPF facility under controlled conditions, including temperature (23±3°C), humidity (50±20%), lighting (12-hour artificial light and dark cycles; light from 8:00 to 20:00), and air exchange. High pressure was maintained in the laboratory to prevent facility contamination.

[0466] Animals were housed in TPX cages (CLEA Japan), with a maximum of 4 mice per cage. Sterilization was performed using Palmas-µ (Material Research Center).(Japan) Bedding was used and changed weekly.

[0467] Sterilized solid HFD was provided at will, placed on a metal cap on top of the cage. Pure water was provided at will from a water bottle equipped with a rubber stopper and a straw. The water bottle was changed weekly, cleaned, sterilized in an autoclave, and reused.

[0468] Mice were identified by ear punching. Each cage was marked with a specific identification code.

[0469] 6. Measurement of plasma biochemistry

[0470] For plasma biochemistry, non-fasting blood was collected in polypropylene tubes containing an anticoagulant (Novo-Heparin, Mochida Pharmaceutical Co. Ltd., Japan) and centrifuged at 1,000 xg for 15 minutes at 4°C. The supernatant was collected and stored at -80°C until use. Plasma ALT was measured using a FUJI DRI-CHEM 7000 (Fujifilm, Japan).

[0471] 7. Instructions for Measurement of Liver Triglyceride Content 50 / 68 pages 52 CN 121846117 A

[0472] The total lipid extract of liver was 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. The liver triglyceride content was measured by the triglyceride E-test (FUJIFILM Wako Pure Chemical Corporation, Japan).

[0473] 8. Histological Analysis

[0474] For HE staining, sections were excised from paraffin blocks of liver tissue prefixed in Bouin solution and stained with Lillie-Mayer hematoxylin (Muto Pure Chemical Co., Ltd., Japan) and eosin solution (FUJIFILM Wako Pure Chemical Corporation). NAFLD activity score (NAS) was calculated according to the criteria of Kleiner (Kleiner DE. et al., Hepatology, 2005; 41:1313). For visualization of collagen deposition, Bouin-fixed liver sections were stained with pico-Sirius red solution (Waldeck, Germany). For quantitative analysis of fibrosis area, bright-field images of Sirius red-stained sections around the central vein were captured at 200x magnification using a digital camera (DFC295; Leica, Germany), and the positive area in 5 fields / sections was analyzed using ImageJ software (National Institute of Health, 2000).USA) Measurement.

[0475] 9. Sample Collection

[0476] For plasma samples, non-fasting blood was collected in polypropylene tubes containing an anticoagulant (Novo-Heparin) and centrifuged at 1,000 xg 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 transport. For frozen liver samples, the left lobe was collected and cut into 6 pieces. Two pieces from the left lobe, left and right middle lobes, and tail lobe were rapidly frozen in liquid nitrogen and stored at -80°C for transport. Two more pieces from the left lobe were fixed in Bouin solution and then embedded in paraffin. The paraffin blocks were stored at room temperature for histological analysis. The remaining pieces from the left lobe were embedded in an O.C.T. compound and rapidly frozen in liquid nitrogen. The sample was stored at -80°C. The right lobe was rapidly frozen in liquid nitrogen and stored at -80°C for liver biochemistry.

[0477] 10. Statistical Tests

[0478] Statistical analysis was performed using the Bonferroni multiple comparison test on GraphPad Prism 6 (GraphPad Software Inc., USA). A p-value < 0.05 was considered statistically significant. A trend or tendency was indicated by a p-value < 0.1 returned by a one-tailed t-test. Results are expressed as mean ± SD.

[0479] B. Experimental Design and Treatment

[0480] 1. Study Groups

[0481] Group 1: Mediator

[0482] Eight NASH mice were orally administered mediators [20% mediator-A1 and 80% mediator-A2] at a volume of 10 mL / kg once daily from 6 to 9 weeks of age.

[0483] Group 2: Low Compound A

[0484] Eight NASH mice were orally administered mediators supplemented with compound A at a dose of 10 mg / kg once daily from 6 to 9 weeks of age.

[0485] Group 3: Compound A

[0486] Eight NASH mice were orally administered a mediator supplemented with Compound A once daily from 6 to 9 weeks of age at a dose of 20 mg / kg.

[0487] Group 4: Compound A High

[0488] Eight NASH mice were orally administered a mediator supplemented with Compound A once daily from 6 to 9 weeks of age at a dose of 40 mg / kg. (Instructions for Use, Pages 51 / 68, CN 121846117 A)

[0489] Group 5: Compound B

[0490] Eight NASH mice were orally administered a mediator supplemented with Compound B once daily from 6 to 9 weeks of age at a dose of 40 mg / kg.

[0491] Group 6: Telmisartan

[0492] Eight NASH mice were orally administered purified water supplemented with telmisartan once daily from 6 to 9 weeks of age.Dosage: 10 mg / kg.

[0493] Table 4 below summarizes the treatment plan:

[0494] Table 4

[0495] 2. Animal monitoring and sacrifice

[0496] Survival, 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, morbidity and death. Animals were sacrificed at 9 weeks of age by direct cardiac puncture and exsanguination under isoflurane anesthesia (Pfizer Inc.).

[0497] C. Results

[0498] 1. Changes in body weight and general condition

[0499] From day 9 to day 21, the mean body weight in the telmisartan group was significantly lower than that in the carrier group. There were no significant changes in mean body weight between the carrier group and other treatment groups on any day during the treatment period.

[0500] No animals died in any group during the treatment period. No animals showed deterioration in general condition in this study.

[0501] 2. Body weight and liver weight on the day of sacrifice

[0502] 2.1. Body weight on the day of sacrifice (Table 5)

[0503] On the day of sacrifice, the telmisartan group showed a significant decrease in mean body weight compared to the drug group. On the day of sacrifice,There was no significant difference in mean weight between the mediator group and other treatment groups.

[0504] 2.2. Liver weight and liver weight to body weight ratio (Table 5)

[0505] The telmisartan group showed a significant decrease in mean liver weight compared to the mediator group. The low compound A group showed a significant increase in mean liver weight compared to the mediator group. The high compound A and compound B groups tended to have an increase in mean liver weight compared to the mediator group. There was no significant difference in mean liver weight between the mediator group and the medium compound A group.

[0506] The mean liver weight to body weight ratio in the telmisartan group tended to be lower compared to the mediator group. The mean liver weight to body weight ratio in the low, medium and high compound A groups and the compound B group tended to be higher compared to the mediator group.

[0507] Table 5: Body weight and liver weight

[0508] 3. Biochemistry

[0509] 3. Biochemistry

[0510] 3.1. Plasma ALT

[0511] The high-compound A group showed a significant increase in plasma ALT levels compared to the mediator group. Plasma ALT levels in the low- and medium-compound A groups and the compound B group tended to be increased compared to the mediator group. There was no significant difference in plasma ALT levels between the mediator group and the telmisartan group. 3.2. Liver Triglycerides

[0512] Liver triglyceride levels in the telmisartan group tended to be decreased compared to the mediator group. Liver triglyceride levels in the compound B group tended to be increased compared to the mediator group. There was no significant difference in liver triglyceride levels between the mediator group and other treatment groups.

[0513] Table 6: Biochemistry

[0514] 4. Histological Analysis

[0515] 4.1. HE Staining and NAFLD Activity Scores (Table 7 and Figures 1, 2, 3 and 4)

[0516] Representative micrographs 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 the ballooning degeneration score.

[0517] Liver sections from the mediator group showed small and large vesicular fat deposits.Hepatocellular ballooning degeneration and inflammatory cell infiltration. The telmisartan group showed a significant reduction in NAS compared to the mediator group. The low, medium, and high NAS groups of compound A and the compound B group tended to have lower NAS compared to the mediator group.

[0518] Table 7: NAFLD Activity Score Instructions 53 / 68 pages 55 CN 121846117 A

[0519] Definition of NAS components

[0520] 4.2. Sirius Red Staining and Fibrosis Area (Table 8 and Figure 5)

[0521] Representative micrographs of Sirius Red-stained liver sections were analyzed. Figure 5 represents the fibrosis area.

[0522] Liver sections from the mediator group showed increased collagen deposition in the pericentral region of the liver lobule. The fibrosis area (Sirius Red-positive area) in the compound A group tended to be lower compared to the mediator group. The fibrosis area in the compound B group tended to be higher compared to the mediator group. There was no significant difference in fibrosis area between the mediator group and other treatment groups.

[0523] Table 8: Fibrosis area

[0524] 4.3 A-SMA immunostaining and a-SMA-positive area

[0525] A-SMA immunostaining of liver sections from the mediator group showed that a-SMA-positive cells mainly accumulated in region 3. The A-SMA-positive area in the high compound A and telmisartan groups tended to be lower than that in the mediator group. (Table 9 below)

[0526] 4.4 F4 / 80 immunostaining

[0527] F4 / 80 immunostaining of liver sections from the mediator group showed that F4 / 80-positive cells mainly accumulated in region 3.

[0528] The high compound A group showed a significant reduction in F4 / 80-positive area compared to the mediator group. The F4 / 80-positive area in the medium compound A and compound B groups tended to be lower than that in the mediator group. (Table 9) Specification 54 / 68 pages 56 CN 121846117 A

[0529] Table 9:

[0530] Conclusion

[0531] Telmisartan

[0532] Treatment with telmisartan showed a significant reduction in NAS compared to the mediator group,It is noted that the drug successfully served as a positive control in this study. Treatment with telmisartan showed a decreasing trend in liver triglyceride levels compared to the mediator group.

[0533] Compound A

[0534] Treatment with Compound A at low doses showed a decreasing trend in NAS compared to the mediator group. Treatment with Compound A at low doses showed an increasing trend in plasma ALT levels compared to the mediator group.

[0535] Treatment with Compound A at medium doses showed a decreasing trend in NAS and fibrosis area compared to the mediator group. Treatment with Compound A at medium doses showed an increasing trend in plasma ALT levels compared to the mediator group. Treatment with Compound A at high doses showed a significant increase in plasma ALT levels compared to the mediator group. Treatment with Compound A at high doses showed a decreasing trend in NAS compared to the mediator group.

[0536] Compound B

[0537] Treatment with Compound B showed a decreasing trend in NAS compared to the mediator group.

[0538] Treatment with Compound B showed an increasing trend in plasma ALT levels, liver triglyceride levels, and fibrosis area compared to the mediator group.

[0539] In this study, compounds A and B showed a decreasing trend in NAS compared to the mediator group. In addition, compound A showed a decreasing trend in collagen pathological deposition in the liver, as indicated 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.

[0540] Example 3: In vivo efficacy study of compounds in a Sugen hypoxia model of pulmonary arterial hypertension (PAH) in rats

[0541] Experimental procedure

[0542] Study design

[0543] Induction of PAH

[0544] Animals were randomized between treatment groups based on their body weight and the results of transthoracic echocardiography (on day 21) by study guidance. Animals in the same treatment group were housed in pairs.

[0545] 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, group 1 animals received a single subcutaneous injection of 2 mL / kg DMSO (sugen medium) and were returned to their respective cages.

[0546] Groups 2–5 were placed in cages with controlled air conditioning to receive the equivalent of 0.10 (10%) FiO2, using a nitrogen and ambient air mixture controlled by a ventilation cage system. They were maintained under these low-oxygen conditions for 21 days. Under hypoxic conditions, the cages were cleaned and changed weekly.Animals were exposed 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 (normative) levels for 56 days. Animals were observed daily for any changes in behavior and general health status as described on page 57 of the instruction manual (55 / 68 pages) of CN 121846117 A.

[0547] Treatment

[0548] On day 22 (groups 2-5), animals were treated with compound A, sildenafil, or the mediator as planned and described in Table 10. Groups 2-4 received a single dose daily. Group 5 received sildenafil twice daily. Food and water were provided on an ad hoc basis. Animals were observed daily for behavior and general health status. Weekly body weight was recorded.

[0549] Echocardiography

[0550] All animals were monitored for disease progression by echocardiography on day 0, day 21, and on the day of surgery (day 56).

[0551] Blood Sampling

[0552] Venous blood (0.5 ml, anticoagulated with EDTA) was collected from all animals (including normoxic controls) on days 0, 22, and 56 immediately after the first dose. The EDTA-anticoagulated whole blood was centrifuged to produce plasma, which was then decanted into clean tubes labeled with at least the animal number, group ID, and time point, and stored frozen at -80°C until transferred to the donor.

[0553] Table 10. Treatment Group Assignment and Treatment Information

[0554] *Groups of n=10 or 12 animals were started to compensate for the approximately 10-20% mortality rate in this model.

[0555] Surgical instruments and equipment and instructions for measuring hemodynamic and functional parameters in efficacy study animals, 56 / 68 pages, 58 CN 121846117 A

[0556] 1. On the selected surgical day, anesthetize the rats with a mixture of 2 to 2.5% isoflurane USP (Abbot Laboratories, Montreal, Canada) / oxygen and place them on a heating pad to maintain body temperature.

[0557] 2. Incise the rat's trachea and immediately ventilate it through a positive pressure rodent respirator set to ≈10 ml / kg body weight and a frequency of 65-70 pulses / min.

[0558] 3. Place lead II ECG contact electrodes on the rats to continuously monitor ECG during the surgical procedure.

[0559] 4. Insert a cannula connected to a pressure transducer into the left femoral artery to measure arterial blood pressure.

[0560] 5. Insert a cannula connected to a pressure transducer into the right atrium through the right jugular vein to measure right atrial pressure.

[0561] 6. Expose the heart via sternotomy, introduce 20GA 1.16 / Insyte into the right ventricle and quickly hook the saline-filled PE-50 catheter connected to the transducer.

[0562] 7. After recording right ventricular pressure for several seconds,Insyte was further pushed into the pulmonary artery for an additional 60 seconds of PAP recording.

[0563] 8. Hemodynamic parameters were continuously recorded for the duration of the procedure or until the PAP signal was lost.

[0564] 9. After hemodynamic monitoring, the thoracic 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.

[0565] 10. For lung histology and casting, the procedure was as follows: 1) Eight (8) rats were retained per group to evaluate the left lung histology and therefore the treatment described in point 12 of section 8.2; 2) Two (2) rats were retained per group so that the three-dimensional vascular structure of the left lung could be quantitatively characterized and therefore the treatment described in section 8.3 was used for left lung casting.

[0566] 11. For histology, the left lobe was inflated with a 10 mL syringe filled with fixative (10% NBF) and with a blunt pin (23 g) attached. Insert the needle tip into the trachea and fix it in place with a suture while simultaneously ligating another syringe to the pulmonary artery. Gently inflate the lungs at physiological pressure (20–25 mmHg) until all lobes are fully, evenly, and uniformly expanded (the fixative should not leak through the lung surface). This provides optimal vascular and airway expansion without causing excessive tissue rupture. The needle is then removed, the trachea is ligated with a suture, and the tissue is immersed in 10% NBF at a 1:20 tissue:fixative ratio. The tissue is kept in formalin for 24–48 hours. It is then cut into three parts (upper, middle, and lower). Each part is sent to the Institute for Research in Immunology and Cancer (IRIC) in Montreal (Quebec, Canada) for embedding, sectioning, and endothelial cell staining with hematoxylin and eosin (H&E) or von Willebrand factor (VWF).

[0567] 12. As part of the Fulton index, the heart is dissected to separate the right ventricle from the diaphragmatic left ventricle, and then weighed separately.

[0568] Pulmonary Artery Casting Procedure

[0569] 1. After recording hemodynamic parameters, lungs and hearts were harvested from 2 out of 10 rats and pulmonary artery castings were prepared for the left lung.

[0570] 2. A polyethylene (PE190) tube was cut to a length of 40 cm, one end of which 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 the right lung casting, the catheter was pushed into the right pulmonary artery (PA) and fixed there to avoid perfusion of the left lung.

[0571] 3. 2 ml of diluted heparin sodium (5 units / ml) (APP Pharmaceuticals, Inc., Schaumburg, IL) was pumped using a continuous infusion pump set at 2 ml / min.(USA) Rinse the blood from the PA. Make a small incision in the left atrial appendage of the left ventricle to allow the solution to drain out of the pulmonary circulation.

[0572] 4. To ensure uniform filling, especially in the lower lung segment, keep the lung in an upright position.

[0573] 5. Mix the silicone polymer casting compound, namely MV-Yellow Microfil (cP; 0.01 g / cm-s) with a medium viscosity (MV) diluent at a 5:4 (diluent:compound) volume ratio and add to 5% (volume) of the curing agent. Then pump the freshly mixed silicone polymer casting material through the catheter at 2 ml / min until the polymer reaches the RV. Reduce the flow rate to 0.05 ml / min as the polymer enters the pulmonary circulation.

[0574] 6. Stop pumping when the polymer is uniformly visible on the lung surface. Ligate the PA irrigating the left lung before resection from the heart-lung segment.

[0575] 7. The left lung with the PA ligated 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 a right lung cast, the right PA was ligated.

[0576] 8. Once polymerized, 10% formalin was added to the container to immerse the left lung (or right lobe) in formalin and stored at 4°C for an additional 48 hours.

[0577] 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 Skyscan at Bruker (Manning Park, MA, USA). The images were then transferred to Fluidda Inc. for analysis.

[0578] Results:

[0579] Mean pulmonary pressure in females

[0580] Mean pulmonary pressure in males

[0581] As a conclusion, treatment of rats with compound A at 70 mg / kg in the Sugen hypoxia model showed a tendency to reduce mean pulmonary artery pressure.

[0582] Example 4: In vivo efficacy study of compound in a rat model of pulmonary hypertension lily alkaloid (Instructions for use, pages 58 / 68, CN 121846117 A)

[0583] Experimental System

[0584] Data Acquisition System

[0585] Data acquisition was performed using a networked personal computer running Microsoft Windows XP Professional 2007. The acquisition software was AxoScope 10.2, using the Digidata interface of Axon Instruments. AxoScope 10.2 has been fully validated in the relevant environment in which it was used.

[0586] Analysis System

[0587] The analysis software was Clampfit 10.2.0.14 of Axon Instruments.Installed on a networked PC running Microsoft Windows XP Professional 2016. Clampfit 10.2.0.14 was fully validated in its intended environment. The image analysis software was Microsoft Office Excel 2016, installed on a networked PC running Microsoft Windows 10 Famille.

[0588] Compiling Experimental Data

[0589] 1. Open the experimental trace to be analyzed in Clampfit.

[0590] 2. Record right atrial pressure for 1 minute.

[0591] 3. Extract mean, diastolic, and systolic lung pressure using PAP continuously recorded for at least 1 minute or until the signal is lost.

[0592] 4. Extract mean, diastolic, and systolic arterial pressure using continuously recorded systemic arterial pressure (SAP).

[0593] 5. At the end of the hemodynamic parameter recording, the right and left ventricles, including the diaphragm and lobes, were removed to determine wet weight.

[0594] 6. Compile the parameters for each group and present them in a bar chart, and perform appropriate statistical analysis.

[0595] Experimental Procedure:

[0596] Preparation of Lilium alkaloid solution

[0597] Weigh an appropriate amount of lilium alkaloid and add 1 / 3 of the correct volume of 1.0N HCl, mix to ensure solubilization of the lilium alkaloid. The solution is then neutralized with 1 / 3 of the correct volume of 1.0N NaOH. The pH of the solution is checked with pH test paper / strip or electronic pH meter and adjusted to neutral as needed; the final volume is made up with injectable water to obtain a solution of 20 mg / mL. The lilium alkaloid solution is subcutaneously injected into the loose skin on the neck of each rat at a dose of 3 mL / kg body weight (60 mg / kg).

[0598] Preparation of Compound A solution

[0599] Compound A is administered as a suspension in the medium. To achieve the required concentration, Compound A is ground into a fine powder using a mortar and pestle, and then mixed with 20% (final volume) of medium A1 until a suspension is obtained. Then, 80% of medium A2 is added to the suspension under magnetic stirring.

[0600] Media A1: 0.5% (w / v) carboxymethyl cellulose (CMC) (400-800 centipoise, in water for injection) + 2.5% (w / v) Tween 80

[0601] Media A2: 0.5% (w / v) carboxymethyl cellulose (CMC) (400-800 centipoise,

[0602] In water for injection)

[0603] Media for dosing: 20% media A1 + 80% media A2

[0604] Stir the control and compound A dosage formulations for at least 15 minutes before administration and keep them under continuous magnetic stirring throughout the dosing procedure. Instructions for use 59 / 68 pages 61 CN 121846117 A

[0605] Table 11. Concentration solutions and administration volumes of compound A

[0606] Preparation of sildenafil

[0607] Weigh an appropriate amount of sildenafil and add an appropriate volume of distilled water to obtain a suspension of 5 mg / mL. Mix the suspension with a stir bar for 30-60 minutes until a homogeneous suspension is obtained. Carefully maintain the homogeneous suspension (continuous stirring) while aspirating the dose into a gavage syringe. Fill one gavage syringe at a time and administer before filling the next syringe. Store the solution frozen at 2 to 8°C and protected from light. The expiration date is set to 7 days after preparation.

[0607] Table 12. Sildenafil Concentration Solutions and Dosage Volumes

[0608] Experimental Procedure

[0609] Study Design

[0610] Induction of PAH

[0611] Animals were randomized between treatment groups based on their body weight and the results of transthoracic echocardiography (day 7) as directed by the study. Animals in the same treatment group were housed in pairs.

[0612] Animals in groups 2 to 5 (see Table 13) received a single subcutaneous injection of limonene (60 mg / kg) solution on day 0 and were returned to their cages. Animals in group 1 received a single subcutaneous injection of the MCT mediator on day 0 and were returned to their respective cages.

[0613] Treatment

[0614] On day 7 (groups 2–5), compound A, sildenafil, or the mediator were administered as planned and described in Table 13. Groups 2–4 received a single dose daily. Control group 5 received sildenafil twice daily. Food and water were provided freely. Complete daily observations of animal behavior and general health status. Record body weight weekly.

[0615] Echocardiography

[0616] Echocardiographic monitoring of disease progression was performed on all animals on day 0, day 7, and on the day of surgery (day 28).

[0617] Blood sampling

[0618] Venous blood (0.5 ml, anticoagulated with EDTA) was collected from all animals (including normoxic controls) on day 0 and day 7 immediately after administration of the first dose. On the day of surgery (day 28), after hemodynamic measurements, 3 ml of blood was collected from rats via cardiac puncture. The EDTA-anticoagulated whole blood was centrifuged to produce plasma, which was then decanted into clean tubes labeled with at least the animal number, group ID, and time point.And stored frozen at -80°C until transferred to the sponsor.

[0619] Table 13: Treatment group allocation and treatment information instructions 60 / 68 pages 62 CN 121846117 A

[0620] *Start with groups of n=10 or 12 animals to compensate for the approximately 10-20% mortality rate in this model.

[0621] Measurement of hemodynamic and functional parameters and surgical instruments in efficacy study animals

[0622] 1. On the selected surgical day, anesthetize rats with a mixture of 2 to 2.5% isoflurane USP (Abbot Laboratories, Montreal, Canada) / oxygen and place them on a heating pad to maintain body temperature.

[0623] 2. Cut the rat's trachea and immediately ventilate it through a positive pressure rodent respirator set at a frequency of approximately 10 ml / kg body weight and 65-70 pulses / min.

[0624] 3. Place lead II ECG contact electrodes on the rats to continuously monitor ECG during the surgical procedure.

[0625] 4. Insert the cannula connected to the pressure transducer into the left femoral artery to measure arterial blood pressure.

[0626] 5. Insert the cannula connected to the pressure transducer into the right atrium via the right jugular vein to measure right atrial pressure.

[0627] 6. Expose the heart via sternotomy and introduce 20GA 1.16 / Insyte into the right ventricle and quickly hook the saline-filled PE-50 catheter connected to the transducer.

[0628] 7. After recording right ventricular pressure for several seconds, push the Insyte further into the pulmonary artery for an additional 60 seconds of PAP recording.

[0629] 8. Record hemodynamic parameters continuously for the duration of the procedure or until the PAP signal is lost.

[0630] 9. After hemodynamic monitoring, open the thoracic cavity to expose the lungs. Dissect the muscles above the trachea to remove the lungs and heart. Rinse the harvested tissue with PBS to remove any excess blood before weighing. Instructions for Use, pages 61 / 68, 63 CN 121846117 A

[0631] 10. Further open the thoracic cavity to expose the lungs. Dissect the muscles above the trachea to remove the lungs and heart. Rinse the harvested tissue with PBS to remove any excess blood before weighing.

[0632] 11. For lung histology and casting, the procedure is as follows: 1) Eight (8) rats per group are retained to evaluate the left lung histology and therefore treated as described in point 12 of section 8.2; 2) Two (2) rats per group are retained so that the three-dimensional vascular structure of the left lung can be quantitatively characterized and therefore treated as described in section 8.3 for left lung casting.

[0633] 12. For histology, the left lobe is inflated with a 10 mL syringe filled with fixative (10% NBF) and with an attached blunt needle (23 g). Insert the needle tip into the trachea,While securing the position with sutures, another syringe is ligated to the pulmonary artery. The lungs are gently inflated at physiological pressure (20–25 mmHg) until all lobes are fully, evenly, and uniformly expanded (fixative is not allowed to leak through the lung surface). This provides optimal vascular and airway expansion without causing excessive tissue rupture. The needle is then removed, sutures are ligated around the trachea, and the tissue is immersed in 10% NBF at a 1:20 tissue:fixative ratio. The tissue is held in formalin for 24–48 hours. It is then cut into three parts (upper, middle, and lower). The parts are sent to the Institute for Research in Immunology and Cancer (IRIC) (Quebec, Canada) in Montreal for embedding, sectioning, and staining with hematoxylin and eosin (H&E) and von Willebrand factor (VWF) for endothelial cell staining.

[0634] 13. As part of the Fulton index, the heart is dissected to separate the right ventricle from the diaphragmatic left ventricle, which is then weighed separately.

[0635] Pulmonary Artery Casting Procedure

[0636] 1. After recording hemodynamic parameters, lungs and hearts were harvested from 2 out of 10 rats and pulmonary artery castings were prepared for the left lung.

[0637] 2. A polyethylene (PE190) tube was cut to a length of 40 cm, with one end connected to an 18-G needle and the other end, which was heat-passivated, 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 the right lung casting, the catheter was pushed into the right pulmonary artery (PA) and fixed there to avoid perfusion of the left lung.

[0638] 3. Blood was flushed from the PA by pumping 2 ml of diluted heparin sodium (5 units / ml) (APP Pharmaceuticals, Inc., Schaumburg, IL, USA) using a continuous infusion 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 drain out of the pulmonary circulation.

[0639] 4. To ensure uniform filling, especially in the lower lung segment, the lung is kept in an upright position.

[0640] 5. The silicone polymer casting compound, namely MV-Yellow Microfil with a viscosity of 25 centipoise (cP; 0.01 g / cm-s),Mix with a medium viscosity (MV) diluent at a 5:4 (diluent:compound) volume ratio and add to 5% (volume) curing agent. Then pump the freshly mixed silicone polymer casting material through a catheter at 2 ml / min until the polymer reaches the RV. Reduce the flow rate to 0.05 ml / min as the polymer enters the pulmonary circulation.

[0641] 6. Stop pumping when the polymer is uniformly visible on the lung surface. Ligate the PA irrigating the left lung before the heart-lung segmentectomy.

[0642] 7. Then transfer the left lung with the ligated PA into a small container and store at 4°C for 24 hours to allow the silicone polymer to fully polymerize. In the case of the right lung casting, ligate the right PA.

[0643] 8. Once polymerized, add 10% formalin to the container to immerse the left lung (or right lobe) in formalin and store at 4°C for an additional 48 hours.

[0644] 9. The left lung (or right lobe) was then transported to the Department of Engineering at Sherbrooke University (Quebec, Canada) for micro-CT imaging using Skyscan at Bruker (Manning Park, MA, USA). The images were then transferred to Fluidda Inc. for analysis.

[0645] Results: Specification 62 / 68 pages 64 CN 121846117 A

[0646] Mean lung pressure:

[0647] Conclusion

[0648] In this study, treatment with compound A significantly reduced lung pressure in female rats that had been induced with pulmonary hypertension by lily alkaloids, with no effect on male rats.

[0649] Other exemplary embodiments:

[0650] 1. A method for treating an inflammatory disease, disorder, or condition in a patient in need, wherein the inflammatory disease, disorder, or condition is selected from:

[0651] a. An inflammatory disease, disorder, or condition in the pancreas, selected from type 1 diabetes, type 2 diabetes, acute and chronic pancreatitis;

[0652] b. An inflammatory disease, disorder, or condition in the kidney, selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, pulmonary hemorrhage nephritis syndrome, Wegener's granulomatosis, and acute or chronic rejection after kidney transplantation;

[0653] 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 after liver transplantation;

[0654] d Inflammatory diseases, disorders, or conditions of the lungs or heart, selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcomatoid disease, myocarditis, pericarditis, and acute or chronic rejection of lung or heart transplantation;

[0655] e. Inflammatory diseases, disorders, or conditions of the skin, selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoderma, hypersensitivity vasculitis, urticaria,Bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne, keloids, and other inflammatory or allergic conditions of the skin;

[0656] f. Inflammatory diseases, disorders, or conditions of the blood vessels / blood, selected from Behcet disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative angiopathy, and restenosis;

[0657] g. Inflammatory diseases, disorders, or conditions of the eye, selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, chorioretinitis, optic nerve retinitis, uveitis, orbital inflammatory disease, and optic neuritis;

[0658] h. Inflammatory diseases, disorders, or conditions of the central or peripheral nervous system, selected from nonviral 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 Shah-Ma-Tu3 disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Crout-Felter-Jacob disease, demyelinating polyneuropathy, and peripheral neuropathy;

[0659] i. Autoimmune diseases, disorders, or conditions, selected from lupus, including cutaneous and renal lupus, Graves-Barré syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis;

[0660] j. Inflammatory diseases, disorders, or conditions of the intestines, selected from intestinal failure, ulcerative colitis, and Crohn's disease;

[0661] k. Inflammatory diseases, disorders, or conditions of the reproductive system, selected from endometriosis, uterine fibroids, prostatic dysplasia or growth, and cervical dysplasia; and the instructions for use, pages 63 / 68, CN 121846117 A

[0662] l. Inflammatory diseases, disorders, or conditions of 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 a compound of formula (I) to a patient:

[0663]

[0664] or a pharmaceutically acceptable salt thereof, wherein: Z is C or N;

[0665] V is C or N;

[0666] 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;

[0667] Each R is independently hydrogen, halogen, -CN, hydroxyl, (C1-C3) fluoroalkyl, (C1-C3) fluoroalkoxy, (C3-C6) cycloalkyl, -NO2, -NR1R2, (C1-C4) alkoxy, phenoxy, -NR1-SO2-NR1R2, -NR1-SO2-R1, -NR1-C(=O)-R1, -NR1-C(=O)-NR1R2, -SO2-NR1R2, -SO3H, -O-SO2-OR3.-O-P(=O)-(OR3)(OR4), -O-CH2-COOR3, (C1-C3)alkyl, wherein the alkyl group is optionally mono- or di-substituted with the following groups: hydroxyl, group of formula (IIa):

[0668] or group of formula (IIIa): ;

[0669] Q is N or O, provided that R" is absent when Q is O;

[0670] Each R1 and R2 is independently hydrogen or (C1-C3)alkyl;

[0671] Each R3 and R4 is independently hydrogen, Li+, Na+, K+, N+(Ra)4 or benzyl;

[0672] n is 1, 2 or 3;

[0673] n' is 1, 2 or 3;

[0674] Each R' is independently hydrogen, (C1-C3)alkyl, hydroxyl, halogen, -NO2, -NR1R2, morpholinyl, morpholino, N-methylpiperazinyl, (C1-C3)fluoroalkyl, (C1-C4)alkoxy, -O-P(=O)-(OR3)(OR4), -CN, a group of formula (IIa):

[0675] or a group of formula (IIIa):

[0676] A is covalent, oxygen or NH; B is covalent or NH;

[0677] m is 1, 2, 3, 4 or 5;

[0678] p is 1, 2 or 3;

[0679] Each Ra and Rb is independently hydrogen, (C1-C5)alkyl or (C3-C6)cycloalkyl, or

[0680] Ra and Rb together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocycle, said heterocycle optionally substituted with one or more Ra, provided that R' is a group (IIa) or (IIIa), and n' can be 2 or 3 only if the other R' groups are different from said group (IIa) or (IIIa); and

[0681] R" is hydrogen, (C1-C4) alkyl or a group of formula (IIa) as defined herein.

[0682] 2. The method of embodiment 1, wherein the compound has the following formula (Ia): Specification 64 / 68 pages 66 CN 121846117 A

[0683]

[0684] or a pharmaceutically acceptable salt thereof.

[0685] 3. The method of embodiment 1, wherein the compound has the following formula (Ib):

[0686]

[0687] or a pharmaceutically acceptable salt thereof.

[0688] 4. The method of Embodiment 1, wherein the compound has the following formula (Ic):

[0689]

[0690] or a pharmaceutically acceptable salt thereof.

[0691] 5. The method of Embodiment 1, wherein the compound has the following formula (Ib'):

[0692]

[0693] or a pharmaceutically acceptable salt thereof.

[0694] 6. The method of Embodiment 1,The compound having the following formula (Id):

[0695] (Id)

[0696] or a pharmaceutically acceptable salt thereof.

[0697] 7. Compound of formula (IV):

[0698]

[0699] 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

[0700] .

[0701] 8. Compound of Embodiment 7, wherein the compound having the following formula (IVa): Specification 65 / 68 pages 67 CN 121846117 A

[0702]

[0703] or a pharmaceutically acceptable salt thereof.

[0704] 9. Compound of Embodiment 7, wherein the compound having the following formula (IVb):

[0705]

[0706] or a pharmaceutically acceptable salt thereof.

[0707] 10. The compound of Embodiment 7, wherein the compound has the following formula (IVc):

[0708]

[0709] or a pharmaceutically acceptable salt thereof.

[0710] 11. The compound of Embodiment 7, wherein the compound has the following formula (IVb'):

[0711]

[0712] or a pharmaceutically acceptable salt thereof.

[0713] 12. The compound of Embodiment 7, wherein the compound has the following formula (IVd):

[0714]

[0715] or a pharmaceutically acceptable salt thereof.

[0716] 13. A pharmaceutical composition comprising a compound of any one of Embodiments 7-12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0717] 14. A method for treating an inflammatory disease, disorder, or condition, comprising administering to a patient in need a compound of any one of Embodiments 7-12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 13.

[0718] 15. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder, or condition is in the pancreas, selected from type A diabetes, type 2 diabetes, acute and chronic pancreatitis.

[0719] 16. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder, or condition is in the kidney, selected from glomerulosclerosis, glomerulonephritis, nephritis, acute kidney injury, Berger's disease, pulmonary hemorrhage nephritis syndrome, Wegener's granulomatosis, and acute or chronic rejection of kidney transplantation.

[0720] 17. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder, or condition is 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 liver transplantation.

[0721] 18. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition is in the lungs or heart,Selected from chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary hypertension, sarcomatoid disease, myocarditis, pericarditis, and acute or chronic rejection of lung or heart transplantation.

[0722] 19. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder, or condition in the skin is selected from contact dermatitis, atopic dermatitis, psoriasis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, leukoplakia, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired bullous epidermolysis bullosa, acne, keloids, and other inflammatory or allergic conditions of the skin.

[0723] 20. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition in the blood vessels / blood is selected from Behcet disease, vasculitis, sepsis, tumor angiogenesis, atherosclerosis, proliferative angiopathy and restenosis.

[0724] 21. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder or condition in the eye is selected from conjunctivitis, scleritis, episcleritis, panuveitis, choroiditis, choroidoretinitis, optic nerve retinitis, uveitis, orbital inflammatory disease, and optic neuritis.

[0725] 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 nonviral and viral encephalitis and meningitis, depression, neuropathic pain, including chronic pain, traumatic brain injury, including stroke, Alzheimer's disease, Parkinson's disease, myelitis, type I Shayma-Tuss disease (including CMT1A and CMT1B), multiple sclerosis, amyotrophic lateral sclerosis (ALS), Kreutzfeldt-Jacob disease, demyelinating polyneuropathy, and peripheral neuropathy.

[0726] 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 cutaneous and renal lupus, Graves' syndrome, myasthenia gravis, Hashimoto's thyroiditis, idiopathic purpura, aplastic anemia, Graves' disease, and myocarditis.

[0727] 24. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder, or condition is in the intestine, selected from intestinal failure, ulcerative colitis, and Crohn's disease.

[0728] 25. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder, or condition is in the reproductive system, selected from endometriosis, uterine fibroids, prostatic dysplasia or growth, and cervical dysplasia.

[0729] 26. The method of any one of embodiments 1-6 and 14, wherein the inflammatory disease, disorder, or condition is in the bone / skeletal structure and / or joints, selected from juvenile idiopathic arthritis, psoriatic arthritis, periodontitis,Arthritis and / or demineralization of the hands, feet, ankles, knees, hips, shoulders, elbows, or spine.

[0730] 27. The method of any one of Embodiments 1-6 and 14-26 further includes measuring the level of compound (I) or a pharmaceutically acceptable salt thereof in patient blood, plasma, tissue, saliva, and / or serum samples.

[0731] 28. The method of any one of Embodiments 1-6 and 14-27 further includes measuring the level of compound (IV) or a pharmaceutically acceptable salt thereof in patient blood, plasma, tissue, saliva, and / or serum samples. Specification 67 / 68 pages 69 CN 121846117 A

[0732] 29. The method of any one of Embodiments 1-6 and 14-28 further includes measuring the total level of compounds (I) and (IV) or pharmaceutically acceptable salts thereof in patient blood, plasma, tissue, saliva, and / or serum samples.

[0733] ​​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 patient blood and / or tissue samples before and during the treatment process.

[0734] 31. The method of any one of embodiments 1-6 and 14-30, further comprising selecting patients by measuring the presence and / or expression level of miR-124 in patient blood and / or tissue samples.

[0735] 32. The method of any one of embodiments 1-6 and 14-31, further comprising using an algorithm to monitor the severity of a disease, disorder, or condition and / or monitor the efficacy of treatment, said algorithm combining miR-124 levels with levels of cytokines or another biomarker, or the levels of compound (I) or (IV) or a pharmaceutically acceptable salt thereof.

[0736] 33. The method 31 of any one of embodiments 1-6 and 14, further comprising selecting a patient for treatment using an algorithm that combines miR-124 levels with levels of a cytokine or another biomarker, or the levels of compound (I) or (IV) or a pharmaceutically acceptable salt thereof.

[0737] 34. An algorithm for monitoring the severity of a disease, disorder, or condition and / or monitoring the efficacy of treatment, which combines miR-124 levels with selected cytokines or another biomarker,The present disclosure relates to quinoline derivatives for use in the treatment of inflammatory diseases. Specifically, it relates to a compound of Formula (I) or any of its metabolites or a pharmaceutically acceptable salt thereof, for use for treating and / or preventing an inflammatory disease, disorder, or condition. The present disclosure further relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, for use for treating and / or preventing an inflammatory disease, disorder, or condition.

Claims

1,8-Chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prevention of inflammatory diseases, disorders or conditions. The inflammatory diseases, disorders, or conditions mentioned therein are selected from: (c) An inflammatory disease, disorder or condition of the liver, selected from non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD); (d) An inflammatory disease, disorder or condition in the lungs or heart, such as pulmonary hypertension.

2. The following compounds The use of its pharmaceutically acceptable salts in the preparation of a medicament for the treatment and / or prevention of an inflammatory disease, disorder, or condition as defined in claim 1.

3. The use according to claim 1 or 2, wherein the inflammatory disease, disorder or condition is in the liver, selected from non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

4. The use according to claim 1 or 2, wherein the inflammatory disease, disorder or condition is in the lungs, which is pulmonary hypertension.

5. The use according to claim 1 or 2, wherein the medicament is used to treat a patient, wherein during use the levels of the compound as defined in claim 1 or the compound as defined in claim 2 or a pharmaceutically acceptable salt thereof are measured in the patient’s blood, plasma, tissue, saliva and / or serum samples.

6. The use according to claim 1 or 2, wherein the drug is used to treat 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.

7. The use according to claim 1 or 2, wherein the algorithm is used to monitor the severity of a disease, disorder, or condition and / or the effectiveness of the monitoring purpose, said algorithm combining miR-124 levels with levels of cytokines or another biomarker, or levels of compounds as defined in claim 1 or as defined in claim 2, or pharmaceutically acceptable salts thereof.

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