Compounds that induce immune cell production of proteins

Abstract

The present invention relates to compounds of formula (I) and their use in the production of interleukin-10 by immune cells. The present invention also relates to induced immune cells capable of producing interleukin-10. The present invention also relates to the use of the induced immune cells in the prevention and / or treatment of immune-mediated diseases.

Description

[Technical field]

[0001] The present invention relates to compounds that induce the production of proteins, in particular interleukin-10 (IL-10), by immune cells and their use in the prevention and / or treatment of immune mediated diseases, in particular neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammatory responses having detrimental effects on the risk of cancer development or progression, and ageing. [Background technology]

[0002] Immune-mediated diseases are chronic inflammatory diseases perpetuated by antibodies and cellular immunity. The immune response damages healthy organs either accidentally as a result of attacking foreign components that have invaded the body, or by attacking self-tissues, a process called autoimmunity. These diseases include many forms of arthritis (e.g., rheumatoid arthritis and psoriatic arthritis), inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis, autism spectrum disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating diseases (CID)), and vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis). These diseases are not uncommon and have a large socio-economic impact.

[0003] Currently, the main focus of treatment is to suppress immunity and inhibit inflammation by using immunosuppressants, blockers of cytokine or cytokine receptor signaling, or by temporary depletion of leukocyte subsets.However, these approaches do not take into account the need to restore dominant immune regulation, and are often incomplete in restoring a healthy and stable immune system in these pathologies.The majority of patients treated with these drugs do not respond, or become resistant after a period of time, or relapse when treatment is stopped. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there is a need for new and effective forms of treatment, particularly treatments that can provide controlled and sustained therapy, either alone or in combination with other therapies, while improving the quality of life for patients and reducing treatment-related side effects.

[0006] To prevent and / or treat immune-mediated diseases, the inventors have developed new compounds that induce the production of proteins, in particular interleukin-10 (IL-10), by immune cells, allowing the generation of IL-10-producing immune cells that can be used in adoptive cell therapy. [Means for solving the problem]

[0007] The present invention relates to compounds of formula (I) which induce the production of proteins, in particular interleukin-10 (IL-10), by immune cells:

[0008] [ka]

[0009] Provide [In the formula, -X 1 , X 2 , X 3 are each independently a nitrogen atom or a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -NHCORa group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p and p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4, and 5; and each Z 6 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j and j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 , R 7 and R 8 each independently represents a hydrogen atom, a cyano group, a halogen atom, or -NHCOR b R b is (C 1 ~C 6 ) cycloalkyl group, (C 1~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 8 ) b and b is selected from 0, 1, 2, 3, 4 and 5; and each Z 8 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; however, -X 1 is a nitrogen atom, R 8 does not exist; -X 2 is a nitrogen atom, R 7 does not exist; -X 3 is a nitrogen atom, R 6 does not exist.

[0010] The present invention also provides a method for inducing immune cells, characterized in that said immune cells are contacted with at least one compound of formula (I) that induces the production of a protein, in particular interleukin-10.

[0011] The present invention also provides immune cells capable of producing proteins, particularly interleukin-10.

[0012] The present invention also provides a pharmaceutical composition comprising a dose of induced immune cells and at least one pharma- ceutically acceptable carrier and its use in the prevention and / or treatment of immune-mediated diseases, in particular neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing. [Brief description of the drawings]

[0013] [Figure 1] 1 is a graph showing the effect of compounds 77, 133, and 161 on IL-10 induction by human B cells. [Diagram 2] 1 is a graph showing the effect of compounds 212, 213, 216, 217, 219, 220, 224, 228, 238, 271, 279 and 344 on IL-10 induction by human B cells. [Diagram 3] FIG. 1 is a graph showing the effect of induction of human B cells with compound 133 on IL-10 production by human B cells. [Figure 4] FIG. 1 is a graph showing the effect of induction of human B cells with Compound 77 on IL-10 production by human B cells. [Diagram 5] FIG. 1 is a graph showing the effect of induction of human B cells with compound 161 on IL-10 production by human B cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present invention relates to compounds of formula (I) which induce the production of proteins, in particular interleukin-10 (IL-10), by immune cells:

[0015] [ka]

[0016] Provide [In the formula, -X 1 , X 2 , X 3 are each independently a nitrogen atom or a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R ais a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p and p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 )n wherein n is selected from 0, 1, 2, 3, 4, and 5; and each Z 6 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j and j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 , R 7 and R 8 each independently represents a hydrogen atom, a cyano group, a halogen atom, or -NHCOR b R b is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 8 ) band b is selected from 0, 1, 2, 3, 4 and 5; and each Z 8 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; however, -X 1 is a nitrogen atom, R 8 does not exist; -X 2 is a nitrogen atom, R 7 does not exist; -X 3 is a nitrogen atom, R 6 does not exist.

[0017] The inventors have shown that compounds of formula (I) can induce immune cell production of proteins, particularly interleukin 10 (IL-10), without increasing the production of interleukin-6 (Il-6). Advantageously, compounds of formula (I) can generate pure and stable IL-10-producing immune cells. In particular, the inventors have shown that compounds of formula (I) increase interleukin production, particularly IL-10 production, by immune cells, particularly B cells, T cells or myeloid cells, activated via i) Toll-like receptors (TLR) and IgM in B cells, ii) TLR in myeloid cells, and also iii) CD3, CD28 and IL-27 receptors in T cells, indicating that IL-10 production is not restricted to any particular activation condition. Furthermore, the inventors have shown that compounds of formula (I) induce distinct molecular programs in immune cells, particularly B cells, T cells or myeloid cells, accompanied by upregulation of transcription factors known to promote IL-10 expression in these cells.

[0018] The inventors have shown that immune cells induced with a compound of formula (I), when subsequently washed and re-cultured under a variety of conditions including the compound of formula (I), continue to uniformly express proteins, particularly IL-10, whilst the immune cells are unresponsive in terms of IL-6 production.

[0019] As used herein, the term "compound that induces the production of a protein" refers to a compound that can increase protein production by immune cells. Advantageously, the compound inducing the production of a protein is capable of generating an immune cell culture in which more than 5%, advantageously more than 10%, advantageously more than 15%, advantageously more than 20%, advantageously more than 25%, advantageously more than 30%, advantageously more than 35%, advantageously more than 40%, advantageously more than 45%, advantageously more than 50%, advantageously more than 55%, advantageously more than 60%, advantageously more than 65%, advantageously more than 70%, advantageously more than 75%, advantageously more than 80%, advantageously more than 85%, advantageously more than 90%, advantageously more than 91%, advantageously more than 92%, advantageously more than 93%, advantageously more than 94%, advantageously more than 95%, advantageously more than 96%, advantageously more than 97%, advantageously more than 98%, advantageously more than 99% of the immune cells of the culture are capable of producing proteins. Advantageously, the compounds of the invention induce the production of a protein, in particular one of the following proteins: interleukin-10, PDL1, PDL2, CD200, KLRA4 and LAG-3, advantageously the production of interleukin-10.

[0020] As used herein, the term "interleukin-10," also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. As used herein, the terms "interleukin-10" or "IL10" or "IL-10" are interchangeable.

[0021] As used herein, the term "Ct-Cz" refers to a carbon chain that may contain t to z carbon atoms, where t and z can range from 1 to 10; for example, (C 1 ~C 6 ) is a carbon chain that may contain 1 to 6 carbon atoms.

[0022] As used herein, the term "alkyl group" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms and which is saturated or unsaturated (i.e., contains one or more double and / or triple bonds). 1 ~C 6 "C)alkyl group" refers to an alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl, and the like. 1 "Alkyl" refers to methyl, and "C 2 "Alkyl" refers to ethyl, and "C 3 "Alkyl" refers to propyl, and "C 4 "Alkyl" refers to butyl.

[0023] As used herein, "(C 1 ~C 6 The term "alkoxy group" refers to a straight or branched hydrocarbon chain group containing the specified number of carbon atoms, preferably between 1 and 6 carbon atoms, and an oxygen atom (-OC). Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and hexoxy, among others. 1 "Alkoxy" refers to methoxy, and "C 2 "Alkoxy" refers to ethoxy, and "C 3 "Alkoxy" refers to propoxy, and "C 4 "Alkoxy" refers to butoxy. Additionally, as used herein, "OMe" refers to methoxy and "OEt" refers to ethoxy.

[0024] As used herein, the term "cycloalkyl" refers to a mono- or polyvalent saturated ring having 1 to 12 ring carbon atoms as a monocyclic, bicyclic, or tricyclic ring system, which bicyclic or tricyclic ring systems may include fused, bridged, and spiro rings. In some embodiments, cycloalkyl groups contain 1 to 6 ring carbon atoms (C 1 ~C 6 ) cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl radicals may be optionally substituted with one or more substituents described herein.

[0025] As used herein, the term "pyridine" refers to a six-membered heteroaromatic ring having one nitrogen atom.

[0026] As used herein, the term "phenyl" refers to an aromatic ring system containing six carbon atoms, commonly referred to as a benzene ring. Phenyl may be optionally substituted with one or more substituents described herein.

[0027] As used herein, the term "aryl group" refers to a monovalent unsaturated hydrocarbon, such as "CH 2 =CH-CH 2 -" or a derivative thereof (e.g., allyl chloride).

[0028] As used herein, the term "cyano" refers to a -CN group, or an -alkyl-CN group, where alkyl is as defined herein.

[0029] As used herein, the term "alkyl ether group" refers to any alkyl group, as defined above, in which at least one carbon-carbon bond is replaced with a carbon-oxygen bond. The carbon-oxygen bond may be terminal (as in an alkoxy group) or the carbon-oxygen bond may be internal (i.e., COC).

[0030] As used herein, the term "hydroxyl" refers to a monovalent group of formula --OH.

[0031] As used herein, the term "halogen atom" refers to an atom selected from fluorine, chlorine, bromine or iodine. The halogen atom may advantageously be a chlorine, fluorine or bromine atom.

[0032] In the context of the present disclosure, the various embodiments described herein can be combined.

[0033] According to the present invention, the compounds of formula (I) according to the present invention can be used in the form of pharma- ceutically acceptable salts, which may include salts, hydrates and solvates prepared by conventional methods well known to those skilled in the art. Examples include, in particular, carboxylic acids, e.g., carboxylates (COO - ), but also sulfonates (-SO 3 - ), phosphonates (PO 3 2- ), quaternary ammonium (NR 4 + ) or sulfonamine (SO 2 - NH 3 + ) can be mentioned. Advantageously, suitable salts include pharmaceutically or physiologically acceptable acid addition salts. Advantageously, suitable salts include acid addition salts formed with various pharmaceutically or physiologically acceptable free acids. Examples of acids can include, but are not limited to, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholineethanesulfonic acid, camphorsulfonic acid, nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, ruktu knife, EMBO acid, glutamic acid, aspartic acid, and the like.

[0034] In addition, pharma- ceutically acceptable metal salts can be prepared using bases. For example, alkali metal or alkaline earth metal salts can be obtained by dissolving the compound in excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, evaporating the filtrate, and drying. Here, sodium, potassium, lithium, cesium, magnesium, or calcium salts are pharma-ceutically suitable metal salts, but are not limited thereto. In addition, silver salts corresponding to metal salts can be obtained by reacting alkali metals or alkaline earth metals with appropriate silver salts (e.g., nitrates). Ammonium (NH 4 + ) or ammonium form, such as diethylamine (EDTA), pyrrolidine, piperidine and pyridine.

[0035] In some embodiments, the compound of formula (I) is not one of the following compounds: 6-iodo-2-phenylimidazo[1,2-a]pyridine; 6-iodo-2-(pyridin-3-yl)imidazo[1,2-a]pyridine; 6-Chloro-2-(pyridin-3-yl)imidazo[1,2-a]pyridine; 6-Bromo-2-(pyridin-3-yl)imidazo[1,2-a]pyridine N-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl)benzamide; N-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl)-2-methoxybenzamide; N-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl]-3-methoxy-benzamide; 2-(3,4-difluorophenyl)-6-iodoimidazo[1,2-a]pyridine; 6-Bromo-2-(3,4-difluorophenyl)imidazo[1,2-a]pyridine; 2-(4-bromophenyl)-6-iodoimidazo[1,2-a]pyridine; 2-(4-fluorophenyl)-6-iodoimidazo[1,2-a]pyridine; 6-Bromo-2-(4-fluorophenyl)-imidazo[1,2-a]pyridine; N-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl]acetamide; 1-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl]-3-phenyl-urea; 2-(3-fluorophenyl)-6-iodoimidazo[1,2-a]pyridine; N-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-2-methoxy-benzamide; N-(2,4-dimethoxyphenyl)-2-phenyl-imidazo[1,2-a]pyridine-6-carboxamide; 2-(4-chlorophenyl)imidazo[1,2-a]pyridine; 2-(4-bromophenyl)imidazo[1,2-a]pyridine; 6-Chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine; 6-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine.

[0036] In some embodiments, compounds according to the invention that induce the production of proteins, particularly interleukin-10 (IL-10), include: -X 1 , X 2 and X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) nwherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a cyano group, or a halogen atom.

[0037] In some embodiments, compounds of formula (I) according to the invention that induce the production of proteins, in particular interleukin-10 (IL-10), include:

[0038] [ka]

[0039] is selected from.

[0040] In some embodiments, compounds according to the invention that induce the production of proteins, particularly interleukin-10 (IL-10), include: -X 1 is a nitrogen atom; -X 2 , X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) pwherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

[0041] In some embodiments, compounds according to the invention that induce the production of proteins, particularly interleukin-10 (IL-10), include: -X 2 is a nitrogen atom; -X 1 , X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; Rc However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; Z 5 are the same or different, and each independently represents a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 group, -CF 3 selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

[0042] In some embodiments, compounds of formula (I) according to the invention that induce the production of proteins, in particular interleukin-10 (IL-10), include:

[0043] [ka]

[0044] It is.

[0045] In some embodiments, compounds according to the invention that induce the production of proteins, particularly interleukin-10 (IL-10), include: -X 3 is a nitrogen atom; -X 1 and X 2 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; Ra is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 7 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

[0046] In some embodiments, the compound that induces the production of a protein according to the invention, in particular interleukin-10 (IL-10), is -X 2 is a nitrogen atom; -X 1 and X 3 is a carbon atom; - R 2 and R 3 each independently represents a hydrogen atom, a halogen atom, or -NHCOR a R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

[0047] In some embodiments, compounds according to the invention that induce the production of proteins, particularly interleukin-10 (IL-10), include: -X 2 is a nitrogen atom or a carbon atom; -X 1 and X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom or a halogen atom; - R 4 , R 5 , R 6 and R 8are each independently a hydrogen atom, a cyano group, or a halogen atom.

[0048] In some embodiments, the compound of formula (I) is

[0049] [ka]

[0050] is selected from.

[0051] In some embodiments, compounds of formula (I) according to the invention that induce the production of proteins, in particular interleukin-10 (IL-10), include:

[0052] [ka]

[0053] is selected from.

[0054] The chemical structures and some spectroscopic data of preferred compounds of formula (I) that induce the production of interleukin-10 (IL-10) are shown in Table 1 below.

[0055] [Table 1A]

[0056] [Table 1B]

[0057] [Table 1C]

[0058] [Table 1D]

[0059] [Table 1E]

[0060] synthesis The following general scheme can be carried out to obtain various compounds of formula (I′), (I″), (Ia), (Ib), (Ic) or (Id) starting from a compound of formula (1), as presented in Scheme 1 hereinafter.

[0061] The synthesis is based on the condensation reaction of a substituted 2-aminopyridine of formula (1) with a carbonyl group of a substituted 2-bromoacetophenone of formula (2) via route (A) to generate an imidazopyridine intermediate of formula (I'), followed by intramolecular cyclization, followed by the introduction of a benzamide group via Cu-catalyzed coupling between a halogenated compound of formula (I') and a benzamide derivative of formula (3) via route (B) to obtain a compound of formula (Ia), (Ib) or (Ic), respectively, or the introduction of an amine group via Pd-catalyzed coupling between a halogenated compound of formula (I') and an amine derivative via route (C), or the introduction of a urea group via Pd-catalyzed coupling between a halogenated compound of formula (I') and a urea derivative via route (D). 2 or R 3 The subsequent reaction between a carboxylic acid derivative of formula (I″), obtained by saponification of a compound of formula (I′), in which is an alkyl ester group, and an amine derivative to introduce the opposite amide group, gives the compound of formula (Id).

[0062] [ka]

[0063] Route (A) According to route (A), R 2 or R 3A compound of formula (1) where X is a halogen atom such as iodine, or an alkyl ester group, can be placed in an aprotic polar solvent such as acetone. 1 , X 2 and X 3 A 2-bromoacetophenone compound (2), in which X is a carbon atom, can be added to the compound of formula (1) in a molar ratio ranging from, for example, 0.8 to 1.2. The reaction mixture can be heated at a temperature ranging from 40° C. to 70° C., for example at 60° C., and stirred for a period ranging from, for example, 4 to 18 hours, for example 12 hours. The precipitate formed can then be filtered, washed with an aprotic polar solvent such as acetone, and dried under vacuum to obtain the product X. 1 , X 2 , X 3 is a carbon atom, and R 2 or R 3 is a halogen atom or an alkyl ester group.

[0064] According to route (A), R 2 or R 3 A compound of formula (1) where X is a halogen atom such as iodine, or an alkyl ester group, can be placed in a protic polar solvent such as ethanol. 1 , X 2 Or X 3 is a nitrogen atom to the compound of formula (1) in a molar ratio of, for example, 0.8 to 1, and NaHCO 3 The reaction mixture can be added in the presence of an inorganic base such as hexane, hexanediamine ... 1 , X 2 Or X 3is a nitrogen atom, and R 2 or R 3 is a halogen atom or an alkyl ester group, the product (I') can be obtained.

[0065] Route (B) According to route (B), R 2 or R 3 The compound of formula (I') in which is a halogen atom such as iodine can be placed in a non-polar solvent such as toluene. Then, a benzamide compound of formula (3) is added to the compound of formula (I) in a molar ratio of, for example, 1 to 1.5, and a benzamide compound of formula (4) is added to the compound of formula (I) in a molar ratio of, for example, 1.5 to 3. 3 PO 4 In the presence of an inorganic base such as dimethyl ether, in the presence of a copper catalyst such as copper(I) iodide in an amount ranging from 10 mol% to 25 mol% relative to the total amount of the compound of formula (I'), in the presence of a ligand such as trans-N,N'-dimethylcyclohexane-1,2-diamine in an amount ranging from 10 mol% to 25 mol% relative to the total amount of the compound of formula (I'). The reaction mixture can then be heated at a temperature ranging from 100°C to 160°C, for example at 120°C, and stirred under an inert gas, for example argon, in a sealed tube for a period ranging from 15 to 72 hours, for example 48 hours. The reaction mixture can be diluted with an organic solvent such as dichloromethane and filtered through a Celite pad. The filtrate can be concentrated under reduced pressure. The resulting residue can be purified by column chromatography on silica gel to obtain the product (Ia). The starting compound of formula (3) can be obtained or prepared by methods known to those skilled in the art.

[0066] Route (C) According to route (C), R 2 or R 3A compound of formula (I') in which is a halogen atom such as a bromine atom can be placed in a test tube sealed with a screw cap. A palladium catalyst such as tris(dibenzylideneacetone)dipalladium in an amount ranging from 1 mol% to 5 mol% relative to the total amount of the compound of formula (I'), a ligand such as rac-BINAP in an amount ranging from 2 mol% to 10 mol% relative to the total amount of the compound of formula (I'), and an inorganic base such as sodium tert-butylate in a molar ratio ranging from, for example, 1 to 2 relative to the compound of formula (I') can then be added to the preceding tube. The tube can be evacuated and backfilled with an inert gas, for example argon. An amine compound of formula (5) can then be added (1.1 mmol) in a molar ratio ranging from, for example, 1 to 1.5 relative to the compound of formula (I'), and a non-polar solvent such as toluene can be added by syringe at room temperature. The tube can be sealed with a Teflon-lined cap and the reaction mixture can be heated at a temperature ranging from 85° C. to 130° C., for example at 112° C., and stirred for a time ranging from 18 to 48 hours, for example 20 hours. After cooling to room temperature, the suspension can be diluted with an organic solvent such as dichloromethane and filtered through a Celite pad. The solvent can be removed under reduced pressure. The resulting residue can be purified by column chromatography on silica gel to provide the product (Ib). The starting compound of formula (5) can be obtained or prepared by methods known to those skilled in the art.

[0067] Route (D) According to route (D), R 2 or R 3 The compound of formula (I'), where is a halogen atom such as an iodine atom, can be placed in a test tube sealed with a screw cap. Then, the urea compound of formula (6), when it is a solid, is added to the compound of formula (I') in a molar ratio of, for example, 1 to 1.5, and the urea compound of formula (6), when it is a solid, is added to the compound of formula (I') in a molar ratio of, for example, 1.5 to 3 .... 3 PO 4In the presence of an inorganic base such as dimethyl ether, ethyl ... Starting compounds of formula (6) are either available or can be prepared by methods known to those skilled in the art.

[0068] Route (E) According to route (E), R 2 or R 3 A compound of formula (I'), where R is an alkyl ester group such as -COOMe, can be placed in a mixture of protic polar solvent such as water / methanol. An inorganic base such as sodium hydroxide can then be added, for example in a molar ratio ranging from 3 to 6 relative to the compound of formula (I'). The reaction mixture can then be heated at a temperature ranging from 60°C to 100°C, for example at 70°C, and stirred for a time ranging from 15 to 24 hours, for example for 20 hours. The reaction mixture can be cooled and concentrated under reduced pressure. The residue can be diluted with water and acidified to pH 6-7 with an acidic solution such as a solution of 1M hydrochloric acid to precipitate the compound of formula (I''). The precipitate can then be filtered, washed with water and dried under vacuum overnight to give R 2 or R 3 is a carboxylic acid group.

[0069] Route (F) According to route (F), R 2 or R 3 A compound of formula (I'') where is a carboxylic acid group can be placed in an aprotic polar solvent such as dimethylformamide. An amine compound of formula (4) can be added in the presence of an organic base such as DIPEA in a molar ratio ranging from 0.7 to 1.5 relative to the compound of formula (I''), for example, in a molar ratio ranging from 2 to 5 relative to the compound of formula (I''), and then a coupling reagent such as HATU (hexafluorophosphate azabenzotriazole tetramethyluronium) can be added in a molar ratio ranging from 1 to 2 relative to the compound of formula (I''), and the reaction mixture can be stirred at room temperature for a period ranging from 1 to 18 hours, for example, 2 hours. Water can be poured into the reaction mixture to precipitate the compound of formula (Id). The precipitate can then be filtered, washed with water, and dried under vacuum overnight. Alternatively, the reaction mixture can be diluted with an organic solvent such as ethyl acetate. The organic phase can be washed with water, decanted, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue can be dried under vacuum overnight or purified by column chromatography on silica gel to give the product (Id). The starting compound of formula (4) is either available or can be prepared by methods known to those skilled in the art.

[0070] The phrases "between" and "in the range of" should be understood to mean that the limits are included, unless otherwise specified.

[0071] Methods for inducing immune cells In some embodiments, the immune cells of the present invention are selected from T lymphocytes, B lymphocytes, dendritic cells, natural killer cells, lymphoid cells, mesenchymal cells, and myeloid cells. In some embodiments, the immune cells are T lymphocytes. In some embodiments, the immune cells are B lymphocytes. In some embodiments, the immune cells are myeloid cells.

[0072] Another aspect of the present invention relates to a method for inducing the production of proteins, in particular interleukin-10, by immune cells, comprising contacting immune cells with at least one compound of formula (I) which induces the production of interleukin-10 as described above.

[0073] In some embodiments, immune cells were cultured for two consecutive days in the presence of at least one compound of formula (I) at a final concentration of 0.25 μM in the presence of anti-IgM and CpG, thereby inducing the production of interleukin-10.

[0074] As used herein, the phrases "immune cells induced by at least a compound of formula (I)" or "induced immune cells" or "immune cells capable of producing interleukin-10" refer to immune cells that are capable of producing interleukin-10 (IL-10) after contacting with at least one compound of formula (I) and incubating them with such compound of formula (I).

[0075] In some embodiments, the present invention also provides an immune cell capable of producing interleukin-10, obtainable by a method as defined above.

[0076] Another object of the present invention relates to immune cells induced by at least one compound of formula (I) as defined above for use as a medicament.In particular, the present invention relates to immune cells induced by at least one compound of formula (I) as defined above for use in the prevention and / or treatment of neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0077] In some embodiments, the immune cells induced by at least one compound of formula (I) as defined above are particularly useful for preventing and / or treating neurodegenerative diseases. The term "neurodegenerative disease" as used herein refers to a condition or disorder in which neuronal cells are lost through cell death, resulting in cognitive deterioration or damage, impairment, or complications that may be characterized by neurological, neurodegenerative, physiological, mental, or behavioral abnormalities. Neurodegenerative diseases include, but are not limited to, multiple sclerosis, autism spectrum disorder, depression, age-related macular degeneration, Creutzfeldt-Jakob disease, Alzheimer's disease, radiation therapy-induced dementia, axonal injury, acute cortical spreading depression, alpha-synucleinopathy, cerebral ischemia, Huntington's disease, Guillain-Barre syndrome, permanent focal cerebral ischemia, peripheral nerve regeneration, post-status epilepticus model, spinal cord injury, sporadic amyotrophic lateral sclerosis, transmissible spongiform encephalopathy, myasthenia gravis, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, chronic idiopathic demyelinating disease (CID), anxiety, obsessive-compulsive disorder (such as obsessive-compulsive disorder), meningitis, neurosis, psychosis, insomnia and sleep disorders, sleep apnea, and substance abuse.

[0078] In some embodiments, the immune cells induced by at least one compound of formula (I) as defined above are particularly useful for preventing and / or treating inflammatory diseases. Inflammatory diseases include inflammatory diseases of the digestive tract, in particular the intestinal tract (in particular the colon in the case of irritable bowel syndrome, ulcerative hemorrhagic colorectal or Crohn's disease); pancreatitis, hepatitis (acute and chronic), inflammatory bladder pathology and gastritis; inflammatory diseases of the locomotor system, including rheumatoid arthritis, osteoarthritis, osteoporosis, traumatic arthritis, post-infectious arthritis, muscle degeneration and dermatomyositis; inflammatory diseases of the genitourinary tract, in particular glomerulonephritis; inflammatory diseases of the cardiac organ, in particular pericarditis and myocarditis, as well as diseases in which inflammation is an underlying factor (atherosclerosis, transplant atheroma, etc.). sclerosis, peripheral vascular disease, inflammatory vascular disease, intermittent claudication or claudication, restenosis, stroke, transient ischemic attack, myocardial ischemia and myocardial infarction, etc.), hypertension, hyperlipidemia, coronary artery disease, unstable angina (or angina pectoris), thrombosis, the consequences of thrombin-induced platelet aggregation and / or thrombosis and / or the formation of atherosclerotic plaques; in particular inflammatory diseases of the respiratory and ORL organs, including asthma, acute respiratory distress syndrome, hay fever, allergic rhinitis and chronic obstructive pulmonary disease; inflammatory diseases of the skin, in particular urticaria, scleroderma, contact dermatitis, atopic dermatitis, Dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; treatment of pain whatever its origin, for example postoperative pain, neuromuscular pain, headache, cancer-related pain, dental pain or osteoarticular pain; diseases involving pigmentation disorders, in particular benign skin diseases, for example vitiligo, albinism, melasma, lentigines, freckles, melanocytic nevi and all post-inflammatory pigmentations; also modulation of pigmentation for treating pigmented tumors, for example melanoma and their local (translucent nodules), regional or systemic metastases; harmful effects of sunlight, for example actinic erythema, skin aging, skin Photoprotection for the purpose of preventing cancer (squamous cell, basal cell and melanoma), especially diseases which promote their development (xeroderma pigmentosum, basal cell nevus syndrome and familial melanoma); photodermatoses caused by exogenous photosensitizers, especially those caused by contact photosensitizers (e.g. furocoumarins, halogenated salicylanilides and derivatives, and topical sulfamides and derivatives) or caused by systemic photosensitizers (e.g. psoralens, tetracyclines, sulfamides, phenothiazines, nalidixic acid and tricyclic antidepressants);Skin diseases with photosensitivity, especially photoaggravated skin diseases (e.g. lupus erythematosus, recurrent herpes, congenital poikiloderma or telangiectatic conditions with photosensitivity (Bloom's syndrome, Cockayne's syndrome or Rothmund-Thomson syndrome), actinic lichen planus, actinic granuloma, superficial disseminated actinic porokeratosis, acne rosacea, juvenile acne, bullous skin diseases, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, chronic actinic dermatitis (CAD), follicular mucinosis, erythema multiforme, fixed drug eruption, cutaneous lymphocytoma, reticular erythematous mucinosis, and attacks or exacerbations of melasma; Skin diseases with photosensitivity due to a defence system defect with abnormalities in melanin formation or distribution (e.g., oculocutaneous albinism, phenylketonuria, hypopituitarism, vitiligo and mottling) and with a defect in the DNA repair system (e.g., xeroderma pigmentosum and Cockayne's syndrome), skin diseases with photosensitivity due to metabolic abnormalities, such as cutaneous porphyrias (e.g., porphyria cutanea tarda, mixed porphyria, erythropoietic protoporphyria, congenital erythropoietic porphyria (Günther's disease), and erythropoietic coproporphyria), pellagra or pellagra-like erythema (e.g., pellagra, pellagra-like erythema and disorders of tryptophan metabolism); idiopathic actinic dermatoses, especially PMLE (polymorphous light eruption), benign summer light eruption, actinic prurigo, persistent photosensitivity (actinic reticulosis, chronic actinic dermatosis and photosensitive eczema), solar urticaria, variola vacciniformis, juvenile vernal eruption and solar pruritus attacks or exacerbations; especially by increasing melanin synthesis, resulting in tanning of the skin, or by interfering with melanin synthesis, resulting in skin discoloration, and by causing white or grey hair and body hair (e.g., for the regulation of skin or hair and hair colour by preventing the formation of inflammatory cells (e.g. canities and mottling); also for modifying hair and hair colour in cosmetic applications; for the regulation of sebaceous gland function, in particular for the treatment of conditions involving hyperseborrhea, in particular acne, seborrheic dermatitis, greasy skin and hair, hyperseborrhea in Parkinson's disease and epilepsy, and hyperandrogenism; for conditions involving reduced sebaceous gland secretion, in particular xerosis and all dry skin; for benign or malignant sebaceous cell and sebaceous gland proliferation; for inflammatory conditions of the pilosebaceous follicles, in particular acne, furuncles, carbuncles and folliculitis; for male or female sexual dysfunction;Male sexual dysfunction, including, but not limited to, impotence, loss of libido, and erectile dysfunction; female sexual dysfunction, including, but not limited to, sexual arousal disorders or disorders related to desire, sexual receptivity, orgasm, and disorders of the cardinal points of sexual function; pain, premature labor, dysmenorrhea, excessive menstruation, and endometriosis; weight-related disorders, including, but not limited to, obesity and anorexia (such as alterations or disorders of appetite, splenic metabolism, or harmless intake of fats or carbohydrates); diabetes (due to decreased glucose tolerance and / or insulin resistance); cancer, particularly lung cancer, prostate cancer, intestinal cancer, breast cancer, ovarian cancer, bone cancer, or angiogenesis disorders, including the formation or growth of solid tumors;

[0079] In some embodiments, the immune cells induced by at least one compound of formula (I) as defined above are particularly useful for preventing and / or treating immune-mediated diseases. Immune-mediated diseases include, but are not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, vasculitis, vitiligo, and alopecia). Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, transplant rejection (allograft rejection), graft-versus-host disease (GVDH).

[0080] In some embodiments, immune cells induced by at least one compound of formula (I) as defined above are particularly useful for preventing and / or treating allergic diseases. As used herein, the term "allergy" or "allergies" or "allergic reaction" or "allergic response" refers to a disorder (or inappropriate reaction) of the immune system. Allergic reactions occur to normally harmless environmental substances known as allergens; these reactions are acquired, predictable, and rapid. Technically, allergies are one of four forms of hypersensitivity, and are called type I (or immediate) hypersensitivity. It is characterized by the excessive activation of certain white blood cells called mast cells and basophils by a type of antibody known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees. Mild allergies, such as hay fever, are widespread in the human population, causing symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies may play a major role in conditions such as asthma. In some people, some allergies to environmental or dietary allergens, or to drugs, can lead to life-threatening anaphylactic reactions and potentially death. Thus, treatment of allergies by immunosuppression is one embodiment of the present invention.

[0081] In some embodiments, the immune cells induced by at least one compound of formula (I) as defined above are particularly useful for preventing and / or treating transplant-related adverse events. Transplant-related adverse events relate to any medical condition surrounding the rejection of transplanted material or immune response caused by the transplantation of tissue into a recipient subject. Advantageously, transplant-related adverse events may target the kidney, liver, heart, lung, pancreas, bone marrow, cornea, intestine or skin (such as skin allograft, allograft or xenograft).

[0082] In some embodiments, the immune cells induced by at least one compound of formula (I) as defined above are particularly useful for preventing and / or treating autoimmune diseases. Examples of autoimmune diseases include, but are not limited to, arthritis (rheumatoid arthritis, juvenile onset rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and ankylosing spondylitis), psoriasis, dermatitis including atopic dermatitis, chronic idiopathic urticaria including chronic autoimmune urticaria, polymyositis / dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as progressive systemic sclerosis, inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, autoimmune inflammatory bowel disease), pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleral ulcers, and psoriasis. inflammation), respiratory distress syndromes including adult respiratory distress syndrome (ARDS), meningitis, IgE mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis, uveitis or autoimmune uveitis, colitis such as microscopic colitis and collagenous colitis, glomerulonephritis (GN), such as membranous GN (membranous nephropathy), idiopathic membranous GN, membranous proliferative GN (MPGN) including types I and II, and rapidly progressive GN, allergic conditions, allergic reactions, eczema, asthma , conditions involving T cell infiltration and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), e.g., cutaneous SLE, subacute cutaneous lupus erythematosus, lupus (including nephritis, encephalitis, pediatric, non-nephritis, discoid, alopecia), juvenile-onset (type I) diabetes, including insulin-dependent diabetes mellitus (IDDM) of childhood, adult-onset diabetes mellitus (type II diabetes), multiple sclerosis (MS), e.g., spino-optical MS, acute myocardial infarction mediated by cytokines and T-lymphocytes, and immune responses associated with delayed hypersensitivity, tuberculosis, sarcoidosis, granulomatous diseases including lymphomatoid granulomatosis, Wegener's granulomatosis, granulocytopenia, vasculitis (including large-vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu) arteritis), medium-vessel vasculitis (including Kawasaki disease and polyarteritis nodosa), CNS vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis such as Churg-Strauss vasculitis or syndrome (CSS)), temporal arteritis, aplastic anemia, Coombs positive anemia, Diamond-Blackfan anemia,Hemolytic anemia or immune hemolytic anemia, including autoimmune hemolytic anemia (AIHA), pernicious anemia, pure red cell aplasia (PRCA), factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases with leukocyte extravasation, CNS inflammatory disorders, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, antiphospholipid syndrome, allergic neuritis, Behcet's disease (Bechet's or Behcet's syndrome) disease), Castleman syndrome, Good-Basture's syndrome, Raynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid, e.g. bullous pemphigoid, pemphigus (including vulgaris, foliaceus, and pemphigus mucosal pemphigoid), autoimmune polyendocrinopathy, Reiter's disease, immune complex nephritis, chronic neuropathy, e.g. IgM polyneuropathy or IgM mediated neuropathy, thrombocytopenia (such as occurs in myocardial infarction patients), including thrombotic thrombocytopenic purpura (TTP) and autoimmune or immune mediated thrombocytopenia, e.g. idiopathic thrombocytopenic purpura (ITP), including chronic or acute ITP, autoimmune diseases of the testes and ovaries, including autoimmune orchitis and oophoritis, autoimmune endocrine disorders, including primary hypothyroidism, hypoparathyroidism, thyroiditis, e.g. autoimmune thyroiditis, chronic ... thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Addison's disease, Graves' disease, polyendocrine syndromes, e.g. autoimmune polyendocrine syndrome (or polyendocrinopathy syndrome), paraneoplastic syndromes including neurological paraneoplastic neurological syndromes, e.g. Lambert-Eaton myasthenic syndrome or Lambert-Eaton syndrome, stiff-man or stiff-person syndrome, encephalomyelitis, e.g. allergic encephalomyelitis, myasthenia gravis, cerebellar degeneration, limbic and / or brainstem encephalitis, neurogenic myotonia, opsoclonus or opsoclonus-myoclonus syndrome (OMS), and sensory neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphocytic interstitial pneumonia, bronchiolitis obliterans (non-transplant) vs. NSIP, Guillain-Barré syndrome, Berger's disease (IgA nephropathy), primary biliary cirrhosis, steatorrhea (gluten enteropathy), refractory sprue, dermatitis herpetiformis, cryoglobulinemia,Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune inner ear disease (AIED) or autoimmune hearing loss, opsoclonus-myoclonus syndrome (OMS), polychondritis, e.g., refractory polychondritis, pulmonary alveolar proteinosis, amyloidosis, giant cell hepatitis, scleritis, non-cancerous lymphocytosis, primary lymphocytosis including monoclonal B-cell lymphocytosis (e.g., monoclonal globulinemia and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndromes, channelopathies, e.g., epilepsy, migraine, cardiac arrhythmias, myopathy, hearing loss, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathies, focal segmental glomerulosclerosis (FSGS), endocrine ophthalmopathy, grapefruit Membrane retinitis, autoimmune liver disorders, fibromyalgia, polyendocrine deficiency, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases, Dressler's syndrome, alopecia areata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, digital sclerosis, and telangiectasia), male and female autoimmune infertility, ankylosing spondylitis, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, postpericardiotomy syndrome, Cushing's syndrome, bird breeder's disease, Alport's syndrome, alveolitis, e.g. allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reactions, leprosy, malaria, leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter's syndrome syndrome), Kaplan's syndrome, dengue fever, endocarditis, endomyocardial fibrosis, endophthalmitis, erythema elevatum, erythroblastosis fetalis, eosinophilic fasciitis, Schulman's syndrome, Felty's syndrome, filariasis, cyclitis, e.g., chronic cyclitis, heterochronic cyclitis, or Fuchs' cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndrome, congenital rubella infection, Epstein-Barr virus infection, mumps, Evans' syndrome, autoimmune gonadal dysfunction, Sydenham's chorea, post-streptococcal nephritis, thromboangiitis obliterans, hyperthyroidism, spinal fistula, and giant cell polymyalgia.Treatment of autoimmune disorders through immunosuppression is one embodiment of the present invention.

[0083] In some embodiments, the dose of immune cells is provided as a composition or formulation, e.g., a pharmaceutical composition or formulation, which can be used in the methods provided and / or in conjunction with the articles of manufacture or compositions provided, such as in the treatment of diseases, conditions, and disorders.

[0084] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredients contained therein to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation will be administered.

[0085] "Pharmaceutically acceptable carrier" refers to an ingredient, other than an active ingredient, in a pharmaceutical formulation that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0086] In some embodiments, the subject may be a human, male or female, regardless of age. In some embodiments, the patient may be a non-human animal, advantageously a non-human mammal, such as a dog, cat, mouse, rat, hamster, rabbit, chinchilla, horse, cow, pig, sheep, goat, or primate.

[0087] In some embodiments, the pharmaceutical composition comprises a dose of immune cells induced by at least one compound of formula (I) as defined above and at least one pharma- ceutically acceptable carrier.

[0088] In some embodiments, the pharmaceutical composition comprises a dose of immune cells induced by a compound of formula (I) and at least one pharma- ceutically acceptable carrier, wherein the compound of formula (I) is selected from the group consisting of the following compounds:

[0089] [ka]

[0090] It is one of them.

[0091] Carrier In some embodiments, the immune cells are formulated with a pharma- ceutically acceptable carrier. In some aspects, the choice of carrier is determined in part by the particular cells or agents and / or by the method of administration. Thus, there are a variety of suitable formulations. For example, the pharmaceutical composition may contain a preservative. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. In some aspects, a mixture of two or more preservatives is used. The preservative or mixtures thereof are typically present in an amount of about 0.0001% to about 2% by weight of the total composition. Carriers are described, for example, by Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to, buffers, such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) amines, such as ethyl esters, butyl ... proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants, such as polyethylene glycol (PEG).

[0092] In some embodiments, a buffering agent is included in the composition.Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts.In some embodiments, a mixture of two or more buffering agents is used.The buffering agent or its mixture is typically present in an amount of about 0.001% to about 4% by weight of the total composition.

[0093] The formulation may comprise an aqueous solution. The formulation or composition may contain more than one active ingredient useful for a particular indication, disease or condition treated with induced immune cells, where the respective activities do not adversely affect each other. Such second active ingredients are suitably present in an amount that, in combination, is effective for the intended purpose. In an advantageous embodiment, the pharmaceutical composition according to the invention also comprises at least one other active ingredient. In a particularly advantageous embodiment of the invention, at least one other active ingredient may synergistically interact with the immune cells induced by at least one compound of formula (I) according to the invention.

[0094] Examples of other active ingredients include, but are not limited to, estrogen receptor modulators; androgen receptor modulators; glucocorticoids, retinoid receptor modulators; cytotoxic drugs; antiproliferative drugs including adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, or platinum derivatives; corticosteroids, TNF blockers, IL-1 Anti-inflammatory drugs including RA, azathioprine, cyclophosphamide, JAK inhibitors (e.g. tofacitinib and baricitinib), SYK inhibitors, BTK inhibitors, or sulfasalazine; prenyl-protein transferase inhibitors; HMG-CoA reductase inhibitors; HIV protease inhibitors; reverse transcriptase inhibitors; angiogenesis inhibitors including sorafenib, sunitinib, pazopanib, or everolimus; immunomodulatory or immunosuppressive drugs including cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, or sulfasalazine; PPAR-gamma agonists including thiazolidinediones; PPAR-delta agonists; inhibitors of multidrug resistance;agents for treating anemia, including erythropoiesis stimulating factors, vitamins, or iron supplements;antiemetics, including 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, H1 histamine receptor antagonists, cannabinoids, benzodiazepines, anticholinergics, or steroids;agents for treating neutropenia;immunostimulants;proteasome inhibitors;HDAC inhibitors;inhibitors of chemotrypsin-like activity in the proteasome;E3 ligase inhibitors;interferon-alpha, which may induce release of cytokines, interleukins, TNF, or death receptor ligands, including TRAIL, Bacillus Calmette-Guerin Modulators of the immune system, including anti-inflammatory drugs such as anti-inflammatory drugs (Anti-inflammatory drugs), ...Antiparkinsonian drugs including anticholinergics, or dopaminergics including dopamine aminergic precursors, monoamine oxidase B inhibitors, COMT inhibitors, dopamine receptor agonists; drugs for treating cardiovascular disease including beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, or statins; drugs for treating liver disease including corticosteroids, cholestyramine, or interferons; antiviral drugs including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, chemokine receptor antagonists, polymerase inhibitors, viral protein synthesis inhibitors, viral protein modification inhibitors, neuraminidase inhibitors, fusion or entry inhibitors; Agents for treating blood disorders, including thyrosteroids, anti-leukemias, or growth factors; agents for treating immune deficiency disorders, including gamma globulins, adalimumab, etanercept, tocilizumab, or infliximab; HMG-CoA reductase inhibitors, including torvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, or pitavastatin, or in combination or sequence with radiation, or at least one chemotherapeutic agent, such as asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine;

[0095] In some embodiments, when the pharmaceutical composition comprises another active ingredient, the pharmaceutical composition is adapted for simultaneous or sequential administration of the immune cells induced by at least one compound of formula (I) as defined above and the other active ingredient.

[0096] Within the meaning of the present invention, "co-administration" means the administration of immune cells induced by at least one compound of formula (I) as defined above and other active ingredients at the same time, contemporaneously to a patient in therapeutically effective amounts to allow the synergistic effect of the pharmaceutical composition. This does not necessarily mean that immune cells induced by at least one compound of formula (I) as defined above and other active ingredients must be administered in the form of a mixture; they can in fact be administered simultaneously, but separately, in the form of separate compositions.

[0097] "Existing in two separate compositions" means that the immune cells induced by at least one compound of formula (I) as defined above and other active ingredients are physically separate, and then they are packaged and administered separately in multiple (at least two) dosage forms (e.g., two separate compositions) without prior mixing, in a therapeutically effective amount that allows the synergistic effect of the pharmaceutical composition.

[0098] In some embodiments, the immune cells induced by at least one compound of formula (I) as defined above and other active ingredients may be present in one and the same composition in a therapeutically effective amount that allows the synergistic effect of the pharmaceutical composition. Within the meaning of the present invention, "present in one and the same composition" means the physical combination of the immune cells induced by at least one compound of formula (I) as defined above and other active ingredients. Thus, the immune cells induced by at least one compound of formula (I) as defined above and other active ingredients should be administered simultaneously, since they are administered together in the form of a mixture, in one and the same dosage form, in a therapeutically effective amount that allows the synergistic effect of the pharmaceutical composition.

[0099] Within the meaning of the present invention, the expression "sequential administration" means that the immune cells induced by at least one compound of formula (I) as defined above and the other active ingredient are not administered simultaneously, but separately from each other over time, in a therapeutically effective amount that allows a synergistic effect of the pharmaceutical composition. The terms "preceding" or "preceding" and "following" or "subsequently" therefore apply. The term "preceding" or "preceding" is used when the components of the pharmaceutical composition according to the invention are administered minutes or hours, or even days before the administration of the other components of the pharmaceutical composition. Conversely, the term "following" or "subsequently" is used when the components of the pharmaceutical composition according to the invention are administered minutes or hours, or even days after the administration of the other components of the pharmaceutical composition. In one particularly advantageous embodiment of the present invention, the immune cells induced by at least one compound of formula (I) as defined above are administered several days before the other active ingredient.

[0100] In some embodiments, when the pharmaceutical composition comprises another active ingredient, the pharmaceutical composition is adapted for sequential administration of immune cells induced by at least one compound of formula (I) as defined above and the other active ingredient.

[0101] In some embodiments, the pharmaceutical composition comprises the induced immune cells in an amount effective for treating a disease or condition, e.g., a therapeutically effective or prophylactically effective amount. Within the meaning of the present invention, the term "therapeutically effective" or "treatment effective amount" or "pharmaceutical effective" refers to the amount of immune cells induced by at least one compound of formula (I) as defined above necessary to inhibit or reverse a disease, advantageously to treat a disease selected from neurodegenerative diseases, inflammatory diseases, immune-mediated diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and aging. The determination of a therapeutically effective amount depends specifically on factors such as toxicity and efficacy of the pharmaceutical. These factors will vary depending on other factors such as activity, relative bioavailability, patient weight, severity of adverse effects, and preferred route of administration. Toxicity can be determined by using methods well known in the art. The same applies to efficacy. As a result, a pharmaceutical effective amount is an amount that is toxicologically acceptable and deemed effective by the clinician. In some embodiments, therapeutic effectiveness is monitored by periodic evaluation of the subject being treated. For repeated administration over several days or longer, depending on the condition, treatment is repeated until the desired suppression of disease symptoms occurs. However, other administration regimes may be useful and can be determined. The desired dosage can be delivered by a single bolus administration of the composition, by multiple boluses of the composition, or by continuous infusion administration of the composition.

[0102] The induced immune cells of the present invention can be administered using standard administration techniques, formulations, and / or devices. Formulations and devices, such as syringes and vials, are provided for storing and administering the compositions. With respect to cells, administration can be autologous or xenogeneic. For example, immunoresponsive cells or progenitor cells can be obtained from one subject and administered to the same subject or a comparable different subject. Peripheral blood-derived immunoresponsive cells or their progeny (e.g., derived in vivo, ex vivo, or in vitro) can be administered by local injection, including catheter administration, systemic injection, local injection, intravenous injection, or parenteral administration. When a therapeutic composition (e.g., a pharmaceutical composition comprising the induced immune cells of the present invention) is administered, it is generally formulated in a unit dosage injectable form (solution, suspension, emulsion).

[0103] Formulations include those for oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intradermal, intratumoral, intralesional, intramuscular, intranasal, buccal, sublingual, topical, local, auricular, inhalation, retinal, intraocular, periocular, subretinal, intravitreal, or suppository administration, septal, subscleral, intrachoroidal, intracameral, subconjectval, subconjuntival, subtenon, retrobulbar, peribulbar, or posterior juxtascleral administration. The term "parenteral" as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. In some embodiments, the agent or cell population is administered to a subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection.

[0104] The composition in some embodiments is provided as a sterile liquid preparation, such as an isotonic aqueous solution, suspension, emulsion, dispersion, or viscous composition, which in some aspects may be buffered to a selected pH. Liquid preparations are usually easier to prepare than gels, other viscous compositions, and solid compositions. In addition, liquid compositions are more or less convenient to administer, especially by injection. On the other hand, viscous compositions can be formulated within a suitable viscosity range to provide a longer contact period with specific tissue. The liquid or viscous composition may contain a carrier, which may be a solvent or dispersion medium, such as water, saline, phosphate buffered saline, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol), and suitable mixtures thereof.

[0105] Sterile injectable solutions can be prepared by incorporating the cells into a vehicle, such as by mixing with a suitable carrier, diluent, or excipient, such as sterile water, saline, glucose, dextrose, or the like.

[0106] Formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, for example, by filtration through sterile filtration membranes.

[0107] dosage In some embodiments, a dose of the induced immune cells of the present invention is administered to a subject in accordance with the provided methods and / or the provided products or compositions. In some embodiments, the size or timing of the dose is determined according to the specific disease or condition in the subject. In some cases, the size or timing of the dose for a specific disease can be empirically determined in view of the provided explanation.

[0108] In some embodiments, the dose of the induced immune cells of the present invention is 2×10 cells. 5 (or its approximation) / kg to 9 × 10 cells 14 (or an approximation thereof) / kg, advantageously between 2×10 cells 5 (or its approximation) / kg to 9 × 10 cells 13(or an approximation thereof) / kg, advantageously between 2×10 cells 5 (or its approximation) / kg to 9 × 10 cells 12 (or an approximation thereof) / kg, advantageously between 2×10 cells 5 (or its approximation) / kg to 9 × 10 cells 11 (or an approximation thereof) / kg, advantageously between 2×10 cells 5 (or its approximation) / kg to 9 × 10 cells 10 (or an approximation thereof) / kg, advantageously between 2×10 cells 5 (or its approximation) / kg to 9 × 10 cells 9 (or its approximation) / kg, advantageously between 2×10 5 cells (or approximate number) / kg to 9 x 10 cells 8 (or its approximation) / kg.

[0109] In some embodiments, the dose of induced immune cells of the invention is at least, at least about, or at or about 2×10 cells (e.g., IL10-expressing cells) per kilogram of body weight of the subject. 5 (cells / kg), e.g., at least that many, at least about that many, or at or about 3×10 cells. 5 / kg, at least that many, at least that many, or at or near that many, or 4 x 10 cells 5 / kg, at least that many, at least that many, or at or near that many, or 5 x 10 cells 5 / kg, at least that many, at least that many, or at or near that many, or 6 x 10 cells 5 / kg, at least that many, at least that many, or at or near that many, or 7 x 10 cells 5 / kg, at least that many, at least that many, or at or near that many, or 8 x 10 cells 5 / kg, at least that many, at least that many, or at or near that many, or 9 x 10 cells 5 / kg, at least that many, at least that many, or at or near that many, or 1 x 10 cells 62 x 10 cells / kg, or at least that many, or at least that many, or at or near that many 6 / kg, at least that many, at least that many, or at or near that many, or 3 x 10 cells 6 / kg, at least that many, at least that many, or at or near that many, or 4 x 10 cells 6 / kg, at least that many, at least that many, or at or near that many, or 5 x 10 cells 6 / kg, at least that many, at least that many, or at or near that many, or 6 x 10 cells 6 / kg, at least that many, at least that many, or at or near that many, or 7 x 10 cells 6 / kg, at least that many, at least that many, or at or near that many, or 8 x 10 cells 6 / kg, at least that many, at least that many, or at or near that many, or 9 x 10 cells 6 / kg, at least that many, at least that many, or at or near that many, or 1 x 10 cells 7 2 x 10 cells / kg, or at least that many, or at least that many, or at or near that many 7 / kg, at least that many, at least that many, or at or near that many, or 3 x 10 cells 7 / kg, at least that many, at least that many, or at or near that many, or 4 x 10 cells 7 / kg, at least that many, at least that many, or at or near that many, or 5 x 10 cells 7 / kg, at least that many, at least that many, or at or near that many, or 6 x 10 cells 7 / kg, at least that many, at least that many, or at or near that many, or 7 x 10 cells 7 / kg, at least that many, at least that many, or at or near that many, or 8 x 10 cells 7 / kg, at least that many, at least that many, or at or near that many, or 9 x 10 cells 7 / kg, at least that many, at least that many, or at or near that many, or 1 x 10 cells8 2 x 10 cells / kg, or at least that many, or at least that many, or at or near that many 8 / kg, at least that many, at least that many, or at or near that many, or 3 x 10 cells 8 / kg, at least that many, at least that many, or at or near that many, or 4 x 10 cells 8 / kg, at least that many, at least that many, or at or near that many, or 5 x 10 cells 8 / kg, at least that many, at least that many, or at or near that many, or 6 x 10 cells 8 / kg, at least that many, at least that many, or at or near that many, or 7 x 10 cells 8 / kg, at least that many, at least that many, or at or near that many, or 8 x 10 cells 8 / kg, at least that many, at least that many, or at or near that many, or 9 x 10 cells 8 / kg, at least that many, at least that many, or at or near that many, or 1 x 10 cells 9 2 x 10 cells / kg, or at least that many, or at least that many, or at or near that many 9 / kg, at least that many, at least that many, or at or near that many, or 3 x 10 cells 9 / kg, at least that many, at least that many, or at or near that many, or 4 x 10 cells 9 / kg, at least that many, at least that many, or at or near that many, or 5 x 10 cells 9 / kg, at least that many, at least that many, or at or near that many, or 6 x 10 cells 9 / kg, at least that many, at least that many, or at or near that many, or 7 x 10 cells 9 / kg, at least that many, at least that many, or at or near that many, or 8 x 10 cells 9 / kg, at least that many, at least that many, or at or near that many, or 9 x 10 cells 9 / kg, at least that many, at least that many, or at or near that many, or 1 x 10 cells 10 2 x 10 cells / kg, or at least that many, or at least that many, or at or near that many 10 / kg, at least that many, at least that many, or at or near that many, or 3 x 10 cells 10 / kg, at least that many, at least that many, or at or near that many, or 4 x 10 cells 10 / kg, at least that many, at least that many, or at or near that many, or 5 x 10 cells 10 / kg, at least that many, at least that many, or at or near that many, or 6 x 10 cells 10 / kg, at least that many, at least that many, or at or near that many, or 7 x 10 cells 10 / kg, at least that many, at least that many, or at or near that many, or 8 x 10 cells 10 / kg, at least that many, at least that many, or at or near that many, or 9 x 10 cells 10 / kg, at least that many, at least that many, or at or near that many, or 1 x 10 cells 11 2 x 10 cells / kg, or at least that many, or at least that many, or at or near that many 11 / kg, dosages may vary depending on the disease or disorder and / or patient and / or other treatment specific attributes. In some embodiments, the dose of cells is a flat dose of cells or a fixed dose of cells, such that the dose of cells is not tied to or based on the subject's body surface area or weight.

[0110] In some embodiments, the dose of induced immune cells of the present invention is administered to a subject as a single dose, or only once within a period of two weeks, one month, three months, six months, one year or longer.

[0111] In the context of adoptive cell therapy, administration of a given "dose" includes administration of a given amount or number of cells as a single composition and / or a single continuous administration, e.g., as a single injection or continuous infusion, and also includes administration of a given amount or number of cells as split doses provided in multiple separate compositions or infusions over a specified period of time, e.g., up to 3 days, or as multiple compositions. Thus, in some situations, a dose is a single or continuous administration of a specified number of cells given or initiated at a single time point. However, in some situations, a dose is administered in multiple injections or infusions over a period of up to 3 days, e.g., once a day for 3 or 2 days, or by multiple infusions over a period of 1 day.

[0112] Thus, in some aspects, the dose of cells is administered in a single pharmaceutical composition, hi some embodiments, the dose of induced immune cells is administered in multiple compositions that together contain the dose of cells.

[0113] In some embodiments, the term "split dose" refers to a dose that is divided to be administered over more than one day. This type of dosing is encompassed by the present methods and is considered to be a single dose.

[0114] Thus, the dose of induced immune cells can be administered as split doses, e.g., split doses administered over time. For example, in some embodiments, the dose can be administered to the subject over two days or over three days. An exemplary method for split administration includes administering 25% of the dose on day 1 and administering the remaining 75% of the dose on day 2. In other embodiments, 33% of the dose can be administered on day 1 and the remaining 67% on day 2. In some embodiments, 10% of the dose is administered on day 1, 30% of the dose is administered on day 2, and 60% of the dose is administered on day 3. In some embodiments, the split dose is not divided over more than three days.

[0115] In some embodiments, administration of a composition or dose, e.g., administration of multiple cellular compositions, involves administration of the cellular compositions separately. In some aspects, the separate administrations are performed simultaneously, sequentially, and in any order. In some embodiments, the dose comprises a first composition and a second composition, and the first composition and the second composition are administered within 48 hours of each other, e.g., within 36 hours of each other, or within 24 hours of each other. In some embodiments, the first composition and the second composition are administered 0-12 hours apart, 0-6 hours apart, or 0-2 hours apart. In some embodiments, the start of administration of the first composition and the start of administration of the second composition are within 2 hours, 1 hour, or 30 minutes apart, within 15 minutes, 10 minutes, or 5 minutes apart. In some embodiments, the initiation and / or completion of administration of the first composition and the initiation and / or completion of administration of the second composition are performed within 2 hours, 1 hour, or 30 minutes apart, within 15 minutes, 10 minutes, or 5 minutes apart.

[0116] In some embodiments, the first composition and the second composition are mixed before administration to a subject.In some embodiments, the first composition and the second composition are mixed shortly before administration (e.g., within 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1.5 hours, 1 hour, or 0.5 hours), and in some embodiments, the first composition and the second composition are mixed immediately before administration.

[0117] In some embodiments, the subject is administered multiple doses of induced immune cells, e.g., two or more doses or multiple sequential doses. In some embodiments, two doses are administered to the subject. In some embodiments, the subject is administered sequential doses, e.g., the second dose, approximately 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after the first dose. In some embodiments, multiple sequential doses are administered after the first dose, and an additional dose or doses are administered after administration of the sequential dose. In some aspects, the number of cells administered to the subject in the additional dose is the same or similar to the first dose and / or the sequential dose. In some embodiments, the additional dose or doses are higher than the preceding dose.

[0118] Preventive measures Another aspect of the invention relates to a pharmaceutical composition comprising immune cells induced by at least one compound of formula (I) for its use in the prevention of immune-mediated diseases, advantageously selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0119] As used herein, the terms "prevention" or "prophylaxis" or "preventative treatment" or "prophylactic treatment" include treatments that result in the prevention of a disease as well as treatments that reduce and / or delay the risk of development of a disease or the appearance of a disease.

[0120] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) for its use in the prevention of immune-mediated diseases. Advantageously, the immune-mediated diseases are selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0121] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of at least immune cells induced by a compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of immune-mediated diseases. Advantageously, the immune-mediated diseases are selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0122] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) induced immune cells as an active ingredient and at least one pharma- ceutically acceptable carrier as defined above for its use in the prevention of neurodegenerative diseases. The term "neurodegenerative disease" as used herein refers to a condition or disorder in which neuronal cells are lost through cell death, resulting in deterioration of cognitive function or resulting in damage, impairment, or complications that may be characterized by neurological, neurodegenerative, physiological, psychiatric, or behavioral abnormalities. Neurodegenerative diseases include, but are not limited to, multiple sclerosis, autism spectrum disorder, depression, age-related macular degeneration, Creutzfeldt-Jakob disease, Alzheimer's disease, radiation therapy-induced dementia, axonal injury, acute cortical spreading depression, alpha-synucleinopathy, cerebral ischemia, Huntington's disease, Guillain-Barre syndrome, permanent focal cerebral ischemia, peripheral nerve regeneration, post-status epilepticus model, spinal cord injury, sporadic amyotrophic lateral sclerosis, transmissible spongiform encephalopathy, myasthenia gravis, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, chronic idiopathic demyelinating disease (CID), anxiety, obsessive-compulsive disorder (such as obsessive-compulsive disorder), meningitis, neurosis, psychosis, insomnia and sleep disorders, sleep apnea, and substance abuse.

[0123] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cells and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of inflammatory diseases.

[0124] Advantageously, the inflammatory disease is selected from: inflammatory diseases of the digestive tract, in particular the intestinal tract (in particular the colon in the case of irritable bowel syndrome, ulcerative hemorrhagic colorectal or Crohn's disease); pancreatitis, hepatitis (acute and chronic), inflammatory bladder pathology and gastritis; inflammatory diseases of the musculoskeletal system, including rheumatoid arthritis, osteoarthritis, osteoporosis, traumatic arthritis, post-infectious arthritis, myodegeneration and dermatomyositis; inflammatory diseases of the genitourinary tract, in particular glomerulonephritis; inflammatory diseases of the cardiac organs, in particular pericarditis and myocarditis, as well as diseases in which inflammation is an underlying factor ( atherosclerosis, transplant atherosclerosis, peripheral vascular disease, inflammatory vascular disease, intermittent claudication or claudication, restenosis, stroke, transient ischemic attack, myocardial ischemia and myocardial infarction, etc.), hypertension, hyperlipidemia, coronary artery disease, unstable angina (or angina pectoris), thrombosis, the consequences of thrombin-induced platelet aggregation and / or thrombosis and / or the formation of atheromatous plaques; in particular inflammatory diseases of the respiratory and ORL organs, including asthma, acute respiratory distress syndrome, hay fever, allergic rhinitis and chronic obstructive pulmonary disease; inflammatory diseases of the skin, in particular urticaria, scleroderma, rhinitis ... touch dermatitis, atopic dermatitis, psoriasis, ichthyosis, acne and other forms of folliculitis, rosacea and alopecia; treatment of pain whatever its origin, for example postoperative pain, neuromuscular pain, headache, cancer-related pain, dental pain or osteoarticular pain; diseases involving pigmentation disorders, in particular benign skin diseases, for example vitiligo, albinism, melanosis, lentigines, freckles, melanocytic nevi and all post-inflammatory pigmentations; also modulation of pigmentation for treating pigmented tumors, for example melanoma and their local (translucent nodules), regional or systemic metastases; harmful effects of sunlight, for example actinic erythema, skin Photoprotection for the purpose of preventing skin aging, skin cancer (squamous cell, basal cell and melanoma), in particular diseases which promote their development (xeroderma pigmentosum, basal cell nevus syndrome and familial melanoma); photodermatoses caused by exogenous photosensitizers, in particular those caused by contact photosensitizers (e.g. furocoumarins, halogenated salicylanilides and derivatives, and topical sulfamides and derivatives) or those caused by systemic photosensitizers (e.g. psoralens, tetracyclines, sulfamides, phenothiazines, nalidixic acid and tricyclic antidepressants);attacks or exacerbations of skin diseases with photosensitivity, especially photoaggravated skin diseases (e.g. lupus erythematosus, recurrent herpes, congenital poikiloderma or telangiectatic conditions with photosensitivity (Bloom's syndrome, Cockayne's syndrome or Rothmund-Thomson syndrome), actinic lichen planus, actinic granuloma, superficial disseminated actinic porokeratosis, acne rosacea, juvenile acne, bullous skin diseases, Darier's disease, cutaneous lymphoma, psoriasis, atopic dermatitis, contact eczema, chronic actinic dermatitis (CAD), follicular mucinosis, erythema multiforme, fixed drug eruption, cutaneous lymphocytoma, reticular erythematous mucinosis, and melasma); Skin diseases with photosensitivity due to a defence system defect with abnormalities in melanin formation or distribution (e.g. oculocutaneous albinism, phenylketonuria, hypopituitarism, vitiligo and mottling) and with a defect in the DNA repair system (e.g. xeroderma pigmentosum and Cockayne's syndrome), skin diseases with photosensitivity due to metabolic abnormalities, such as cutaneous porphyrias (e.g. porphyria cutanea tarda, mixed porphyria, erythropoietic protoporphyria, congenital erythropoietic porphyria (Günther's disease), and erythropoietic coproporphyria), pellagra or pellagra-like erythema (e.g. pellagra, pellagra-like erythema and disorders of tryptophan metabolism); attacks or exacerbations of idiopathic actinic dermatoses, especially PMLE (polymorphous light eruption), benign summer light eruption, actinic prurigo, persistent photosensitization (actinic reticulosis, chronic actinic dermatosis, photosensitive eczema), solar urticaria, variola vacciniformis, juvenile vernal eruption and solar pruritus; especially by increasing melanin synthesis, resulting in tanning of the skin, or by interfering with melanin synthesis, resulting in skin discoloration, and whitening or greying of hair and body hair (e.g. regulating the colour of the skin or hair and hair by preventing sebaceous gland formation (canities, greying and mottling); also modifying the colour of hair and hair in the application of cosmetics; regulating sebaceous gland function, in particular conditions involving hyperseborrhea, in particular acne, seborrheic dermatitis, greasy skin and hair, the treatment of hyperseborrhea in Parkinson's disease and epilepsy, and hyperandrogenism; conditions involving reduced sebaceous gland secretion, in particular xerosis and all dry skin; benign or malignant sebaceous cell and sebaceous gland proliferation; inflammatory conditions of the pilosebaceous follicles, in particular acne, furuncles, carbuncles and folliculitis; male or female sexual dysfunction;Male sexual dysfunction, including but not limited to, impotence, loss of libido, and erectile dysfunction; female sexual dysfunction, including but not limited to, sexual arousal disorder or disorders related to desire, sexual receptivity, orgasm, and disorders of the cardinal points of sexual function; pain, premature labor, dysmenorrhea, excessive menstruation, and endometriosis; weight-related disorders, including but not limited to, obesity and anorexia (such as alterations or disorders of appetite, splenic metabolism, harmless intake of fats or carbohydrates); diabetes (due to decreased glucose tolerance and / or insulin resistance); cancer, particularly lung cancer, prostate cancer, intestinal cancer, breast cancer, ovarian cancer, bone cancer, or angiogenesis disorders, including the formation or growth of solid tumors;

[0125] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cells and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of immune-mediated diseases. Immune-mediated diseases include, for example, but are not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), depression, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., acne dermatomyositis vulgaris, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, vasculitis, vitiligo, and alopecia). Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, transplant rejection (allograft rejection), graft-versus-host disease (GVDH).

[0126] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of immune cells induced by at least one compound of formula (I) as an active ingredient and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of allergic diseases. As used herein, the term "allergy" or "allergies" or "allergic reaction" or "allergic response" refers to a disorder (or inappropriate reaction) of the immune system. Allergic reactions occur against normally harmless environmental substances known as allergens; these reactions are acquired, predictable, and rapid. Technically, allergy is one of four forms of hypersensitivity, called Type I (or immediate) hypersensitivity. It is characterized by the excessive activation of certain white blood cells called mast cells and basophils by a type of antibody known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees. Mild allergies such as hay fever are widespread in the human population, causing symptoms such as allergic conjunctivitis, itching, and runny nose. Allergies may play a major role in conditions such as asthma. In some people, some allergies to environmental or dietary allergens, or to drugs, can lead to life-threatening anaphylactic reactions and potentially death. Thus, treatment of allergies by immunosuppression is one embodiment of the present invention.

[0127] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of transplant-related adverse events.

[0128] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of autoimmune diseases.

[0129] Examples of autoimmune diseases include, but are not limited to, arthritis (rheumatoid arthritis, juvenile onset rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and ankylosing spondylitis), psoriasis, dermatitis including atopic dermatitis, chronic idiopathic urticaria including chronic autoimmune urticaria, polymyositis / dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as progressive systemic sclerosis, inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, autoimmune inflammatory bowel disease), pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis), respiratory diseases including adult respiratory distress syndrome (ARDS). Distress syndrome, meningitis, IgE mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis, uveitis or autoimmune uveitis, colitis such as microscopic colitis and collagenous colitis, glomerulonephritis (GN) such as membranous GN (membranous nephropathy), idiopathic membranous GN, membranoproliferative GN (MPGN) including types I and II, and rapidly progressive GN, allergic conditions, allergic reactions, eczema, asthma, conditions with T cell infiltration and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, Systemic lupus erythematosus (SLE), e.g. cutaneous SLE, subacute cutaneous lupus erythematosus, lupus (including nephritis, encephalitis, childhood, non-nephropathy, discoid, alopecia), juvenile onset (Type I) diabetes mellitus including insulin-dependent diabetes mellitus (IDDM) of childhood, adult onset diabetes mellitus (Type II diabetes), multiple sclerosis (MS), e.g. spino-ocular MS, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatous diseases including lymphomatoid granulomatosis, Wegener's granulomatosis, granulocytopenia, vasculitis (large vessel vasculitis (polymyalgia rheumatica and and giant cell (Takayasu) arteritis), medium vessel vasculitis (including Kawasaki disease and polyarteritis nodosa), CNS vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis, e.g., Churg-Strauss vasculitis or syndrome (CSS)), temporal arteritis, aplastic anemia, Coombs positive anemia, Diamond-Blackfan anemia, hemolytic anemia or immune hemolytic anemia, including autoimmune hemolytic anemia (AIHA), pernicious anemia, pure red cell aplasia (PRCA), factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases with leukocyte extravasation,CNS inflammatory disorders, multiple organ injury syndromes, antigen-antibody complex-mediated diseases, antiglomerular basement membrane diseases, antiphospholipid syndrome, allergic neuritis, Behcet's disease (Bechet's or Behcet's syndrome) disease), Castleman syndrome, Good-Basture's syndrome, Raynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid, e.g. bullous pemphigoid, pemphigus (including vulgaris, foliaceus, and pemphigus mucosal pemphigoid), autoimmune polyendocrinopathy, Reiter's disease, immune complex nephritis, chronic neuropathy, e.g. IgM polyneuropathy or IgM mediated neuropathy, thrombocytopenia (such as occurs in myocardial infarction patients), including thrombotic thrombocytopenic purpura (TTP) and autoimmune or immune mediated thrombocytopenia, e.g. idiopathic thrombocytopenic purpura (ITP), including chronic or acute ITP, autoimmune diseases of the testes and ovaries, including autoimmune orchitis and oophoritis, autoimmune endocrine disorders, including primary hypothyroidism, hypoparathyroidism, thyroiditis, e.g. autoimmune thyroiditis, chronic ... thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Addison's disease, Graves' disease, polyendocrine syndromes, e.g. autoimmune polyendocrine syndrome (or polyendocrinopathy syndrome), paraneoplastic syndromes including neurological paraneoplastic neurological syndromes, e.g. Lambert-Eaton myasthenic syndrome or Lambert-Eaton syndrome, stiff-man or stiff-person syndrome, encephalomyelitis, e.g. allergic encephalomyelitis, myasthenia gravis, cerebellar degeneration, limbic and / or brainstem encephalitis, neurogenic myotonia, opsoclonus or opsoclonus-myoclonus syndrome (OMS), and sensory neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphocytic interstitial pneumonia, bronchiolitis obliterans (non-transplant) vs. NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), primary biliary cirrhosis, steatorrhea (gluten enteropathy), refractory sprue, dermatitis herpetiformis, cryoglobulinemia, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune inner ear disease (AIED) or autoimmune hearing loss, opsoclonus-myoclonus syndrome (OMS), polychondritis, e.g. refractory polychondritis, pulmonary alveolar proteinosis,Amyloidosis, Giant cell hepatitis, Scleritis, Non-cancerous lymphocytosis, Primary lymphocytosis including monoclonal B-cell lymphocytosis (e.g., monoclonal globulinemia and monoclonal gammopathy of undetermined significance, MGUS), Peripheral neuropathy, Paraneoplastic syndromes, Channelopathies such as epilepsy, migraine, cardiac arrhythmias, myopathy, hearing loss, blindness, periodic paralysis, and CNS channelopathies, Autism, Inflammatory myopathies, Focal segmental glomerulosclerosis (FSGS) , endocrine ophthalmopathy, uveoretinitis, autoimmune liver disease, fibromyalgia, polyendocrine deficiency, Schmidt syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases, Dressler syndrome, alopecia areata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal motility disorder, digital sclerosis, and telangiectasia), male and female autoimmune infertility, ankylosing spondylitis, mixed connective tissue disease, Chagas disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, postpericardiotomy syndrome, Cushing's syndrome, bird breeder's disease, alopecia ... alveolitis, e.g. allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reactions, leprosy, malaria, leishmaniasis, kipanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sumpter's syndrome, Kaplan's syndrome, dengue fever, endocarditis, endomyocardial fibrosis, endophthalmitis, erythema elevatum, erythroblastosis fetalis, eosinophilic fasciitis, Schulman's syndrome, Felty's syndrome, filariasis, cyclitis, e.g. chronic cyclitis, heterochronic cyclitis, These include Fuchs' cyclitis, Henoch-Schönlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndrome, congenital rubella infection, Epstein-Barr virus infection, mumps, Evans syndrome, autoimmune gonadal dysfunction, Sydenham chorea, post-streptococcal nephritis, thromboangiitis obliterans, hyperthyroidism, fistula spinalis, and giant cell polymyalgia. Thus, the treatment of autoimmune disorders through immunosuppression is one embodiment of the present invention.

[0130] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of metabolic diseases with an inflammatory component, such as arteriosclerosis resulting in coronary heart disease, obesity or diabetes.

[0131] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of aging.

[0132] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the prevention of inflammation that promotes cancer initiation or progression.

[0133] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I), at least one pharma- ceutically acceptable carrier as defined above, and another active ingredient, for its use in the prevention of immune-mediated diseases. Advantageously, the immune-mediated diseases are selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0134] Another aspect of the present invention relates to a method for the prophylactic treatment of an immune-mediated disease, comprising administering to a patient at least one immune cell induced by a compound of formula (I) or a pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of at least one immune cell induced by a compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression and ageing.

[0135] According to the present invention, the immune cells induced by at least one compound of formula (I) are particularly effective in preventing such diseases in adoptive cell therapy, because the immune cells induced by at least one compound of formula (I) act directly in the target organ, where they rapidly home and locally block the activation of microglia and CNS-associated macrophages. The immune cells induced by at least one compound of formula (I) directly block inflammatory responses in the target organ. The immune cells induced by at least one compound of formula (I) directly produce IL-10 at the site of inflammation.

[0136] In some embodiments, the present invention relates to a method for the prophylactic treatment of an immune-mediated disease, comprising administering to a patient at least one compound of formula (I) induced immune cell or a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cell and at least one pharma- ceutically acceptable carrier as defined above. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression and ageing.

[0137] In some embodiments, the present invention relates to a method for the prophylactic treatment of a neurodegenerative disease, comprising administering to a patient at least one compound of formula (I)-induced immune cell or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least a compound of formula (I)-induced immune cell and at least one pharma- ceutically acceptable carrier as defined above.

[0138] In some embodiments, the present invention relates to a method for the prophylactic treatment of an inflammatory disease, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0139] In some embodiments, the present invention relates to a method for the prophylactic treatment of an immune-mediated disease, comprising administering to a patient at least one compound of formula (I)-induced immune cell or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cell and at least one pharma- ceutically acceptable carrier as defined above.

[0140] In some embodiments, the present invention relates to a method for the prophylactic treatment of an allergic disease, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0141] In some embodiments, the present invention relates to a method for the prophylactic treatment of transplant-related adverse events, comprising administering to a patient at least one compound of formula (I)-induced immune cell or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cell and at least one pharma- ceutically acceptable carrier as defined above.

[0142] In some embodiments, the present invention relates to a method for the prophylactic treatment of a metabolic disease with an inflammatory component, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0143] In some embodiments, the present invention relates to a method for the prophylactic treatment of aging, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0144] In some embodiments, the present invention relates to a method for the prophylactic treatment of inflammation that promotes cancer development or progression, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0145] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for the prevention of an immune-mediated disease. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0146] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for the prevention of a neurodegenerative disease.

[0147] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for the prevention of an inflammatory disease.

[0148] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for the prevention of an immune-mediated disease.

[0149] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for the prevention of an allergic disease.

[0150] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for the prevention of adverse events associated with transplantation.

[0151] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for the prevention of an autoimmune disease.

[0152] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for the prevention of a metabolic disease with an inflammatory component.

[0153] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for preventing aging.

[0154] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for preventing inflammation that promotes cancer development or progression.

[0155] Curative treatment Another aspect of the invention relates to a pharmaceutical composition comprising immune cells induced by at least one compound of formula (I) for its use in the treatment of an immune-mediated disease, advantageously selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0156] As used herein, the term "treatment" or "curative treatment" is defined as a treatment that brings about recovery or that relieves, ameliorates, and / or eliminates, reduces, and / or stabilizes the symptoms of a disease or the suffering it causes.

[0157] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) for its use in the treatment of an immune-mediated disease. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0158] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of immune-mediated diseases. Advantageously, the immune-mediated diseases are selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, transplant-related adverse events, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0159] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of neurodegenerative diseases.

[0160] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of inflammatory diseases.

[0161] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cells and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of immune-mediated diseases.

[0162] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of allergic diseases.

[0163] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of transplant-related adverse events.

[0164] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cells and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of autoimmune diseases.

[0165] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of metabolic diseases with an inflammatory component.

[0166] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of aging.

[0167] In some embodiments, the present invention relates to a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I) and at least one pharma- ceutically acceptable carrier as defined above, for its use in the treatment of inflammation that promotes cancer initiation or progression.

[0168] In some embodiments, the present invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of immune cells induced by at least one compound of formula (I), at least one pharma- ceutically acceptable carrier as defined above, and another active ingredient, for its use in the treatment of an immune-mediated disease. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0169] Another aspect of the present invention relates to a method for the curative treatment of an immune-mediated disease, comprising administering to a patient at least one compound of formula (I) induced immune cell or a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cell and at least one pharma- ceutically acceptable carrier as defined above. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression and ageing.

[0170] In some embodiments, the present invention relates to a method for the curative treatment of an immune mediated disease, comprising administering to a patient at least one compound of formula (I) induced immune cell or a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cell and at least one pharma- ceutically acceptable carrier as defined above. Advantageously, the immune mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression and ageing.

[0171] In some embodiments, the present invention relates to a method for the curative treatment of a neurodegenerative disease comprising administering to a patient at least one compound of formula (I)-induced immune cell or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cell and at least one pharma- ceutically acceptable carrier as defined above.

[0172] In some embodiments, the present invention relates to a method for the curative treatment of an inflammatory disease comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0173] In some embodiments, the present invention relates to a method for the curative treatment of an immune-mediated disease comprising administering to a patient at least one compound of formula (I)-induced immune cell or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cell and at least one pharma- ceutically acceptable carrier as defined above.

[0174] In some embodiments, the present invention relates to a method for the curative treatment of an allergic disease, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0175] In some embodiments, the present invention relates to a method for the curative treatment of transplant-related adverse events, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0176] In some embodiments, the present invention relates to a method for the curative treatment of a metabolic disease with an inflammatory component, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0177] In some embodiments, the present invention relates to a method for the curative treatment of aging, comprising administering to a patient at least one compound of formula (I) induced immune cells or a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of at least one compound of formula (I) induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0178] In some embodiments, the present invention relates to a method for the curative treatment of inflammation promoting cancer development or progression, comprising administering to a patient at least one compound of formula (I)-induced immune cells or a pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of at least one compound of formula (I)-induced immune cells and at least one pharma- ceutically acceptable carrier as defined above.

[0179] Another aspect of the invention relates to the use of a pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for treating an immune-mediated disease, advantageously selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0180] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for treating a neurodegenerative disease.

[0181] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for treating an inflammatory disease.

[0182] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for treating an immune-mediated disease.

[0183] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for treating an allergic disease.

[0184] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least immune cells induced by a compound of formula (I) in the manufacture of a medicament intended for treating adverse events associated with transplantation.

[0185] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I) in the manufacture of a medicament intended for treating an autoimmune disease.

[0186] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for treating a metabolic disease with an inflammatory component.

[0187] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising a therapeutically effective amount of immune cells induced by at least one compound of formula (I) as an active ingredient in the manufacture of a medicament intended for treating aging.

[0188] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of immune cells induced by at least one compound of formula (I), in the manufacture of a medicament intended for treating inflammation that promotes cancer development or progression.

[0189] Another subject of the present invention relates to a method for the curative treatment of an immune-mediated disease in a patient in need thereof, comprising administering to the patient at least one compound of formula (I) induced immune cell or a pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of at least one compound of formula (I) induced immune cell and at least one pharma- ceutically acceptable carrier as defined above. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0190] Another subject of the present invention relates to a method for the curative treatment of an immune-mediated disease in a patient in need thereof, comprising administering to the patient at least one immune cell induced by a compound of formula (I) or a pharmaceutical composition comprising, as active ingredient, a therapeutically effective amount of at least one immune cell induced by a compound of formula (I), at least one pharma- ceutically acceptable carrier as defined above and another active ingredient as defined above. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0191] In some embodiments, the present invention relates to the use of a pharmaceutical composition comprising a therapeutically effective amount of immune cells induced by at least one compound of formula (I) as active ingredient in the manufacture of a medicament intended for treating an immune-mediated disease. Advantageously, the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, adverse events associated with transplantation, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and ageing.

[0192] Another aspect of the present invention provides the use of a compound of formula (I) for inducing immune cells as defined herein:

[0193] [ka]

[0194] [In the formula, -X 1 , X 2 , X 3 are each independently a nitrogen atom or a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHRe selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p and p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j and j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 , R 7 and R 8 each independently represents a hydrogen atom, a cyano group, a halogen atom, or -NHCOR b R b is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4) alkoxy groups, pyridine groups and (Z 8 ) b and b is selected from 0, 1, 2, 3, 4 and 5; and each Z 8 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; however, -X 1 is a nitrogen atom, R 8 does not exist; -X 2 is a nitrogen atom, R 7 does not exist; -X 3 is a nitrogen atom, R 6 does not exist. EXAMPLES

[0195] Example 1 Synthesis of compounds of formula (I) The following examples illustrate the present invention without limiting its scope. The following examples illustrate in detail the preparation of some compounds according to the invention. The structures of the products obtained have been confirmed by NMR and mass spectrometry.

[0196] In the examples, the following abbreviations are used: "DMF" means dimethylformamide; "EtOH" means ethanol, "NaOH" means sodium hydroxide; "HCl" means hydrochloric acid; "DIPEA" means N,N-diisopropylethylamine; "HATU" means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0197] 1) Synthesis of compound 218 According to route (A), 2-amino-5-iodopyridine (500 mg, 2.27 mmol, 1 equiv) was placed in acetone (10 mL). Then, 2-bromo-1-(2-fluorophenyl)ethan-1-one (493.24 mg, 2.27 mmol, 1 equiv) was added. The reaction was heated at 60° C. and stirred for 20 h. The precipitate that formed was then filtered, washed with acetone, and dried under vacuum to give 2-(2-fluorophenyl)-6-iodoimidazo[1,2-a]pyridine (218) (764 mg, 99%).

[0198] 2) Synthesis of Compound 91 According to route (A), 2-amino-5-iodopyridine (6.82 g, 30.99 mmol, 1.24 equiv.) was placed in ethanol (50 mL). Then 2-bromo-1-(pyridin-3-yl)ethan-1-one hydrobromide (5 g, 25 mmol, 1 equiv.) was dissolved in NaHCO 3 (3.045 g, 36.25 mmol, 1.45 equiv.). The reaction mixture was heated at 80° C. and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give 6-iodo-2-(pyridin-3-yl)imidazo[1,2-a]pyridine (91) (642 mg, 8%).

[0199] 3) Synthesis of compound 264 By route (A), methyl 6-aminonicotinate (1000 mg, 6.57 mmol, 1 equiv.) was placed in acetone (10 mL). 2-Bromo-4'-fluoroacetophenone (1426 mg, 6.57 mmol, 1 equiv.) was then added. The reaction was heated at 60°C and stirred for 20 h. The precipitate that formed was then filtered, washed with acetone, and dried under vacuum to give methyl 2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6-carboxylate (1760 mg, 99%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.71 (s, 1H), 8.01 (dd, J = 8.8, 5.5 Hz, 1H), 7.88 (d, J = 9.4, 1H), 7.43 (t, J = 8.8 Hz, 2H). [M+H] + = 271.13

[0200] According to route (E), 2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6-carboxylate (1760 mg, 6.6 mmol, 1 equiv.) was dissolved in a mixture of water / methanol 1 / 2 (30 mL). NaOH (1332 mg, 33.3 mmol, 5 equiv.) was then added. The reaction mixture was stirred at 70° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and acidified to pH 6-7 with a solution of 1 M HCl to precipitate compound (264). The precipitate was then filtered, washed with water, and dried under vacuum overnight to give 2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6-carboxylic acid (264) (1280 mg, 75%).

[0201] 4) Synthesis of compound 133 According to route (B), 6-iodo-2-(pyridin-3-yl)imidazo[1,2-a]pyridine (91) (50 mg, 0.16 mmol, 1 equiv.) was placed in toluene (1 mL). Then, 2-methoxybenzamide (1.2 equiv., 28.33 mg, 0.19 mmol) was added to K 3 PO 4(66.305 mg, 0.31 mmol, 2 equiv.), copper(I) iodide (5.95 mg, 0.031 mmol, 0.2 equiv.), and trans-N,N'-dimethylcyclohexane-1,2-diamine (4.44 mg, 0.031 mmol, 0.2 equiv.). The reaction mixture was heated at 120°C and stirred for 48 hours in a sealed tube under argon. The reaction mixture was diluted with dichloromethane and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 2-methoxy-N-(2-(pyridin-3-yl)imidazo[1,2-a]pyridin-6-yl)benzamide (133) (10 mg, 19%).

[0202] 5) Synthesis of compound 271 According to route (F), 2-(4-fluorophenyl)imidazo[1,2-a]pyridine-6-carboxylic acid (264) (1230 mg, 0.47 mmol, 1.2 equiv.) was dissolved in anhydrous DMF (5 mL). O-anisidine (44 μL, 0.39 mmol, 1 equiv.) and DIPEA (204 μL, 1.17 mmol, 3 equiv.) were added. HATU (222 mg, 0.59 mmol, 1.5 equiv.) was then added to the reaction mixture, which was stirred at room temperature for 2 h. Water was poured into the reaction mixture to precipitate compound (271). The precipitate was then filtered, washed with water, and dried under vacuum overnight to give 2-(4-fluorophenyl)-N-(2-methoxyphenyl)imidazo[1,2-a]pyridine-6-carboxamide (271) (140 mg, 99%).

[0203] Further synthetic processes are summarized in the following Table 2, showing the reaction conditions under which they were carried out.

[0204] [Table 2A]

[0205] [Table 2B]

[0206] [Table 2C]

[0207] Example 2 Identification of compounds of the invention with comparable IL-10 induction potential in human B cells Human B cells magnetically isolated by negative selection (B Cell Isolation Kit II, human, Miltenyi ref:130-091-151) were cultured for two consecutive days in the presence of anti-IgM and CpG, at a final concentration of 0.25 μM of the indicated molecules (see table 3). IL-10 was measured in the cell culture supernatants.

[0208] [Table 3A]

[0209] [Table 3B]

[0210] Example 3 Effects of compounds 133, 161, and 77 on IL-10 induction by human B cells Human B cells magnetically isolated by negative selection (B Cell Isolation Kit II, human, Miltenyi ref:130-091-151) were cultured for two consecutive days in the presence of anti-IgM and CpG, in the presence of DMSO (as control) or in the presence of the molecules to be tested at a final concentration of 0.25 microM. IL-10 was measured in the cell culture supernatant. NS: unstimulated B cell culture conditions. The results are presented in figure 1. Conclusion: These compounds enhance IL-10 induction by human B cells.

[0211] Example 4 Effects of compounds 212, 213, 216, 217, 219, 220, 224, 228, 238, 271, 279 and 344 on IL-10 induction by human B cells Human B cells magnetically isolated by negative selection (B Cell Isolation Kit II, human, Miltenyi ref: 130-091-151) were cultured for two consecutive days in the presence of anti-IgM and CpG, in the presence of DMSO (as control) or in the presence of the molecules to be tested at a final concentration of 0.25 microM. IL-10 was measured in the cell culture supernatant. NS: unstimulated B cell culture conditions. The results are presented in figure 2. Conclusion: These compounds enhance IL-10 induction by human B cells.

[0212] Example 5 Effect of induction of human B cells with compounds 133, 161 and 77 on IL-10 production by human B cells Human B cells magnetically isolated by negative selection (B Cell Isolation Kit II, human, Miltenyi ref: 130-091-151) were cultured for two consecutive days in the presence of anti-IgM and CpG, in the presence of DMSO (as control) or in the presence of the molecules to be tested at a final concentration of 0.25 microM. IL-10 was measured in the cell culture supernatant. NS: unstimulated B cell culture conditions. The results are presented in figures 3 to 5. Conclusion: These compounds increase IL-10 production by human B cells.

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In the formula, -X 1 , X 2 , X 3 are each independently a nitrogen atom or a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R c is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p and p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4, and 5; and each Z 6 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j and j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 , R 7 and R 8 each independently represents a hydrogen atom, a cyano group, a halogen atom, or -NHCOR b R b is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 8 ) b and b is selected from 0, 1, 2, 3, 4 and 5; and each Z 8 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; however, -X 1 is a nitrogen atom, R 8 does not exist; -X 2 is a nitrogen atom, R 7 does not exist; -X 3 is a nitrogen atom, R 6 does not exist, The following compound: 6-iodo-2-phenylimidazo[1,2-a]pyridine; 6-iodo-2-(pyridin-3-yl)imidazo[1,2-a]pyridine; 6-Chloro-2-(pyridin-3-yl)imidazo[1,2-a]pyridine; 6-Bromo-2-(pyridin-3-yl)imidazo[1,2-a]pyridine; N-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl)benzamide; N-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl)-2-methoxybenzamide; N-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl]-3-methoxy-benzamide; 2-(3,4-difluorophenyl)-6-iodoimidazo[1,2-a]pyridine; 6-Bromo-2-(3,4-difluorophenyl)imidazo[1,2-a]pyridine; 2-(4-bromophenyl)-6-iodoimidazo[1,2-a]pyridine; 2-(4-fluorophenyl)-6-iodoimidazo[1,2-a]pyridine; 6-Bromo-2-(4-fluorophenyl)-imidazo[1,2-a]pyridine; N-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl]acetamide; 1-[2-(4-fluorophenyl)imidazo[1,2-a]pyridin-6-yl]-3-phenyl-urea; 2-(3-fluorophenyl)-6-iodoimidazo[1,2-a]pyridine; N-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-2-methoxy-benzamide; N-(2,4-dimethoxyphenyl)-2-phenyl-imidazo[1,2-a]pyridine-6-carboxamide; 2-(4-chlorophenyl)imidazo[1,2-a]pyridine; 2-(4-bromophenyl)imidazo[1,2-a]pyridine; 6-Chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine; 6-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine not one of them].

2. -X 1 , X 2 and X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1～ C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 7 are each independently a hydrogen atom, a cyano group, or a halogen atom.

3. -X 1 is a nitrogen atom; -X 2 , X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

4. -X 2 is a nitrogen atom, -X 1 , X 3 is a carbon atom, - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

5. -X 3 is a nitrogen atom; -X 1 and X 2 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 7 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

6. -X 2 is a nitrogen atom; -X 1 and X 3 is a carbon atom; - R 2 and R 3 each independently represents a hydrogen atom, a halogen atom, or -NHCOR a R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom.

7. -X 2 is a nitrogen atom or a carbon atom; -X 1 and X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom or a halogen atom; - R 4 , R 5 , R 6 and R 8 are each independently a hydrogen atom, a cyano group, or a halogen atom. 【Request 8】 【Chemical 2】 2. The compound of claim 1, selected from:

9. 【Chemical 3】 2. The compound of claim 1,

10. 【Chemical 4】 2. The compound of claim 1,

11. An in vitro method for inducing the production of a protein by an immune cell, comprising the steps of contacting the immune cell with a compound of formula (I), thereby obtaining an induced immune cell: 【Chemistry 5】 [In the formula, -X 1 , X 2 , X 3 are each independently a nitrogen atom or a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, or -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R c is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p and p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4, and 5; and each Z 6 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j and j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 , R 7 and R 8 each independently represents a hydrogen atom, a cyano group, a halogen atom, or -NHCOR b R b is (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 8 ) b and b is selected from 0, 1, 2, 3, 4 and 5; and each Z 8 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; however, -X 1 is a nitrogen atom, R 8 does not exist; -X 2 is a nitrogen atom, R 7 does not exist; -X 3 is a nitrogen atom, R 6 does not exist.

12. In formula (I), -X 1 , X 2 and X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1～ C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 7 The method according to claim 11, wherein each independently represents a hydrogen atom, a cyano group, or a halogen atom.

13. In formula (I), -X 1 is a nitrogen atom; -X 2 , X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 The method according to claim 11, wherein each independently represents a hydrogen atom, a cyano group, or a halogen atom.

14. In formula (I), -X 2 is a nitrogen atom, -X 1 , X 3 is a carbon atom, - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 is a halogen atom, a hydroxyl group, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 The method according to claim 11, wherein each independently represents a hydrogen atom, a cyano group, or a halogen atom.

15. In formula (I), -X 3 is a nitrogen atom; -X 1 and X 2 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom, a halogen atom, -NHCOR a group, -NHR c Group, -NHCONHR d Group, and -CONHR e selected from the group; R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R c However, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 5 ) p wherein p is selected from 0, 1, 2, 3, 4 and 5; and each Z 5 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; R d is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 6 ) n wherein n is selected from 0, 1, 2, 3, 4 and 5; and each Z 6 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Group, and -CF 3 are independently selected from the group; R e is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 7 ) j wherein j is selected from 0, 1, 2, 3, 4 and 5; and each Z 7 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 7 and R 8 The method according to claim 11, wherein each independently represents a hydrogen atom, a cyano group, or a halogen atom.

16. In formula (I), -X 2 is a nitrogen atom; -X 1 and X 3 is a carbon atom; - R 2 and R 3 each independently represents a hydrogen atom, a halogen atom, or -NHCOR a R a is a hydrogen atom, (C 1 ~C 6 ) cycloalkyl group, (C 1 ~C 4 ) alkyl group, aryl group, (C 1 ~C 4 ) alkoxy groups, pyridine groups and (Z 4 ) q q is selected from 0, 1, 2, 3, 4 and 5; and each Z 4 However, halogen atoms, hydroxyl groups, (C 1 ~C 6 ) alkoxy group, (C 1 ~C 4 ) alkyl group, -NH 2 group, -NO 2 group, -OCF 3 Groups, and -CF 3 are independently selected from the group; - R 4 , R 5 , R 6 and R 8 The method according to claim 11, wherein each independently represents a hydrogen atom, a cyano group, or a halogen atom.

17. In formula (I), -X 2 is a nitrogen atom or a carbon atom; -X 1 and X 3 is a carbon atom; - R 2 and R 3 are each independently a hydrogen atom or a halogen atom; - R 4 , R 5 , R 6 and R 8 The method according to claim 11, wherein each independently represents a hydrogen atom, a cyano group, or a halogen atom.

18. The compound of formula (I) 【Chemistry 6】 The method of claim 11, wherein the compound is selected from the group consisting of

19. The compound of formula (I) 【Chemistry 7】 The method of claim 11, wherein

20. The compound of formula (I) 【Chemistry 8】 The method of claim 11, wherein the compound is selected from the group consisting of

21. 21. The method of any one of claims 11 to 20, wherein the immune cells are selected from T lymphocytes, B lymphocytes, and myeloid cells.

22. 22. The method of any one of claims 11 to 21, wherein the protein is interleukin-10.

23. An induced immune cell obtained by the method of claim 22.

24. 24. A pharmaceutical composition comprising a dose of the induced immune cells of claim 23 and at least one pharmaceutical carrier.

25. 25. The pharmaceutical composition of claim 24, further comprising at least one other active ingredient.

26. 26. A pharmaceutical composition according to claim 24 or 25 for use in the prevention or treatment of an immune-mediated disease.

27. 27. The pharmaceutical composition for use according to claim 26, wherein the immune-mediated disease is selected from neurodegenerative diseases, inflammatory diseases, allergic diseases, transplant-related adverse events, autoimmune diseases, metabolic diseases with an inflammatory component, inflammation promoting cancer development or progression, and aging.

28. 21. A compound of formula (I) as defined in any one of claims 11 to 20 for use in a method for treating an immune mediated disease, said method comprising: (i) contacting immune cells with said compound of formula (I), thereby obtaining induced immune cells; and (ii) administering said induced immune cells to a patient in need thereof.

Images