6H-Imidazo[1,2-a]pyrrolo[2,3-e]pyridine derivatives for therapeutic use

Abstract

The present invention relates to a compound of formula (I): (wherein R1 represents a hydrogen atom, a (C1-C4) alkyl group, a halogen atom or a (C1-C4) fluoroalkyl group; R2 represents a hydrogen atom, a (C1-C3) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C3) fluoroalkyl group, a C(O)NHRa group (wherein Ra is a (C1-C3) alkyl group) or a halogen atom; R3 represents a hydrogen atom, a (C1-C4) alkyl group, a (C1-C4) fluoroalkyl group or a halogen atom; and Ar represents a (C5-C6) heteroarylene group or a divalent aromatic ring), or a pharma- ceutically acceptable salt thereof. Furthermore, the present invention relates to therapeutic uses thereof, particularly as an anticancer agent. [Formula 1] TIFF2024525792000022.tif28103

Description

[Technical field]

[0001] Disclosed herein are 6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine derivatives, their preparation methods and their therapeutic uses, particularly as anti-cancer agents, via modulation of the nuclear receptor subfamily NR4A, in particular NR4A2, Nurr1, also known as NOT, TINUR, RNR-1 or HZF3, and Nur77, also known as NR4A1, also known as Nur77 / TR3 / NGFIB.

[0002] Said derivatives are particularly useful in the treatment of diseases such as autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer. [Background technology]

[0003] As used herein, Nurr1 and Nur77 are orphan nuclear receptors related to nuclear receptor subfamily 4 group A member 2 (NR4A2) and 1 (NR4A1), respectively. Nurr1 and Nur77 are members of the nuclear receptor superfamily that are expressed as early response genes and regulate the expression of multiple target genes.

[0004] Nurr1 and Nur77 have a typical nuclear receptor structure, including an N-terminal domain, a DNA-binding domain, and a ligand-binding domain. Nurr1 and Nur77 share 90-95% homology in the DNA-binding domain, but differ in the N-terminal domain. The expression and localization of Nurr1 and Nur77 are closely related to their roles in cell proliferation and apoptosis. Furthermore, Nurr1 and Nur77 are expressed and function in the immune system (Non-Patent Document 1).

[0005] Nurr1 encodes an orphan nuclear receptor for the nerve growth factor-inducible gene B (NGFI-B) family of transcription factors.

[0006] The NR4A subfamily plays a role in metabolic regulation. Nurr1 regulates the expression of several genes related to metabolism and gluconeogenesis. Nur77 is involved in lipid and cholesterol metabolism, hepatic steatosis, hepatic gluconeogenesis, and pancreatic islet β-cell proliferation.

[0007] The NR4A subfamily also plays a role in regulating inflammatory responses: Nurr1 in particular has been found to be associated with inflammatory arthritis and inflammation of cartilage and joints.

[0008] The activities of Nurr1 and Nur77, which are regulated by various cell signaling pathways in cancer, have also been demonstrated. For example, Nurr1 expression is associated with colorectal cancer, and Nur77 is overexpressed in colon, lung and breast cancer. Dysregulation of both Nurr1 and Nur77 expression may also contribute to tumorigenesis.

[0009] The NR4A subfamily is also associated with neurological and neurological diseases. In particular, Nurr1 is involved in the control of several physiological functions of the human central nervous system, such as memory and learning, and has demonstrated activity in dopamine synthesis and metabolism. Nur77 is expressed in various regions of the brain, and its overexpression ameliorates oxygen- and glucose-deprivation-induced neuronal damage, whereas its knockdown exacerbates these conditions. Both Nurr1 and Nur77 have been specifically implicated in Parkinson's disease.

[0010] Although some compositions that regulate Nur77 are already known, further investigations are needed to identify compositions that modulate Nurr1 and Nur77 and their therapeutic activity. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Front.Immunol., August 3, 2018, https: / / doi.org / 10.3389 / fimmu.2018.01797 Summary of the Invention [Problem to be solved by the invention]

[0012] The discovery of new compositions with Nur77 and / or Nurr1 modulating effects is a persistent need, particularly for new cancer treatments and, in particular, for targeted therapies that can be used to attack tumor cells with minimal effects on healthy cells. [Means for solving the problem]

[0013] The present inventors have now found that a composition defined by formula (I) below has a Nur77 and Nurr1 modulating effect.

[0014] Said compounds of formula (I) are therefore useful for the treatment and / or prevention of diseases such as autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases.

[0015] Thus, according to a first aspect, the present invention relates to compounds of formula (I) as defined below or any pharma- ceutically acceptable salt thereof.

[0016] Further provided herein are compounds of formula (I) as defined below for use as a medicament.

[0017] There is also provided herein a compound of formula (I) as defined below for use in the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer. Compounds of formula (I) may also be used as a treatment in connection with stem cell transplantation and / or grafts.

[0018] There is also provided herein a compound of formula (I) as defined below for use in the treatment and / or prophylaxis of neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases.

[0019] There is also provided herein compounds of formula (I) as defined below for use in the treatment and / or prevention of autoimmune disorders and cancer.

[0020] There is also provided herein the use of a compound of formula (I) as defined below for the manufacture of a medicament, in particular a medicament for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer.

[0021] Finally, there is provided herein a pharmaceutical composition comprising a compound of formula (I) or any pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient for use in the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer.

[0022] In particular, the present invention relates to a medicament comprising a compound of formula (I) or any pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer.

[0023] definition As used herein, the term "patient" refers to an animal, such as an animal valuable for breeding, companionship, or conservation purposes, or, preferably, a human or human child who is afflicted or likely to be afflicted by one or more of the diseases described herein.

[0024] In particular, as used in this application, the term "patient" refers to a mammal, such as a rodent, cat, dog, primate, or human; preferably, the subject is a human.

[0025] Identifying patients in need of treatment for the diseases described herein is well within the ability and knowledge of one of ordinary skill in the art, and a veterinarian or physician of ordinary skill in the art can readily identify such patients by using clinical tests, physical examinations, medical / family history, or biological and diagnostic tests.

[0026] In the context of the present invention, the term "treat" or "treatment" as used herein means preventing, reversing, alleviating, inhibiting the progression of a disease or preventing the disease and the cognitive, motor or metabolic changes that result from the disease.

[0027] Thus, the term "treat" or "treatment" includes within the framework of the present invention the improvement of the condition of a patient suffering from a disease described herein, in particular in the "Conditions" section.

[0028] As used herein, "effective amount" refers to an amount of a compound of the present invention that is effective to prevent, reduce, eliminate, treat or control the symptoms of a disease described herein.

[0029] The term "control" is intended to refer to any manner in which the progression of the diseases described herein can be slowed, hindered, halted or stopped, but does not necessarily indicate the complete elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.

[0030] The term "effective amount" includes "prophylactically effective amount" and "therapeutically effective amount."

[0031] As used herein, the term "prevent" refers to any phenomenon, in this invention, reducing the risk of developing or delaying the onset of a disease as described herein.

[0032] As used herein, "prevent" also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0033] The term "prophylactically effective amount" refers to a concentration of a compound of the present invention effective to inhibit, prevent, or reduce the likelihood of occurrence of any of the diseases described herein.

[0034] Similarly, the term "therapeutically effective amount" refers to a concentration of a compound effective to treat a disease described herein.

[0035] As used herein, the term "pharmacologically acceptable" refers to a compound, material, excipient, composition or dosage form that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other significant complications, commensurate with a reasonable benefit / risk ratio.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases, as will become apparent from the detailed description below.

[0037] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a pharmaceutically acceptable excipient, such as any non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] Compounds of formula (I) Surprisingly, the inventors have found that the compounds of formula (I) disclosed herein are useful for preventing and / or treating autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer.

[0039] Thus, according to a first aspect, the subject of the invention is a compound of formula (I): [ka] (In the formula: R1 represents a hydrogen atom, a (C1-C4) alkyl group, a halogen atom or a (C1-C4) fluoroalkyl group; R2 represents a hydrogen atom, a (C1-C3) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C3) fluoroalkyl group, a C(O)NHRa group (wherein Ra is a (C1-C3) alkyl group) or a halogen atom; R3 represents a hydrogen atom, a (C1-C4) alkyl group, a (C1-C4) fluoroalkyl group or a halogen atom; Ar is (C5~C 11 ) a heteroarylene group, particularly a (C5-C6) heteroarylene group, or a divalent aromatic ring. or a pharma- ceutically acceptable salt thereof.

[0040] In the context of the present invention, the terms: "halogen" is understood to mean chlorine, bromine or iodine, in particular chlorine or bromine; As used herein, (C5-C 11 A (C-C) heteroarylene group refers to a divalent monocyclic aromatic group or a divalent bicyclic aromatic group, where at least one ring is aromatic and further where one to three carbon atoms of the ring are replaced with a heteroatom, such as nitrogen, oxygen, or sulfur. In certain embodiments, the (C-C) heteroarylene group, as used herein, is 11 A (C5-C6)heteroarylene group refers to a divalent monocyclic aromatic (C5-C6)heteroarylene group in which one to three ring carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, or sulfur. Examples of (C5-C6)heteroarylene groups include, but are not limited to, the divalent groups corresponding to the following (C5-C6)heteroaryl groups: oxazole, isoxazole, pyridine, pyrimidine, pyridazine, triazine, pyrazine, oxadiazole, furan, pyrazole, thiazole, isothiazole, thiadiazole, imidazole, triazole, and the like. - Aromatic ring means that one molecule has 4n+2π electrons according to Hückel's rule. According to one embodiment, the divalent aromatic ring is a phenylene group. As used herein, (C1-C x A fluoroalkyl group is a C1-C6 alkyl group as defined herein above, in which one or more hydrogens are replaced by halogen atoms. x ) alkyl. In one embodiment, all hydrogen atoms are replaced with fluorine atoms to form a perfluoroalkyl group, such as trifluoromethyl.

[0041] The compounds of formula (I) can exist in the form of pharma- ceutically acceptable salts, which are also part of the invention; these salts can be prepared with pharma- ceutically acceptable acids, such as methanesulfonic acid (P. Stahl, C. Wermuth; Handbook of pharmaceutical salts; Wiley eds.), but other salts, for example obtained by purification or isolation of the compounds of formula (I), are also part of the invention.

[0042] In particular, "pharmaceutically acceptable salts" refers to inorganic and organic acid addition salts.

[0043] The compounds of formula (I) or any of their pharma- ceutically acceptable salts may form solvates or hydrates and the present invention includes all such solvates and hydrates.

[0044] The terms "hydrate" and "solvate" simply mean that the compound (I) according to the invention may be in the form of a hydrate or solvate, i.e. in a state of combination or association with one or more water or solvent molecules, which is merely a chemical characteristic of such compounds and is applicable to all organic compounds of this type.

[0045] In one embodiment, in the compounds of formula (I) or a pharma- ceutically acceptable salt thereof as defined above, Ar is a phenylene group.

[0046] In another embodiment, in the compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined above, R1 and R3 are independently a hydrogen atom or a halogen atom, more particularly a chlorine atom, and R2 is a hydrogen atom.

[0047] In another embodiment, the compound of formula (I) is the compound: [ka] or a pharma- ceutically acceptable salt thereof, in particular the methanesulfonate salt thereof.

[0048] A compound of the following formula (1) [ka] is also called 1-chloro-2-(4-chlorophenyl)-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine, hereinafter referred to as compound (1).

[0049] A compound of the following formula (2) [ka] is also known as 2-(4-chlorophenyl)-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine.

[0050] The compounds of formula (I) may be prepared by conventional methods of organic synthesis practiced by those skilled in the art.

[0051] Compounds of formula (I) and other related compounds with different substituents are synthesized using techniques and materials as described below or otherwise known to those of skill in the art. Additionally, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those of skill in the art.

[0052] The general method for preparing the compounds of formula (I) below is optionally modified by using appropriate reagents and conditions to introduce the various substructures found in formula (I) described below.

[0053] Scheme 1: Preparation of Compound (I) Wherein R3 is a Halogen Atom [ka]

[0054] According to scheme 1, where Ar, R1 and R2 are as defined above and R3 is a halogen atom, in step 1, a compound of formula (VI) where R1 is as defined above can be reacted with a compound of formula (V) where R2 is as defined above in a solvent such as dimethoxyethane at ambient temperature to obtain a compound of formula (IV) where Ar, R1 and R2 are as defined above.

[0055] The compound of formula (IV), which may or may not be isolated, that allows compound (1) to be obtained is called 2-(5-amino-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl)-1-(4-chlorophenyl)ethanone bromide (compound (IVa)).

[0056] The compound of formula (IV) may then be reacted directly in a solvent such as ethanol or isopropanol, particularly at a temperature in the range of 100-140° C., for a period in the range of, for example, 1 hour to 3 hours, to synthesize a compound of formula (II) in which Ar, R1 and R2 are as defined above, which corresponds to the compound of formula (I) in which R3 is a hydrogen atom.

[0057] The compound of formula (II), which allows obtaining compound (1) and which is also novel, is called 2-(4-chlorophenyl)-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine (compound (2)).

[0058] Step 2 can then be carried out by introducing substitutions in the 6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine skeleton with radical R3, which is a halogen atom. In step 2 above, the compound of formula (II) can be placed in a solvent such as tetrahydrofuran, dichloromethane, chloroform or toluene under an inert atmosphere, for example under argon, and at a temperature, in particular, below −5° C. Then, the succinimide derivative of formula (III), in which R3 is the above halogen atom, can be added to the mixture, and the mixture can be stirred, in particular at a temperature, in particular, below −5° C., for a period ranging from 30 minutes to 3 hours, and then at ambient temperature, for a period ranging from 10 hours to 20 hours, to allow obtaining the compound of formula (I).

[0059] Scheme 1': Preparation of Compound (I) Wherein R3 is Selected from a (C1-C4) alkyl group or a (C1-C4) fluoroalkyl group [ka]

[0060] Alternatively, according to scheme 1', in step 1', a compound of formula (VI') in which R1 is as defined above and R3 is selected from a (C1-C4) alkyl group or a (C1-C4) fluoroalkyl group can be reacted with a compound of formula (V) in which R2 is as defined above in a solvent such as dimethoxyethane at ambient temperature to obtain a compound (IV') in which Ar, R1 and R2 are as defined above and R3 is selected from a (C1-C4) alkyl group or a (C1-C4) fluoroalkyl group.

[0061] The compound of formula (IV') may then be reacted directly in a solvent such as ethanol or isopropanol, particularly at a temperature in the range of 100-140°C, for example for a period in the range of 1 hour to 3 hours, to synthesize a compound of formula (I) where Ar, R1 and R2 are as defined above and R3 is selected from a (C1-C4) alkyl group or a (C1-C4) fluoroalkyl group.

[0062] Compounds of formula (VI), formula (VI') and formula (V) are either commercially available or may be obtained by methods known to those skilled in the art.

[0063] As described above, the present invention relates to a compound represented by formula (II) [ka] wherein Ar, R1 and R2 are as defined above, Formula (III) [ka] There is also provided a process for preparing a compound of formula (I) as above, wherein Ar, R1 and R2 are as defined above and R3 is a halogen atom, by reacting a succinimide derivative of the formula (I) as above, wherein R3 is a halogen atom, with a phenyl group of the formula (I) as above, wherein R3 is a halogen atom, under an inert atmosphere in a solvent such as tetrahydrofuran, dichloromethane, chloroform or toluene.

[0064] In particular, the present invention relates to a compound of formula (VI) [ka] With a compound of formula (V) [ka] wherein Ar, R1 and R2 are as defined above, to obtain a compound of formula (II).

[0065] As described above, the present invention relates to a compound represented by formula (VI') [ka] (wherein Ar and R1 are as defined above, and R3 is selected from a (C1-C4) alkyl group or a (C1-C4) fluoroalkyl group), [ka] wherein Ar, R1 and R2 are as defined above and R3 is selected from a (C1-C4)alkyl group or a (C1-C4)fluoroalkyl group, by reacting a compound of formula (I) as above with a compound of formula (I)

[0066] Pathological condition As used herein, unless otherwise stated, "cancer" may refer to any disorder associated with abnormal cell growth, and thus includes malignant and benign, metastatic and non-metastatic, solid and non-solid tumors. In particular, cancer encompasses metastasis and / or dysplasia, as well as precancerous conditions, early cancers or non-metastatic cancers.

[0067] By "early stage cancer" or "early stage tumor" is meant a cancer that is not invasive or metastatic, or is classified as stage 0, I, or II.

[0068] The term "precancerous" refers to a condition or growth that typically precedes or develops into cancer. A "precancerous" growth is one having cells characterized by abnormal cell cycle regulation, proliferation or differentiation, as can be determined by markers of cell cycle regulation, cell proliferation or differentiation.

[0069] Unless otherwise specified, the term "cancer" also encompasses early onset and non-early onset cancers, recurrent and non-recurrent cancers, and relapses of cancer.

[0070] "Metastasis" means the spread of cancer from its primary site to other parts of the body. Cancer cells can break off from the primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow at distant foci in other normal tissues in the body (metastasize). Metastasis can be local or distant.

[0071] "Non-metastatic" means cancer that is benign or confined to the primary site and has not penetrated into the lymphatic or vascular system or into tissues outside the primary site. Generally, non-metastatic cancers are any stage 0, I, or II cancers.

[0072] References to a tumor or cancer being "Stage 0," "Stage I," "Stage II," "Stage III," or "Stage IV" refer to the classification of the tumor or cancer using a comprehensive staging system or Roman numeral staging known in the art. The actual stage of a cancer depends on the type of cancer, but generally, stage 0 cancer is a disease in situ, stage I cancer is a small localized tumor, stage II is a locally aggressive tumor, stage III cancer has invaded lymph nodes or surrounding tissues, and stage IV cancer is a metastatic cancer. The specific stages of each type of tumor are known to those of skill in the art.

[0073] As used herein, "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.

[0074] By "primary tumor" or "primary cancer" is meant the original cancer, and not a metastatic lesion located in another tissue, organ, or site within the subject's body.

[0075] As used herein, "cancer recurrence" refers to the return of cancer after treatment, and includes the return of cancer in the organ of origin and distant recurrence, i.e., the return of cancer outside the organ of origin.

[0076] The compounds of formula (I), as defined above, are useful for treating and / or preventing cancer, in particular for treating and / or preventing solid tumours, in particular neuroblastoma, colorectal cancer, androgen-induced bladder cancer, lung cancer, hepatocellular carcinoma, prostate cancer, breast cancer, esophageal cancer and thyroid cancer.

[0077] Said autoimmune disorders induce chronic inflammatory diseases, a group of which is provided herein: inflammatory bowel disease, systemic lupus erythematosus, childhood acute lymphoblastic leukemia, inflammatory myopathies and rheumatoid arthritis.

[0078] Other autoimmune diseases which may be mentioned within the framework of the present invention include multiple sclerosis (MS), type 1 diabetes, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy and psoriasis.

[0079] The compounds of formula (I), as defined above, are useful for treating and / or preventing neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease or tauopathies (e.g. progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration or Pick's disease); brain trauma, such as ischemia and cranial trauma and epilepsy; psychiatric disorders, such as schizophrenia, depression, substance addiction or attention-deficit hyperactivity disorder; inflammatory diseases of the central nervous system, such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis, as well as other inflammatory diseases, such as vascular pathologies, atherosclerosis, joint inflammation, arthropathy or rheumatoid arthritis; osteoarthritis, Crohn's disease, ulcerative colitis; allergic inflammatory diseases, such as asthma; autoimmune diseases, such as type 1 diabetes, lupus, scleroderma, Guillain-Barré syndrome, Addison's disease and other immune-mediated diseases; osteoporosis; or cancer.

[0080] Further described herein is a compound of formula (I) as defined above for use in treating and / or preventing a neurodegenerative disorder. Further described herein is a compound of formula (I) as defined above for use in which the neurodegenerative disorder is Parkinson's disease. Further described herein is a compound of formula (I) as defined above for use in which the neurodegenerative disorder is Alzheimer's disease. Further described herein is a compound of formula (I) as defined above for use in which the neurodegenerative disorder is tauopathy.

[0081] Further described herein is a compound of formula (I) as defined above for use, wherein the tauopathy is progressive supranuclear palsy. Further described herein is a compound of formula (I) as defined above for use, wherein the tauopathy is frontotemporal dementia. Further described herein is a compound of formula (I) as defined above for use, wherein the tauopathy is corticobasal degeneration. Further described herein is a compound of formula (I) as defined above for use, wherein the tauopathy is Pick's disease.

[0082] Further described herein is a compound of formula (I) as defined above for use in treating and / or preventing brain trauma. Further described herein is a compound of formula (I) as defined above for use in which the brain trauma is ischemia. Further described herein is a compound of formula (I) as defined above for use in which the brain trauma is cranial trauma. Further described herein is a compound of formula (I) as defined above for use in which the brain trauma is epilepsy.

[0083] Further described herein is a compound of formula (I) as defined above for use in treating and / or preventing a psychiatric disorder. Further described herein is a compound of formula (I) as defined above for use in which the psychiatric disorder is schizophrenia. Further described herein is a compound of formula (I) as defined above for use in which the psychiatric disorder is depression. Further described herein is a compound of formula (I) as defined above for use in which the psychiatric disorder is substance addiction. Further described herein is a compound of formula (I) as defined above for use in which the psychiatric disorder is attention deficit hyperactivity disorder.

[0084] Further described herein is a compound of formula (I) as defined above for use in treating and / or preventing an inflammatory disease of the central nervous system. Further described herein is a compound of formula (I) as defined above for use in which the inflammatory disease of the central nervous system is multiple sclerosis. Further described herein is a compound of formula (I) as defined above for use in which the inflammatory disease of the central nervous system is encephalitis. Further described herein is a compound of formula (I) as defined above for use in which the inflammatory disease of the central nervous system is myelitis. Further described herein is a compound of formula (I) as defined above for use in which the inflammatory disease of the central nervous system is encephalomyelitis.

[0085] Further described herein are compounds of formula (I) as defined above for use in treating and / or preventing other inflammatory diseases. Further described herein are compounds of formula (I) as defined above for use in which the other inflammatory disease is a vascular condition. Further described herein are compounds of formula (I) as defined above for use in which the other inflammatory disease is atherosclerosis. Further described herein are compounds of formula (I) as defined above for use in which the other inflammatory disease is joint inflammation. Further described herein are compounds of formula (I) as defined above for use in which the other inflammatory disease is arthropathy. Further described herein are compounds of formula (I) as defined above for use in which the other inflammatory disease is rheumatoid arthritis. Further described herein are compounds of formula (I) as defined above for use in which the other inflammatory disease is osteoarthritis. Further described herein are compounds of formula (I), as defined above, for use, wherein the other inflammatory disease is Crohn's disease. Further described herein are compounds of formula (I), as defined above, for use, wherein the other inflammatory disease is ulcerative colitis.

[0086] Further described herein are compounds of formula (I), which are as defined above, for use for treating and / or preventing osteoporosis.

[0087] The compounds of formula (I), as defined above, are useful for treating and / or preventing rheumatoid arthritis, atherosclerosis, diabetes, Parkinson's disease, psychiatric disorders such as schizophrenia, depression, substance addiction or attention deficit hyperactivity disorder, and cancer.

[0088] Administration of Compounds of Formula (I) The compounds of formula (I) defined above may be formulated into pharmaceutical compositions, in particular medicaments, suitable for administration to patients.

[0089] Thus, the present invention further relates to a pharmaceutical composition or medicament comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0090] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or any pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use in the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer.

[0091] In particular, the present invention relates to a medicament comprising a compound of formula (I) or any pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer.

[0092] Alternatively, the present invention relates to the use of a compound of formula (I) or any of its pharma- ceutically acceptable salts as defined above for the manufacture of a pharmaceutical composition or medicament for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, brain trauma, psychiatric disorders and / or inflammatory diseases, more particularly cancer.

[0093] According to another aspect, provided herein is a method of treating the above-noted pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In one embodiment of this method of treatment, the subject is a human.

[0094] The pharma- ceutically acceptable excipient is more particularly selected from a pharmaceutical carrier, adjuvant or vehicle.

[0095] The selection of an acceptable excipient for use in combination with the compounds of formula (I) as defined herein is part of the general knowledge of a person of ordinary skill in the formulation of pharmaceutical compositions, particularly medicaments.

[0096] Such excipients are well known to those skilled in the art and are described, inter alia, in "Ullman's Encyclopedia of Industrial Chemistry, 6th Edition" (Various Editors, 1989-1998, Marcel Dekker & Co.) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (Ansell et al., 1994, Williams & Wilkins).

[0097] The above excipients are selected depending on the dosage form and the desired mode of administration.

[0098] The compounds and compositions of the present invention may be administered in any manner, including but not limited to, orally, parenterally, sublingually, transdermally, vaginally, rectally, mucosally, topically, intranasally by inhalation, via buccal or intranasal administration, ophthalmically, or via an implanted reservoir, or any combination thereof. Parenteral administration includes but is not limited to intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, intraarticular, intrasynovial, intrasternal, intrahepatic, intralesional, intratracheal, and intracranial injection or infusion techniques. The compositions of the present invention may be administered in the form of implants and slow controlled intravenous drips that allow for slow release of the composition.

[0099] For example, the compounds of formula (I) may be present, together with suitable excipients, in any pharmaceutical form suitable for enteral or parenteral administration, such as plain or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories, or drinkable preparations such as suspensions and syrups, or injectable solutions or suspensions.

[0100] The composition of the present invention in sterile injectable form may be an aqueous or oily suspension. These suspensions are formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0101] Orally acceptable dosage forms include, but are not limited to, capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Typically, lubricants such as magnesium stearate are also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifying or suspending agent. If necessary, certain sweeteners, flavors or colorings can also be added.

[0102] Alternatively, the pharma- ceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These are prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature and liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0103] Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0104] In a particular embodiment, the compounds of formula (I) according to the invention are administered orally or intravenously.

[0105] Such pharma- ceutically acceptable compositions may be contemplated in combination with other active compounds or, alternatively, may contain compounds according to the invention in combination with other active agents.

[0106] The amount of the compounds of the present invention that can be combined with excipients to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0107] The compounds of formula (I) or their bases, acids, zwitterions or salts thereof in pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, in admixture with conventional pharmaceutical excipients, in unit dosage forms, are administered to animals and humans for the treatment of the above disorders or diseases.

[0108] Suitable unit dosage forms include tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions, oral forms such as sublingual, buccal, intratracheal, ocular and intranasal dosage forms, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous forms, rectal dosage forms and implants. For topical application, the compounds of formula (I) may also be used in creams, gels, ointments or lotions.

[0109] As one example, a unit dosage form of a compound of formula (I) in tablet form may include the following components: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Corn starch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0110] There may be special cases in which higher or lower doses are appropriate. According to normal practice, the dose appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

[0111] It is also to be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, combination drug, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in the composition.

[0112] The following examples are offered by way of illustration and are not intended to limit the scope of the invention in any way. EXAMPLES

[0113] Synthesis of 1-chloro-2-(4-chlorophenyl)-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine (1)

[0114] 1. 2-(4-chlorophenyl)-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine In a round bottom flask, 2.0 g of 1H-pyrrolo[3,2-b]pyridin-5-amine and 3.5 g of 2-bromo-4'-chloroacetophenone were placed in 50 ml of dimethoxyethane. The mixture was stirred at ambient temperature for 15 hours and concentrated under reduced pressure. 5.51 g of 2-(5-amino-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl)-1-(4-chlorophenyl)ethanone was obtained. 50 ml of isopropanol was added. The reaction mixture was stirred at 120° C. for 75 minutes, cooled to ambient temperature and concentrated under reduced pressure. 4.0 g of compound was obtained. 1H NMR (CDCI3, δ in ppm): 8.7 (d, 1H); 8.0 (d, 2H); 7.5 (d, 2H); 7.49 (s, 1H); 7.4 (d, 1H); 7.2 (d, 1H); 6.8 (d, 1H).

[0115] 2. 1-Chloro-2-(4-chlorophenyl)-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine In a round bottom flask, 380 mg of the compound obtained in step 1 was placed in 6 ml of tetrahydrofuran at -10° C. under argon. 180 mg of N-chlorosuccinimide was added in portions with stirring. The mixture was stirred at -10° C. for 1 hour. Distilled water was then added. The reaction mixture was stirred at ambient temperature for 15 hours. A precipitate was formed, which was collected by filtration, washed with water and dried in an oven under reduced pressure to give 380 mg of compound. 1H NMR (CDCI3, δ in ppm): 7.22 (m, 1H); 7.3 (d, 1H); 7.45 (m, 1H); 7.52 to 7.62 (m, 3H); 8.12 (m, 2H); 11.9 (s, 1H). M+H = 205; M+H = 303 ; MP: 252℃ EXAMPLES

[0116] biological activity 2.1. Regulation of Nur77-activity on HEK a) Materials and methods HEK293 cells stably expressing Gal4-DBD-FL-NOT, -hNur77, -hNOR1 and Pfr-Luc were obtained by limiting dilution. HEK cells were cultured at 75 cm 2 Cells were grown in flasks in DMEM high glucose 30-2002™ containing 10% calf serum, 250 μg / ml hygromycin, 2 μg / ml doxycycline (for expression induction) and 0.4 mg / ml penicillin. After one week of culture, cells were harvested by trypsinization and then plated in 96-well dishes at a density of 20,000 cells per well in 75 μl of medium. After 24 hours, compounds were added at different concentrations (25 μl per well) for another 24 hours. The medium was removed and 50 μl of Steadyglo (Promega, E2510) was added per well with 50 μl of PBS, left for 15 minutes and measurements were taken. Plates were read using a microplate luminescence reader.

[0117] b) Results IC of a compound of formula (1) as defined above 50 The activity was 10 pM. IC of a compound of formula (2) as defined above 50 The activity was 0.3 pM.

[0118] 2.2. Regulation of Nurr1 – activity on neuroblastoma cell lines a) Materials and methods N2A cells obtained from ATCC were stably transfected with tandemly arranged NBRE8x(50-AAGGTCA-30) linked to a luciferase reporter gene. Each NBRE sequence was separated by 5 nucleotides. N2A was transfected with 75 cm 2Cells were grown in flasks in DMEM containing 10% calf serum, 4.5 g / L glucose and 0.4 mg / ml geneticin. After one week of culture, cells were harvested by trypsinization (0.25%, 30 min) and then plated in 96-well dishes at a density of 60,000 cells per well in 75 μl DMEM without phenol red but containing 4.5 g / l glucose and 10% lipid-free serum from Hyclone. After 24 hours, compounds were added at different concentrations (25 μl per well) and left for another 24 hours. 100 μl Steadylite was added per well, left for 30 minutes and measurements were taken. Plates were read using a microplate fluorescence reader.

[0119] b) Results The EC of the compound of formula (1) is as defined above. 50 The activity was 0.2 nM. The EC of the compound of formula (2) is as defined above. 50 The activity was 0.03 nM.

Claims

1. Formula (I): 【Chemical 1】 (wherein R1 represents a hydrogen atom, a (C １ ~C ４ ) alkyl group, a halogen atom or a (C １ ~C ４ ) fluoroalkyl group, R2 is a hydrogen atom, (C １ ~C ３ ), an alkyl group, (C ３ ~C ６ ), a cycloalkyl group, (C １ ~C ３ ), a fluoroalkyl group, a C(O)NHRa group (where Ra is a (C １ ~C ３ ), an alkyl group) or a halogen atom, R3 represents a hydrogen atom, a (C １ -C ４ alkyl group, a (C １ -C ４ fluoroalkyl group or a halogen atom, Ar represents a (C ５ ~C ６ ) heteroarylene group or a divalent aromatic ring) the compound or a pharmaceutically acceptable salt thereof).

2. The compound of formula (I) according to claim 1, wherein Ar is a phenylene group, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) according to claim 1, wherein R1 and R3 are independently a hydrogen atom or a halogen atom, more specifically a chlorine atom, and R2 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) according to claim 1, which is selected from among the following compounds 【Chemical 2】 or a pharmaceutically acceptable salt thereof, particularly its methanesulfonate.

5. A method for producing a compound of formula (I) wherein Ar, R1 and R2 are as defined in claim 1 and R3 is a halogen atom, which comprises reacting a compound of formula (II) [Chemical 3] (wherein Ar, R1 and R2 are as defined in claim 1) with a succinimide derivative of formula (III) (wherein R3 is a halogen atom) in a solvent such as tetrahydrofuran, dichloromethane, chloroform or toluene under an inert atmosphere. 【Chemical Formula 4】

6. The method according to claim 5, wherein a compound of formula (VI) is reacted with a compound of formula (V) [Chemical Formula 5] (wherein Ar, R1 and R2 are as defined in claim 1) to obtain a compound of formula (II). 【Chemical Formula 6】

7. Formula (VI')

8. 【Chemical Formula 7】 (wherein Ar and R1 are as defined in claim 1, and R3 is (C １ -C ４ ) alkyl group or (C １ -C ４ ) fluoroalkyl group selected from the group consisting of) a compound of formula (V) 【Chemical 8】 React with a compound of (wherein R2 is as defined in claim 1), wherein Ar, R1 and R2 are as defined in claim 1 and R3 is (C １ -C ４ ) alkyl group or (C １ -C ４ ) A process for producing a compound of formula (I) selected from fluoroalkyl groups.

9. A medicament comprising the compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

11. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof for use as a medicament.

12. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of autoimmune disorders, neurodegenerative diseases, brain injuries, mental diseases, inflammatory diseases and / or cancer, more specifically cancer.

13. The compound for use according to claim 11, wherein the cancer is a solid tumor, particularly neuroblastoma, colorectal cancer, androgen-induced bladder cancer, lung cancer, hepatocellular carcinoma, breast cancer, esophageal cancer or thyroid cancer.

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