Imidazo[1,2-b][1,2,4]triazole derivatives for therapeutic use - Patents.com

Abstract

The present invention relates to a compound represented by formula (I): (wherein R1 represents a hydrogen atom, a halogen atom or a (C1-C4) hydroxyalkyl group, R2 represents a (C1-C6) alkyl group, R3 represents a hydrogen atom, a (C1-C4) alkyl group or a halogen atom, and Ar represents a divalent aromatic ring or a (C5-C 11 ) a heteroarylene group, or a pharma- ceutically acceptable salt thereof. The present invention further relates to the therapeutic use thereof, in particular as an anti-cancer agent. [Formula 1] TIFF2024525791000021.tif2899

Description

[Technical field]

[0001] Disclosed herein are imidazo[1,2-b][1,2,4]triazole 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 diseases 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 "Pathological 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 halogen atom, or a (C1-C4) hydroxyalkyl group; R2 represents a (C1-C6) alkyl group; R3 represents a hydrogen atom, a (C1-C4) alkyl group or a halogen atom; Ar is a divalent aromatic ring or (C5-C 11 ) represents a heteroarylene group or a pharma- ceutically acceptable salt thereof.

[0040] In the context of the present invention, the terms: "halogen" is understood to mean chlorine, fluorine, bromine or iodine, in particular chlorine, fluorine or bromine, preferably fluorine; As used herein, "(C1-C x )Alkyl" is C1 to C x It refers to a normal, secondary or tertiary monovalent saturated, linear or branched hydrocarbon group, such as (C1-C6) alkyl, including, but not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups; - 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, (C5-C 11) Heteroarylene groups refer to divalent monocyclic aromatic groups or divalent bicyclic aromatic groups, where at least one ring is aromatic and where one to three carbon atoms of the ring are replaced by heteroatoms such as nitrogen, oxygen or sulfur. Examples of heteroaryl groups are, but are not limited to, the divalent groups corresponding to the following heteroaryls: oxazole, isoxazole, pyridine, pyrimidine, pyridazine, triazine, pyrazine, oxadiazole, furan, pyrazole, thiazole, isothiazole, thiadiazole, imidazole, triazole, indole, etc. Within the framework of the present invention, the heteroarylene group is advantageously an indolylene group.

[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 trifluoroacetic 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 compound of formula (I) as defined above, R1 is a halogen atom, in particular a fluorine atom, or a -CH2OH group, R2 and R3 are as defined above; Ar is a phenylene group or an indolylene group.

[0046] In another embodiment, in the compounds of formula (I) as defined above, R2 is a methyl group; R3 is a hydrogen atom or a fluorine atom.

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

[0048] A compound of the following formula (1) [ka] is also called 6-[2-(4-fluorophenyl)-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl]-1H-indole, hereinafter referred to as compound (1).

[0049] A compound of the following formula (2) [ka] is also known as 5-(3-fluorophenyl)-2-(4-fluorophenyl)-4-methyl-4H-imidazo[1,2-b][1,2,4]triazole.

[0050] A compound of the following formula (3) [ka] is also known as [3-(4-methyl-5-phenyl-4H-imidazo[1,2-b][1,2,4]triazol-2-yl)phenyl]methanol.

[0051] The compounds of formula (I) may be prepared by conventional methods of organic synthesis practiced by those skilled in the art.

[0052] Those skilled in the art can refer to, for example, the contents of WO2009 / 144392.

[0053] 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.

[0054] 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.

[0055] [ka]

[0056] According to Scheme 1, where Ar, R1 and R3 are as defined above, a compound of formula (II) can be reacted with a catalyst such as a palladium catalyst, e.g. - palladium acetate in a solvent such as toluene, in particular under an inert atmosphere, for example under argon, in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, or -tetrakis(triphenylphosphine)palladium(0) in acetonitrile and toluene; Formula (III) [ka] where R1 is as defined above. The reaction is then heated to reflux in the presence of a base such as K3PO4 or Na2CO3 to give a compound of formula (I).

[0057] When Ar is an indenylene group, the N atom can be protected with a phenylsulfonyl group or a tosylate group in all reaction steps described herein for the intermediate compounds (IIa) and (IVa) described below.

[0058] The compound of formula (II) which makes it possible to obtain compound (1) is called 1-(benzenesulfonyl)-6-(2-bromo-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl)indole (compound (IIa)).

[0059] The compound of formula (II) which makes it possible to obtain compound (2) is called 2-bromo-5-(3-fluorophenyl)-4-methyl-4H-imidazo[1,2-b][1,2,4]triazole (compound (IIb)).

[0060] The compound of formula (II) which makes it possible to obtain compound (3) is called 2-bromo-4-methyl-5-phenyl-4H-imidazo[1,2-b][1,2,4]triazole (compound (IIc)).

[0061] Compounds of formula (II) are prepared according to Scheme 2 below.

[0062] [ka]

[0063] According to scheme 2, where Ar, R2 and R3 are as defined above, in step 1, a compound of formula (VI) is mixed with a solution containing a metal bromide, such as copper bromide, in a solvent such as ethyl acetate and refluxed. Said process is described in WO2009 / 144392, page 38, point 6.4. The mixture is refluxed, for example, for 3 to 6 hours, to obtain a compound of formula (V), where R3 is as defined above. After this step 1, step 2 is carried out by mixing said compound of formula (V) with 3,5-dibromo-1,2,4-triazole in a solvent such as dichloromethane, dimethylformamide or dimethylsulfoxide, and stirring the mixture at room temperature, for example, for 10 to 20 hours, to obtain a compound of formula (IV), where Ar and R3 are as defined above.

[0064] Step 3 allows the formation of compound (II) by reacting the compound of formula (IV) obtained in step 2 in the presence of a solution containing an amine of formula H2NR2 (wherein R2 is a (C1-C6) alkyl group) in a solvent such as toluene, benzene or dichloromethane, for example at a temperature range of 120-160°C, in particular for a period of 20-30 hours.

[0065] Thus, in this specification, the formula (IV) [ka] There is also provided a process for preparing a compound of formula (II) above, which comprises reacting a compound of formula HNR, wherein Ar and R are as defined above, with an amine of formula HNR, wherein R is as defined above, in a solvent such as toluene, benzene or dichloromethane, at a temperature range, for example, of 120-160° C., in particular for a period of 20-30 hours.

[0066] The compound of formula (IV) which makes it possible to obtain compound (1) is called 1-[1-(benzenesulfonyl)indol-6-yl]-2-(3,5-dibromo-1,2,4-triazol-1-yl)ethenone (compound (IVa)).

[0067] The compound of formula (V) which gives access to compound (1) is called 2-bromo-1-[1-(phenylsulfonyl)indol-6-yl]ethanone.

[0068] The compound of formula (VI) which gives access to compound (1) is called 6-acetyl-1-(phenylsulfonyl)indole.

[0069] Compounds of formula (VI) are prepared according to Scheme 3 below.

[0070] [ka]

[0071] According to scheme 3, where R3 is as defined above, step 1 can be carried out according to WO2009 / 144392, page 37, points 6.1 to 6.3.

[0072] Compounds of formula (VIII) and formula (IX) are either commercially available or may be obtained by methods known to those skilled in the art.

[0073] As described above, the present invention relates to a compound represented by formula (II) [ka] wherein Ar, R2 and R3 are as defined above, is reacted with a catalyst such as a palladium catalyst, for example: - palladium acetate in a solvent such as toluene, in particular under an inert atmosphere, for example under argon, in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, or -tetrakis(triphenylphosphine)palladium(0) in acetonitrile and toluene; Formula (III) [ka] There is also provided a process for preparing a compound of formula (I) by reacting in the presence of a compound of the formula:

[0074] Also provided herein are intermediate compounds selected from compounds of formula (IIa) and (IVa). [ka]

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Unless otherwise specified, the term "cancer" also encompasses early onset and non-early onset cancers, recurrent and non-recurrent cancers, and relapses of cancer.

[0079] "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.

[0080] "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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] Further described herein are compounds of formula (I), which are as defined above, for use for treating and / or preventing osteoporosis.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] The pharma- ceutically acceptable excipient is more particularly selected from a pharmaceutical carrier, adjuvant or vehicle.

[0104] 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.

[0105] 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).

[0106] The above excipients are selected depending on the dosage form and the desired mode of administration.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] In a particular embodiment, the compounds of formula (I) according to the invention are administered orally or intravenously.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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

[0119] 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.

[0120] 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.

[0121] The following examples are offered by way of illustration and are not intended to limit the scope of the invention in any way. EXAMPLES

[0122] Synthesis of 6-[2-(4-fluorophenyl)-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl]-1H-indole (1)

[0123] 1. N-Methoxy-N-methylindole-6-carboxamide (as described on page 36 of WO 2009 / 144392) In a round-bottom flask, 5.0 g of indole-6-carboxylic acid, 3.3 g of N,O-dimethylhydroxylamine hydrochloride, 11.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 10 ml of pyridine were placed in 150 ml of tetrahydrofuran. The mixture was stirred at ambient temperature for 40 hours. The mixture was concentrated, the residue was taken up and placed in 150 ml of ethyl acetate and 50 ml of water. The organic phase was washed with 50 ml of 1N sodium hydroxide solution and 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. 6.8 g of compound was obtained. 1H NMR (CDCI3, δ in ppm): 3.3 (s, 3H); 3.5 (s, 3H); 6.45 (m, 1H); 7.25 (t, 1H); 7.4 (dd, 1H);7.55 (d, IH); = 205

[0124] 2. N-Methoxy-N-methyl-1-(phenylsulfonyl)indole-6-carboxamide (as described on page 36 of WO2009 / 144392) In a round-bottom flask, 6.8 g of the compound obtained in step 1, N-methoxy-N-methylindole-6-carboxamide, were placed in 100 ml of N,N-dimethylformamide at 0° C. 1.45 g of NaH were added dropwise, followed by 6.52 g of benzenesulfonyl chloride. The mixture was stirred at ambient temperature for 40 hours. 150 ml of water were added, then the mixture was extracted with 60 ml of ethyl acetate. The organic phase was washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, elution being carried out with a heptane / ethyl acetate mixture. 9.5 g of compound was obtained. 1H NMR (CDCl3, δ in ppm): 3,4 (s, 3H); 3.55 (s, 3H); 6.7 (d, IH); 7.45 to 7.6 (m, 5H); 7.7 (d, IH); 7.95 (m, 2H); 8.4 (s, 1H). M+H = 345.

[0125] 3. 6-Acetyl-1-(phenylsulfonyl)indole (as described on page 37 of WO2009 / 144392) In a round-bottom flask, 9.2 g of the compound obtained in step 2, N-methoxy-N-methyl-1-(phenylsulfonyl)indole-6-carboxamide, was placed in 250 ml of tetrahydrofuran at 0° C. under argon. 27 ml of methylmagnesium bromide (3M in diethyl ether) was added dropwise. The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 20 hours. The mixture was cooled to 0° C. and 150 ml of water and 50 ml of saturated ammonium chloride solution were added. The mixture was extracted with 60 ml of ethyl acetate. The organic phase was washed with 40 ml of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. 7.3 g of compound was obtained. 1HNMR (CDCl3, δ in ppm): 2.7 (s, 3H); 6.75 (d, 1H); 7.45 to 7.65 (m, 4H); 7.8 (d, 1H); 7.95 (in, 3H); 8.65 (s, 1H). M+H = 300; Mp = 160 -163℃

[0126] 4. 2-Bromo-1-[1-(phenylsulfonyl)indol-6-yl]ethanone (as described on page 37 of WO2009 / 144392) In a round-bottom flask, 3 g of copper bromide was placed in 120 ml of ethyl acetate and the mixture was brought to reflux. 2 g of 6-acetyl-1-(phenylsulfonyl)indole was added. The mixture was stirred at reflux for 4 hours. The mixture was filtered through paper and then the filtrate was poured into 150 ml of 20% sodium thiosulfate solution. The mixture was extracted with 60 ml of ethyl acetate. The organic phase was washed with 40 ml of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. 2.6 g of compound was obtained. 1HNMR (CDCl3, δ in ppm): 4.45 (s, 2H); 6.65 (d, 1H); 7.35 to 7.55 (m, 4H); 7.7 (d, 1H); 7.9 (m, 3H); 8.6 (s, IH). M+H = 378

[0127] 5. 1-[1-(benzenesulfonyl)indol-6-yl]-2-(3,5-dibromo-1,2,4-triazol-1-yl)ethanone 1.7 g of 3,5-dibromo-1,2,4-triazole and 2.61 ml of diisopropylethylamine were dissolved in 51 ml of dichloromethane and a solution of 2.7 g of 2-bromo-1-[1-(phenylsulfonyl)indol-6-yl]ethanone in 34 ml of dichloromethane was added dropwise. The mixture was stirred at room temperature for 16 hours. The mixture was washed twice with 20 ml of water, the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, elution was carried out with a dichloromethane / ethyl acetate mixture. 2.85 g of compound was obtained. 1H NMR (DMSO-d6, δ in ppm): 6.18 (s, 2H); 7.05 (s, 1H); 7.55 to 7.7 (m, 4H); 7.8 (d, 1H); 8.05 (d, 1H); 8.1 (m, 2H); 8.2 (s, IH); 8.6 (s, IH). M+H = 525

[0128] 6. 1-(Benzenesulfonyl)-6-(2-bromo-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl)indole 500 mg of the compound obtained in step 5 was weighed into a test tube. 10 ml of toluene was added thereto, followed by 0.60 ml of methylamine solution (8M in ethanol). The test tube was sealed and then stirred at 140° C. for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was taken up in 50 ml of dichloromethane and 20 ml of water. The organic phase was washed with 20 ml of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, elution being carried out with a dichloromethane / ethyl acetate mixture. 0.134 g of compound was obtained. 1H NMR (DMSO-d6, δ in ppm): 3.65 (s, 3H); 6.9 (d, 1H); 7.5 (d, 1H); 7.58 to 7.8 (m, 4H); 7.95 (d, 1H); 8.1 (m, 4H); M+H = 457

[0129] 7. 6-[2-(4-fluorophenyl)-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl]-1H-indole In a reactor, 134 mg of the compound obtained in step 6 were placed in 2 ml of toluene and the mixture was degassed with argon for 10 minutes. Then 1.3 mg of palladium acetate, 4.8 mg of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, 125 mg of K3PO4, 53 mg of 4-fluorophenylboronic acid and a few drops of ethanol were added. The reaction mixture was heated at 115°C for 16 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue was then purified by silica gel chromatography, elution being carried out with a dichloromethane / methanol mixture. 44 mg of compound was obtained. 1H NMR (DMSO-d6, δ in ppm): 3.72 (s, 3H); 6.55 (m, 1H); 7.25 (m, 1H); 7.32 (m, 2H); 7.48 (m, 1H); 7.62 (s, 1H); 7.72 (d, 1H); 7.85 (s, 1H); 8.12 (m, 2H); 11.35 (s, 1H); M+H = 332; MP: 256-258℃ EXAMPLES

[0130] 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 2The 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, the 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. The plates were read using a microplate luminescence reader.

[0131] b) Results IC of a compound of formula (1) as defined above 50 The activity was 0.03 nM. IC of a compound of formula (2) as defined above 50 The activity was 0.1 pM. IC of a compound of formula (3) as defined above 50 The activity was 0.9 nM. IC of the trifluoroacetate salt of the compound of formula (2) as defined above 50 The activity was 0.1 pM.

[0132] 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.

[0133] b) Results The EC of the compound of formula (1) is as defined above. 50 The activity was 0.7 nM. The EC of the compound of formula (2) is as defined above. 50 The activity was 63 nM. The EC of the compound of formula (3) is as defined above. 50 The activity was 0.4 nM. The EC of the trifluoroacetate salt of the compound of formula (2) is as defined above. 50 The activity was 63 nM.

Claims

1. Formula (I): 【Chemical 1】 (wherein: R1 represents a hydrogen atom, a halogen atom or a (C １ -C ４ ) hydroxyalkyl group, R2 represents a (C １ ~C ６ ) alkyl group, R3 represents a hydrogen atom, a (C １ -C ４ ) alkyl group or a halogen atom, Ar represents a divalent aromatic ring or a (C ５ -C １１ ) heteroarylene group) the compound of or a pharmaceutically acceptable salt thereof.

2. wherein, R1 is a halogen atom, particularly a fluorine atom, or -CH ２ OH group, and R2 and R3 are as defined in Claim 1, Ar is a phenylene group or an indolylene group, the compound of formula (I) according to Claim 1, or a pharmaceutically acceptable salt thereof.

3. wherein, R2 is a methyl group, R3 is a hydrogen atom or a fluorine atom, the compound of formula (I) according to Claim 1, or a pharmaceutically acceptable salt thereof.

4. The following compound: 【Chemical 2】 selected from one of the compound of formula (I) according to Claim 1, or its pharmaceutically acceptable salt, especially its trifluoroacetate.

5. Formula (II) 【Chemical Formula 3】 (wherein Ar, R2 and R3 are as defined in Claim 1) of the compound with a catalyst such as a palladium catalyst, for example: - especially under an inert atmosphere, for example under argon, in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, palladium acetate in a solvent such as toluene or - tetrakis(triphenylphosphine)palladium(0) in acetonitrile and toluene, Formula (III) 【Chemical Formula 4】 (wherein R1 is as defined in Claim 1) in the presence of the compound of the reaction, a process for producing the compound of formula (I) according to Claim 1.

6. Formula (IV) [Chemical Formula 5] (wherein Ar and R3 are as defined in claim 1) of the compound with the formula H ２ NR2 (wherein R2 is as defined in claim 1) of the amine, for example, in a solvent such as toluene, benzene or dichloromethane, for example, in the temperature range of 120 to 160 ° C, in particular for 20 to 30 hours The method for producing the compound of formula (II) according to claim 5, which is reacted between.

7. Compounds selected from the compounds of formula (IIa) and (IVa) 【Chemical Formula 6】

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

9. A pharmaceutical composition characterized by 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.

10. 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.

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

12. The use according to Claim 11, wherein the cancer is a solid tumor, especially neuroblastoma, colorectal cancer, androgen-induced bladder cancer, lung cancer, hepatocellular carcinoma, breast cancer, esophageal cancer or thyroid cancer Compounds therefor.

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