Imidazo[1,2-b][1,2,4]triazole derivatives for use in therapy

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R1 represents a hydrogen atom, a halogen atom or a (C1-C4)hydroxyalkyl group, R2 represents a (C1-C6)alkyl group, and R3 represents a hydrogen atom, a (C1-C4)alkyl group or a halogen atom, and Ar represents a divalent aromatic ring or a (C5-C11)heteroarylene group. The present invention further relates to the therapeutic use of said compound or of a pharmaceutically acceptable salt thereof, in particular as an anticancer agent.

Description

Technical Field

[0001] This article discloses imidazo[1,2-b][1,2,4]triazole derivatives, their preparation methods and their therapeutic uses, particularly as anticancer agents, especially via the NR4A subfamily of nuclear receptors, such as Nurr1 (also known as NR4A2, NOT, TINUR, RNR-1 or HZF3) and Nurr77 (also known as NR4A1; also known as Nurr77 / TR3 / NGFIB).

[0002] The derivatives can be used in particular to treat diseases such as autoimmune diseases, cancer, neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases, and more particularly cancer. Background Technology

[0003] As used in this article, Nurr1 and Nurr77 are orphan nuclear receptors and belong to group 4A members 2 (NR4A2) and 1 (NR4A1), respectively. They are members of the nuclear receptor superfamily and are expressed as early response genes to regulate the expression of multiple target genes.

[0004] Nurr1 and Nur77 possess the typical structure of nuclear receptors, comprising an N-terminal domain, a DNA-binding domain, and a ligand-binding domain. They share 90% to 95% homology in their DNA-binding domains but differ in their N-terminal domains. Their expression and localization are closely related to their roles in cell proliferation and apoptosis. Furthermore, they are also expressed and functional in the immune system (Front. Immunol., August 3, 2018 | https: / / doi.org / 10.3389 / fimmu.2018.01797).

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

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

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

[0008] Nurr1 and Nur77 have also been shown to have activity in cancer, regulated by multiple cell signaling pathways. 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 be a contributing factor to tumorigenesis.

[0009] The NR4A subfamily is also associated with neurological and nervous system disorders. Specifically, Nurr1 is involved in the regulation of several physiological functions of the human central nervous system, such as memory and learning, and has demonstrated activity in dopamine synthesis and metabolism. Nurr77 is expressed in multiple regions of the brain, and its overexpression improves oxygen and glucose deprivation-induced neurological damage, while its knockdown exacerbates these conditions. Both Nurr1 and Nurr77 are associated with Parkinson's disease.

[0010] Some compounds are known to regulate Nur77, but further research is needed to identify compounds that regulate Nurr1 and Nur77 and their therapeutic activities.

[0011] There is a ongoing need to find new compounds with Nur77 and / or Nurr1 regulatory effects. In particular, there is a need to find new cancer treatments, and especially targeted therapies that attack tumor cells while minimizing their impact on healthy cells. Summary of the Invention

[0012] The inventors have now discovered that compounds defined in the following formula (I) have Nur77 and Nurr1 regulatory effects.

[0013] Therefore, the compound of formula (I) can be used to treat and / or prevent diseases such as autoimmune disorders, cancer, neurodegenerative diseases, brain injuries, mental illnesses and / or inflammatory diseases.

[0014] Therefore, according to a first aspect, the present invention relates to any one of the compounds of formula (I) as defined below or a pharmaceutically acceptable salt thereof.

[0015] This article further provides compounds of formula (I) as defined below for use as pharmaceutical agents.

[0016] This document also provides compounds of formula (I) as defined below for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illnesses, and / or inflammatory diseases, particularly cancer. Compounds of formula (I) can also be used for treatments related to stem cell transplantation and / or grafts.

[0017] This article also provides compounds of formula (I) as defined below for the treatment and / or prevention of neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases.

[0018] This article also provides compounds of formula (I) as defined below for the treatment and / or prevention of autoimmune disorders and cancer.

[0019] This document also provides the use of compounds of formula (I) as defined below for the manufacture of pharmaceutical agents, particularly for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases, and more particularly for cancer.

[0020] Finally, this document provides a pharmaceutical composition comprising any one of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illness, and / or inflammatory diseases, particularly cancer.

[0021] In particular, the present invention relates to an agent comprising any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases, more particularly cancer.

[0022] definition

[0023] As used herein, the term “patient” means an animal (such as a valuable animal used for breeding, companionship or conservation purposes) or preferably a human or human child that has or is likely to have 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, and preferably, the subject is a human.

[0025] The identification of patients requiring treatment for the diseases described herein is entirely within the competence and knowledge of those skilled in the art. Veterinarians or physicians skilled in the art can readily identify those patients requiring such treatment using clinical tests, physical examinations, medical / family history, or biological and diagnostic tests.

[0026] As used herein, in the context of this invention, the term "treating" or "treatment" means preventing, reversing, or alleviating a disease and its resulting cognitive, motor, or metabolic changes; inhibiting the progression of a disease and its resulting cognitive, motor, or metabolic changes; or preventing a disease and its resulting cognitive, motor, or metabolic changes.

[0027] Therefore, the term "treating" or "treatment" within the framework of this invention covers medical conditions that improve the health of patients suffering from diseases as described herein, particularly in the paragraph "pathology".

[0028] As used herein, "effective amount" means the amount of the compound of the present invention that is effective in preventing, reducing, eliminating, treating or controlling the symptoms of the diseases described herein.

[0029] The term “control” is intended to refer to all processes that may slow, interrupt, prevent or stop the progression of the disease described herein, but does not necessarily indicate the complete elimination of all disease and symptom symptoms, and is intended to include preventative treatment.

[0030] The term "effective dose" includes both "preventive effective dose" and "therapeutic effective dose".

[0031] As used herein, the term “prevention” means reducing the risk of a given phenomenon (i.e., in this invention, a disease as described herein) or slowing its occurrence.

[0032] As used in this article, “prevention” also encompasses “reducing the likelihood of it happening” or “reducing the likelihood of it happening again”.

[0033] The term "preventive effective dose" refers to the concentration of the compound of the present invention that effectively inhibits, prevents, or reduces the likelihood of the occurrence of any of the diseases described herein.

[0034] Similarly, the term "therapeutic effective dose" refers to the concentration of a compound that is effective in treating the disease described in this article.

[0035] As used herein, the term “pharmaceutically acceptable” means those compounds, materials, excipients, compositions, or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problematic complications, within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio.

[0036] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with human and lower animal tissues within a reasonable medical judgment without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases, as will become clear from the detailed description below.

[0037] The term “pharmaceuticalally acceptable carrier, adjuvant, or mediator” can refer to any pharmaceutically acceptable excipient, such as a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound formulated with it. Detailed Implementation

[0038] Compound of formula (I)

[0039] The inventors have unexpectedly discovered that compounds of formula (I) disclosed below can be used to prevent and / or treat autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases, especially cancer.

[0040] Therefore, according to a first aspect, the subject matter of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0041]

[0042] in:

[0043] R1 represents a hydrogen atom, a halogen atom, or a (C1-C4) hydroxyalkyl group.

[0044] R2 represents (C1-C6) alkyl.

[0045] R3 represents a hydrogen atom, a (C1-C4) alkyl group, or a halogen atom, and

[0046] Ar represents a divalent aromatic ring or (C5-C) 11 ) Hybrid aryl.

[0047] In the context of this invention, the terminology is:

[0048] - "Halogen" should be understood to mean chlorine, fluorine, bromine or iodine, and especially chlorine, fluorine or bromine, with fluorine preferred;

[0049] -As used in this article, "(C1-C x "alkyl" refers to C1-C1 alkyl groups respectively. x Monovalent saturated straight-chain or branched hydrocarbon groups, such as (C1-C6) alkyl groups. Examples include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.

[0050] According to Hückel's rule, an aromatic ring means that the molecule has 4n+2 π electrons. In one embodiment, the divalent aromatic ring is a phenylene ring.

[0051] -As used in this article, (C5-C 11A heteroarylene refers to a divalent monocyclic aromatic group or a divalent dicyclic aromatic group, wherein at least one ring is aromatic and one to three ring carbon atoms are replaced by heteroatoms (such as nitrogen, oxygen, or sulfur). Examples of heteroarylenes include, but are not limited to, divalent groups corresponding to the following heteroarylenes: oxazoles, isoxazoles, pyridines, pyrimidines, pyridazines, triazines, pyrazines, oxadiazoles, furans, pyrazoles, thiazoles, isothiazoles, thiadiazoles, imidazoles, triazoles, indoles, etc. Within the framework of this invention, a heteroarylene is advantageously an indoleyl group.

[0052] Compounds of formula (I) may exist in the form of pharmaceutically acceptable salts, which are part of this invention; these salts may be prepared with pharmaceutically acceptable acids (such as trifluoroacetic acid) (P. Stahl, C. Wermuth; Handbook of pharmaceutical salts; edited by Wiley), but other salts obtained, for example for the purification or isolation of compounds of formula (I), are part of this invention.

[0053] Specifically, "pharmaceutically acceptable salts" refer to addition salts of inorganic and organic acids.

[0054] Compounds of formula (I) or any pharmaceutically acceptable salt thereof may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0055] The terms "hydrate" and "solvent" simply mean that the compound (I) according to the invention can be in the form of a hydrate or a solvate, i.e., combined or associated with one or more water or solvent molecules. This is merely a chemical characteristic of such compounds, and can be applied to all organic compounds of this type.

[0056] In one implementation, in a compound of formula (I) as defined above,

[0057] R1 is a halogen atom, especially a fluorine atom, or a -CH2OH group.

[0058] R2 and R3 are defined above, and

[0059] Ar is either phenylene or indoleene.

[0060] In another embodiment, in a compound of formula (I) as defined above,

[0061] R2 is a methyl group, and

[0062] R3 is a hydrogen atom or a fluorine atom.

[0063] In another embodiment, the compound of formula (I) is selected from the following compounds or their pharmaceutically acceptable salts, particularly their trifluoroacetate salts:

[0064]

[0065] and

[0066] Or its pharmaceutically acceptable salt.

[0067] The following compound (1)

[0068]

[0069] Also known as 6-[2-(4-fluorophenyl)-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl]-1H-indole, and hereinafter referred to as compound (1).

[0070] The compound of formula (2) below

[0071]

[0072] It is also known as 5-(3-fluorophenyl)-2-(4-fluorophenyl)-4-methyl-4H-imidazo[1,2-b][1,2,4]triazole.

[0073] The compound of formula (3) below

[0074]

[0075] Also known as [3-(4-methyl-5-phenyl-4H-imidazo[1,2-b][1,2,4]triazol-2-yl)phenyl]methanol.

[0076] Compounds of formula (I) can be prepared by conventional organic synthesis methods practiced by those skilled in the art.

[0077] Those skilled in the art may refer, for example, to the contents of WO 2009 / 144392.

[0078] Compounds of formula (I) with different substituents, as well as other related compounds, can be synthesized using the techniques and materials described below or in other ways known to those skilled in the art. Furthermore, the solvents, temperatures, and other reaction conditions given below may be varied as deemed appropriate by those skilled in the art.

[0079] The general method described below for preparing compounds of formula (I) may optionally be modified by using appropriate reagents and conditions to introduce the multiple moieties found in formula (I) as described below.

[0080] Option 1 Preparation of compound (I)

[0081]

[0082] According to Scheme 1, where Ar, R1, and R3 are as defined above, the compound of formula (II) can react with a catalyst, such as a palladium catalyst, for example:

[0083] - Palladium acetate in solvents such as toluene, in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, especially under an inert atmosphere, such as argon, or

[0084] -Tetra(triphenylphosphine)palladium(0) in acetonitrile and toluene,

[0085] In the compound of formula (III) The reaction is carried out in the presence of a base (such as K3PO4 or Na2CO3), where R1 is as defined above. The reaction is then heated to solvent reflux in the presence of a base to give the compound of formula (I).

[0086] When Ar is indenyl, the N atom can be protected by a benzenesulfonyl group or a toluenesulfonate group during all reaction steps as described herein, as in intermediate compounds (IIa) and (IVa) described below.

[0087] Compounds of formula (II) that allow the acquisition of compound (1) are called 1-(benzenesulfonyl)-6-(2-bromo-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl)indole (compound (IIa)).

[0088] The compound of formula (II) that allows the acquisition of compound (2) is called 2-bromo-5-(3-fluorophenyl)-4-methyl-4H-imidazo[1,2-b][1,2,4]triazole (compound (IIb)).

[0089] The compound of formula (II) that allows the production of compound (3) is called 2-bromo-4-methyl-5-phenyl-4H-imidazo[1,2-b][1,2,4]triazole (compound (IIc)).

[0090] The compound of formula (II) can be prepared according to scheme 2 below.

[0091] Option 2:

[0092]

[0093] According to Scheme 2, where Ar, R2, and R3 are as defined above, in step 1, the compound of formula (VI) can be mixed with a solution containing a metal bromide (such as copper bromide) in a solvent (such as ethyl acetate) that has been refluxed. This step is described in WO 2009 / 144392, page 38, point 6.4. The mixture can be refluxed, for example, for 3 to 6 hours, to obtain the compound of formula (V), where R3 is as defined above. After step 1, step 2 can be performed, where the compound of formula (V) is mixed with 3,5-dibromo-1,2,4-triazole in a solvent (such as dichloromethane, dimethylformamide, or dimethyl sulfoxide), and the mixture is stirred at room temperature for, for example, 10 to 20 hours, to obtain the compound of step (IV), where Ar and R3 are as defined above.

[0094] Step 3 allows the formation of compound (II) by reacting a compound of formula (IV) obtained in step 2 in a solvent (such as toluene, benzene or dichloromethane) in the presence of a solution containing an amine of formula H2NR2 (where R2 is (C1-C6)alkyl), for example at a temperature ranging from 120°C to 160°C, particularly for 20 to 30 hours.

[0095] Therefore, this document also provides a method for preparing compounds of formula (II) as described above, wherein the compounds of formula (IV) are...

[0096]

[0097] Ar and R3, as defined above, react with an amine of the formula H2NR2, for example in a solvent such as toluene, benzene or dichloromethane and at a temperature ranging from 120°C to 160°C, particularly over a period of 20 to 30 hours.

[0098] The compound that allows the production of compound (1) of formula (IV) is called 1-[1-(benzenesulfonyl)indol-6-yl]-2-(3,5-dibromo-1,2,4-triazol-1-yl)ketene (compound (IVa)).

[0099] The compound that allows the production of compound (1) of formula (V) is called 2-bromo-l-[l-(benzenesulfonyl)indol-6-yl]ethyl ketone.

[0100] Compounds of formula (VI) that allow the production of compound (1) are called 6-acetyl-l-(benzenesulfonyl)indole.

[0101] The compound of formula (VI) can be prepared according to scheme 3 below.

[0102] Option 3:

[0103]

[0104] According to Scheme 3, where R3 is as defined above, steps 1 to 3 can be performed according to WO 2009 / 144392, page 37, points 6.1 to 6.3.

[0105] The compounds of formulas (VIII) and (IX) are commercially available or can be obtained by methods known to those skilled in the art.

[0106] This article also provides a method for preparing compounds of formula (I) as described above, wherein compounds of formula (II) are...

[0107]

[0108] Ar, R2, and R3, as defined above, are associated with catalysts, such as palladium catalysts, for example:

[0109] - Palladium acetate in solvents such as toluene, in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, especially under an inert atmosphere, such as argon, or

[0110] -Tetra(triphenylphosphine)palladium(0) in acetonitrile and toluene,

[0111] In the compound of formula (III) The reaction occurs in the presence of R1, which is defined above.

[0112] This article also provides intermediate compounds selected from compounds of formulas (IIa) and (IVa).

[0113]

[0114] Pathology

[0115] As used herein, and unless otherwise stated, “cancer” can refer to any disorder associated with abnormal cell growth, and therefore includes malignant and benign tumors, metastatic and non-metastatic tumors, solid and non-solid tumors. In particular, it encompasses metastatic and / or developmental abnormalities, as well as precancerous conditions, early-stage cancer, or non-metastatic cancer.

[0116] "Early-stage cancer" or "early-stage tumor" refers to non-invasive or non-metastatic cancer, or cancer classified as stage 0, stage I, or stage II.

[0117] The term "precancerous" refers to a condition or growth that typically precedes or develops into cancer. Precancerous growth will have cells characterized by abnormal cell cycle regulation, proliferation, or differentiation, which can be identified by markers of cell cycle regulation, cell proliferation, or differentiation.

[0118] Unless otherwise stated, the term “cancer” also includes cancers in adolescents and non-adolescents, recurrent and non-recurrent cancers, and cancer recurrence.

[0119] "Metastasis" refers to the spread of cancer from its primary site to other parts of the body. Cancer cells detach from the primary tumor, penetrate lymphatic vessels and blood vessels, circulate through the bloodstream, and grow in distant lesions in normal tissues elsewhere in the body (metastasis). Metastasis can be local or distant.

[0120] "Non-metastatic" refers to benign cancer or cancer that remains at the primary site and has not yet penetrated into the lymphatic or vascular system or other tissues. Typically, non-metastatic cancer is any of stage 0, I, or II cancer.

[0121] Referring to a tumor or cancer as "Stage 0," "Stage I," "Stage II," "Stage III," or "Stage IV" indicates that the tumor or cancer has been classified using Overall Stage Grouping or Roman Numeral Staging methods known in the art. Although the actual stage of cancer depends on the type of cancer, generally speaking, Stage 0 cancer is an in situ lesion, Stage I cancer is a small localized tumor, Stage II is a locally advanced tumor, Stage III cancer is invasion of lymph nodes or surrounding tissues, and Stage IV cancer indicates metastatic cancer. The specific stage for each type of tumor is known to a skilled clinician.

[0122] As used in this article, “tumor” refers to the growth and proliferation of all proliferative cells (whether malignant or benign), as well as all precancerous and cancerous cells and tissues.

[0123] "Primary tumor" or "primary cancer" refers to the original cancer, rather than a metastatic lesion located in another tissue, organ, or location in the subject's body.

[0124] In this article, "cancer recurrence" refers to the recurrence of cancer after treatment, including recurrence of cancer in the primary organ and distant recurrence, including recurrence of cancer outside the primary organ.

[0125] Compounds of formula (I) as defined above can be used to treat and / or prevent cancer, particularly solid tumors, especially neuroblastoma, colorectal cancer, androgen-induced bladder cancer, lung cancer, hepatocellular carcinoma, prostate cancer, breast cancer, esophageal cancer, and thyroid cancer.

[0126] The autoimmune disorders mentioned can include chronic inflammatory diseases. This article provides a group of such inflammatory diseases: inflammatory bowel disease, systemic lupus erythematosus, childhood acute lymphoblastic leukemia, inflammatory myopathy, and rheumatoid arthritis.

[0127] Other autoimmune diseases that can be cited in the framework of this invention include multiple sclerosis (MS), type 1 diabetes, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and psoriasis.

[0128] Compounds of formula (I) as defined above can be used to treat and / or prevent neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, or tau protein diseases (e.g., progressive supranuclear palsy, frontotemporal dementia, corticobasal degeneration, or Pick's disease); traumatic brain injury, such as ischemic and craniocerebral injury, and epilepsy; mental illnesses such as schizophrenia, depression, substance dependence, 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 diseases, atherosclerosis, joint inflammation, arthropathy, or rheumatoid arthritis; osteoarthritis, Crohn's disease, and 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.

[0129] This document further describes compounds of formula (I) as defined above for the treatment and / or prevention of neurodegenerative disorders. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the neurodegenerative disorder is Parkinson's disease. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the neurodegenerative disorder is Alzheimer's disease. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the neurodegenerative disorder is tau protein disease.

[0130] This document further describes compounds of formula (I) as defined above for the purposes described herein, wherein the tau protein disease is progressive supranuclear palsy. This document further describes compounds of formula (I) as defined above for the purposes described herein, wherein the tau protein disease is frontotemporal dementia. This document further describes compounds of formula (I) as defined above for the purposes described herein, wherein the tau protein disease is cortical-basal ganglia degeneration. This document further describes compounds of formula (I) as defined above for the purposes described herein, wherein the tau protein disease is Pick's disease.

[0131] This document further describes compounds of formula (I) as defined above for the treatment and / or prevention of traumatic brain injury. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the brain injury is local ischemia. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the brain injury is skull injury. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the brain injury is epilepsy.

[0132] This document further describes compounds of formula (I) as defined above for the treatment and / or prevention of mental illnesses. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the mental illness is schizophrenia. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the mental illness is depression. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the mental illness is substance dependence. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the mental illness is attention deficit hyperactivity disorder.

[0133] This document further describes compounds of formula (I) as defined above for the treatment and / or prevention of inflammatory diseases of the central nervous system. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the inflammatory disease of the central nervous system is multiple sclerosis. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the inflammatory disease of the central nervous system is encephalitis. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the inflammatory disease of the central nervous system is myelitis. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the inflammatory disease of the central nervous system is encephalomyelitis.

[0134] This document further describes compounds of formula (I) as defined above for the treatment and / or prevention of other inflammatory diseases. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the other inflammatory disease is a vascular condition. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the other inflammatory disease is atherosclerosis. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the other inflammatory disease is joint inflammation. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the other inflammatory disease is arthropathy. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the other inflammatory disease is rheumatoid arthritis. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the other inflammatory disease is osteoarthritis. This document further describes compounds of formula (I) as defined above for the stated uses, wherein the other inflammatory disease is Crohn's disease. This document further describes compounds of formula (I) as defined above for the purposes described herein, wherein the other inflammatory disease is ulcerative colitis.

[0135] This article further describes compounds of formula (I) as defined above for the treatment and / or prevention of osteoporosis.

[0136] Compounds of formula (I) as defined above can be used to treat and / or prevent rheumatoid arthritis, atherosclerosis, diabetes, Parkinson's disease, mental illnesses (such as schizophrenia, depression, substance dependence or attention deficit hyperactivity disorder) and cancer.

[0137] Application of the compound of formula (I)

[0138] Compounds of formula (I) as defined above can be formulated into pharmaceutical compositions, particularly into agents suitable for administration to patients.

[0139] Therefore, the present invention further relates to pharmaceutical compositions or agents comprising compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0140] The present invention also relates to a pharmaceutical composition comprising any one of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, the pharmaceutical composition being used to treat and / or prevent autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases, more particularly cancer.

[0141] In particular, the present invention relates to an agent comprising any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases, more particularly cancer.

[0142] Alternatively, the present invention relates to the use of any of the compounds of formula (I) as defined above or any pharmaceutically acceptable salt thereof for the preparation of pharmaceutical compositions or agents for the treatment and / or prevention of autoimmune disorders, cancer, neurodegenerative diseases, traumatic brain injury, mental illness and / or inflammatory diseases, more particularly cancer.

[0143] According to another aspect, this document also provides a method for treating the pathological condition indicated above, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment of this treatment method, the subject is a human being.

[0144] Pharmaceutically acceptable excipients are more specifically selected from pharmaceutical carriers, adjuvants, or mediators.

[0145] The selection of one or more acceptable excipients for use in combination with compounds of formula (I) as defined herein is part of the common sense of those skilled in the art in formulating pharmaceutical compositions, particularly pharmaceutical preparations.

[0146] Such excipients are well known to those skilled in the art and noteworthyly described in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition" (edited by multiple authors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, WILLIAMS & WILKINS).

[0147] Select the above excipients according to the dosage form and desired method of application.

[0148] The compounds and compositions of the present invention can be administered in any manner, including but not limited to oral, parenteral, sublingual, transdermal, vaginal, rectal, transmucosal, topical, intranasal inhalation, buccal or intranasal administration, ophthalmic administration, or via implanted receptacles or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, intra-articular, intra-synovial, intrasternal, intrahepatic, intralesional, intratracheal, and intracranial injection or infusion techniques. The compositions of the present invention can also be administered in the form of implants, which allow for slow release of the composition and slow, controlled intravenous infusion.

[0149] For example, compounds of formula (I) may be present in any pharmaceutical form suitable for oral or parenteral administration, in combination with appropriate excipients, such as in plain or coated tablets, hard gelatin, soft-shell capsules and other capsules, suppositories, or drinkable (such as suspensions, syrups) or injectable solutions or suspensions.

[0150] The sterile injectable form of the compositions of the present invention can be an aqueous or oil-based suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixing oils are conventionally used as solvents or suspending media.

[0151] Orally acceptable dosage forms include, but are not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of oral tablets, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added as well. 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 emulsifiers and suspending agents. Sweeteners, flavoring agents, or coloring agents may also be added if desired.

[0152] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the reagent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0153] Such compositions are prepared according to techniques well known in the field of pharmaceutical formulations and can be prepared into solutions in saline using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and / or other conventional solubilizers or dispersants.

[0154] In one specific implementation, the compound of formula (I) according to the invention is administered orally or intravenously.

[0155] Such pharmaceutically acceptable compositions may also be considered in combination with other active compounds, or alternatively may include compounds according to the invention in combination with other active agents.

[0156] The amount of the compounds of the present invention, which can be combined with one or more excipients to produce compositions in a single dosage form, will vary depending on the host being treated and the specific method of administration.

[0157] In pharmaceutical compositions intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, tracheal, nasal, transdermal, or rectal administration, the compound of formula (I) above, or its base, acid, zwitterion, or salt, may be administered in units in a mixture with conventional pharmaceutical excipients to animals and humans for the treatment of the above-mentioned disorders or diseases.

[0158] Appropriate forms of administration include oral forms such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions; sublingual, buccal, intratracheal, intraocular, and intranasal forms; forms for inhalation, external, transdermal, subcutaneous, intramuscular, or intravenous administration; rectal forms; and implants. For external application, compounds of formula (I) in the form of creams, gels, ointments, or lotions may be used.

[0159] As an example, a unit administration form of a compound of formula (I) in tablet form may contain the following components:

[0160] 50.0 mg of compound of formula (I)

[0161]

[0162] There may be specific situations where a higher or lower dose is appropriate. According to general practice, the appropriate dose for each patient is determined by the physician based on the administration method and the patient's weight and response.

[0163] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, as well as the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[0164] The following examples are provided for illustration and are in no way limiting of the scope of the invention.

[0165] Example

[0166] Example 1 Synthesis of 6-[2-(4-fluorophenyl)-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl]-1H-indole (1)

[0167] 1. N-methoxy-N-methylindole-6-carboxamide (as described on page 36 of WO 2009 / 144392)

[0168] 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 h. The mixture was concentrated, and the residue was absorbed into 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 to obtain 6.8 g of the compound.

[0169] 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); 7.75 (s, IH); 8.8 (s, IH). M+H=205

[0170] 2. N-methoxy-N-methyl-1-(benzenesulfonyl)indole-6-carboxamide (as described on page 36 of WO 2009 / 144392)

[0171] In a round-bottom flask, at 0°C, 6.8 g of the compound N-methoxy-N-methylindole-6-carboxamide obtained in step 1 was placed in 100 mL of N,N-dimethylformamide. 1.45 g of NaH was added in portions, followed by 6.52 g of benzenesulfonyl chloride. The mixture was stirred at ambient temperature for 40 h. 150 mL of water was added, and the mixture was then 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, eluting with a heptane / ethyl acetate mixture. 9.5 g of the compound was obtained.

[0172] ¹H NMR (CDCl₃, δ, in ppm): 3,4 (s, 3H); 3.55 (s, 3H); 6.7 (d, 1H); 7.45 to 7.6 (m, 5H); 7.7 (d, 1H); 7.95 (m, 2H); 8.4 (s, 1H). M+H = 345.

[0173] 3,6-Acetyl-1-(benzenesulfonyl)indole (as described on page 37 of WO 2009 / 144392)

[0174] In a round-bottom flask, at 0°C and under argon atmosphere, 9.2 g of the compound N-methoxy-N-methyl-1-(benzenesulfonyl)indole-6-carboxamide obtained in step 2 was placed in 250 mL of tetrahydrofuran. 27 mL of methyl magnesium bromide (3M in diethyl ether) was added dropwise. The mixture was stirred at 0°C for one hour and then at ambient temperature for 20 h. 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 the compound was obtained.

[0175] ¹H NMR (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℃

[0176] 4.2-Bromo-1-[1-(benzenesulfonyl)indol-6-yl]acetone (as described on page 37 of WO 2009 / 144392)

[0177] In a round-bottom flask, 3 g of copper bromide was placed in 120 mL of ethyl acetate, and the mixture was refluxed. 2 g of 6-acetyl-l-(benzenesulfonyl)indole was added. The mixture was stirred under reflux for 4 hours. The mixture was filtered through filter paper, and 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 the compound was obtained.

[0178] ¹H NMR (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, 1H). M + H = 378

[0179] 5,1-[1-(benzenesulfonyl)indol-6-yl]-2-(3,5-dibromo-1,2,4-triazol-1-yl)ethyl ketone

[0180] 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-[l-(benzenesulfonyl)indol-6-yl]acetone in 34 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 16 h. The mixture was washed with 2 x 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, eluting with a dichloromethane / ethyl acetate mixture. 2.85 g of the compound was given.

[0181] 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

[0182] 6,1-(benzenesulfonyl)-6-(2-bromo-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl)indole

[0183] 500 mg of the compound obtained in step 5 was weighed into a tube. 10 mL of toluene was added, followed by 0.60 mL of methylamine solution (8 M in ethanol). The tube was sealed and stirred at 140 °C for 24 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was absorbed 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, eluting with a dichloromethane / ethyl acetate mixture. 0.134 g of the compound was obtained.

[0184] 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

[0185] 7,6-[2-(4-fluorophenyl)-4-methyl-imidazo[1,2-b][1,2,4]triazol-5-yl]-1H-indole

[0186] In a reactor, 134 mg of the compound obtained in step 6 was placed in 2 mL of toluene, and the mixture was degassed with argon for 10 min. 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 h, cooled to ambient temperature, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography using a dichloromethane / methanol mixture. 44 mg of the compound was obtained.

[0187] 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℃

[0188] Example 2: biological activity

[0189] 2.1. Regulation of HEK activity by Nur77

[0190] a) Materials and Methods

[0191] Stable HEK293 cells expressing Gal4-DBD-FL-NOT, -hNur77, -hNOR1, and Pfr-Luc were obtained through limiting dilution. HEK cells were then cultured at 75 cm⁻¹. 2 Flasks containing 10% fetal bovine serum, hygromycin at 250 μg / ml, doxycycline at 2 μg / ml (for inducing expression), and penicillin at 0.4 mg / ml were prepared in DMEM high glucose solution 30-2002. TM Cells were harvested by trypsin digestion after one week of culture and seeded at a density of 20,000 cells per well into 75 μl of culture medium in 96-well plates. After 24 hours, different concentrations of the compound (25 μl per well) were added, followed by another 24 hours. The culture medium was then removed, and measurements were taken by adding 50 μl Steadyglo (Promega, E2510) and 50 μl PBS to each well for 15 minutes, and the plates were read using a microplate chemiluminescence reader.

[0192] b) Results

[0193] IC of compounds of formula (1) as defined above 50 The activity is 0.03 nM.

[0194] IC of compounds of formula (2) as defined above 50 The activity level is 0.1 pM.

[0195] IC of compounds of formula (3) as defined above 50 The activity is 0.9 nM.

[0196] IC50 of the trifluoroacetate of the compound of formula (2) as defined above 50 The activity is 0.1 pM.

[0197] 2.2. Regulation of Nurr1 activity in neuroblastoma cell lines

[0198] a) Materials and Methods

[0199] N2A cells obtained from ATCC were stably transfected with NBRE8x (50-AAGGTCA-30) tandemly coupled to a luciferase reporter gene. Each NBRE sequence was separated by 5 nucleotides. N2A cells were then incubated at 75 cm⁻¹. 2 Cells were grown in DMEM containing 10% fetal bovine serum, 4.5 g / L glucose, and 0.4 mg / ml genimycin in flasks. After one week of culture, cells were harvested by trypsin digestion (0.25%, 30 min) and seeded at a density of 60,000 cells per well into 75 μl of phenol red-free DMEM (containing 4.5 g / L glucose and 10% lipid-free serum from Hyclone) in 96-well dishes. After 24 hours, different concentrations of the compound (25 μl / well) were added, followed by another 24 hours. Measurements were performed by adding 100 μl of Steadylite per well for 30 min, and the plates were read using a microplate fluorescence reader.

[0200] b) Results

[0201] EC of compounds of formula (1) as defined above 50 The activity is 0.7 nM.

[0202] EC of compounds of formula (2) as defined above 50 The activity is 63 nM.

[0203] EC of compounds of formula (3) as defined above 50 The activity is 0.4 nM.

[0204] EC of trifluoroacetate of the compound as defined in formula (2) above 50 The activity is 63 nM.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: R1 represents a halogen atom or a C1-C4 hydroxyalkyl group. R2 represents a C1-C6 alkyl group. R3 represents a hydrogen atom or a halogen atom, and Ar represents phenylene or indoleyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in: R1 is a fluorine atom or a -CH2OH group. Ar, R2, and R3 are as defined in claim 1.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in R2 is a methyl group, and R3 is a hydrogen atom or a fluorine atom.

4. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following compounds: (1) (2) and (3)。 5. A method for preparing a compound of formula (I) according to any one of claims 1 to 3, wherein the compound of formula (II) is... (I) Ar, R2, and R3 are as defined in any one of claims 1 to 3, and are associated with the catalyst. in the presence of a compound of formula (III) (III) wherein R1 is as defined in claim 1 or 2.

6. A method for preparing a compound of formula (II) as defined in claim 5, wherein the compound of formula (IV) is... (IV) Ar and R3, as defined in any one of claims 1 to 3, react with an amine of the formula H2NR2, wherein R2 is defined in any one of claims 1 to 3.

7. A compound selected from those of formulas (IIa) and (IVa): (IIa) and (IVa)。 8. A pharmaceutical preparation, characterized in that... The pharmaceutical preparation comprises a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition, characterized in that... The pharmaceutical composition comprises a 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. Use of a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of autoimmune disorders, neurodegenerative diseases, traumatic brain injury, mental illness, inflammatory diseases, and / or cancer, wherein said cancer is a solid tumor.

11. The use according to claim 10, wherein the cancer is neuroblastoma, colorectal cancer, androgen-induced bladder cancer, lung cancer, hepatocellular carcinoma, breast cancer, esophageal cancer, and / or thyroid cancer.

Images