Novel imidazolone derivatives as inhibitors of protein kinases in specific DYRK1A, CLK1, and / or CLK4

Abstract

The present invention relates to a compound of formula (I) or any pharmaceutically acceptable salt thereof: In the above formula, R1 represents a (C1-C6)alkyl group, a spiro(C5-C11)bicyclic ring, a fused phenyl group, a substituted phenyl group, an R'-L- group (wherein L is a single bond or a (C1-C3)alkanidiyl group, and R' represents a (C3-C8)cycloalkyl group, a bridged (C6-C10)cycloalkyl group, a (C3-C8)heterocycloalkyl group, or a (C3-C8)heteroaryl group), or an R'-L- group (wherein L is a (C1-C3)alkanidiyl group, R' is an optionally substituted phenyl group, and R2 represents a hydrogen atom or a (C1-C3)alkyl group). The present invention also relates to a composition comprising a compound of formula (I), and a process for manufacturing said compound and a synthetic intermediate thereof. Furthermore, said compound relates to said compound for use as a pharmaceutical agent, particularly for cognitive deficits associated with Down syndrome; Alzheimer's disease; dementia; tauopathy; Parkinson's disease; CDKL5 deficiency disorder; Phelan-McDiarmid syndrome; autism; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis; Duchenne muscular dystrophy; a number of cancers; the treatment and / or prevention of neuroinflammation, anemia and viral and unicellular infections, and for regulating body temperature.

Description

Technology Field

[0001] The present invention relates to leucettinib, a class of novel compounds useful as a medicinal agent. The novel compounds are particularly useful as kinase inhibitors, and more particularly as inhibitors of DYRK1A and / or CLK1 and / or CLK4. They are effective for the treatment and / or prevention of cognitive deficits associated with Down syndrome; Alzheimer's disease and related diseases; dementia; tauopathy; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency disorders; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis; Duchenne muscular dystrophy; a number of cancers and leukemias; viral infections; and for regulating body temperature.

[0002] Some of the above compounds are additional inhibitors of other kinases, namely other DYRKs (DYRK1B, 2, 3, 4) and closely related cdc2-like kinases (CLK) (CLK 2, 3, 4). Subsequently, the above compounds may be more effective in treating and / or preventing Phelan-McDermid syndrome; autism; viral infection; cancer; neuroinflammation; anemia; and infection by unicellular parasites.

[0003] In addition, the present invention also relates to a pharmaceutical composition comprising the novel compound and a chemical synthesis method for obtaining the same. Background Technology

[0004] The DYRK and CLK kinase families belong to the CMGC group of kinases, which includes mitogen-activated protein kinase (MAPK), cyclin-dependent kinase (CDK), and glycogen synthase kinase-3 (GSK-3). They phosphorylate many substrates involved in signaling pathways. DYRK and CLK play key roles in mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle, differentiation, homocysteine / methionine / folic acid regulation, endocytosis, neurodevelopment and function, and synaptic plasticity.

[0005] DYRK1A and Down syndrome (DS)

[0006] The gene encoding DYRK1A is located on chromosome 21, specifically in the Down syndrome critical region (DSCR), and its triploidization is involved in most DS-related deficiencies. There is substantial genetic and pharmacological evidence showing that a simple 1.5-fold overexpression of DYRK1A is the cause of most cognitive deficits observed in DS patients, particularly memory and learning deficits (Reference [Rueda N et al., 2020. Translational validity and implications of pharmacotherapies in preclinical models of Down syndrome. Prog Brain Res 251, 245]). Pharmacological or genetic normalization of DYRK1A levels restores cognitive function (Nguyen TL et al., 2017. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature. Expert Opin. Ther. Pat. 27, 1183-1199; Nguyen TL et al., 2018. Correction of cognitive deficits in mouse models of Down syndrome by pharmacological inhibitor of DYRK1A. Dis. Model Mech. 11, dmm035634).

[0007] DYRK1A and Alzheimer's disease (AD), tauopathy

[0008] Evidence regarding the role of DYRK1A in the pathogenesis of AD is increasing. DYRK1A phosphorylates Tau, Septin 4, Amyloid Progenitor Protein (APP), Presenilin 1, Neprilysin, Munc18-1, α-synuclein, RCAN1, and β-Tubulin, which are major substrates associated with AD and dementia. There is evidence of abnormal expression and post-translational modification of DYRK1A in AD. By regulating the alternative splicing of Exon 10, DYRK1A favors the generation of the 3R-Tau splice isoform (a characteristic of DS / AD / tauopathy) over the normal 4R-Tau isoform. Inhibition of DYRK1A promotes autophagy that can offset the autophagic deficiency observed in AD.

[0009] DYRK1A and Parkinson's disease (PD) and Pick's disease

[0010] GWAS studies have revealed that DYRK1A is a risk factor for PD (Nalls MA et al., 2019. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol 18, 1091). DYRK1A phosphorylates key factors of PD such as parkin, septin 4, and α-synuclein. Upregulation of microRNAs specific to PD-targeted DYRK1A expression (Chiu CC et al., 2019. Upregulated expression of microRNA-204-5p leads to the death of dopaminergic cells by targeting DYRK1A-mediated apoptotic signaling cascade. Front Cell Neurosci 13, 399). There is additional evidence that DYRK1A expression is increased in PD. DYRK1A is overexpressed in Pick's disease.

[0011] DYRK1A and other diseases (viral infections, type 1 and type 2 diabetes, cancer)

[0012] DYRK1A and DYRK1B are utilized during HCMV placental replication. Inhibition of DYRK suppresses the replication of various viruses, including herpes simplex viruses, cytomegaloviruses, and HIV-1. DYRK1A inhibitors stimulate the proliferation of pancreatic insulin-producing β-cells, which is a promising approach for type 1 and type 2 diabetes (references [Ackeifi C et al., 2020. Pharmacologic and genetic approaches define human pancreatic β-cell mitogenic targets of DYRK1A inhibitors. JCI Insight 5, e132594; Kumar K et al., 2021. DYRK1A inhibitors as potential therapeutics for β-Cell regeneration for diabetes. J Med Chem. 2021 Mar 8. doi: 10.1021 / acs.jmedchem.0c02050. Epub ahead of print. PMID: 33682417]). There is a lot of literature linking DYRK1A to cancer. The most prominent examples are megakaryoblastic leukemia, acute lymphoblastic leukemia, pancreatic cancer, and brain tumors (glioblastoma).

[0013] Therefore, abnormalities in DYRK1A dosage are associated with cognitive impairment observed in Down syndrome and Alzheimer's disease. DYRK1A is a risk factor for Parkinson's disease. Inhibition of DYRK1A additionally induces proliferation of insulin-producing β cells in the pancreas. Therefore, DYRK1A inhibitors can be applied to the treatment and / or prevention of DS, AD, and other tauopathy, dementia, PD, Niemann-Pick disease type C, CDKL5 deficiency disorder, type 1 and type 2 diabetes, viral infections, numerous cancers (leukemia, pancreatic cancer, glioblastoma), osteoarthritis, and infections caused by monocellular parasites, as well as to thermoregulation.

[0014] Other Dyrk and human diseases

[0015] DYRK1B is involved in the replication of various viruses, including hepatitis C virus, Chikungunya virus, Dengue virus, SARS coronavirus, cytomegalovirus, and human papillomavirus. Similar to DYRK1A, inhibition of DYRK1B induces the proliferation of insulin-producing β cells in the pancreas. DYRK1B is involved in neuroinflammation. Targeting DYRK1B provides a new basis for the treatment of various cancers, such as liposarcoma and breast cancer.

[0016] In relation to GSK-3β, DYRK2 regulates neuronal morphogenesis. DYRK2 is involved in the development of cancer in various ways.

[0017] DYRK3 promotes hepatocellular carcinoma. DYRK3 links stress granule condensation / lysis to mTORC1 signaling. DYRK3 regulates the phase transition of membrane-free organelles during mitosis. DYRK3 and DYRK4 are involved in the regulation of neuronal cytoskeletal organization and process derivatives.

[0018] DYRK1A reduces axon growth, DYRK3 and DYRK4 increase dendritic branching, and DYRK2 reduces axon and dendritic growth and branching.

[0019] CLK and Human Diseases

[0020] Note that CLK is a confusing acronym because it has the following meanings: (a) monooxygenase CLK-1 (human homolog COQ7); (b) polyactive Ca(2+)-dependent lectin collectin-K1 (CL-K1 or CL-11); (c) corn pathogen Curvalaria luneita ( Curvularia lunata), Clk1's MAPK gene; (d) mitochondrial membrane-binding enzyme Clock-1 (CLK-1); (e) Choletotrichum lindemutianum ( Colletotrichum lindemuthianum ) kinase 1(clk1).

[0021] CLK plays an essential role in alternative splicing. CLK acts as a body temperature sensor that controls alternative splicing and gene expression holistically. The activity of CLK is actually highly sensitive to physiological temperature changes, which is conferred by structural rearrangements within the kinase-activating fragment (Haltenhof T et al., 2020. A conserved kinase-based body-temperature sensor globally controls alternative splicing and gene expression. Mol Cell 78, 57).

[0022] CLK1 and human diseases

[0023] CLK1 triggers periodic replacement splicing during the cell division cycle. CLK1 regulates influenza A virus mRNA splicing, and its inhibition inhibits viral replication. CLK1 and CLK2 also regulate HIV-1 gene expression. CLK1 is an autophagy inducer. CLK1 inhibition can suppress chemoresistant gliomas, and CLK1 inhibition by TG693 can cause the omission of the mutated exon 31 of the dystrophin gene in Duchenne muscular dystrophy.

[0024] Other CLK and human diseases

[0025] Inhibition of CLK2 has been proposed as a method to improve neurological function in Phelan-McDiarmid syndrome (PMDS) and to treat intellectual disability and autism. Dual inhibition of CLK2 and DYRK1A by loresibivint is a potential disease-modifying approach for knee osteoarthritis. CLK2 inhibition impairs MYC-induced breast tumors, triple-negative breast cancer, and glioblastoma. Inhibition of CLK2 improves autistic features in Phelan-McDiarmid syndrome (PMDS). Alternative splicing of tau exon 10 is regulated by CLK2 and other CLKs, causing changes in the 3R / 4R isoform ratio and neurodegeneration in sporadic AD. Inhibition of CLK2, CLK3, and CLK4 blocks HIV-1 production. By regulating alternative splicing, CLK controls the balance between pro-apoptotic and anti-apoptotic regulators, and thus, inhibition of CLK can be applied to the treatment of numerous cancers.

[0026] CLK3 is involved in hepatocellular carcinoma and prostate cancer.

[0027] Table 1 below summarizes the significance of DYRK and CLK kinases in various diseases.

[0028] Kinase Target disease DYRK1A Down syndrome (DS) DYRK1A Alzheimer's disease (AD) and other tauopathy DYRK1A Parkinson's disease DYRK1A Pick disease DYRK1A CDKL5 deficiency disorder DYRK1A Type 1 and Type 2 diabetes DYRK1A Folic acid and methionine metabolism disorders DYRK1A glioblastoma DYRK1A Head and neck squamous cell carcinoma DYRK1A pancreatic ductal adenocarcinoma DYRK1A megakaryoblastic leukemia DYRK1A Acute Lymphoblastic Leukemia (ALL) DYRK1A knee osteoarthritis DYRK1A Human Immunodeficiency Virus Type 1 (HIV-1) DYRK1A, DYRK1B Human cytomegalovirus (HCMV) DYRK1B Hepatitis C virus, Chikungunya virus, Dengue fever virus, and Severe Acute Respiratory Syndrome coronavirus, Cytomegalovirus, Human papillomavirus DYRK1B Type 1 and Type 2 diabetes DYRK1B nerve inflammation DYRK1B Liposarcoma, breast cancer, Hedgehog / GLI-dependent cancer DYRK2 Triple-negative breast cancer (TNBC) and multiple myeloma (MM) DYRK2 glioblastoma DYRK3 hepatocellular carcinoma DYRK3 Influenza virus replication DYRK3 anemia DYRK glioblastoma DYRK Herpes simplex virus, cytomegalovirus, varicella-zoster virus LmDYRK1 Leishmania TbDYRK Trypanosoma Blue Say ( Trypanosoma brucei ) CLK1 glioblastoma CLK1 Duchenne muscular dystrophy CLK1 Influenza A CLK2 HIV-1 CLK1 / CLK2 triple-negative breast cancer CLK2 Autism, Phelan-McDiarmid Syndrome (PMDS) CLK2 knee osteoarthritis CLK2 Breast cancer, triple-negative breast cancer, glioblastoma CLK2 Alzheimer's disease (replacement splicing of Tau Exon 10) CLK3 Hepatocellular carcinoma, prostate cancer CLK temperature CLK Prostate cancer, gastrointestinal cancer PfCLK malaria DYRK / CLK Glioblastoma and other neurological cancers

[0029] DYRK and CLK inhibitors

[0030] A number of DYRK1A inhibitors have been reported in recent years. Most DYRK1A inhibitors also inhibit DYRK1B, 2, 3, and 4, which have multiple possible inhibitory properties, as well as the closely related CLK1, 2, 3, and 4.

[0031] Some imidazolone derivatives named leucetin in the following content are disclosed in WO2009 / 050352 as kinase inhibitors, more specifically as inhibitors of DYRK1A kinase.

[0032] As mentioned above, there is still a need to identify novel compounds to treat and / or prevent diseases, particularly through the inhibition of DYRK1A, other DYRK and related CLK kinases, especially through selective inhibition.

[0033] Subsequently, a compound as defined by formula (I) in this specification was found to be useful for the treatment and / or prevention of diseases selected from cognitive deficits associated with Down syndrome; Alzheimer's disease and related diseases; dementia; tauopathy; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency disorder; Phelan-McDiarmid syndrome; autism; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis; a number of cancers and leukemia; neuroinflammation, anemia, infections caused by single-cell parasites, and viral infections, and for regulating body temperature.

[0034] The present invention therefore relates to a compound of formula (I) as defined below.

[0035] The present invention relates to a compound of formula (I) as defined below for use as a pharmaceutical agent.

[0036] The present invention further relates to a compound of formula (I) as defined below for use in the treatment and / or prevention of a disease selected from cognitive deficits associated with Down syndrome; Alzheimer's disease and related diseases; dementia; tauopathy; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency disorder; Phelan-McDiarmid syndrome; autism; type 1 and type 2 diabetes; abnormal folic acid and methionine metabolism; osteoarthritis; a number of cancers and leukemia, neuroinflammation, anemia, infections caused by single-cell parasites, and viral infections, and for regulating body temperature.

[0037] The present invention further relates to a pharmaceutical composition comprising the same and a method for manufacturing the same.

[0038] The present invention relates to a synthetic intermediate of formula (II) as defined below.

[0039] definition

[0040] As used herein, the term “patient” refers to an animal, such as an animal of value for breeding, accommodation, or preservation, that has or is likely to have one or more of the diseases and conditions described herein, or preferably a human or human child.

[0041] In particular, as used in this application, the term "patient" refers to mammals such as rodents, cats, dogs, primates, or humans, preferably said subjects are humans and also extend to birds.

[0042] The identification of patients requiring treatment for the diseases and conditions described herein is within the scope of the ability and knowledge of those skilled in the art. Veterinarians or those skilled in the art can easily identify patients requiring such treatment by using clinical examinations, physical examinations, medical history / family history, or biological and diagnostic tests.

[0043] In the context of the present invention, as used herein, the term “therapeutic” or “therapeutic” means preventing, reversing, alleviating, inhibiting progression or preventing disease and cognitive, motor, or metabolic changes associated with diseases derived from high DYRK1A kinase and / or CLK1 expression and activity, optionally associated with other DYRKs (DYRK1B, 2, 3, 4) and closely related additional cdc2-like kinases (CLK) (CLK 2, 3, 4), more particularly as described later in the “pathology” paragraph.

[0044] Accordingly, the terms “treating” or “treatment” include, within the scope of the present invention, the improvement of the medical condition of a patient suffering from a disease as described later in the “pathology” paragraph, which is associated with high expression and activity of one of DYRK1A and CLK1 kinases, and optionally with abnormalities of other DYRK (DYRK1B, 2, 3, 4) and closely related cdc2-like kinase (CLK) (CLK 2, 3, 4).

[0045] As used herein, "effective amount" refers to an amount of the compound of the present invention effective in preventing, reducing, eliminating, treating, or controlling the symptoms of the diseases and pathological conditions described herein.

[0046] The term "control" is intended to refer to any process capable of delaying, interrupting, inhibiting, or stopping the progression of diseases and pathological conditions described herein, but does not necessarily imply the complete elimination of all symptoms of diseases and pathological conditions, and is intended to include preventive treatment.

[0047] The term "effective dose" includes "preventive effective dose" and "therapeutic effective dose."

[0048] As used in this specification, the term “preventing” means reducing the risk of onset or delaying the onset of a specific phenomenon, namely, a disease caused by abnormal DYRK / CLK kinase activity in the present invention, particularly DYRK1A kinase activity.

[0049] As used in this specification, "inhibiting" also includes "reduction in likelihood of occurrence" or "reduction in likelihood of recurrence."

[0050] The term "preventive effective amount" refers to a concentration of the compound of the present invention that is effective in suppressing, preventing, or reducing the likelihood of any one of the diseases described above.

[0051] Similarly, the term “therapeutic-effective dose” refers to a concentration of a compound effective in treating the disease described above, e.g., DYRK1A and / or CLK1 kinase activity, and optionally additionally inducing a reduction or normalization of DYRK / CLK kinase activity after testing, generally when administered after the onset of the disease.

[0052] As used herein, the term “pharmaceuticalally acceptable” refers to a compound, substance, excipient, composition, or dosage form suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problematic complications, corresponding to a reasonable benefit / risk ratio within the scope of sound medical judgment. Specific details for implementing the invention

[0053] The inventors have surprisingly discovered that a compound of formula (I) as disclosed herein inhibits DYRK1A, other DYRKs (DYRK1B, DYRK2, DYRK3, DYRK4), and CLKs (CLK1, CLK2, CLK3, CLK4). This claim is based on data described in the following examples, which will be described in more detail later.

[0054] According to a first aspect, the subject of the present invention relates to a compound of formula (I) or any pharmaceutically acceptable salt thereof:

[0055]

[0056] In the above equation, R 1 silver:

[0057] (i). -COOR a A (C1-C6)alkyl group substituted by one or two groups selected from a hydroxyl group, a halogen atom, a (C1-C4)alkoxy group and a benzyloxy group (wherein the benzyloxy is optionally substituted at the phenyl group by 1 to 3 halogen atoms),

[0058] (ii). Spiro(C5-C 11 )bicyclic ring,

[0059] (iii). A fused phenyl group selected from a phenyl group fused with a (C5-C6)cycloalkyl or (C5-C6)heterocycloalkyl (wherein the (C5-C6)cycloalkyl and (C5-C6)heterocycloalkyl rings optionally include an insaturation, and a (C1-C4)alkyl group, a hydroxyl group, a halogen atom, a (C1-C3)alkoxy group or -COR a (Selectively substituted by the gi),

[0060] (iv). A phenyl group substituted by one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy, halogen atoms, and (C4-C7)heterocycloalkyl groups (wherein the (C4-C7)heterocycloalkyl group is optionally substituted for itself by a (C1-C4)alkyl group), or

[0061] (v). R'-L- group (wherein L is a (C1-C3)alkanedyl group or a single bond optionally substituted by a group selected from a hydroxyl group and a (C1-C3)alkoxy group, and

[0062] R' is

[0063] (v.1) A (C3-C8) cycloalkyl group optionally substituted by one, two, or three groups selected from (C1-C4) alkyl groups, hydroxyl groups, halogen atoms, and (C1-C3) alkoxy groups,

[0064] (v.2) (C1-C4)alkyl group, (C1-C4)alkoxy group, halogen atom, hydroxyl group, -OC(O)-R d Gi, -OC(O)-NHR d Gi and - NH-C(O)-R d -SO2-R d Gi, -N(R e )2nd term and -COORa Bridged (C6-C) selectively substituted by 1 to 3 groups selected from the group 10 )cycloalkyl group,

[0065] (v.3) -COOR a (C3-C8) heterocycloalkyl group optionally substituted by 1 to 3 groups selected from a hydroxyl group, a halogen atom, a (C1-C4)alkyl group and an oxo group,

[0066] (v.4) Halogen atoms, (C1-C4)alkyl groups, (C1-C4)alkoxy groups and N - A (C3-C8) heteroaryl group optionally substituted by 1 to 3 groups selected from methylpiperazinyl groups, or

[0067] (v.5) Bridged (C6-C 10 )heterocycloalkyl group

[0068] indicates), or

[0069] (vi). R'-L- group(where L is -NR b R c group, (C1-C4)alkoxy group, hydroxyl group, -COOR a It is a (C1-C3)alkanedyl group selectively substituted by a group selected from a halogen atom, and

[0070] R' represents a phenyl group optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups and fluoro(C1-C4)alkoxy groups, halogen atoms and hydroxyl groups, and

[0071] R a represents a (C1-C4)alkyl group or a hydrogen atom,

[0072] R b and R c represents an (C1-C6)alkyl group or a hydrogen atom independently,

[0073] Rd represents a (C1-C4)alkyl group or a cyclopropyl group,

[0074] R e represents a (C1-C3)alkyl group, and

[0075] R 2 represents a hydrogen atom or a (C1-C3)alkyl group.

[0076] The inventors have surprisingly discovered that a compound having a scaffold of the following chemical formulas (A) to (F) exhibits significantly reduced kinase inhibitory activity against DYRK1A and other related kinases compared to its benzothiazole homologue (compound according to the present invention): IC 50 The value decreased by 10 to 1000 times, and some compounds were completely inactivated at the highest dose tested (10 μM).

[0077]

[0078] This significantly reduced kinase inhibitory activity was confirmed, for example, by individual comparison of the compound of formula (I) and compounds having scaffolds of formulas (A) to (F), wherein both R 2 is a hydrogen atom, and R 1 It is selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, and 2-methoxy-1-phenyl-ethyl.

[0079] According to specific embodiments, the present invention relates to a compound of formula (I) as defined above in this specification or any pharmaceutically acceptable salt thereof:

[0080] In the above equation, R 1 silver:

[0081] (i). -COOR aA (C2-C6)alkyl group substituted by one or two groups selected from a hydroxyl group, a halogen atom, a (C1-C4)alkoxy group and a benzyloxy group (wherein the benzyloxy is optionally substituted at the phenyl group by one to three halogen atoms),

[0082] (ii). Spiro(C7-C9) bicyclic ring,

[0083] (iii) A fused phenyl group selected from a phenyl group fused with a cyclopentyl or heterocyclopentyl (wherein the cyclopentyl and heterocyclopentyl groups optionally include unsaturation, a (C1-C4) alkyl group, a hydroxyl group, a halogen atom, a (C1-C3) alkoxy group, or -COR a (Selectively substituted by the gi),

[0084] (iv). A phenyl group substituted by one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy halogen atoms, and (C4-C7)heterocycloalkyl groups (wherein the (C4-C7)heterocycloalkyl group is optionally substituted for itself by a (C1-C4)alkyl group), or

[0085] (v). R'-L- (here,

[0086] · L is a (C1-C3)alkanedyl group or a single bond selectively substituted by a group selected from a hydroxyl group and a (C1-C3)alkoxy group, and

[0087] · R' is

[0088] (v.1) A (C3-C8) cycloalkyl group optionally substituted by one, two, or three groups selected from (C1-C4) alkyl groups, hydroxyl groups, fluorine atoms, and (C1-C3) alkoxy groups,

[0089] (v.2) (C1-C4)alkyl group, (C1-C4)alkoxy group, hydroxyl group, halogen atom, -OC(O)-R dGi, -OC(O)-NHR d Gi, -NH-C(O)-R d -SO2-R d Gi, -N(R e )2nd term and -COOR a Bridged (C7-C) selectively substituted by 1 to 3 groups selected from the group 10 )cycloalkyl group,

[0090] (v.3) -COOR a (C4-C7) heterocycloalkyl group optionally substituted by 1 to 3 groups selected from a hydroxyl group, a halogen atom, a (C1-C4)alkyl group and an oxo group,

[0091] (v.4) Halogen atom, (C1-C4)alkyl group, (C1-C4)alkoxy group, N - A heteroaryl group optionally substituted by 1 to 3 groups selected from the methylpiperazinyl group, or

[0092] (v.5) Bridged (C6-C 10 )heterocycloalkyl group

[0093] indicates), or

[0094] (vi). R'-L- (here,

[0095] · L is -NR b R c group, (C1-C3)alkoxy group, hydroxyl group, -COOR a It is a (C1-C3)alkanedyl group selectively substituted by a group selected from a halogen atom, and

[0096] · R' represents a phenyl group optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups and fluoro(C1-C4)alkoxy groups, hydroxyl groups and halogen atoms, and

[0097] R arepresents a (C1-C4)alkyl group or a hydrogen atom,

[0098] R b and R c represents an (C1-C6)alkyl group or a hydrogen atom independently,

[0099] R d represents a (C1-C4)alkyl group or a cyclopropyl group,

[0100] R e represents a (C1-C3)alkyl group, and

[0101] R 2 represents a hydrogen atom or a (C1-C3)alkyl group.

[0102] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification or any pharmaceutically acceptable salt thereof, wherein R 1 silver:

[0103] (i). -COOCH3 group, hydroxyl group, fluorine atom, methoxy group, ethoxy group, tert - A (C2-C6)alkyl group substituted by one or two groups selected from butoxy, cyclopropoxy, and benzyloxy groups (wherein the benzyloxy is optionally substituted at the phenyl group by a fluorine atom),

[0104] (ii). Spiro(C7-C8) bicyclic rings, in particular spiro[3.3]heptyl, spiro[2.5]octanyl or 7-azaspiro[3.5]nonyl,

[0105] (iii). A fused phenyl group selected from a phenyl group fused with a cyclopentyl or heterocyclopentyl (wherein the cyclopentyl and heterocyclopentyl groups optionally include unsaturation and are optionally substituted by a methyl, hydroxyl, methoxyl, and -COCH3 group),

[0106] (iv). Methyl, hexyl, trifluoromethyl, difluoromethoxy groups, halogen atoms, particularly fluorine atoms, morpholino groups and N - A phenyl group substituted by one or two groups selected from the methylpiperazinyl group, or

[0107] (v). R'-L- group (wherein L is a (C1-C3)alkanedyl group or a single bond optionally substituted by a group selected from a hydroxyl group and a (C1-C3)alkoxy group, and

[0108] R' is

[0109] (v.1). (C3-C8) cycloalkyl groups optionally substituted by one, two, or three groups selected from methyl, isopropyl, hydroxyl, and methoxy groups, particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl,

[0110] (v.2). Bridged (C7-C) optionally substituted by 1 to 3 groups selected from methyl group, methoxy group, hydroxyl group, fluorine atom, -OC(O)-CH3 group, -OC(O)-C(CH3)3 group, -OC(O)-NH-C(CH3)3 group, -NH-C(O)-CH3 group, -NH-C(O)-C3H4 group, -S(O)2-CH3 group, -S(O)2-C3H4 group, -N(CH3)2 group and -C(O)-O-CH3 group. 10 )cycloalkyl groups, particularly adamantyl or bicyclo[3.1.1]heptyl,

[0111] (v.3). -COOR f (C5-C8) heterocycloalkyl groups optionally substituted by 1, 2, or 3 groups selected from hydroxyl groups, methyl groups, and oxo groups, in particular tetrahydropyranyl, piperidinyl, oxetanyl, tetrahydrofuranyl or oxephanyl, tetrahydrothiopyranyl, pyrrolidinyl, dioxephanyl or piperidinyl (R f represents an ethyl or isopropyl group),

[0112] (v.4). Methyl group, methoxy group and N - A heteroaryl group optionally substituted by 1 to 3 groups selected from methylpiperazinyl groups, in particular pyrimidinyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, furyl, or

[0113] (v.5). Bridged (C7-C 10 )cycloalkyl groups, particularly quinuclidein-3-yl

[0114] Selected from a group consisting of), or

[0115] (vi). R'-L- group(where L is -NR b R c group, (C1-C4)alkoxy group, hydroxyl group, -COOR a It is a (C1-C3)alkanedyl group selectively substituted by a group selected from the group consisting of halogen atoms and, in particular, fluorine atoms, and

[0116] R' represents a phenyl group optionally substituted by one or two groups selected from the group consisting of methyl groups, trifluoromethyl groups and trifluoromethoxy groups, and

[0117] R a represents a (C1-C3)alkyl group, and

[0118] R b and R c is independently selected from a methyl group or a hydrogen atom, and

[0119] R 2 represents a hydrogen atom or a (C1-C3)alkyl group.

[0120] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification or any pharmaceutically acceptable salt thereof, wherein R 1is an R'-L- group (where, L is a -CH2- group, -CH(CH3)- group, -CH(CH2OH)-CH2- group, -CH(CH2OH)- group, -CH(CH2OCH3)- group, -CH(OH)-CH2- group, -CH2-CH(CH2OCH3)- group, -CH(OCH3)-CH2- group, -CH2-CH(COOCH3)- group, -CH(CH2F)- group, -CH(CH2NH2)- group, -CH(CH2NHCH3)- group, -CH(CH2N(CH3)2)- group, -CH2-CH(CH2OH)- group, -CH(OCH3)-CH2- group, -CH2-CH(OCH3)- group, -CH2-CH(OH)-CH2- group, -CH2-CH(OCH3)-CH2 group, -(CH2)3- group, It is selected from the group consisting of -(CH2)2- and -CH(CH2OC(CH3)3) groups.

[0121] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification, wherein R 1 The R'-L- group (here,

[0122] (v.1). Where R' is a (C3-C8)cycloalkyl group, L is selected from the group consisting of a single bond, -CH2- group, -CH(CH3)- group, -CH(CH2OH)-CH2- group, -CH(CH2OH)- group, -CH(CH2OCH3)- group, -CH(OH)-CH2- group, and -CH(OCH3)-CH2- group, and

[0123] (v.2). R' is bridged (C7-C 10 ) In the case of a cycloalkyl group, L is a single bond, a -CH2- group, or a -CH(CH3)- group, and

[0124] (v.3). Where R' is a (C5-C8)heterocycloalkyl group containing a spiro(C3-C8)heterocycloalkyl, L is a single bond or a -CH2- group, and

[0125] (v.4). Where R' is phenyl, L is selected from the group consisting of a single bond, -CH2- group, -CH2-CH(COOCH3)- group, -CH(CH2F)- group, -CH(CH2NH2)- group, -CH(CH2NHCH3)- group, -CH(CH2N(CH3)2)- group, -CH2-CH(CH2OH)- group, -CH(CH2OH)- group, -CH(CH2OCH3)- group, -CH(OH)-CH2- group, -CH2-CH(CH2OCH3)- group, -CH2-CH(OH)-CH2- group and -CH2-CH(OCH3)-CH2- group, and

[0126] (v.5). If R' is a heteroaryl group, L is selected from the group including a single bond, -CH2- group, -(CH2)3- group and -(CH2)2- group)

[0127] It represents.

[0128] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification, wherein R 1 silver:

[0129] - an adamantyl group (wherein the adamantyl group is preferably not substituted), optionally substituted by one to three groups selected from -OC(O)-CH3 group, -OC(O)-C(CH3)3 group, -OC(O)-NH-C(CH3)3 group, -NH-C(O)-CH3 group, -NH-C(O)-C3H4 group, -S(O)2-CH3 group, -S(O)2-C3H4 group, -N(CH3)2 group and -C(O)-O-CH3 group, and particularly substituted by one group (wherein the adamantyl group is preferably not substituted); or

[0130] - R"-O-CH2(R"')- (here,

[0131] o R" is a (C1-C4)alkyl group, preferably a methyl or ethyl group, and

[0132] oR"' is a (C1-C4)alkyl group, particularly a (C3-C4)alkyl group, and preferably an isopropylmethyl group,

[0133] o R"' is a phenyl group (wherein the phenyl group is preferably not substituted), which is optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups, fluoro(C1-C4)alkoxy groups, halogen atoms, and hydroxyl groups, and in particular substituted by one group.

[0134] It represents.

[0135] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification or any pharmaceutically acceptable salt thereof, wherein R 1 silver:

[0136] - -COOR a A (C1-C6)alkyl group substituted by one or two groups selected from a hydroxyl group, a fluorine atom, a (C1-C4)alkoxy group and a benzyloxy group (wherein the benzyloxy group is optionally substituted by a halogen atom at its phenyl group),

[0137] - Spiro (C5-C 11 )bicyclic ring, or

[0138] - R'-L- (here,

[0139] o L is a single bond or (C1-C3)alkanidiyl group selectively substituted by a group selected from hydroxyl groups and (C1-C3)alkoxy groups, and

[0140] o R' is

[0141] · A (C3-C8)cycloalkyl group optionally substituted by one, two, or three groups selected from a halogen atom, a (C1-C4)alkyl group, a hydroxyl group, and a (C1-C3) alkoxy group, and

[0142] · (C1-C4)alkyl group, (C1-C4)alkoxy group, halogen atom, hydroxyl group, -OC(O)-R d Gi, -OC(O)-NHR d Ki and -NH-C(O)-R d -SO2-R d Gi, -N(R e )2nd term and -COOR a Bridged (C6-C) optionally substituted by 1 to 3 groups selected from the group 10 )selected from the group consisting of cycloalkyl groups), representing,

[0143] R a represents a (C1-C4)alkyl group, and R d represents a (C1-C4)alkyl group or a cyclopropyl group, and R e represents a (C1-C3)alkyl group, and

[0144] R 2 represents a hydrogen atom or a (C1-C3)alkyl group.

[0145] The above subgroup of the compound is classified as a compound of type "A1" within the present specification following Table 1.

[0146] According to the above embodiment, R 1...is more particularly cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylmethyl, cyclohexyl, cycloheptylmethyl, cycloheptyl, cyclooctyl, 3-hydroxy-2,2-dimethyl-propyl, 2-benzyloxyethyl, 2-methylcyclohexyl, 1-cyclohexylethyl, 1-adamantylmethyl, 1-(1-adamantyl)ethyl, 1-adamantyl, 2-adamantyl, 3,5-dimethyl-1-adamantyl, 5-hydroxy-2-adamantyl, 3-hydroxy-1-adamantyl, 3-methoxy-1-adamantyl, 2,6,6-trimethylnorfinan-3-yl, 6,6-dimethylnorfinan-2-yl, spiro[2.5]octan-2-yl, spiro[3.3]Heptane-2-yl, 1,7,7-trimethylnorbornan-2-yl, norbornan-2-yl, 2-isopropyl-5-methyl-cyclohexyl, 1-(cyclohexylmethyl)-2-hydroxy-ethyl, 1-(cyclopentylmethyl)-2-hydroxy-ethyl, 1-(cyclobutylmethyl)-2-hydroxy-ethyl, 1-(cyclopropylmethyl)-2-hydroxy-ethyl, 1-(hydroxymethyl)-3-methyl-butyl, 1-(methoxymethyl)-3-methyl-butyl, 1-(hydroxymethyl)propyl, 1-(fluoromethyl)-3-methyl-butyl, 1-cyclohexyl-2-hydroxy-ethyl, 1-cyclohexyl-2-methoxy-ethyl, 2-cyclohexyl-2-hydroxy-ethyl, 2-cyclohexyl-2-methoxy-ethyl, 2-hydroxycyclopentyl, 2-methoxycyclopentyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2-methoxycyclohexyl, 4-methoxycyclohexyl, 2-hydroxycycloheptyl, 3-hydroxycycloheptyl, 2-methoxycycloheptyl, -CH(COOCH3)-CH(CH3)2, -CH(COOCH3)-CH3, -CH(COOCH3)-CH2-CH(CH3)2, -CH(COOCH3)-CHOH-CH3, 3,3-difluorocyclopentyl, 4,4-difluorocyclohexyl, 3,3-difluorocyclohexyl, 2,2-difluorocyclohexyl, 3,3-Difluorocycloheptyl, 3-Acetoxy-1-adamanthyl, 3-Pivaloyloxy-1-adamanthyl, 3-Methoxycyclohexyl, 4-Hydroxycycloheptyl, 3-Methoxycycloheptyl, 3-Methoxycycloheptyl, 4-Methoxycycloheptyl, 3-Noradamanthyl, 3-. tert -butylcarbamoyloxy-1-adamantyl, 3-fluoro-1-adamantyl, 1-( tertIt represents -butoxymethyl)-3-methyl-butyl, 3-acetamido-1-adamantyl, 3-(cyclopropanecarbonylamino)-1-adamantyl, 3-(methanesulfonamido)-1-adamantyl, 3-(cyclopropylsulfonylamino)-1-adamantyl, 3-(dimethylamino)-1-adamantyl, 2-methoxycarbonyl-2-adamantyl, 3,5-dihydroxy-1-adamantyl, 3,5,7-trifluoro-1-adamantyl, 1-(ethoxymethyl)-3-methyl-butyl, 1-(benzyloxymethyl)-3-methyl-butyl, 1-[(4-fluorophenyl)methoxymethyl]-3-methyl-butyl or 1-(cyclopropoxymethyl)-3-methyl-butyl.

[0147] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification or any pharmaceutically acceptable salt thereof, wherein R 1 silver:

[0148] - A fused phenyl group selected from a phenyl group fused with a (C5-C6)cycloalkyl or (C5-C6)heterocycloalkyl (wherein the (C5-C6)cycloalkyl and (C5-C6)heterocycloalkyl groups optionally include unsaturation, (C1-C4)alkyl groups, hydroxyl groups, halogen atoms, (C1-C3)alkoxy groups and -COR a (Selectively substituted by the gi),

[0149] - A phenyl group substituted by one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy halogen atoms, and (C4-C7)heterocycloalkyl groups (wherein the (C4-C7)heterocycloalkyl group is optionally substituted for itself by a (C1-C4)alkyl group), or

[0150] - R'-L- (here,

[0151] o L is a hydroxyl group, a (C1-C4)alkoxy group, -NR b R c Gi, -COORa It is a (C1-C3)alkanedyl group selectively substituted by a group selected from a halogen atom, and

[0152] o R' represents a phenyl group optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups and fluoro(C1-C4)alkoxy groups, halogen atoms and hydroxyl groups, and

[0153] R a is a (C1-C4)alkyl or hydrogen atom, and R b and R c is independently selected from (C1-C6)alkyl and hydrogen atoms, and

[0154] R 2 represents a hydrogen atom or a (C1-C3)alkyl group.

[0155] The above subgroups of the compounds are classified into compounds of type "A2" and "A5" within this specification following Table 1.

[0156] According to the above embodiment, R 1 ...is more particularly benzyl, indan-2-yl, (3,4-dimethylphenyl)methyl, (2,4-dimethylphenyl)methyl, [2-(trifluoromethyl)phenyl]methyl, [2-(trifluoromethoxy)phenyl]methyl, 2-hydroxyindan-1-yl, 2-methoxyindan-1-yl, -CH(COOCH3)-CH2-Ph, -CH(CH2F)Ph, 2-amino-1-phenyl-ethyl, 2-(methylamino)-1-phenyl-ethyl, 2-(dimethylamino)-1-phenyl-ethyl, 1-benzyl-2-hydroxy-ethyl, 1-benzyl-2-methoxy-ethyl, 2-hydroxy-1-phenyl-ethyl, 2-methoxy-1-phenyl-ethyl, 2-hydroxy-2-phenyl-ethyl, 2-methoxy-2-phenyl-ethyl, 2-hydroxy-3-phenyl-propyl, 2-methoxy-3-phenyl-propyl, 3-fluoro-4-methyl-phenyl, 4-fluorophenyl, 4- n-hexylphenyl, 4-(4-methylpiperazine-1-yl)phenyl, 3-(difluoromethoxy)phenyl, 1-acetylindolin-6-yl, 3-(trifluoromethyl)phenyl, indan-5-yl, 4-morpholinophenyl, 1-methylindazole-7-yl or 2- tert - It can represent butoxy-1-phenyl-ethyl.

[0157] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification, wherein R 2 represents a hydrogen atom or a methyl group.

[0158] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification or any pharmaceutically acceptable salt thereof, wherein R 1 The R'-L- group (here,

[0159] - R' is a halogen atom, (C1-C4)alkyl group, (C1-C4)alkoxy group and N - A (C3-C8) heteroaryl group selectively substituted by 1 to 3 groups selected from the methylpiperazinyl group, and

[0160] - L represents (C1-C3)alkanedyl or a single bond,

[0161] R 2 It can represent a hydrogen atom.

[0162] The above subgroups of the compounds are classified into compounds of the "A3" and "A6" types within this specification following Table 1.

[0163] According to the above embodiment, R 1...is even more particularly (5-methylpyrazine-2-yl)methyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, (5-methyl-2-furyl)methyl, (4-methylthiazole-2-yl)methyl, 3-imidazole-1-ylpropyl, 2-(2-pyridyl)ethyl, 1,3-benzothiazole-2-ylmethyl, 2-pyrimidinyl, 2-pyridyl, 1-methylpyrazol-3-yl, 2-methoxy-6-methyl-3-pyridyl, pyrimidine-5-yl, 3-pyridyl, 1,3,4-thiadiazole-2-yl, 5-(4-methylpiperazine-1-yl)-2-pyridyl, 6-(4-methylpiperazine-1-yl)-3-pyridyl, It may represent 2-(4-methylpiperazine-1-yl)pyrimidine-5-yl, 5-(4-methylpiperazine-1-yl)pyrimidine-2-yl, 5-(4-methylpiperazine-1-yl)pyrazine-2-yl, or 6-(4-methylpiperazine-1-yl)pyridazine-3-yl.

[0164] According to another specific embodiment, the present invention relates to a compound of formula (I) as defined above in this specification or any pharmaceutically acceptable salt thereof, wherein R 1 The R'-L- group (here,

[0165] - R' is a hydroxyl group, (C1-C4)alkyl group, oxo group, and -COOR a A (C3-C5) heterocycloalkyl group optionally substituted by 1 to 3 groups selected from the group (R a is as defined in the above specification, and

[0166] - L represents methylene or a single bond,

[0167] R 2 represents a hydrogen atom.

[0168] The above subgroups of the compounds are classified into compounds of type "A4" and "A7" within this specification following Table 1.

[0169] According to the above embodiment, R 1 is even more particularly (1-methyl-4-piperidyl)methyl, tetrahydropyran-4-yl-methyl, 1- tert-Butyloxycarbonylpiperidine-4-yl-methyl, 7-methyl-7-azaspiro[3.5]nonane-2-yl, tetrahydropyran-4-yl, 1- tert -butyloxycarbonylpiperidine-4-yl, 1-ethyloxycarbonylpiperidine-4-yl, 1-methyl-4-piperidyl, 1-methyl-3-piperidyl, oxetane-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, 6,6-dimethyltetrahydropyran-3-yl, 4-hydroxytetrahydropyran-3-yl, oxephane-3-yl, 2-oxo-piperidine-3-yl, 2-oxo-piperidine-5-yl, quinuclidein-3-yl, tetrahydrothiopyran-3-yl, 1,4-dioxephane-6-yl, 2-oxo-pyrrolidine-3-yl, 1-methyl-2-oxo-pyrrolidine-3-yl, It may represent 4,4-dimethyl-2-oxo-pyrrolidin-3-yl, 1-methyl-2-oxo-piperidin-3-yl, 3-methyl-2-oxo-pyrrolidin-3-yl, or 1,3-dimethyl-2-oxo-pyrrolidin-3-yl.

[0170] In the context of the present invention, terms:

[0171] - "Halogen" is understood to mean chlorine, fluorine, bromine, or iodine, specifically referring to chlorine, fluorine, or bromine, and

[0172] As used in this specification, "(C1-C x )alkyl" are each C1-C x It refers to normal, secondary, or tertiary monovalent saturated hydrocarbon radicals, e.g., (C1-C6)alkyl groups. Examples are, but are not limited to, methyl, ethyl, propyl, n -Propyl, isopropyl, butyl, isobutyl, sec -butyl, tert - Includes butyl, pentyl, isopentyl, hexyl, and isohexyl groups, etc.

[0173] - "(C1-C3)alkanedil" as used herein is a branched or linear divalent saturated hydrocarbon radical comprising 1 to 3 carbon atoms, more specifically methylene, ethylene, or propylene, e.g. linear propylene or isopropylene, and said alkanedil may be substituted as is apparent from the following description.

[0174] - "(C3-C8)cycloalkyl" as used herein refers to cyclic saturated hydrocarbons having 3 to 8 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0175] - "(C3-C8)heterocycloalkyl group" as used herein refers to a (C3-C8)cycloalkyl group in which one or two carbon atoms are replaced by heteroatoms such as oxygen, nitrogen, or sulfur, more specifically, oxygen or nitrogen atoms. Such heterocycloalkyl groups may be saturated or partially saturated and may be unsubstituted or substituted. Examples include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxephanyl, diazephanyl, dioxanyl, and tetrahydrothiopyranyl, and more particularly piperidinyl and piperazinyl, and more particularly piperazinyl.

[0176] - "(C1-C x ")alkoxy" as used herein, -O-(C1-C x )alkyl or -O-(C3-C x)refers to a cycloalkyl moiety, and alkyl and cycloalkyl are as defined above, e.g., (C1-C6)alkoxy. Examples are not limited to but include methoxy, ethoxy, 1-propoxy, 2-propoxy, cyclopropoxy, butoxy, tert - It is butoxy and pentoxy.

[0177] - "Spiro(C5-C 11 A "bicyclic ring" refers to two rings connected through a single common atom. These spiro-bicyclic alkyls are generally defined as "spiro(C5-C 11 It comprises 5 to 11 carbon atoms designating a "bicyclic alkyl group". In certain embodiments, one or more carbon atoms of the ring are replaced with heteroatom(s), such as oxygen, nitrogen, or sulfur, more particularly, such as nitrogen atoms, to form a spiro(C5-C 11 ) Forms a bicyclic heteroalkyl group. This spirobicyclic ring may be substituted or unsubstituted by at least one (C1-C3)alkyl group, particularly methyl. Examples include, but are not limited to, spiro[3.3]heptanyl, spiro[2.5]octanyl, and 7-azaspiro[3.5]nonanyl.

[0178] - "Bridged (C6-C 10 As used herein, the "cycloalkyl" group refers to a bicyclic or tricyclic compound in which the ring is cycloalkyl, the ring shares three or more atoms, and the bridge comprises at least one atom, e.g., one, two, or three atoms. Such bridged cycloalkyl groups may be substituted with one or more C1-C3 alkyls. Examples include, but are not limited to, adamantyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, 6,6-dimethylbicyclo[3.1.1]heptyl, bicyclo[3.1.1]heptyl, and 1,6,6-trimethylbicyclo[3.1.1]heptyl.

[0179] - "Bridged (C6-C 10The "heterocycloalkyl" group, as used herein, is a bridged (C6-C) group in which one or more carbon atoms of the ring are replaced by heteroatom(s), e.g., oxygen, nitrogen, or sulfur, more specifically, by a nitrogen atom, as defined herein. 10 ) refers to cycloalkyl. Examples include, but are not limited to, quinuclidein-3-yl.

[0180] - "Fused phenyl group" refers to a bicyclic radical that includes a phenyl moiety and can be substituted. The fused phenyl group may be fused to a cycloalkyl or heterocycloalkyl and may be bonded to the rest of the molecule by its phenyl moiety or by the cycloalkyl or heterocycloalkyl. Examples include, but are not limited to, indanyl, acetylindoline, methylindazole, hydroxyindanyl, benzothiazolyl, indole, indazole, methoxyindanyl, etc.

[0181] - (C5-C 11 As used herein, a heteroaryl group refers to a monocyclic aromatic group or a bicyclic aromatic group in which at least one of the rings is aromatic and one to three ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, or sulfur. Examples of heteroaryl groups may be mentioned, but are not limited to: oxazole, isoxazole, pyridine, pyrimidine, pyridazine, triazine, pyrazine, oxadiazole, furan, pyrazol, thiazole, isothiaazole, thiadiazole, imidazole, triazole, etc. Within the scope of the invention, the heteroaryl is advantageously pyridine, imidazole, pyrazine, furan, thiazole, pyrazol, thiadiazole, pyridazine, and pyrimidine.

[0182] - According to Huckel's law, an aromatic ring means that the molecule has 4n + 2 π-electrons.

[0183] - (C1-C x)fluoroalkyl groups, as used herein, in which one or more fluorines are substituted with hydrogen, such as (C1-C as defined herein) x ) refers to an alkyl group. In one embodiment, all hydrogen atoms are replaced with fluorine atoms to form a perfluoroalkyl group such as trifluoromethyl.

[0184] - (C1-C x )fluoroalkoxy as used herein, wherein hydrogen is substituted with one or more fluorines, such as trifluoromethoxy, as defined herein (C1-C x ) refers to an alkoxy. In one embodiment, all hydrogen atoms are replaced with fluorine atoms to form a perfluoroalkoxy group such as trifluoromethoxy.

[0185] In the context of the present invention, the terms "aromatic ring" and "heteroaryl" include all positional isomers.

[0186] The names of the following compounds (1) to (216) were generated using Accelrys Draw 4.1 SP1 in accordance with the principles of the International Union of Pure and Applied Chemistry. To avoid confusion, the "(±)" symbol was added to designate racemic mixtures; the prefixes "cis" and "trans" were also used to designate the relative stereochemistry of two adjacent chiral centers.

[0187] According to a preferred embodiment of the present invention, a compound of formula (I) or any pharmaceutically acceptable salt thereof is selected from the following:

[0188] (1). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclopropylmethylamino)-1 H -Imidazole-5-one,

[0189] (2). (4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclopropylamino)-1 H -Imidazole-5-one,

[0190] (3). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclobutylamino)-1 H -Imidazole-5-one,

[0191] (4). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclopentylamino)-1 H -Imidazole-5-one,

[0192] (5). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclohexylmethylamino)-1 H -Imidazole-5-one,

[0193] (6). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclohexylamino)-1 H -Imidazole-5-one,

[0194] (7). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cycloheptylmethylamino)-1 H -Imidazole-5-one,

[0195] (8). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cycloheptylamino)-1 H -Imidazole-5-one,

[0196] (9). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclooctylamino)-1 H -Imidazole-5-one,

[0197] (10). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-hydroxy-2,2-dimethyl-propyl)amino]-1 H -Imidazole-5-one,

[0198] (11). (4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-(2-benzyloxyethylamino)-1 H -Imidazole-5-one,

[0199] (12). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methylcyclohexyl]amino]-1 H -Imidazole-5-one,

[0200] (13). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-cyclohexylethyl]amino]-1 H -Imidazole-5-one,

[0201] (14). (4 Z )-2-(1-adamantylmethylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,

[0202] (15). (±)-(4 Z )-2-[1-(1-adamantyl)ethylamino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,

[0203] (16). (4 Z )-2-(1-adamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,

[0204] (17). (4 Z )-2-(2-adamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,

[0205] (18). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[3,5-dimethyl-1-adamantyl]amino]-1 H -Imidazole-5-one,

[0206] (19). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[( trans -5-hydroxy-2-adamantyl)amino]-1H -Imidazole-5-one,

[0207] (20). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1 H -Imidazole-5-one,

[0208] (21). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1 H -Imidazole-5-one,

[0209] (22). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R ,3 R ,5 S )-2,6,6-trimethylnorpinan-3-yl]amino]-1 H -Imidazole-5-one,

[0210] (23). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S ,3 S ,5 R )-2,6,6-trimethylnorpinan-3-yl]amino]-1 H -Imidazole-5-one,

[0211] (24). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R ,5 R )-6,6-dimethylnorpinan-2-yl]methylamino]-1 H -Imidazole-5-one,

[0212] (25). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(spiro[2.5]octane-2-ylamino)-1 H -Imidazole-5-one,

[0213] (26). (4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-(spiro[3.3]heptane-2-ylamino)-1 H -Imidazole-5-one,

[0214] (27). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(2 R )-1,7,7-trimethylnorbornan-2-yl]amino]-1 H -Imidazole-5-one,

[0215] (28). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(norbornan-2-ylamino)-1 H -Imidazole-5-one,

[0216] (29). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 S ,5 R )-2-isopropyl-5-methyl-cyclohexyl]amino]-1 H -Imidazole-5-one,

[0217] (30). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclohexylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,

[0218] (31). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclopentylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,

[0219] (32). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclobutylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,

[0220] (33). (4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclopropylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,

[0221] (34). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0222] (35). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(methoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0223] (36). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazole-5-one,

[0224] (37). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(methoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0225] (38). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(hydroxymethyl)propyl]amino]-1 H -Imidazole-5-one,

[0226] (39). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(hydroxymethyl)propyl]amino]-1 H -Imidazole-5-one,

[0227] (40). (±)-(4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[[1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0228] (41). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-cyclohexyl-2-hydroxy-ethyl)amino]-1 H -Imidazole-5-one,

[0229] (42). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-cyclohexyl-2-methoxy-ethyl)amino]-1 H -Imidazole-5-one,

[0230] (43). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-cyclohexyl-2-hydroxy-ethyl)amino]-1 H -Imidazole-5-one,

[0231] (44). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-cyclohexyl-2-methoxy-ethyl)amino]-1 H -Imidazole-5-one,

[0232] (45). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxycyclopentyl]amino]-1 H -Imidazole-5-one,

[0233] (46). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxycyclopentyl]amino]-1 H -Imidazole-5-one,

[0234] (47). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,

[0235] (48). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,

[0236] (49). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0237] (50). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0238] (51). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 S )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0239] (52). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 R )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0240] (53). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0241] (54). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0242] (55). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0243] (56). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0244] (57). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[( trans -4-hydroxycyclohexyl)amino]-1 H -Imidazole-5-one,

[0245] (58). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0246] (59). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0247] (60). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[( trans -4-Methoxycyclohexyl)amino]-1 H -Imidazole-5-one,

[0248] (61). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0249] (62). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0250] (63). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0251] (64). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0252] (65). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0253] (66). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0254] (67). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0255] (68). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0256] (69). Methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H-imidazole-2-yl]amino]-3-methyl-butanoate,

[0257] (70). Methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]propanoate,

[0258] (71). Methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-4-methyl-pentanoate,

[0259] (72). Methyl (2 R )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-4-methyl-pentanoate,

[0260] (73). Methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-3-hydroxy-butanoate,

[0261] (74). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(benzylamino)-1 H -Imidazole-5-one,

[0262] (75). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(indane-2-ylamino)-1 H -Imidazole-5-one,

[0263] (76). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,4-dimethylphenyl)methylamino]-1 H -Imidazole-5-one,

[0264] (77). (4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2,4-dimethylphenyl)methylamino]-1 H -Imidazole-5-one,

[0265] (78). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1 H -Imidazole-5-one,

[0266] (79). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(trifluoromethoxy)phenyl]methylamino]-1 H -Imidazole-5-one,

[0267] (80). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,

[0268] (81). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,

[0269] (82). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,

[0270] (83). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,

[0271] (84). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxyindane-1-yl]amino]-1 H-Imidazole-5-one,

[0272] (85). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans- 2-methoxyindane-1-yl]amino]-1 H -Imidazole-5-one,

[0273] (86). Methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-3-phenyl-propanoate,

[0274] (87). Methyl (2 R )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-3-phenyl-propanoate,

[0275] (88). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-fluoro-1-phenyl-ethyl)amino]-1 H -Imidazole-5-one,

[0276] (89). (±)-(4 Z )-2-[(2-amino-1-phenyl-ethyl)amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride,

[0277] (90). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(methylamino)-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one dihydrochloride,

[0278] (91). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(dimethylamino)-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,

[0279] (92). (±)-(4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-benzyl-2-hydroxy-ethyl)amino]-1 H -Imidazole-5-one,

[0280] (93). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-benzyl-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,

[0281] (94). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-benzyl-2-methoxy-ethyl)amino]-1 H -Imidazole-5-one,

[0282] (95). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1 H -Imidazole-5-one,

[0283] (96). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-2-hydroxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,

[0284] (97). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-2-hydroxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,

[0285] (98). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-1-phenyl-ethyl)amino]-1 H -Imidazole-5-one,

[0286] (99). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-2-phenyl-ethyl)amino]-1 H -Imidazole-5-one,

[0287] (100). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-2-phenyl-ethyl)amino]-1 H -Imidazole-5-one,

[0288] (101). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-3-phenyl-propyl)amino]-1 H -Imidazole-5-one,

[0289] (102). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-3-phenyl-propyl)amino]-1 H -Imidazole-5-one,

[0290] (103). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(5-methylpyrazine-2-yl)methylamino]-1 H -Imidazole-5-one,

[0291] (104). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(2-pyridylmethylamino)-1 H -Imidazole-5-one,

[0292] (105). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-pyridylmethylamino)-1 H -Imidazole-5-one,

[0293] (106). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-pyridylmethylamino)-1 H -Imidazole-5-one,

[0294] (107). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(5-methyl-2-furyl)methylamino]-1 H -Imidazole-5-one,

[0295] (108). (4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[(4-methylthiazole-2-yl)methylamino]-1 H -Imidazole-5-one,

[0296] (109). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-imidazole-1-ylpropylamino)-1 H -Imidazole-5-one,

[0297] (110). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[2-(2-pyridyl)ethylamino]-1 H -Imidazole-5-one,

[0298] (111). (4 Z )-2-(1,3-benzothiazole-2-ylmethylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,

[0299] (112). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-4-piperidyl)methylamino]-1 H -Imidazole-5-one,

[0300] (113). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1 H -Imidazole-5-one,

[0301] (114). Tert -butyl 4-[[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]methyl]piperidine-1-carboxylate,

[0302] (115). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(7-methyl-7-azaspiro[3.5]nonane-2-yl)amino]-1 H -Imidazole-5-one,

[0303] (116). (4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-fluoro-4-methyl-anilino)-1 H -Imidazole-5-one,

[0304] (117). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-fluoroanilino)-1 H -Imidazole-5-one,

[0305] (118). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-hexylanilino)-1 H -Imidazole-5-one,

[0306] (119). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[4-(4-methylpiperazine-1-yl)anilino]-1 H -Imidazole-5-one,

[0307] (120). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[3-(difluoromethoxy)anilino]-1 H -Imidazole-5-one,

[0308] (121). (4 Z )-2-[(1-acetylindolin-6-yl)amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,

[0309] (122). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[3-(trifluoromethyl)anilino]-1 H -Imidazole-5-one,

[0310] (123). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(indane-5-ylamino)-1 H -Imidazole-5-one,

[0311] (124). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-morpholinoanilino)-1 H -Imidazole-5-one,

[0312] (125). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methylindazole-7-yl)amino]-1 H -Imidazole-5-one,

[0313] (126). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(pyrimidine-2-ylamino)-1 H -Imidazole-5-one,

[0314] (127). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(2-pyridylamino)-1 H -Imidazole-5-one,

[0315] (128). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methylpyrazole-3-yl)amino]-1 H -Imidazole-5-one,

[0316] (129). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-6-methyl-3-pyridyl)amino]-1 H -Imidazole-5-one,

[0317] (130). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(pyrimidine-5-ylamino)-1 H -Imidazole-5-one,

[0318] (131). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-pyridylamino)-1 H -Imidazole-5-one,

[0319] (132). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(1,3,4-thiadiazole-2-ylamino)-1 H -Imidazole-5-one,

[0320] (133). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[5-(4-methylpiperazine-1-yl)-2-pyridyl]amino]-1 H-Imidazole-5-one,

[0321] (134). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[6-(4-methylpiperazine-1-yl)-3-pyridyl]amino]-1 H -Imidazole-5-one,

[0322] (135). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(4-methylpiperazine-1-yl)pyrimidine-5-yl]amino]-1 H -Imidazole-5-one,

[0323] (136). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[5-(4-methylpiperazine-1-yl)pyrimidine-2-yl]amino]-1 H -Imidazole-5-one,

[0324] (137). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[5-(4-methylpiperazine-1-yl)pyrazine-2-yl]amino]-1 H -Imidazole-5-one,

[0325] (138). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[6-(4-methylpiperazine-1-yl)pyridazine-3-yl]amino]-1 H -Imidazole-5-one,

[0326] (139). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(tetrahydropyran-4-ylamino)-1 H -Imidazole-5-one,

[0327] (140). Tert -butyl 4-[[(4Z)-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidine-1-carboxylate,

[0328] (141). Ethyl 4-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H-imidazole-2-yl]amino]piperidine-1-carboxylate,

[0329] (142). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-4-piperidyl)amino]-1 H -Imidazole-5-one,

[0330] (143). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-3-piperidyl)amino]-1 H -Imidazole-5-one,

[0331] (144). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(oxetane-3-ylamino)-1 H -Imidazole-5-one,

[0332] (145). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R )-tetrahydrofuran-3-yl]amino]-1 H -Imidazole-5-one,

[0333] (146). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-tetrahydrofuran-3-yl]amino]-1 H -Imidazole-5-one,

[0334] (147). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R )-tetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,

[0335] (148). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-tetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,

[0336] (149). (±)-(4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-1 H -Imidazole-5-one,

[0337] (149A). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-6,6-dimethyltetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,

[0338] (149B). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-6,6-dimethyltetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,

[0339] (150). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ,4 R )-4-hydroxytetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,

[0340] (151). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(oxephane-3-ylamino)-1 H -Imidazole-5-one,

[0341] (152). (±)-3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,

[0342] (153). (3 S )-3-[[(4Z)-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,

[0343] (154). (5 S )-5-[[(4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,

[0344] (155). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,3-difluorocyclopentyl)amino]-1 H -Imidazole-5-one,

[0345] (156). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(4,4-difluorocyclohexyl)amino]-1 H -Imidazole-5-one,

[0346] (157). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,3-difluorocyclohexyl)amino]-1 H -Imidazole-5-one,

[0347] (158). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2,2-difluorocyclohexyl)amino]-1 H -Imidazole-5-one,

[0348] (159). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,3-difluorocycloheptyl)amino]-1 H -Imidazole-5-one,

[0349] (160). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0350] (161). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0351] (162). [3-[[(4Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]acetate,

[0352] (163). [3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl] 2,2-dimethylpropanoate,

[0353] (164). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,

[0354] (165). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,

[0355] (166). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0356] (167). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0357] (168). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0358] (169). (±)-(4 Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0359] (169A).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,3 R ) / (1 S ,3 S )-3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0360] (169B).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,3 R ) / (1 S ,3 S )-3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,

[0361] (170). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -4-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0362] (171). (±)-(4Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -4-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0363] (171A).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,4 R ) / (1 S ,4 S )-4-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0364] (171B).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,4 R ) / (1S ,4 S )-4-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0365] (172). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0366] (173). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0367] (174). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -4-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0368] (175). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -4-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,

[0369] (176). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-2-methoxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,

[0370] (177). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-2-methoxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,

[0371] (178). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(2 R )-2-hydroxy-2-phenyl-ethyl]amino]-1H -Imidazole-5-one,

[0372] (179). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(2 S )-2-hydroxy-2-phenyl-ethyl]amino]-1 H -Imidazole-5-one,

[0373] (180). (4 Z )-2-[[(1 R )-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride,

[0374] (181). (4 Z )-2-[[(1 S )-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride,

[0375] (182). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R )-quinuclidein-3-yl]amino]-1 H -Imidazole-5-one,

[0376] (183). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-quinuclidein-3-yl]amino]-1 H -Imidazole-5-one,

[0377] (184). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(tetrahydrothiopyran-3-ylamino)-1 H -Imidazole-5-one,

[0378] (185). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(1,4-dioxephane-6-ylamino)-1 H -Imidazole-5-one,

[0379] (186). (±)-(4Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-oxopyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,

[0380] (187). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,

[0381] (188). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(4,4-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,

[0382] (189). (3 R )-3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,

[0383] (190). (±)-3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-methyl-piperidin-2-one,

[0384] (191). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-methyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,

[0385] (192). (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1,3-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,

[0386] (192A).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-1,3-dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1H -Imidazole-5-one,

[0387] (192B).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-1,3-dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1 H -Imidazole-5-one,

[0388] (193). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S ,4 S )-4-hydroxytetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,

[0389] (194). (4 Z )-2-(3-noradamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,

[0390] (195). [3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl] N - tert -butylcarbamate,

[0391] (196). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-1 H -Imidazole-5-one,

[0392] (197). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-( tert -butoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0393] (198). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-2- tert -butoxy-1-phenyl-ethyl]amino]-1H -Imidazole-5-one,

[0394] (199). N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]acetamide,

[0395] (200). N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]cyclopropanecarboxamide,

[0396] (201). N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]methanesulfonamide,

[0397] (202). N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]cyclopropanesulfonamide,

[0398] (203). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[3-(dimethylamino)-1-adamantyl]amino]-1 H -Imidazole-5-one,

[0399] (204). Methyl 2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]adamantan-2-carboxylate,

[0400] (205). (4 Z )-2-(cyclohexylamino)-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,

[0401] (206). (4 Z)-2-(cycloheptylamino)-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,

[0402] (207). (4 Z )-2-[[(1 R )-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,

[0403] (208). (4 Z )-2-[[(1 R )-2-methoxy-1-phenyl-ethyl]amino]-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,

[0404] (209). (4 Z )-2-(1-adamantylamino)-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one, and

[0405] (210). (4 Z )-2-[(3-hydroxy-1-adamantyl)amino]-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,

[0406] (211). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,5-dihydroxy-1-adamantyl)amino]-1 H -Imidazole-5-one,

[0407] (212). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,5,7-trifluoro-1-adamantyl)amino]-1 H -Imidazole-5-one,

[0408] (213). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(ethoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0409] (214). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(benzyloxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0410] (215). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-[(4-fluorophenyl)methoxymethyl]-3-methyl-butyl]amino]-1 H -Imidazole-5-one,

[0411] (216). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclopropoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one.

[0412] According to a more preferred embodiment of the present invention, the compound of formula (I) is a compound (4), (5), (6), (7), (8), (9), (12), (13), (14), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (27), (28), (30), (31), (32), (34), (35), (36), (38), (40), (41), (42), (43), (44), (46), (48), (49), (50), (51), (53), (55), (56), (57), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (77), (78), (80), (81), (83), (85), (86), (89), (90), (92), (93), (94), (95), (96), (97), (98), (99), (104), (106), (108), (117), (119), (125), (127), (128), (135), (146), (147), (148), (149), (149A), (149B), (150), (151), (154), (155), (157), (158), (159), (160), (161), (162), (164), (165), (167), (168), (169), (169A), (169B), (170), (171), (171A), It is selected from the group consisting of (171B), (172), (173), (174), (175), (176), (178), (179), (180), (181), (182), (184), (185), (191), (192), (192A), (194), (195), (196), (197), (198), (199), (200), (201), (203), (204), (208), (209), (210) and pharmaceutically acceptable salts thereof.

[0413] According to a more preferred embodiment of the present invention, the compound of formula (I) is a compound (6), (7), (8), (9), (12), (14), (16), (17), (19), (20), (21), (22), (24), (25), (27), (28), (31), (32), (34), (35), (36), (38), (40), (41), (43), (44), (46), (48), (49), (51), (53), (55), (56), (57), (59), (61), (62), (63), (64), (65), (66), (67), (68), (69), (74), (77), (78), (81), (83), (85), (86), (89), (90), (92), (93), (95), (96), (97), (98), (99), (108), (119), (125), (146), (148), (149), (149A), (149B), (150), (151), (155), (157), (158), (159), (160), (161), (162), (164), (165), (167), (168), (169), (169A), (169B), (170), (171), (171A), (171B), (172), (173), (174), (175), (176), (178), (179), (180), (181), (182), (184), (185), (191), (192), (192A), (194), (195), (196) It is selected from the group consisting of (197), (198), (199), (200), (201), (203), (204), (208), and pharmaceutically acceptable salts thereof.

[0414] According to a more preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (9), (16), (17), (19), (20), (21), (22), (25), (27), (34), (35), (40), (48), (61), (65), (66), (78), (81), (83), (89), (95), (96), (97), (99), (158), (159), (160), (162), (169), (172), (173), (175), (176), (184), (194), (195), (196), (199), (200), (201), (203), (210) and pharmaceutically acceptable salts thereof.

[0415] According to an alternative embodiment of the present invention, the compound of formula (I) is a compound (1), (3), (4), (5), (6), (7), (8), (9), (10), (12), (13), (14), (16), (17), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), (51), (53), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (75), (76), (77), (78), (79), (80), (81), (82), (83), (85), (86), (88), (89), (90), (92), (93), (94), (95), (96), (97), (98), (99), (100), (101), (102), (103), (104), (105), (106), (107), (108), (109), (110), (111), (113), (117), (119), (120), (121), (126), (127), (128), (129), (130), (131), (132), (135), (137), (139), (141), (144), (145), (146), (147), (148), (149), (149A), (149B), (150), (151), (154), (155), (156), (157), (158), (159), (160), (161), (162), (163), (164), (165), (166), (167), (168), (169), (169A), (169B), (170), (171), (171A), (171B), (172),(173), (174), (175), (176), (178), (179), (180), (181), (182), (183), (184), (185), (191), (192), (192A), (192B), (194), (195), (196), (197), (198), (199), (200), (201), (203), (208), (209), (210), and pharmaceutically acceptable salts thereof are selected from the group consisting of (173), (174), (175), (176), (178), (179), (180), (181), (181), (192), (192A), (192B), (194), (195), (196), (197), (198), (199), (200), (201), (203), (208), (209), (210), and their pharmaceutically acceptable salts.

[0416] According to a preferred embodiment of the present invention, the compound of formula (I) is a compound (1), (4), (5), (6), (7), (8), (9), (10), (12), (13), (14), (16), (17), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (30), (31), (32), (33), (34), (35), (36), (38), (40), (41), (43), (44), (46), (48), (49), (51), (53), (55), (56), (57), (59), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (73), (74), (76), (77), (78), (79), (80), (81), (82), (83), (85), (86), (88), (89), (90), (92), (93), (94), (95), (96), (97), (98), (99), (100), (101), (102), (104), (105), (106), (108), (109), (113), (117), (119), (127), (128), (130), (131), (135), (139), (141), (146), (147), (148), (149), (149A), (149B), (150), (151), (155), (156), (157), (158), (159), (160), (161), (162), (163), (164), (165), (166), (167), (168), (169), (169A), (169B), (170), (171), (171A), (171B), (172), (173), (174), (175), (176), (178), (179), (180), (181), (182), (183), (184), (185), (191), (192), (192A), (192B), (194), (195), (196), (198), (199), (200),(201), (203), (210), and are selected from the group consisting of pharmaceutically acceptable salts thereof.

[0417] According to a more preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (9), (16), (19), (20), (21), (35), (48), (61), (73), (78), (81), (95), (96), (155), (159), (160), (161), (169), (169A), (171A), (176), (184), (196), (199), (200), (201), (203), (210), and pharmaceutically acceptable salts thereof.

[0418] According to an additional embodiment of the present invention, the compound of formula (I) is a compound (7), (8), (9), (10), (12), (16), (17), (19), (20), (21), (23), (25), (26), (28), (32), (33), (34), (35), (40), (41), (43), (44), (46), (48), (55), (56), (57), (59), (61), (62), (63), (65), (66), (67), (68), (69), (70), (73), (77), (78), (81), (83), (88), (89), (90), (95), (96), (97), (98), (99), (100), (101), (102), (104), (105), (106), (117), (119), (127), (131), (139), (148), (149), (149B), (151), (155), (156), (157), (158), (159, (160), (161), (164), (165), (167), (169), (169A), (169B), (170), (171), (171A), (171B), (172), (173), (176), (178), (179), (180), (181), (184), (185), (191), (192), (192A), (194), (196), (198), (199), (200), (201), (203), (210) and pharmaceutically acceptable salts thereof It is selected from the formed group.

[0419] The group of compounds defined by the list of compounds identified in Examples 4 to Tables 4a to 4f below and specifically identified as the most potent kinase inhibitors, as well as multi-target kinase inhibitors, also form part of the present invention.

[0420] According to another aspect, the subject of the present invention is a compound of formula (I) as defined above for use as a pharmaceutical agent, or any pharmaceutically acceptable salt thereof, or at least one of compounds (1) to (216) or any pharmaceutically acceptable salt thereof.

[0421] ≪ Its pharmaceutically acceptable salts ≫ refers to salts formed from acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromide), as well as salts formed from organic acids such as acetic acid, tartaric acid, and succinic acid.

[0422] Physiologically acceptable suitable acid addition salts of the compound of formula (I) include hydrobromide, tartrate, hydrochloride, succinate, and acetate.

[0423] Compounds of formula (I), and any compounds (1) to (216) or any pharmaceutically acceptable salts thereof may form solvates or hydrates, and the present invention comprises all such solvates and hydrates.

[0424] The terms "hydrate" and "solvent" simply mean that the compound (I) according to the present invention may be in the form of a hydrate or solvent, that is, may be combined or bonded with one or more water or solvent molecules. This is merely a chemical property of such a compound that can be applied to all organic compounds of this type.

[0425] The compound of chemical formula (I) may contain one or more asymmetric carbon atoms. Thus, it may exist in the form of enantiomers or diastereomers. These enantiomers, diastereomers, and mixtures thereof, including racemic mixtures, are included within the scope of the present invention.

[0426] The compounds of the present invention can be prepared by conventional organic synthesis methods carried out by those skilled in the art. The general reaction sequence outlined below represents a general method useful for preparing the compounds of the present invention and is not intended to limit the scope or usefulness.

[0427] List of abbreviations

[0428]

[0429]

[0430] The compound of chemical formula (I) can be prepared according to the following schematic 1.

[0431] Diagram 1: Composite path:

[0432]

[0433] The synthesis of the compound according to the present invention is of the compound of formula (II) formula R 1 It is based on the functionalization of NH2 by an amine, and in the above formula, R 1 It is as defined above in accordance with General Procedure 3 (GP3) described in this specification thereafter.

[0434] According to GP3, the compound of formula (II) can be placed in a non-anodenic solvent such as THF or dioxane, or a mixture thereof. Formula R 1 The amine of NH2 can be added, for example, to the compound of formula (II) in a molar ratio ranging from 2 to 6, particularly 4. The reaction mixture can be placed in a sealed tube, and energy can be provided, for example, from a heating block or microwave. When the reaction is complete, the mixture can be returned to room temperature.

[0435] In the embodiment designated as GP3-A, the reaction mixture may be stirred at a temperature in the range of -10°C to 10°C, for example at 0°C, for a period in the range of 30 minutes to 2 hours, for example at 1 hour. Depending on the state of the obtained product (solid, precipitate), purification methods well known to those skilled in the art, such as filtration, washing, grinding, vacuum drying, flash chromatography, precipitation, and reflux, may be performed.

[0436] In an embodiment designated as GP3-B in which the product is not precipitated, the reaction mixture can be concentrated, particularly under vacuum, and purified, particularly by flash chromatography. In particular, a second purification step selected from redeposition, grinding, and recrystallization can be performed.

[0437] In another embodiment designated as GP3-C, in which the product is not precipitated, the reaction mixture may be concentrated, particularly under vacuum, and the resulting unpurified material may be purified by grinding in an anode polar solvent such as ethanol. The grinding may be performed at a temperature of 20 to 100°C, particularly at room temperature. In particular, a second purification step selected from reprecipitation, grinding, and recrystallization may be performed.

[0438] A compound of formula (II) as defined above can be obtained by S-alkylation of a compound of formula (III), wherein R 2 It is as defined above, and Alk is a (C1-C5)alkyl.

[0439] According to general procedure GP2, the compound of formula (III) may be placed in a polar non-polar solvent such as dimethylformamide (DMF). Then, an alkyl halide of formula Alk-Hal, where Hal is a halide such as iodine or bromine, may be added dropwise to the compound of formula (III) in a molar ratio, for example, in the range of 0.75 to 1.50, particularly 1.05, in the presence of an inorganic base such as K2CO3, for example, in a molar ratio of 0.7 to 1.5, particularly 1, to the compound of formula (III). The reaction mixture may be stirred while adding the alkyl halide.

[0440] In certain embodiments, the resulting mixture may then be stirred at room temperature for, for example, 8 to 16 hours, particularly 12 hours.

[0441] In another embodiment, the resulting mixture can be stirred at a temperature in the range of -10°C to 10°C, particularly at 0°C, for example, 2 to 8 hours, particularly 6 hours.

[0442] The compound of formula (III) as defined above can be obtained from the compound of formula (IV) according to general procedure GP1, wherein R 2 is as defined above.

[0443] According to GP1, the compound of formula (IV) may be placed in an anode solvent such as ethanol in the presence of 2-thiohydantoin in a molar ratio of, for example, 0.85 to 1.15, particularly 1 for the compound of formula (IV); in the presence of an organic base such as piperidine in a molar ratio of 0.85 to 1.15, particularly 1 for the compound of formula (IV); and in the presence of an organic acid such as acetic acid in a molar ratio of, for example, 0.85 to 1.15, particularly 1 for the compound of formula (IV). The reaction mixture may be placed in a sealed tube and stirred and heated for a duration of 10 to 100 minutes, particularly 15 to 90 minutes, at a temperature in the range of, for example, 60 to 130°C, particularly 80°C. The reaction mixture may be irradiated, for example, by microwaves.

[0444] Accordingly, the present invention also relates to a synthesis process for producing a compound of the novel formula (I) as defined above, comprising the step of substituting at least a compound of formula (II) with a primary amine. The present invention relates to a synthesis process for producing a compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, or any compounds (1) to (216) as defined above or any pharmaceutically acceptable salt thereof, comprising at least a compound of formula (II) as defined below and formula R 1 The invention relates to a process comprising the step of linking NH2 with an amine, and

[0445]

[0446] In the above formula, Alk is a (C1-C5)alkyl, and

[0447] R 1 and R 2 is as defined above.

[0448] The present invention further relates to a synthetic intermediate of the following chemical formula (II), and

[0449]

[0450] In the above formula, Alk is a (C1-C5)alkyl, in particular, Alk is selected from the group consisting of ethyl and methyl, and R 2 Is As defined above.

[0451] The chemical structures, analysis, and spectroscopic data of some compounds of formula (I) of the present invention are exemplified in Tables 2 and 3 below, respectively.

[0452] The reaction was carried out using oven-dried glass products under an inert atmosphere of argon. Unless otherwise specified, all reagent-grade chemicals and solvents were obtained from commercial suppliers and used as provided. The reaction was monitored by thin-layer chromatography using silica gel 60 F254 pre-coated aluminum plates (0.25 mm). Visualization was performed with UV light and 254 or 312 nm, or with appropriate TLC staining including, but not limited to, phosphomolyvic acid, KMnO4, ninhydrin, CAM, vanillin, and p-anisaldehyde.

[0453] Microwave experiments were performed in an Anton Paar Monowave 400174 microwave reactor. Experiments were conducted in a monomode cavity with a power supply in the range of approximately 850 W, allowing for pressurized reactions (0 to 30 bar) in sealed glass vials (4 to 30 mL) equipped with snap caps and silicone diaphragms. Temperature (0 to 300°C) was monitored using a non-contact infrared sensor and calibrated with a ruby ​​thermometer. Temperature, pressure, and power characteristics were edited and monitored via a touchscreen control panel. The times indicated in the various procedures are the times measured when the mixture reached the planned temperature after a ramp period of 3 minutes.

[0454] Chromatographic purification of the compound was achieved in an automated Interchim Puriflash XS420 equipped with a 30 μm spherical silica-packed pre-packed column as the stationary phase.

[0455] Some compounds of the present invention are described in Table 2 below with their structures, which are merely illustrative and do not limit the scope of the invention.

[0456] [Table 2]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478] Table 3 below lists the analysis and spectroscopic data of the compounds introduced in Table 2.

[0479] 1 1H NMR analysis (400 or 500 MHz) and 13 101 MHz NMR spectra were recorded using a Bruker ULTRASHIELD 500 or 400 spectrometer. Spectral processing and analysis were performed using MestReNova. Data are reported in the order of chemical shifts in ppm, referencing internal solvent signal, multiplicity, proton number, and linkage constant J in Hertz.

[0480] Reverse-phase HPLC / MS analysis was performed on a Waters Alliance 2795 HPLC equipped with an autosampler, inline membrane degassing unit, column oven (T = 45°C), UV detector, and a ZQ quadrupole mass detector operating in ionization electron spray mode. Compounds (0.1 to 0.3 mg) were acetonitrile (V total It was dissolved in a minimum volume of DMSO prepared with (= 1 mL). Standard analytical parameters: Flow rate: 1 mL / min, V inj. = 5μL.

[0481] Acidic conditions: Waters XSelect CSH C18 column (3.5 μm, 2.1 x 50 mm). Gradient: (H2O + 0.04% v / v HCOOH (10 mM)) / ACN 95 / 5 to 0 / 100, 18.5 min.

[0482] Alkaline conditions: Waters Xbridge C18 column (3.5 μm, 2.1 x 50 mm). Gradient: (H2O + 0.06% v / v NH 3(aq) (10mM)) / ACN 95 / 5 to 0 / 100 18.5 min.

[0483] Enantiomers of the racemic products (149), (169), (171), and (192) were separated by preparative chiral SFC by Reach Separations (Bio City, Pennyfoot St., Nottingham, NG1 1GF, UK. www.reachseparations.com). Briefly: The racemic products were dissolved in MeOH and purified by preparative SFC (conditions of Table 3). The combined fraction containing the first eluted enantiomer was evaporated using a rotary evaporator until nearly dry, transferred to a final vessel containing DCM, removed from Biotage V10 at 35°C, and stored in a vacuum oven at 35°C and 5 mbar until a constant weight of pure enantiomer was obtained. The fraction containing the second eluted enantiomer was combined and concentrated and purified as described above. The optical purity of each enantiomer was controlled for the racemate by analytical chiral SFC (conditions in Table 3). The chemical purity of each enantiomer was controlled by analytical UHPLC for Acquity BEH C18 (1.7 µm, 50 x 2.1 mm) (60°C, 1 mL / min, injection volume = 1 μL) (gradient: (H2O + 0.1% v / v TFA) / ACN 98 / 2 to 0 / 100 2.02 min).

[0484] [Table 3]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562] pathology

[0563] Compounds of chemical formula (I) are used for cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tauopathy; and other neurodegenerative diseases (Parkinson's disease; Pick's disease including Niemann-Pick type C); CDKL5 deficiency disorders; McDiarmid syndrome; autism; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; Numerous cancers, such as brain cancer including glioblastoma, leukemia including megakaryoblastic leukemia and acute lymphoblastic leukemia, head and neck squamous cell carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer, breast cancer such as triple-negative breast cancer (TNBC), tissue cancer including liposarcoma, Hedgehog / GLI-dependent cancer, liver cancer including hepatocellular carcinoma, and viral infections caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella-zoster virus, herpes simplex virus (HSV), hepatitis C virus, chikungunya virus, dengue virus, influenza virus, and severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus, and human papillomavirus; neuroinflammation; anemia; It may be useful for the treatment and / or prevention of infections caused by unicellular parasites such as malaria, leishmaniasis, Chagas, and sleeping sickness (Tripanosoma species), and for the regulation of body temperature selected from cattle diseases caused by unicellular pathogens.

[0564] According to specific embodiments, the compound of formula (I) of the present invention is used for cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tauopathy; other neurodegenerative diseases (Parkinson's disease; Pick's disease including Niemann-Pick type C); CDKL5 deficiency disorders; type 1 and type 2 diabetes mellitus; abnormal folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; It may be useful for the treatment and / or prevention of a number of cancers, e.g., brain cancer including glioblastoma; leukemia including megakaryoblastic leukemia and acute lymphoblastic leukemia; head and neck squamous cell carcinoma; pancreatic cancer including pancreatic ductal adenocarcinoma; prostate cancer; gastrointestinal cancer and breast cancer, e.g., triple-negative breast cancer (TNBC); and diseases selected from human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), and for regulating body temperature. The said diseases are more particularly associated with abnormalities upon administration of DYRK1A and / or CLK1.

[0565] According to these specific embodiments, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of diseases selected from Down syndrome, Alzheimer's disease, dementia, tauopathy, Parkinson's disease, Niemann-Pick type C disease, CDKL5 deficiency disorder and Phelan-McDiarmid syndrome and more particularly related cognitive and motor conditions due to high expression and activity of DYRK1A.

[0566] Still, according to these specific embodiments, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of Down syndrome, Alzheimer's disease and related tauopathy, Parkinson's disease, related cognitive / motor impairment, or one or more symptoms of these diseases. Common symptoms of these diseases are a decrease in learning and memory and social interaction.

[0567] According to these specific embodiments, the compound of formula (I) of the present invention may be useful for eliminating learning and memory as mentioned above, particularly cognitive decline associated with Down syndrome (trisomy 21) associated with cognitive or neurodegenerative disorders.

[0568] According to these specific embodiments, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of type 1 and type 2 diabetes.

[0569] The compound of formula (I) of the present invention may be useful for the treatment and / or prevention of type 1 and type 2 diabetes by treating pancreatic islets or β-cells by direct treatment of a diabetic patient or by treating the pancreatic islets or β-cells before transplantation into a diabetic patient.

[0570] According to this particular embodiment, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of viral infections, particularly those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus monkey cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), and particularly those caused by herpes, coronavirus, cytomegalovirus and influenza. These infections may be associated with high expression and activity of DYRK1A and / or CLK1 and selectively additionally with dual inhibitors of CLK / DYRKS.

[0571] Acute respiratory disease has recently been caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV) belonging to the Coronaryidae family and referred to herein as Coronavirus 2019 (COVID-19). A compound of formula (I) according to the present invention can also treat said infection caused by the SARS-CoV-2 virus.

[0572] Still, according to these specific embodiments, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of cancers, such as brain cancer including glioblastoma, leukemia including megakaryoblastic leukemia and acute lymphoblastic leukemia, head and neck squamous cell carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer, and breast cancer, such as triple-negative breast cancer (TNBC). These cancers may be associated with high expression and activity of DYRK1A and / or CLK1 and selectively additionally dual inhibitors of CLK / DYRKS.

[0573] Still, according to these specific embodiments, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of osteoarthritis. Osteoarthritis may be associated with high expression and activity of DYRK1A and / or CLK2.

[0574] Still, according to these specific embodiments, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of infections caused by unicellular parasites, such as malaria, leishmania, Chagas, and sleeping sickness (Tripanosoma species), and bovine diseases caused by unicellular pathogens. The parasitic infections may be associated with the expression and activity of DYRK / CLK.

[0575] Still, according to these specific embodiments, the compound of formula (I) of the present invention may be useful for regulating body temperature. The regulation of body temperature may be related to the expression and activity of CLK.

[0576] According to another specific embodiment, the compound of formula (I) of the present invention may be useful for the treatment and / or prevention of diseases selected from Phelan-McDermid syndrome; autism; additionally, viral infections caused by hepatitis C virus, chikungunya virus, dengue fever virus, influenza virus and severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus and human papillomavirus; additionally, cancers, such as tissue cancer including liposarcoma, Hedgehog / GLI-dependent cancer, liver cancer including hepatocellular carcinoma, neuroinflammation, anemia, infections caused by unicellular parasites such as malaria, leishmania, Chagas and sleeping sickness (Tripanosoma species), and bovine diseases caused by unicellular pathogens. The above disease is particularly associated with abnormalities in other DYRKs (DYR1B, 2, 3, 4) and closely related additional cdc2-like kinases (CLK) (CLK 2, 3, 4).

[0577] The following examples are provided as examples and do not limit the scope of the invention.

[0578] The following examples illustrate in detail the preparation of some compounds according to the present invention. The structure of the obtained product was confirmed by NMR analysis and mass spectrometry.

[0579] Example 1 : General Procedure 1 - Synthesis of (5Z)-5-heteroaryl-2-thioxo-imidazolidin-4-one

[0580]

[0581] In the diagram above, R 2 represents a hydrogen atom or a (C1-C3)alkyl group, in particular R 2 represents a hydrogen atom or a methyl group.

[0582] GP1: A stirred solution of 2-thiohydantoin (1 equivalent), an appropriate amount of heteroarylcarbaldehyde (1 equivalent), piperidine (1 equivalent), and AcOH (1 equivalent) in EtOH (c = 0.3 M) was heated in a sealed tube in a microwave oven (Anton Paar) at the indicated temperature for an appropriate time. Upon completion (thereby consumption of the aldehyde on TLC), the reaction medium was cooled and added dropwise to water. The precipitated solid was stirred for 30 minutes, filtered through a frit glass funnel, completely dried, and could be used in the next step without further purification. If necessary, final grinding in EtOH can help remove trace impurities without significant yield loss.

[0583] Example 1.1: (5 Z Synthesis of )-5-(1,3-benzothiazole-6-ylmethylene)-2-thioxo-imidazolidin-4-one (1.1)

[0584]

[0585] Compound (1.1) was synthesized according to GP1: the reaction was carried out over 4.2 mmol scale of 2-thiohydantoin, benzothiazole-6-carbaldehyde, AcOH, and piperidine. Reaction temperature: 110°C, time: 90 min. The yellow solid was filtered and titrated in EtOH. Yellow solid, 89% (978 mg). 1 ¹H NMR (400 MHz, DMSO- d 6) δ H 12.44 (br s, 1H, NH, D2O exchange), 12.25 (br s, 1H, NH, D2O exchange), 9.47 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 8.6, 1.8 Hz, 1H), 6.64 (s, 1H). 13 13C NMR (101 MHz, DMSO- d 6) δ C179.3, 165.7, 158.0, 153.1, 134.4, 129.8, 128.9, 128.1, 123.7, 123.1, 110.9. M.S. (ESI) + ): [M+H] + 262.1.

[0586] Example 1.2: ( 5Z Synthesis of )-5-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-2-thioxo-imidazolidin-4-one (1.2)

[0587]

[0588] Compound (1.2) was synthesized according to GP1: carried out on a scale of 7.34 mmol over 2-thiohydantoin, 2-methyl-1,3-benzothiazole-6-carbaldehyde, AcOH, and piperidine. Reaction temperature: 110°C, time: 90 min. The yellow solid was filtered and titrated in EtOH. Yellow solid, 94% (1.898 g). 1 ¹H NMR (400 MHz, DMSO- d 6) δ H 12.42 (br s, 1H, NH, D2O exchange), 12.21 (br s, 1H, NH, D2O exchange), 8.48 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 6.60 (s, 1H), 2.82 (s, 3H). 13 13C NMR (101 MHz, DMSO- d 6) δ C 179.2, 169.1, 165.7, 153.1, 136.0, 129.0, 128.8, 127.7, 123.0, 122.0, 111.1, 20.0. M.S. (ESI) + ): [M+H] + 275.9.

[0589] Example 2 : General Procedure 2 - (5 Z )-5-heteroaryl-2-thioxo-imidazolidin-4-one S -alkylation

[0590]

[0591] In the above diagram, Hal represents a halogen atom selected particularly from iodine and bromine atoms, Alk is a (C1-C5) alkyl, and R 2 represents a hydrogen atom or a (C1-C3)alkyl group, in particular R 2 represents a hydrogen atom or a methyl group.

[0592] GP2: A suitable alkyl iodide (1.05 eq) in DMF (c = 0.3 M) at a suitable temperature (5 Z )-5-heteroaryl-2-thioxo-imidazolidin-4-one (1 eq) and K2CO3 (1 eq) were added dropwise to a stirred solution. The resulting mixture was stirred at a set temperature for an appropriate amount of time. Upon completion (TLC), the mixture was poured into water. The precipitated solid was stirred for 30 minutes, filtered over a frit glass funnel, completely dried, and could be used in the next step without further purification. Trace impurities generated from the double alkylation can be removed by FC: Elution: Cyclohexane / AcOEt 7 / 3 to 3 / 7 or by titration.

[0593] Example 2.1: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-ethyl-1 H - Synthesis of imidazole-5-one (2.1)

[0594]

[0595] Compound (2.1) was synthesized according to GP2: reaction (5 Z It was performed with )-5-(1,3-benzothiazole-6-ylmethylene)-2-thioxo-imidazolidin-4-one (7.69 mmol) and EtI at room temperature for 12 hours. Yellow solid, 89% (978 mg). 1 ¹H NMR (400 MHz, DMSO- d 6) δ H 11.85 (br s, 1H, NH, D2O exchange), 9.46 (s, 1H), 8.90 (s, 1H), 8.45

[0596] (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 6.88 (s, 1H), 3.70 - 3.17 (m, 2H), 1.44 (t, J = 7.3 Hz, 3H). 13 13C NMR (101 MHz, DMSO- d 6) δ C 170.5, 165.0, 157.8, 153.2, 139.5, 134.1, 132.0, 129.2, 125.4, 123.0, 119.9, 24.4, 14.5. M.S. (ESI) + ): [M+H] + 289.9.

[0597] Example 2.2: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-methylsulfanyl-1 H - Synthesis of imidazole-5-one (2.2)

[0598]

[0599] Compound (2.2) was synthesized according to GP2: reaction (5 Z The experiment was performed with )-5-(1,3-benzothiazole-6-ylmethylene)-2-thioxo-imidazolidin-4-one (3.83 mmol) and MeI at 0°C for 6 hours. The yellow solid was filtered and titrated in DCM. Yellow solid, 83% (879 mg). 1 ¹H NMR (400 MHz, DMSO- d 6) δ H 11.89 (br s, 1H, NH, D2O exchange), 9.46 (s, 1H), 8.92 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 6.88 (s, 1H), 2.72 (s, 3H). 13 13C NMR (101 MHz, DMSO- d6) δ 171.1, 166.1, 158.3, 153.7, 140.0, 134.6, 132.4, 129.8, 125.9, 123.5, 120.4, 12.8. M.S. (ESI) + ): [M+H] + 275.9.

[0600] Example 2.3: (4 Z )-2-ethylsulfanyl-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H - Synthesis of imidazole-5-one (2.3)

[0601]

[0602] Compound (2.3) was synthesized according to GP2: the reaction ( 5Z )-5-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-2-thioxo-imidazolidin-4-one (1.45 mmol) and EtI were used at room temperature for 12 hours. Yellow solid, 84% (368 mg). 1 ¹H NMR (400 MHz, DMSO- d 6) δ H 11.82 (br s, 1H, NH, D2O exchange), 8.75 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 6.85 (s, 1H), 3.43 - 3.21 (m, 2H), 2.82 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H). 13 13C NMR (101 MHz, DMSO- d 6) δ C 170.5, 169.0, 164.6, 153.3, 139.2, 135.7, 131.2, 129.1, 124.8, 122.0, 120.1, 24.3, 19.9, 14.5. M.S. (ESI) + ): [M+H] + 303.9.

[0603] Example 2.4: (4 Z )-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-2-methylsulfanyl-1 H - Synthesis of imidazole-5-one (2.4)

[0604]

[0605] Compound (2.4) was synthesized according to GP2: the reaction ( 5Z The experiment was performed with )-5-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-2-thioxo-imidazolidin-4-one (3.63 mmol) and MeI at room temperature for 6 hours. The yellow solid was filtered and titrated in DCM. Yellow solid, 92% (962 mg). 1 ¹H NMR (400 MHz, DMSO- d 6) δ H 11.86 (br s, 1H, NH, D2O exchange), 8.77 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 6.85 (s, 1H), 2.82 (s, 3H), 2.71 (s, 3H). 13 13C NMR (101 MHz, DMSO- d 6) δ C 170.6, 169.0, 165.3, 153.3, 139.2, 135.7, 131.2, 129.3, 124.9, 121.9, 120.2, 19.9, 12.3. M.S. (ESI) + ): [M+H] + 290.1.

[0606] Example 3 : General Procedure 3 - (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-alkylulfanyl-1 H - Addition of aliphatic and aromatic amines on the imidazole-5-one phase

[0607]

[0608] In the above diagram, Alk is a (C1-C5) alkyl, and R 2 represents a hydrogen atom or a (C1-C3)alkyl group, in particular R 2 represents a hydrogen atom or a methyl group.

[0609] Suitable amines (a)(x eq) in a sealed tube (heat block or μw) in an appropriate solvent mixture (c = 0.3 M) (4 Z )-4-heteroaryl-2-alkylulfanyl-1 H -Imidazole-5-on (b) It was added to a stirred suspension of (1 eq). The mixture was completely purged with a vacuum / argon cycle at an appropriate temperature for a set time and heated (μw or heating block). Upon completion (after the isothiourea on the TLC was consumed), the mixture was returned to room temperature.

[0610] - GP3-A: Direct precipitation of appropriate product : The reaction medium was stirred at 0°C for 1 hour. The precipitated solid was filtered over a frit glass funnel. High purity can be achieved after filtration by washing, reprecipitation, titration, or recrystallization.

[0611] - GP3-B: The product did not precipitate The reaction mixture was concentrated under vacuum, adsorbed onto silica, and purified by FC. High purity can be achieved after filtration by reprecipitation, titration, or recrystallization.

[0612] - GP3-C: No product precipitated The reaction mixture was concentrated under vacuum. The resulting crude product was titrated in EtOH (at room temperature or under reflux) and filtered over a frit glass funnel. High purity can be achieved after filtration by purification, reprecipitation, titration, or recrystallization.

[0613] (a) When using amine hydrochloride, it was quenched in situ with TEA or DIPEA.

[0614] (b) Depending on the amine, activation to AcOH may be required.

[0615] Example selected from subgroup A1:

[0616] Example 3.1: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclohexylamino)-1 H -Imidazole-5-on (6) synthesis

[0617] The reaction was carried out according to GP3-A in a 2.73 mmol scale (2.1) phase at 110°C (sealed tube, heating block) for 12 hours with 4 equivalents of cyclohexylamine in THF (0.3 M). The product was precipitated directly from the reaction medium; it was filtered and then isolated by washing with cooled THF and then pentane. Yield of isolation: 34%.

[0618] Example 3.2: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cycloheptylmethylamino)-1 H - Synthesis of imidazole-5-one (7)

[0619] The reaction was carried out according to GP3-B in a 1.01 mmol scale (2.1) phase in THF (0.3 M) with 4 equivalents of cycloheptylmethylamine at 110°C (sealed tube, heating block) for 12 hours. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 23%.

[0620] Example 3.3: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cycloheptylamino)-1 H - Synthesis of imidazole-5-one (8)

[0621] The reaction was carried out according to GP3-A in a 4.84 mmol scale (2.1) phase in THF (0.3 M) with 4 equivalents of cycloheptylamine at 110°C (sealed tube, heating block) for 12 hours. The product was precipitated directly from the reaction medium; it was filtered and then isolated by washing with cooled THF and then pentane. Yield of isolation: 49%.

[0622] Example 3.4: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclooctylamino)-1 H - Synthesis of imidazole-5-one (9)

[0623] The reaction was carried out according to GP3-A in THF (0.3 M) with 2.73 mmol (2.1) and 4 equivalents of cyclooctylamine at 110°C (sealed tube, heating block) for 12 hours. The product was precipitated directly from the reaction medium, filtered, and isolated by washing with cooled THF and then pentane. Isolated yield: 58%.

[0624] Example 3.5: (4 Z )-2-(1-adamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H - Synthesis of imidazole-5-one (16)

[0625] The reaction was carried out according to GP3-B in a 2.54 mmol scale (2.2) phase in THF (0.3 M) at 160°C (sealed tube, heating block) for 24 hours with 3 equivalents of 1-adamanthylamine and 15 equivalents of AcOH. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required two consecutive titrations in reflux EtOH. Isolated yield: 61%.

[0626] Example 3.6: (4 Z )-2-(2-adamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H - Synthesis of imidazole-5-one (17)

[0627] The reaction was carried out according to GP3-B in a 746 μmol scale (2.2) in THF (0.3 M) at 170°C (sealed tube, heating block) for 12 hours with 4 equivalents of 2-adamanthylamine and 15 equivalents of AcOH. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in EtOH at 0°C. Isolated yield: 44%.

[0628] Example 3.7: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[( trans -5-hydroxy-2-adamantyl)amino]-1 H - Synthesis of imidazole-5-one (19)

[0629] The reaction according to GP3-B was performed on a 746 μmol scale (2.2) in THF (0.3 M) with 4 equivalents trans Purification was performed at 170°C (sealed tube, heating block) for 12 hours with -4-aminoadamantan-1-ol and 15 equivalents of AcOH (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in EtOH at 0°C. Isolated yield: 27%.

[0630] Example 3.8: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1 H - Synthesis of imidazole-5-one (20)

[0631] The reaction was carried out according to GP3-B in a 746 μmol scale (2.2) in THF (0.3 M) at 160°C (sealed tube, heating block) for 12 hours with 4 equivalents of 3-amino-1-adamantanol and 15 equivalents of AcOH. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in EtOH at 0°C. Isolated yield: 59%.

[0632] Example 3.9: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R ,3 R ,5 S )-2,6,6-trimethylnorpinan-3-yl]amino]-1 H - Synthesis of imidazole-5-one (22)

[0633] According to the reaction with GP3-B, 4 equivalents (1 on a scale of 746 μmol (2.1) in THF (0.3 M) R ,2 R ,3 R ,5 SPurification was performed with )-3-pinanamine at 120°C (sealed tube, heating block) for 12 hours. Elution by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 60%.

[0634] Example 3.10: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(spiro[2.5]octane-2-ylamino)-1 H - Synthesis of imidazole-5-one (25)

[0635] The reaction was carried out according to GP3-B in a 773 μmol scale (2.1) phase in THF (0.3 M) at 110°C (sealed tube, heating block) for 12 hours with 2 equivalents of (±)-spiro[2.5]octane-2-amine hydrochloride and 2 equivalents of TEA. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 61%.

[0636] Example 3.11: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(2 R )-1,7,7-trimethylnorbornan-2-yl]amino]-1 H - Synthesis of imidazole-5-one (27)

[0637] According to the reaction with GP3-B, 3 equivalents (2.1) on a scale of 746 μmol in THF (0.3 M) R Purification was performed with )-(+)-bornylamine at 150°C (sealed tube, heating block) for 8 hours. Elution by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 34%.

[0638] Example 3.12: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1 H - Synthesis of imidazole-5-one (34)

[0639] The reaction was carried out according to GP3-B with 4 equivalents of D-leucinol in a 746 μmol scale (2.1) phase in THF (0.3 M) at 110°C (sealed tube, heating block) for 12 hours. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 39%.

[0640] Example 3.13: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(methoxymethyl)-3-methyl-butyl]amino]-1 H - Synthesis of imidazole-5-one (35)

[0641] According to the reaction with GP3-B, 2.5 equivalents (2 on a scale of 2.91 mmol (2.2) in THF (0.3 M) R Purification was performed with )-1-methoxy-4-methyl-pentane-2-amine at 120°C (sealed tube, heating block) for 12 hours. Elution by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 74%.

[0642] Example 3.14: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S Synthesis of )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazole-5-one (36)

[0643] The reaction was carried out according to GP3-B with 4 equivalents of L-leucinol in a 746 μmol scale (2.1) phase in THF (0.3 M) at 110°C (sealed tube, heating block) for 12 hours. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 39%.

[0644] Example 3.15: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[1-(fluoromethyl)-3-methyl-butyl]amino]-1 H - Synthesis of imidazole-5-one (40)

[0645] The reaction was carried out according to GP3-B at 150°C (sealed tube, heating block) for 96 hours with 1.2 equivalents of (±)-1-fluoro-4-methyl-pentan-2-amine in a 908 μmol scale (2.2) phase in THF (0.3 M). Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7) followed by PTLC. Isolated yield: 8%.

[0646] Example 3.16: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycyclopentyl]amino]-1 H - Synthesis of imidazole-5-one (48)

[0647] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- trans Purification was performed at 120°C (sealed tube, heating block) for 7 hours with 2-methoxycyclopentanamine hydrochloride and 4 equivalents of DIPEA (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in reflux EtOH. Isolated yield: 81%.

[0648] Example 3.17: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-hydroxycyclohexyl]amino]-1 H - Synthesis of imidazole-5-one (55)

[0649] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- cis Purification was performed at 120°C (sealed tube, heating block) for 24 hours with 3-aminocyclohexanol hydrochloride and 4 equivalents of DIPEA. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 82%.

[0650] Example 3.18: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-hydroxycyclohexyl]amino]-1 H - Synthesis of imidazole-5-one (56)

[0651] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- trans Purification was performed at 120°C (sealed tube, heating block) for 24 hours with 3-aminocyclohexanol hydrochloride and 4 equivalents of DIPEA. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7) followed by PTLC. Isolated yield: 82%.

[0652] Example 3.19: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycyclohexyl]amino]-1 H - Synthesis of imidazole-5-one (59)

[0653] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- trans Purification was performed at 120°C (sealed tube, heating block) for 28 hours with 2-2-methoxycyclohexamine hydrochloride and 4 equivalents of DIPEA. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 82%.

[0654] Example 3.20: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxycycloheptyl]amino]-1 H - Synthesis of imidazole-5-one (61)

[0655] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- cis Purification was performed at 120°C (sealed tube, heating block) for 28 hours with 2-aminocycloheptanol hydrochloride and 4 equivalents of DIPEA. Elution by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in reflux EtOH. Isolated yield: 56%.

[0656] Example 3.21: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxycycloheptyl]amino]-1 H - Synthesis of imidazole-5-one (62)

[0657] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- trans Purification was performed with 2-aminocycloheptanol at 120°C (sealed tube, heating block) for 6 hours. Elution by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in reflux EtOH. Isolated yield: 31%.

[0658] Example 3.22: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxycycloheptyl]amino]-1 H - Synthesis of imidazole-5-one (63)

[0659] According to the reaction with GP3-B, 3 equivalents (1 on a scale of 746 μmol (2.1) in THF (0.3 M) R ,2 R Purification was performed with )-2-aminocycloheptanol at 110°C (sealed tube, heating block) for 12 hours. Elution by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 49%.

[0660] Example 3.23: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-hydroxycycloheptyl]amino]-1 H - Synthesis of imidazole-5-one (65)

[0661] The reaction according to GP3-B was performed on a 218 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- cisPurification was performed at 150°C (sealed tube, μw) for 6 hours with 3-aminocycloheptanol hydrochloride and 4 equivalents of DIPEA. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 46%.

[0662] Example 3.24: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-hydroxycycloheptyl]amino]-1 H - Synthesis of imidazole-5-one (66)

[0663] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- trans Purification was performed at 120°C (sealed tube, heating block) for 31 hours with 3-aminocycloheptanol hydrochloride and 4 equivalents of DIPEA. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7) followed by PTLC. Isolated yield: 67%.

[0664] Example 3.25: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycycloheptyl]amino]-1 H - Synthesis of imidazole-5-one (68)

[0665] The reaction according to GP3-B was performed on a 272 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- trans Purification was performed with 2-methoxycycloheptanamine at 120°C (sealed tube, heating block) for 24 hours. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 79%.

[0666] Example selected from subgroup A2:

[0667] Example 3.26: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(benzylamino)-1 H - Synthesis of imidazole-5-one (74)

[0668] The reaction was carried out according to GP3-A in a 1.38 mmol scale (2.1) phase with 4 equivalents of benzylamine at 110°C (sealed tube, heating block) for 12 hours. The product was precipitated directly from the reaction medium; it was filtered and then isolated by washing with cooled THF and then pentane. Yield of isolation: 80%.

[0669] Example 3.27: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1 H - Synthesis of imidazole-5-one (78)

[0670] The reaction was carried out according to GP3-A in a 272 μmol scale (2.2) phase at 120°C (sealed tube, heating block) for 24 hours with 3 equivalents of [2-(trifluoromethyl)phenyl]methaneamine in THF (0.3 M). The product was precipitated directly from the reaction medium; it was filtered and isolated by washing with cooled THF. The final product required titration in reflux EtOH. Isolated yield: 72%.

[0671] Example 3.28: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxyindane-1-yl]amino]-1 H - Synthesis of imidazole-5-one (81)

[0672] The reaction was performed according to GP3-A in THF (0.3 M) at a scale of 272 μmol (2.2) with 3 equivalents (±)- trans The reaction was carried out with -1-aminoindan-2-ol at 120°C (sealed tube, heating block) for 30 hours. The product was precipitated directly from the reaction medium; it was filtered and isolated by washing with cooled THF. The final product required titration in EtOH at room temperature. Isolated yield: 56%.

[0673] Example 3.29: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxyindane-1-yl]amino]-1 H - Synthesis of imidazole-5-one (83)

[0674] The reaction was performed according to GP3-A in THF (0.3 M) at a scale of 272 μmol (2.2) with 3 equivalents (1 S ,2 S The reaction was carried out with )-1-aminoindan-2-ol at 120°C (sealed tube, heating block) for 40 hours. The product was precipitated directly from the reaction medium; after filtration, it was isolated by washing with cooled THF. The final product required titration in EtOH at room temperature. Isolated yield: 62%.

[0675] Example 3.30: (±)-(4 Z )-2-[(2-amino-1-phenyl-ethyl)amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H Synthesis of -imidazole-5-one dihydrochloride (89)

[0676] The reaction according to GP3-B was performed on a 363 μmol scale (2.2) in THF (0.3 M) with 3 equivalents (±)- tert -butyl N Purification was performed with (2-amino-2-phenyl-ethyl)carbamate at 120°C (sealed tube, heating block) for 48 hours. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7) followed by deprotection with HCl (4M, dioxane). Isolated yield: 63%.

[0677] Example 3.31: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1 H - Synthesis of imidazole-5-one (95)

[0678] The reaction was carried out according to GP3-B in a 272 μmol scale (2.2) phase in THF (0.3 M) at 150°C (sealed tube, heating block) for 8 hours with 3 equivalents of (±)-2-phenylglycinol. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in reflux EtOH. Isolated yield: 37%.

[0679] Example 3.32: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-1-phenyl-ethyl)amino]-1 H - Synthesis of imidazole-5-one (98)

[0680] The reaction was carried out according to GP3-B in a 272 μmol scale (2.2) phase in THF (0.3 M) at 120°C (sealed tube, heating block) for 48 hours with 3 equivalents of (±)-2-methoxy-1-phenyl-ethanolamine. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in reflux EtOH. Isolated yield: 41%.

[0681] Example 3.33: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1 H - Synthesis of imidazole-5-one (99)

[0682] The reaction was carried out according to GP3-B in a 272 μmol scale (2.2) phase in THF (0.3 M) at 120°C (sealed tube, heating block) for 2.5 hours with 3 equivalents of (±)-2-amino-1-phenyl-ethanol hydrochloride and 4 equivalents of DIPEA. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in reflux EtOH. Isolated yield: 41%.

[0683] Example 3.34: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-2-methoxy-1-phenyl-ethyl]amino]-1 H - Synthesis of imidazole-5-one (176)

[0684] The reaction was performed according to GP3-A in THF (0.3 M) at a scale of 12.71 mmol (2.2) with 3 equivalents (1 R The reaction was carried out with )-2-methoxy-1-phenyl-ethanolamine at 140°C (sealed tube, heating block) for 24 hours. The product was precipitated directly from the reaction medium; it was filtered and isolated by washing with cooled THF. The final product required titration in reflux EtOH. Isolated yield: 51%.

[0685] Example selected from subgroup A3:

[0686] Example 3.35: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(5-methylpyrazine-2-yl)methylamino]-1 H - Synthesis of imidazole-5-one (103)

[0687] The reaction was carried out according to GP3-B in a 182 μmol scale (2.2) phase in THF (0.3 M) at 80°C (sealed tube, heating block) for 16 hours with 3 equivalents of (5-methylpyrazine-2-yl)methaneamine. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 47%.

[0688] Example 3.36: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(4-methylthiazole-2-yl)methylamino]-1 H - Synthesis of imidazole-5-one (108)

[0689] The reaction was carried out according to GP3-B in a 182 μmol scale (2.2) phase in THF (0.3 M) at 120°C (sealed tube, heating block) for 24 hours with 3 equivalents of (4-methylthiazole-2-yl)methaneamine. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required titration in reflux EtOH. Isolated yield: 40%.

[0690] Example selected from subgroup A4:

[0691] Example 3.37: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1 H - Synthesis of imidazole-5-one (113)

[0692] The reaction was carried out according to GP3-B in a 182 μmol scale (2.2) at 120°C (sealed tube, heating block) for 2 hours with 3 equivalents of tetrahydropyran-4-ylmethanamine. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 51%.

[0693] Example selected from subgroup A5:

[0694] Example 3.38: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[4-(4-methylpiperazine-1-yl)anilino]-1 H - Synthesis of imidazole-5-one (119)

[0695] The reaction was carried out according to GP3-A in a 182 μmol scale (2.1) phase with 5 equivalents of 4-(4-methylpiperazine-1-yl)aniline at 150°C (sealed tube, μw) for 3 hours. The product was precipitated directly from the reaction medium; it was isolated after filtration. The final product required two consecutive titrations in reflux EtOH. Isolated yield: 65%.

[0696] Example 3.39: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methylindazole-7-yl)amino]-1 H - Synthesis of imidazole-5-one (125)

[0697] The reaction was carried out according to GP3-A in a 182 μmol scale (2.2) phase in THF (0.3 M) at 130°C (sealed tube, heating block) for 5 hours with 5 equivalents of 1-methylindazole-7-amine and 15 equivalents of AcOH. The product was precipitated directly from the reaction medium; it was isolated after filtration. The final product required titration in EtOH at room temperature. Isolated yield: 52%.

[0698] An example selected from subgroup A6:

[0699] Example 3.40: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(2-pyridylamino)-1 H - Synthesis of imidazole-5-one (127)

[0700] The reaction was carried out according to GP3-A in a 1.05 mmol scale (2.2) phase in THF (0.3 M) at 150 °C (sealed tube, μw) for 2 hours with 5 equivalents of pyridine-2-amine and 15 equivalents of AcOH. The product was precipitated directly from the reaction medium; it was isolated after filtration. The final product required titration in reflux EtOH. Isolated yield: 41%.

[0701] Example 3.41: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methylpyrazole-3-yl)amino]-1 H - Synthesis of imidazole-5-one (128)

[0702] The reaction was carried out according to GP3-A in a 182 μmol scale (2.2) with 5 equivalents of 1-methylpyrazole-3-amine at 150°C (sealed tube, μw) for 3 hours. The product was precipitated directly from the reaction medium; it was isolated after filtration. The final product required titration in EtOH at room temperature. Isolated yield: 71%.

[0703] An example selected from subgroup A7:

[0704] Example 3.42: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-tetrahydrofuran-3-yl]amino]-1 H - Synthesis of imidazole-5-one (146)

[0705] According to the reaction with GP3-B, 3 equivalents (3 on a scale of 746 μmol (2.2) in THF (0.3 M) S The reaction was carried out with )-tetrahydrofuran-3-amine at 120°C (sealed tube, heating block) for 12 hours. The product was precipitated directly from the reaction medium; it was isolated after filtration. Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 51%.

[0706] Example 3.43: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R )-tetrahydropyran-3-yl]amino]-1 H - Synthesis of imidazole-5-one (147)

[0707] According to the reaction with GP3-B, 4 equivalents (3 on a scale of 1.04 mmol (2.1) in THF (0.3 M) RPurification was performed at 110°C (sealed tube, heating block) for 12 hours with )-tetrahydropyran-3-amine hydrochloride and 6 equivalents of TEA (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 60%.

[0708] Example 3.44: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-tetrahydropyran-3-yl]amino]-1 H - Synthesis of imidazole-5-one (148)

[0709] According to the reaction with GP3-B, 3 equivalents (3 on a scale of 746 μmol (2.2) in THF (0.3 M) S Purification was performed at 130°C (sealed tube, heating block) for 12 hours with )-tetrahydropyran-3-amine hydrochloride and 4 equivalents of DIPEA (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 62%.

[0710] Example 3.45: (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ,4 R )-4-hydroxytetrahydropyran-3-yl]amino]-1 H - Synthesis of imidazole-5-one (150)

[0711] According to the reaction with GP3-B, 3 equivalents (3 on a scale of 746 μmol (2.2) in THF (0.3 M) R ,4 R Purification was performed with )-3-aminotetrahydropyran-4-ol at 130°C (sealed tube, heating block) for 12 hours. Elution by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0°C. Isolated yield: 35%.

[0712] Example 3.46: (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(oxephane-3-ylamino)-1 H - Synthesis of imidazole-5-one (151)

[0713] The reaction was carried out according to GP3-B at 130°C (sealed tube, heating block) for 12 hours with 1.2 equivalents of (±)-oxephan-3-amine in a 272 μmol scale (2.2) phase in THF (0.3 M). Purification by FC (Elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 33%.

[0714] Example 4 : Biological activity

[0715] Materials and Methods

[0716] Protein kinase analysis

[0717] 1. Overview

[0718] Analysis was performed by ProQinase GmbH (Engesserstr. 4, D-79108 Freiburg, Germany. www.proqinase.com) (Now Reaction Biology; https: / / www.reactionbiology.com / ). IC50 of all compounds 50 Characteristics were determined using 12 protein kinases (CDK5 / p25, CK1ε, CLK1, 2, 3, 4, DYRK1A, 1B, 2, 3, 4, GSK3β). IC 50 The values ​​were measured by testing 10 different concentrations (10 μM to 30 nM) of each compound in a single experiment.

[0719] 2. Test compound

[0720] The compound was provided as a 1 μM stock solution in 100% DMSO. Prior to the test, the 1 μM stock solution was subjected to a series of semi-dilutions using 100% DMSO as the solvent. As a result, 10 distinct concentrations were generated with a dilution endpoint of 3 x 10 nM / 100% DMSO, with 100% DMSO serving as the control. In this process, 90 μL of H2O was added to each well of each compound dilution plate. To minimize the possibility of precipitation, H2O was added to each plate a few minutes prior to transferring the compound solution to the analysis plate. The plates were thoroughly shaken to create a compound dilution plate / 10% DMSO ratio.

[0721] For analysis (see below), 5 μL of the solution from each well of the compound dilution plate / 10% DMSO was transferred to the analysis plate. The final volume of the analysis was 50 μL. All compounds were tested at 10 final analysis concentrations ranging from 10 μM to 30 nM. The final DMSO concentration of the reaction cocktail was 1% in all cases.

[0722] 3. Recombinant protein kinase

[0723] All protein kinases provided by ProQinase were expressed in Sf9 insect cells or E. coli as recombinant GST-fusion proteins or His-tagged proteins, either as full-length or enzymatic active fragments. All kinases were generated from human cDNA and purified by GSH affinity chromatography or immobilized metal. Affinity tags were removed from multiple kinases during purification. The purity of the protein kinases was investigated by SDS-PAGE / Coomassie staining, and their identity was confirmed by mass spectrometry.

[0724] 4. Protein kinase analysis

[0725] A radioactive protein kinase assay (33PanQinase® activity assay) was used to measure the kinase activity of 12 protein kinases. All kinase assays were performed in 50 μL reaction volumes on PerkinElmer (Boston, MA, USA) 96-well FlashPlates™. The reaction cocktail was pipetted in the following four steps:

[0726] · 25 μL of analytical buffer (standard buffer / [γ- 33 P]-ATP),

[0727] · 10 μL of ATP solution (in H2O),

[0728] · 5 μL of test compound (in 10% DMSO),

[0729] · 10 μL of enzyme / substrate mixture.

[0730] Analysis for all protein kinases was performed using 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM Na-orthovanadate, 1.2 mM DTT, 50 μg / ml PEG20000, ATP (variable concentration, apparent ATP-Km of each kinase), [γ- 33 It contained [P]-ATP (approx. 6.5 x 10⁻⁵ cpm per well), protein kinase (variable amount), and substrate (variable amount). The reaction cocktail was incubated at 30°C for 60 minutes. The reaction was stopped with 450 μL of 2% (v / v) H₃PO₄, the plates were aspirated, and washed twice with 200 μL of 0.9% (w / v) NaCl. 33 The incorporation of Pi was determined using a microplate scintillation counter (Microbeta, Wallac). IC50 for all compounds 50 The value was calculated from the dose-response curve.

[0731] 5. Feature Control

[0732] As a parameter for analytical characteristics, the Z'-factor for low and high controls of each assay plate (reference [Zhang et al., J. Biomol. Screen. 2: 67-73, 1999]) (n = 8) was used. The criterion for ProQinase for replicates of the assay plate is a Z'-factor of less than 0.4 (reference [Iversen et al., J. Biomol. Screen. 3: 247-252, 2006]).

[0733] Its activity was classified according to two criteria: kinase inhibitory efficacy and kinase selectivity.

[0734] Classification of kinase inhibitory efficacy IC 50 Performed according to the following range of values:

[0735] Some compounds exhibit various ICs at 0.050 μM or higher 50 They possess activity. These compounds correspond to the Class E reported above. Some compounds have various ICs of 0.025 to 0.050 μM. 50 They have activity. These compounds correspond to the Class D reported above. Some compounds of the present invention have an IC50 of 0.010 to 0.025 μM. 50 They possess activity. These compounds correspond to the Class C reported above. Additionally, some specific compounds exhibit various ICs ranging from 0.005 to 0.010 μM. 50 They possess activity. These compounds correspond to the Class B reported above. IC50 of less than 0.005 μM. 50 A compound of the present invention having activity is more preferable. This compound corresponds to the reported class A. This classification was applied to CLK1 and DYRK1A. The letters A through E were used to cite the activity / efficacy of the compounds of the present invention in Tables 4, 4A and 4B below.

[0736] Kinase selectivity classification is the IC of DYRK1A 50 The value of CLK1 or DYRK1B IC 50It was based on comparison with values. Classification was performed according to the following value ranges: I: IC for DYRK1A exceeding 10 times. 50 IC for CLK1 or DYRK1B 50 The ratio of (most DYRK1A-selective compounds); II: a ratio of 2 to 10 times; III: a ratio of 0.5 to 2 times; IV: a ratio of 0.1 to 0.5 times; V: a ratio greater than 0.1 times (most CLK1- or DYRK1B-selective compounds). The numbers I through V above were used to cite the relative selectivity of the compounds of the present invention in the table below.

[0737] [Table 4]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744] [Table 4a]

[0745] The most potent CLK1 inhibitor (IC10 nM or less) 50 ). Kinase Inhibitory Efficacy Grade : IC 50 Values: A ≤ 0.005 μM; B ≤ 0.010 μM; C ≤ 0.025 μM; D ≤ 0.050 μM; E > 0.050 μM. Based on DYRK1A Kinase selectivity class : Class I (over-10x selectivity), Class II (2 to 10x selectivity), Class III (0.5 to 2x selectivity = equivalent). Some compounds exhibit superior selectivity for CLK1 or DYRK1B compared to DYRK1A. These compounds correspond to the reported Class IV (2 to 10x selectivity) or Class V (over-10x selectivity).

[0746]

[0747] IC 50 The most potent CLK2 inhibitors with less than 10 nM are compounds (9), (16), (20), (21), (22), (24), (25), (81), (83), (89), (95), (96), (159), (181), (194), (196), (199), (200), (201), (202) and (203).

[0748] IC 50 The most potent CLK3 inhibitors with less than 100 nM are compounds (48), (89) (90), (159), (164), (165), (169), (169B), (178) and (181).

[0749] IC 50The most potent CLK4 inhibitors at less than 10 nM are compounds (7), (8), (9), (10), (12), (16), (17), (19), (20), (21), (23), (25), (26), (28), (32), (33), (34), (35), (40), (41), (43), (44), (46), (48), (51), (55), (56), (57), (59), (61), (62), (63), (65), (66), (67), (68), (69), (70), (73), (77), (78), (81), (83), (88), (89), (90), (95), (96), (97), (98), (99), (100), (101), (102), (104), (105), (106), (117), (119), (127), (131), (139), (148), (149), (149B), (151), (155), (156), (157), (158), (159), (160), (161), (164), (165), (167), (169), (169A), (169B), (170), (171), (171A), (171B), (172), (173), (176), (178), (179), (180), (181), (184), (185), (191), (192), (192A), (194), (196), (198), (199), (200), (201), (202), (203) and (210)

[0750] [Table 4b]

[0751] The most potent DYRK1A inhibitor (IC10 nM or less) 50 ). Kinase inhibitory efficacy class and kinase selectivity class as described in Table 4a.

[0752]

[0753]

[0754] IC 50The most potent DYRK1B inhibitors with less than 10 nM are compounds (20), (16), (83), (81), (34), (95), (21), (22), (27), (35), (61), (9), (96), (159), (160), (162), (176), (194), (196), (199), (200), (201), (202), (203) and (210).

[0755] IC 50 The most potent DYRK2 inhibitors with less than 100 nM are compounds (16), (20), (21), (48), (89), (90), (99), (119), (158), (159), (169), (179), (194), (196), (199), (200), (201), (203) and (210).

[0756] IC 50 The most potent DYRK3 inhibitors with less than 100 nM are compounds (16), (20), (21), (89), (90), (119), (162), (159), (181), (194), (196), (199), (200), (201) and (203).

[0757] IC 50 The most potent DYRK4 inhibitors with a concentration of 100 nM or less are compounds (20) and (48), (164), (194) and (196).

[0758] [Table 4c]

[0759] Most DYRK1A selective inhibitor compared to CLK1. Kinase selectivity class as described in Table 4a.

[0760]

[0761] [Table 4d]

[0762] The most CLK1 selective inhibitor compared to DYRK1A. Kinase selectivity class as described in Table 4a.

[0763]

[0764] [Table 4e]

[0765] Most DYRK1A selective inhibitor compared to DYRK1B. Kinase selectivity class as described in Table 4a.

[0766]

[0767]

[0768] [Table 4f]

[0769] Most DYRK1B selective inhibitor compared to DYRK1A. Kinase selectivity class as described in Table 4a.

[0770]

[0771] result

[0772] Most compounds of the present invention have an IC50 of less than 2 μM for CLK or DYRK. 50 It provides activity. All compounds were inhibitors of DYRK1A and CLK1 (Table 4).

[0773] The compounds were preferably inhibitory to CLK1 (Table 4a), CLK4, DYRK1A (Table 4b), and DYRK1B.

[0774] Some are most selective for DYRK1A versus CLK1 (Table 4c), DYRK1A versus DYRK1B (Table 4e), DYRK1B versus DYRK1A (Table 4f), or CLK1 versus DYRK1A (Table 4d). Some compounds exhibit superior selectivity for DYRK1A compared to CLK1 or DYRK1B. These compounds correspond to the reported Class I (over-10x selectivity) or Class II (2 to 10x selectivity). Some compounds are equivalent. These compounds correspond to the reported Class III (0.5 to 2x selectivity). Some compounds exhibit superior selectivity for CLK1 or DYRK1B compared to DYRK1A. These compounds correspond to the reported Class IV (2 to 10x selectivity) or Class V (over-10x selectivity).

[0775] conclusion

[0776] Based on previous results, the compound of formula (I) is associated with cognitive deficits related to Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tauopathy; other neurodegenerative diseases (Parkinson's disease; Pick's disease including Niemann-Pick type C); CDKL5 deficiency disorders; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; It is a compound suitable for the prevention and / or treatment of a number of cancers, such as brain cancer including glioblastoma, leukemia including megakaryoblastic leukemia and acute lymphoblastic leukemia, head and neck squamous cell carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer and breast cancer, such as triple-negative breast cancer (TNBC), malaria, leishmaniasis, Chagas and sleeping sickness (trypanosoma), and bovine disease caused by monocellular pathogens, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), and for the regulation of body temperature.

[0777] It can be further concluded that some compounds of chemical formula (I) are additionally suitable for the treatment and / or prevention of Phelan-McDiarmid syndrome; autism; additional viral infections caused by hepatitis C virus, chikungunya virus, dengue fever virus, influenza virus and severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus and human papillomavirus; additional cancers, e.g., tissue cancer including liposarcoma, Hedgehog / GLI-dependent cancer, liver cancer including hepatocellular carcinoma, neuroinflammation, anemia, malaria, leishmania, Chagas and sleeping sickness (Tripanosoma species), and bovine diseases caused by single-celled pathogens.

[0778] Leucetinib showed significantly increased efficacy compared to the reference compound (sub-micromolar and single-digit micromolar IC50). 50It indicates (up to the value). This also indicates broad selectivity for DYRK1A or CLK1. And some products that are equivalent for CLK and DYRK can also be applied as dual-specificity inhibitors.

[0779] The present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above or any pharmaceutically acceptable salt thereof, or at least one of compounds (1) to (216) as defined above or any pharmaceutically acceptable salt thereof and also at least one pharmaceutically acceptable excipient.

[0780] The pharmaceutical composition of the present invention may include one or more compounds of the present invention in any form as described herein.

[0781] Another object of the present invention is a compound of at least one formula (I) as defined above according to the present invention, and compounds (1) to (216) as defined above, or any pharmaceutically acceptable salt thereof, for cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tauopathy; and other neurodegenerative diseases (Parkinson's disease; Pick's disease including Niemann-Pick type C); CDKL5 deficiency disorder; McDermid syndrome; autism; type 1 and type 2 diabetes; regulation of folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; Numerous cancers, e.g., brain cancer including glioblastoma; leukemia including megakaryoblastic leukemia; head and neck squamous cell carcinoma; pancreatic cancer including pancreatic ductal adenocarcinoma; prostate cancer; gastrointestinal cancer; breast cancer, e.g., triple-negative breast cancer (TNBC); tissue cancer including liposarcoma; Hedgehog / GLI-dependent cancer; liver cancer including hepatocellular carcinoma; and viral infections caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella-zoster virus, herpes simplex virus (HSV), hepatitis C virus, chikungunya virus, dengue virus, influenza virus and severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus, and human papillomavirus; neuroinflammation; anemia; It is intended for use in the prevention and / or treatment of infections caused by unicellular parasites, such as malaria, leishmaniasis, Chagas and sleeping sickness (Tripanosoma species), and diseases selected from bovine diseases caused by unicellular pathogens, and for the manufacture of drugs for thermoregulation.

[0782] Another object of the present invention is a compound of at least one formula (I) as defined above according to the present invention, and compounds (1) to (216) as defined above, or any pharmaceutically acceptable salt thereof, for cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tauopathy; other neurodegenerative diseases (Parkinson's disease; Pick's disease including Niemann-Pick type C); CDKL5 deficiency disorders; type 1 and type 2 diabetes mellitus; regulation of folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; It is configured for use in the manufacture of drugs for the prevention and / or treatment of a number of cancers, e.g., brain cancer including glioblastoma, leukemia including megakaryoblastic leukemia, head and neck squamous cell carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer and breast cancer, e.g., triple-negative breast cancer (TNBC), infections caused by monocellular parasites, such as malaria, leishmaniasis, Chagas and sleeping sickness (trypanosoma species), and bovine diseases caused by monocellular pathogens, and diseases selected from human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus monkey cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), and for the regulation of body temperature.

[0783] Another object of the present invention comprises the use of at least one compound of formula (I) as defined above according to the present invention, and compounds (1) to (216) as defined above, or any pharmaceutically acceptable salt thereof, for the treatment of type 1 and type 2 diabetes, viral infections, particularly as mentioned above, osteoarthritis, cancer, particularly as mentioned above, infections caused by unicellular parasites, such as malaria, leishmaniasis, Chagas and sleeping sickness (Tripanosoma species), and bovine diseases caused by unicellular pathogens, and for the regulation of body temperature.

[0784] According to certain embodiments, treatment is continuous or discontinuous.

[0785] "Continuous treatment" means long-term treatment that can be administered at various frequencies, such as once a day, every three days, once a week, once every two weeks, or once a month, or by transdermal patch delivery.

[0786] According to one embodiment, a compound of formula (I) or any pharmaceutically acceptable salt thereof is administered in a dosage in the range of 0.1 to 1000 mg, particularly in the range of 1 to 500 mg, or for example in the range of 5 to 100 mg.

[0787] Another objective of the present invention is to address, in patients requiring it, cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tauopathy; and other neurodegenerative diseases (Parkinson's disease; Pick's disease including Niemann-Pick type C); CDKL5 deficiency disorders; McDiarmid syndrome; autism; type 1 and type 2 diabetes; regulation of folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; Numerous cancers, e.g., brain cancer including glioblastoma; leukemia including megakaryoblastic leukemia; head and neck squamous cell carcinoma; pancreatic cancer including pancreatic ductal adenocarcinoma; prostate cancer; gastrointestinal cancer; breast cancer, e.g., triple-negative breast cancer (TNBC); tissue cancer including liposarcoma; Hedgehog / GLI-dependent cancer; liver cancer including hepatocellular carcinoma; and viral infections caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella-zoster virus, herpes simplex virus (HSV), hepatitis C virus, chikungunya virus, dengue virus, influenza virus and severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus, and human papillomavirus; neuroinflammation; anemia; The present invention relates to a therapeutic method for the treatment and / or prevention and thermoregulation of infections caused by unicellular parasites, selected from malaria, leishmaniasis, Chagas and sleeping sickness (Tripanosoma species), and bovine diseases caused by unicellular pathogens, comprising at least the step of administering a therapeutically effective amount of a compound of formula (I) as defined above or compounds (1) to (216) or any acceptable salt thereof.

[0788] In certain embodiments, the present invention provides the use of a compound of formula (I) according to the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically active derivative thereof, or a method according to the present invention, wherein the compound of formula (I) must be administered in combination with an adjuvant useful for any of the aforementioned diseases.

[0789] The compound may be administered via any method of administration, such as, for example, intramuscular, intravenous, nasal, or oral routes, transdermal patches, etc.

[0790] The composition of the present invention may further comprise one or more additives, such as diluents, excipients, stabilizers, and preservatives. Such additives are well known to those skilled in the art and, in particular, are described in the literature [" Ullmann's Encyclopedia of Industrial Chemistry, 6 th Ed. " (various editors, 1989-1998, Marcel Dekker) and in " Pharmaceutical Dosage Forms and Drug Delivery Systems " (ANSEL et al, It is listed in [1994, WILLIAMS & WILKINS].

[0791] The aforementioned excipients are selected according to the form of administration and the appropriate method of administration.

[0792] The compositions of the present invention may be administered in any manner including, but not limited to, oral, parenteral, sublingual, transdermal, vaginal, rectal, transmucosal, topical, intranasal, buccal or intranasal administration via inhalation, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, intravertebral, and intra-articular. The compositions of the present invention may also be administered in the form of implants, which enables slow-controlled intravenous infusion as well as slow-release of the compositions.

[0793] For example, the compound of formula (I) may be present in any pharmaceutical form suitable for enteral or parenteral administration with appropriate excipients, e.g., plain or coated tablets, hard gelatin, soft-shell capsules and other capsules, suppositories or beverages, e.g., suspensions, syrups or injectable solutions or suspensions.

[0794] In a specific embodiment, the compound of formula (I) according to the present invention is administered orally.

[0795] An oral administration route is particularly preferred in the preventive or therapeutic aspects of the present invention.

Claims

Claim 1 Compound of formula (I) or any pharmaceutically acceptable salt thereof: [In the middle of the meal, R 1 은:(i). -COOR a (ii). (ii) a (C1-C6)alkyl group substituted by one or two groups selected from a benzyloxy group in which a phenyl group is substituted by one to three halogen atoms, a hydroxyl group, a halogen atom, a (C1-C4)alkoxy group, and optionally a phenyl group substituted by 1 to 3 halogen atoms. (ii) spiro(C5-C 11 ) bicyclic ring, (iii). as a fused phenyl group, selected from a phenyl group fused with a (C5-C6)cycloalkyl or (C5-C6)heterocycloalkyl, wherein the (C5-C6)cycloalkyl and (C5-C6)heterocycloalkyl rings optionally comprise insaturation, and optionally a (C1-C4)alkyl group, hydroxyl group, halogen atom, (C1-C3)alkoxy group or -COR a (iv) a fused phenyl group substituted by a group, as a phenyl group, substituted by one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy groups, halogen atoms, and optionally (C4-C7)heterocycloalkyl groups self-substituted by a (C1-C4)alkyl group, or (v). As an R'-L- group, L is a (C1-C3)alkanediyl group or a single bond optionally substituted by a group selected from a hydroxyl group and a (C1-C3)alkoxy group, and R' is: (v.1) a (C3-C8)cycloalkyl group optionally substituted by 1, 2, or 3 groups selected from a (C1-C4)alkyl group, a hydroxyl group, a halogen atom, and a (C1-C3)alkoxy group, (v.2) optionally a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a halogen atom, a hydroxyl group, -OC(O)-R d Gi, -OC(O)-NHR d Gi, -NH-C(O)-R d -SO2-R d Gi, -N(R e )2nd term and -COOR a Bridged (C6-C) substituted by 1 to 3 groups selected from the group 10 )cycloalkyl group, (v.3) optionally -COOR a (v.4) a (C3-C8) heterocycloalkyl group substituted by 1 to 3 groups selected from a hydroxyl group, a halogen atom, a (C1-C4)alkyl group and an oxo group, optionally a halogen atom, a (C1-C4)alkyl group, a (C1-C4)alkoxy group and N - Substituted by 1 to 3 groups selected from methylpiperazinyl groups, (C5-C 11 )heteroaryl group, or (v.5) bridged (C6-C 10 ) R'-L- group representing a heterocycloalkyl group, or (vi) R f -L f - As a result, L f is optionally -NR b R c group, (C1-C4)alkoxy group, hydroxyl group, -COOR a It is a (C1-C3)alkanedyl group substituted by a group selected from a halogen atom and R f R is a phenyl group optionally substituted by 1 to 3 groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups and fluoro(C1-C4)alkoxy groups, halogen atoms and hydroxyl groups. f -L f - Represents energy, R a represents a (C1-C4)alkyl group or a hydrogen atom, and R b and R c represents an (C1-C6)alkyl group or a hydrogen atom independently, and R d represents a (C1-C4)alkyl group or a cyclopropyl group, and R e represents a (C1-C3)alkyl group, and R 2 [ represents a hydrogen atom or a (C1-C3)alkyl group]. Claim 2 In paragraph 1, R 1 은:(i). -COOR a (ii) a (C2-C6) alkyl group substituted by one or two groups selected from a benzyloxy group in which the phenyl group is substituted by one to three halogen atoms, a hydroxyl group, a halogen atom, a (C1-C4) alkoxy group, and optionally a phenyl group substituted by 1 to 3 halogen atoms; (iii) a spiro(C7-C9) bicyclic ring; (iii) a fused phenyl group selected from a phenyl group fused with a cyclopentyl or heterocyclopentyl, wherein the cyclopentyl and heterocyclopentyl groups optionally comprise unsaturation, and optionally a (C1-C4) alkyl group, a hydroxyl group, a halogen atom, a (C1-C3) alkoxy group, or -COR a (iv) a fused phenyl group substituted by a group, or (v) a phenyl group substituted by one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy groups, halogen atoms, and optionally (C4-C7)heterocycloalkyl groups self-substituted by a (C1-C4)alkyl group. As an R'-L- group, · L is a (C1-C3)alkanediyl group or a single bond optionally substituted by a group selected from a hydroxyl group and a (C1-C3)alkoxy group, and · R' is: (v.1) a (C3-C8)cycloalkyl group optionally substituted by 1, 2, or 3 groups selected from a (C1-C4)alkyl group, a hydroxyl group, a fluorine atom, and a (C1-C3)alkoxy group, (v.2) optionally a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a hydroxyl group, a halogen atom, -OC(O)-R d Gi, -OC(O)-NHR d Gi, -NH-C(O)-R d -SO2-R d Gi, -N(R e )2nd term and -COOR a Bridged (C7-C) substituted by 1 to 3 groups selected from the group 10 )cycloalkyl group, (v.3) optionally -COOR a (v.4) a (C3-C8) heterocycloalkyl group substituted by 1 to 3 groups selected from a hydroxyl group, a halogen atom, a (C1-C4)alkyl group and an oxo group, optionally a halogen atom, a (C1-C4)alkyl group, a (C1-C4)alkoxy group, and N - Substituted by 1 to 3 groups selected from methylpiperazinyl groups, (C5-C 11 )heteroaryl group, or (v.5) bridged (C6-C 10 ) Representing a heterocycloalkyl group, an R'-L- group, or (vi). R f -L f - As, · L f is optionally -NR b R c group, (C1-C4)alkoxy group, hydroxyl group, -COOR a It is a (C1-C3)alkanedyl group substituted by a group selected from a halogen atom and · R f R represents a phenyl group, optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups and fluoro(C1-C4)alkoxy groups, hydroxyl groups, and halogen atoms. f -L- and,R a represents a (C1-C4)alkyl group or a hydrogen atom, and R b and R c represents an (C1-C6)alkyl group or a hydrogen atom independently, and R d represents a (C1-C4)alkyl group or a cyclopropyl group, and R e represents a (C1-C3)alkyl group, and R 2 A compound of formula (I) or any pharmaceutically acceptable salt thereof, representing a hydrogen atom or a (C1-C3)alkyl group. Claim 3 In paragraph 1, R 1 Silver:(i). -COOCH3 group, hydroxyl group, fluorine atom, methoxy group, ethoxy group, tert (ii) a (C2-C6)alkyl group substituted by one or two groups selected from butoxy, cyclopropoxy, and optionally benzyloxy groups substituted by a fluorine atom; (iii) a spiro(C7-C8) bicyclic ring; (iv) a fused phenyl group selected from phenyl groups fused with cyclopentyl or heterocyclopentyl, wherein the cyclopentyl and heterocyclopentyl groups optionally comprise unsaturation and optionally substituted by methyl, hydroxyl, methoxy, and -COCH3 groups; (iv) methyl, hexyl, trifluoromethyl, difluoromethoxy, halogen atoms, morpholino groups and N - A phenyl group substituted by one or two groups selected from methylpiperazinyl groups, or (v). As an R'-L- group, L is a (C1-C3)alkanidiyl group or a single bond optionally substituted by a group selected from hydroxyl groups and (C1-C3)alkoxy groups, and R' is: (v.1). As a (C3-C8)cycloalkyl group, optionally a (C3-C8)cycloalkyl group substituted by one, two or three groups selected from methyl, isopropyl, hydroxyl groups and methoxy groups, (v.2). Bridged (C7-C 10 ) As a cycloalkyl group, optionally substituted by 1 to 3 groups selected from a methyl group, a methoxy group, a hydroxyl group, a fluorine atom, -OC(O)-CH3 group, -OC(O)-C(CH3)3 group, -OC(O)-NH-C(CH3)3 group, -NH-C(O)-CH3 group, -NH-C(O)-C3H5 group, -S(O)2-CH3 group, -S(O)2-C3H5 group, -N(CH3)2 group and -C(O)-O-CH3 group, a bridged (C7-C 10 )cycloalkyl group, (v.3). As a (C5-C8)heterocycloalkyl group, optionally -COOR a Substituted by 1, 2, or 3 groups selected from the group, hydroxyl group, methyl group, and oxo group, and R a represents an ethyl or isopropyl group, a (C5-C8) heterocycloalkyl group, (v.4). (C5-C 11 As a heteroaryl group, optionally a methyl group, a methoxy group and N - Substituted by 1 to 3 groups selected from methylpiperazinyl groups, (C5-C 11 )heteroaryl group, or (v.5). Bridged (C7-C 10 ) An R'-L- group selected from the group consisting of heterocycloalkyl groups, or (vi). R f '-L f - As a result, L f is optionally -NR b R c group, (C1-C4)alkoxy group, hydroxyl group, -COOR a It is a (C1-C3)alkanedyl group substituted by a group selected from the group consisting of a halogen atom and R f R is a phenyl group, optionally substituted by one or two groups selected from the group consisting of methyl groups, trifluoromethyl groups, and trifluoromethoxy groups. f '-L f - Represents energy, R a represents a (C1-C3)alkyl group, and R b and R c is independently selected from a methyl group or a hydrogen atom, and R 2 A compound of formula (I) or any pharmaceutically acceptable salt thereof, representing a hydrogen atom or a (C1-C3)alkyl group. Claim 4 In claim 1, L is selected from the group consisting of -CH2- group, -CH(CH3)- group, -CH(CH2OH)-CH2- group, -CH(CH2OH)- group, -CH(CH2OCH3)- group, -CH(OH)-CH2- group, -CH2-CH(CH2OCH3)- group, -CH(OCH3)-CH2- group, -CH2-CH(CH2OH)- group, -CH(OCH3)-CH2- group, -CH2-CH(OCH3)- group, -CH2-CH(OH)-CH2- group, -CH2-CH(OCH3)-CH2 group, -(CH2)3- group and -(CH2)2- group, and / or L f -CH2- group, -CH(CH3)- group, -CH(CH2OH)-CH2- group, -CH(CH2OH)- group, -CH(CH2OCH3)- group, -CH(OH)-CH2- group, -CH2-CH(CH2OCH3)- group, -CH(OCH3)-CH2- group, -CH2-CH(COOCH3)- group, -CH(CH2F)- group, -CH(CH2NH2)- group, -CH(CH2NHCH3)- group, -CH(CH2N(CH3)2)- group, -CH2-CH(CH2OH)- group, -CH(OCH3)-CH2- group, -CH2-CH(OCH3)- group, -CH2-CH(OH)-CH2- group, -CH2-CH(OCH3)-CH2 group, -(CH2)3- group, -(CH2)2- group and A compound of formula (I) selected from the group consisting of -CH(CH2OC(CH3)3) groups, or any pharmaceutically acceptable salt thereof. Claim 5 In claim 1, - where R' is a (C3-C8)cycloalkyl group, L is selected from the group consisting of a single bond, -CH2- group, -CH(CH3)- group, -CH(CH2OH)-CH2- group, -CH(CH2OH)- group, -CH(CH2OCH3)- group, -CH(OH)-CH2- group, and -CH(OCH3)-CH2- group, and -R' is a bridged (C7-C 10 ) If it is a cycloalkyl group, L is a single bond, a -CH2- group, or a -CH(CH3)- group, and - If R' is a (C5-C8) heterocycloalkyl group containing a spiro(C3-C8) heterocycloalkyl, L is a single bond or a -CH2- group, and - R f If 'a is phenyl, L f is selected from the group consisting of -CH2- group, -CH2-CH(COOCH3)- group, -CH(CH2F)- group, -CH(CH2NH2)- group, -CH(CH2NHCH3)- group, -CH(CH2N(CH3)2)- group, -CH2-CH(CH2OH)- group, -CH(CH2OH)- group, -CH(CH2OCH3)- group, -CH(OH)-CH2- group, -CH2-CH(CH2OCH3)- group, -CH2-CH(OH)-CH2- group and -CH2-CH(OCH3)-CH2- group, and -R' is (C5-C 11 ) In the case of a heteroaryl group, L is selected from the group including a single bond, -CH2- group, -(CH2)3- group and -(CH2)2- group, and -R' is bridged (C7-C 10 ) In the case where L is a heterocycloalkyl group, a compound of formula (I) or any pharmaceutically acceptable salt thereof in which L is a single bond. Claim 6 In paragraph 1, R 1 As an adamantyl group, an adamantyl group optionally substituted by one to three groups selected from a methyl group, a methoxy group, a hydroxyl group, a fluorine atom, -OC(O)-CH3 group, -OC(O)-C(CH3)3 group, -OC(O)-NH-C(CH3)3 group, -NH-C(O)-CH3 group, -NH-C(O)-C3H5 group, -S(O)2-CH3 group, -S(O)2-C3H5 group, -N(CH3)2 group, and -C(O)-O-CH3 group; A compound of formula (I) or any pharmaceutically acceptable salt thereof, wherein o R"-O-CH2-CH(R"')- group, where o R" is a (C1-C4)alkyl group and o R"' is a (C1-C4)alkyl group or o R"' is a phenyl group, optionally substituted by one to three groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups, fluoro(C1-C4)alkoxy groups, halogen atoms and hydroxyl groups, representing an R"-O-CH2(R"')- group which is a phenyl group. Claim 7 In paragraph 1, R 1 은:- -COOR a (C1-C6)alkyl group, substituted by one or two groups selected from a hydroxyl group, a fluorine atom, a (C1-C4)alkoxy group, and optionally a phenyl group substituted by a halogen atom, a benzyloxy group, - spiro(C5-C 11 ) as a bicyclic ring, or - R'-L- group, o L is a (C1-C3)alkanediyl group or a single bond optionally substituted by a group selected from a hydroxyl group and a (C1-C3)alkoxy group, and o R' is: · a (C3-C8)cycloalkyl group optionally substituted by 1, 2, or 3 groups selected from a halogen atom, a (C1-C4)alkyl group, a hydroxyl group, and a (C1-C3)alkoxy group, and · optionally a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a halogen atom, a hydroxyl group, -OC(O)-R d Gi, -OC(O)-NHR d Gi, -NH-C(O)-R d -SO2-R d Gi, -N(R e )2nd term and -COOR a Bridged (C6-C) substituted by 1 to 3 groups selected from the group 10 Representing an R'-L- group selected from the group consisting of cycloalkyl groups, and R a represents a (C1-C4)alkyl group, and R d represents a (C1-C4)alkyl group or a cyclopropyl group, and R e represents a (C1-C3)alkyl group, and R 2 A compound of formula (I) or any pharmaceutically acceptable salt thereof, representing a hydrogen atom or a (C1-C3)alkyl group. Claim 8 In paragraph 1, R 1 Silver: - As a fused phenyl group, selected from a phenyl group fused with a (C5-C6)cycloalkyl or (C5-C6)heterocycloalkyl, wherein the (C5-C6)cycloalkyl and (C5-C6)heterocycloalkyl groups optionally comprise unsaturation, and optionally include a (C1-C4)alkyl group, a hydroxyl group, a halogen atom, a (C1-C3)alkoxy group, and -COR a A fused phenyl group substituted by a group, - as a phenyl group, substituted by one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy groups, halogen atoms, and optionally (C4-C7)heterocycloalkyl groups self-substituted by a (C1-C4)alkyl group, a phenyl group, or - R f '-L f - As, o L f It selectively contains hydroxyl groups, (C1-C4)alkoxy groups, and -NR b R c Gi, -COOR a It is a (C1-C3)alkanedyl group substituted by a group selected from a halogen atom and o R f R is a phenyl group optionally substituted by 1 to 3 groups selected from the group consisting of (C1-C6)alkyl groups, fluoro(C1-C4)alkyl groups and fluoro(C1-C4)alkoxy groups, halogen atoms and hydroxyl groups. f '-L f - Represents energy, R a is a (C1-C4)alkyl or hydrogen atom, and R b and R c is independently selected from (C1-C6)alkyl and hydrogen atoms, and R 2 A compound of formula (I) or any pharmaceutically acceptable salt thereof, representing a hydrogen atom or a (C1-C3)alkyl group. Claim 9 In paragraph 1, R 2 A compound of formula (I) or any pharmaceutically acceptable salt thereof, representing a hydrogen atom or a methyl group. Claim 10 In paragraph 1, R 1 It is an R'-L- group, where -R' is optionally a halogen atom, a (C1-C4)alkyl group, a (C1-C4)alkoxy group and N - Substituted by 1 to 3 groups selected from methylpiperazinyl groups, (C5-C 11 ) It is a heteroaryl group, where -L represents an R'-L- group which is a (C1-C3)alkanidiyl or a single bond, and R 2 is a compound of formula (I) representing a hydrogen atom, or any pharmaceutically acceptable salt thereof. Claim 11 In paragraph 1, R 1 -R' is an R'-L- group, where -R' is a (C3-C5)heterocycloalkyl group, optionally a hydroxyl group, (C1-C4)alkyl group, oxo group, and -COOR a It is substituted by 1 to 3 groups selected from the group, and R a is a (C3-C5)heterocycloalkyl group as defined in claim 1, where -L represents an R'-L- group which is methylene or a single bond, and R 2 is a compound of formula (I) representing a hydrogen atom, or any pharmaceutically acceptable salt thereof. Claim 12 In paragraph 1, (1) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclopropylmethylamino)-1 H -Imidazole-5-one,(2) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclopropylamino)-1 H -Imidazole-5-one,(3) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclobutylamino)-1 H -Imidazole-5-one,(4) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclopentylamino)-1 H -Imidazole-5-one,(5) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclohexylmethylamino)-1 H -Imidazole-5-one,(6) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclohexylamino)-1 H -Imidazole-5-one,(7) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cycloheptylmethylamino)-1 H -Imidazole-5-one,(8) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cycloheptylamino)-1 H -Imidazole-5-one,(9) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(cyclooctylamino)-1 H -Imidazole-5-one,(10) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-hydroxy-2,2-dimethyl-propyl)amino]-1 H -Imidazole-5-one,(11) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(2-benzyloxyethylamino)-1 H -Imidazole-5-one,(12) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methylcyclohexyl]amino]-1 H -Imidazole-5-one,(13) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-cyclohexylethyl]amino]-1 H -Imidazole-5-one,(14) (4 Z )-2-(1-adamantylmethylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,(15) (±)-(4 Z )-2-[1-(1-adamantyl)ethylamino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,(16) (4 Z )-2-(1-adamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,(17) (4 Z )-2-(2-adamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,(18) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[3,5-dimethyl-1-adamantyl]amino]-1 H -Imidazole-5-one,(19) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[( trans -5-hydroxy-2-adamantyl)amino]-1 H -Imidazole-5-one,(20) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1 H -Imidazole-5-one,(21) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1 H -Imidazole-5-one,(22) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R ,3 R ,5 S )-2,6,6-trimethylnorpinan-3-yl]amino]-1 H -Imidazole-5-one,(23) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S ,3 S ,5 R )-2,6,6-trimethylnorpinan-3-yl]amino]-1 H -Imidazole-5-one,(24) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R ,5 R )-6,6-dimethylnorpinan-2-yl]methylamino]-1 H -Imidazole-5-one,(25) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(spiro[2.5]octane-2-ylamino)-1 H -Imidazole-5-one,(26) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(spiro[3.3]heptane-2-ylamino)-1 H -Imidazole-5-one,(27) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(2 R )-1,7,7-trimethylnorbornan-2-yl]amino]-1 H -Imidazole-5-one,(28) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(norbornan-2-ylamino)-1 H -Imidazole-5-one,(29) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 S ,5 R )-2-isopropyl-5-methyl-cyclohexyl]amino]-1 H -Imidazole-5-one,(30) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclohexylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,(31) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclopentylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,(32) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclobutylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,(33) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclopropylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,(34) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(35) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(methoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(36) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazole-5-one,(37) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(methoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(38) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(hydroxymethyl)propyl]amino]-1 H -Imidazole-5-one,(39) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(hydroxymethyl)propyl]amino]-1 H -Imidazole-5-one,(40) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(41) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-cyclohexyl-2-hydroxy-ethyl)amino]-1 H -Imidazole-5-one,(42) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-cyclohexyl-2-methoxy-ethyl)amino]-1 H -Imidazole-5-one,(43) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-cyclohexyl-2-hydroxy-ethyl)amino]-1 H -Imidazole-5-one,(44) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-cyclohexyl-2-methoxy-ethyl)amino]-1 H -Imidazole-5-one,(45) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxycyclopentyl]amino]-1 H -Imidazole-5-one,(46) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxycyclopentyl]amino]-1 H -Imidazole-5-one,(47) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,(48) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,(49) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(50) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(51) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 S )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(52) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 R )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(53) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(54) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(55) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(56) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-hydroxycyclohexyl]amino]-1 H -Imidazole-5-one,(57) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[( trans -4-hydroxycyclohexyl)amino]-1 H -Imidazole-5-one,(58) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(59) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(60) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[( trans -4-Methoxycyclohexyl)amino]-1 H -Imidazole-5-one,(61) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(62) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(63) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(64) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(65) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(66) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(67) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,(68) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-methoxycycloheptyl]amino]-1 H -imidazole-5-one,(69)methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-3-methyl-butanoate,(70) methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]propanoate,(71) methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-4-methyl-pentanoate,(72) methyl (2 R )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-4-methyl-pentanoate,(73) methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-3-hydroxy-butanoate,(74) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(benzylamino)-1 H -Imidazole-5-one,(75) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(indane-2-ylamino)-1 H -Imidazole-5-one,(76) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,4-dimethylphenyl)methylamino]-1 H -Imidazole-5-one,(77) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2,4-dimethylphenyl)methylamino]-1 H -Imidazole-5-one,(78) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1 H -Imidazole-5-one,(79) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(trifluoromethoxy)phenyl]methylamino]-1 H -Imidazole-5-one,(80) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,(81) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,(82) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,(83) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxyindane-1-yl]amino]-1 H -Imidazole-5-one,(84) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -2-methoxyindane-1-yl]amino]-1 H -Imidazole-5-one,(85) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans- 2-methoxyindane-1-yl]amino]-1 H -imidazole-5-one,(86)methyl (2 S )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-3-phenyl-propanoate,(87) methyl (2 R )-2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-3-phenyl-propanoate,(88) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-fluoro-1-phenyl-ethyl)amino]-1 H -Imidazole-5-one,(89) (±)-(4 Z )-2-[(2-amino-1-phenyl-ethyl)amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride,(90) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(methylamino)-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one dihydrochloride,(91) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(dimethylamino)-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,(92) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-benzyl-2-hydroxy-ethyl)amino]-1 H -Imidazole-5-one,(93) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-benzyl-2-hydroxy-ethyl]amino]-1 H -Imidazole-5-one,(94) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-benzyl-2-methoxy-ethyl)amino]-1 H -Imidazole-5-one,(95) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1 H -Imidazole-5-one,(96) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-2-hydroxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,(97) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-2-hydroxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,(98) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-1-phenyl-ethyl)amino]-1 H -Imidazole-5-one,(99) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-2-phenyl-ethyl)amino]-1 H -Imidazole-5-one,(100) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-2-phenyl-ethyl)amino]-1 H -Imidazole-5-one,(101) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-hydroxy-3-phenyl-propyl)amino]-1 H -Imidazole-5-one,(102) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-3-phenyl-propyl)amino]-1 H -Imidazole-5-one,(103) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(5-methylpyrazine-2-yl)methylamino]-1 H -Imidazole-5-one,(104) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(2-pyridylmethylamino)-1 H -Imidazole-5-one,(105) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-pyridylmethylamino)-1 H -Imidazole-5-one,(106) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-pyridylmethylamino)-1 H -Imidazole-5-one,(107) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(5-methyl-2-furyl)methylamino]-1 H -Imidazole-5-one,(108) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(4-methylthiazole-2-yl)methylamino]-1 H -Imidazole-5-one,(109) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-imidazole-1-ylpropylamino)-1 H -Imidazole-5-one,(110) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[2-(2-pyridyl)ethylamino]-1 H -Imidazole-5-one,(111) (4 Z )-2-(1,3-benzothiazole-2-ylmethylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,(112) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-4-piperidyl)methylamino]-1 H -Imidazole-5-one,(113) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1 H -Imidazole-5-one, (114) Tert -butyl 4-[[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]methyl]piperidine-1-carboxylate,(115) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(7-methyl-7-azaspiro[3.5]nonane-2-yl)amino]-1 H -Imidazole-5-one,(116) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-fluoro-4-methyl-anilino)-1 H -Imidazole-5-one,(117) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-fluoroanilino)-1 H -Imidazole-5-one,(118) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-hexylanilino)-1 H -Imidazole-5-one,(119) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[4-(4-methylpiperazine-1-yl)anilino]-1 H -Imidazole-5-one,(120) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[3-(difluoromethoxy)anilino]-1 H -Imidazole-5-one,(121) (4 Z )-2-[(1-acetylindolin-6-yl)amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,(122) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[3-(trifluoromethyl)anilino]-1 H -Imidazole-5-one,(123) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(indane-5-ylamino)-1 H -Imidazole-5-one,(124) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(4-morpholinoanilino)-1 H -Imidazole-5-one,(125) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methylindazole-7-yl)amino]-1 H -Imidazole-5-one,(126) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(pyrimidine-2-ylamino)-1 H -Imidazole-5-one,(127) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(2-pyridylamino)-1 H -Imidazole-5-one,(128) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methylpyrazole-3-yl)amino]-1 H -Imidazole-5-one,(129) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-methoxy-6-methyl-3-pyridyl)amino]-1 H -Imidazole-5-one,(130) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(pyrimidine-5-ylamino)-1 H -Imidazole-5-one,(131) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(3-pyridylamino)-1 H -Imidazole-5-one,(132) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(1,3,4-thiadiazole-2-ylamino)-1 H -Imidazole-5-one,(133) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[5-(4-methylpiperazine-1-yl)-2-pyridyl]amino]-1 H -Imidazole-5-one,(134) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[6-(4-methylpiperazine-1-yl)-3-pyridyl]amino]-1 H -Imidazole-5-one,(135) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[2-(4-methylpiperazine-1-yl)pyrimidine-5-yl]amino]-1 H -Imidazole-5-one,(136) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[5-(4-methylpiperazine-1-yl)pyrimidine-2-yl]amino]-1 H -Imidazole-5-one,(137) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[5-(4-methylpiperazine-1-yl)pyrazine-2-yl]amino]-1 H -Imidazole-5-one,(138) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[6-(4-methylpiperazine-1-yl)pyridazine-3-yl]amino]-1 H -Imidazole-5-one,(139) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(tetrahydropyran-4-ylamino)-1 H -Imidazole-5-one, (140) Tert -butyl 4-[[(4Z)-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidine-1-carboxylate,(141)ethyl 4-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidine-1-carboxylate,(142) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-4-piperidyl)amino]-1 H -Imidazole-5-one,(143) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-3-piperidyl)amino]-1 H -Imidazole-5-one,(144) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(oxetane-3-ylamino)-1 H -Imidazole-5-one,(145) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R )-tetrahydrofuran-3-yl]amino]-1 H -Imidazole-5-one,(146) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-tetrahydrofuran-3-yl]amino]-1 H -Imidazole-5-one,(147) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R )-tetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,(148) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-tetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,(149) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-1 H -Imidazole-5-one,(149A). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-6,6-dimethyltetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,(149B). (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-6,6-dimethyltetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,(150) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ,4 R )-4-hydroxytetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,(151) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(oxephane-3-ylamino)-1 H -Imidazole-5-one,(152) (±)-3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,(153) (3 S )-3-[[(4Z)-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,(154) (5 S )-5-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,(155) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,3-difluorocyclopentyl)amino]-1 H -Imidazole-5-one,(156) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(4,4-difluorocyclohexyl)amino]-1 H -Imidazole-5-one,(157) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,3-difluorocyclohexyl)amino]-1 H -Imidazole-5-one,(158) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2,2-difluorocyclohexyl)amino]-1 H -Imidazole-5-one,(159) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,3-difluorocycloheptyl)amino]-1 H -Imidazole-5-one,(160) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(161) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(162) [3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]acetate,(163) [3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl] 2,2-dimethylpropanoate,(164) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,(165) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-methoxycyclopentyl]amino]-1 H -Imidazole-5-one,(166) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,2 R )-2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(167) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S ,2 S )-2-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(168) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(169) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(169A).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,3 R ) / (1 S ,3 S )-3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(169B).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,3 R ) / (1 S ,3 S )-3-methoxycyclohexyl]amino]-1 H -Imidazole-5-one,(170) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -4-hydroxycycloheptyl]amino]-1 H -imidazole-5-one,(171) (±)-(4Z)-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -4-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(171A).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,4 R ) / (1 S ,4 S )-4-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(171B).(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R ,4 R ) / (1 S ,4 S )-4-hydroxycycloheptyl]amino]-1 H -Imidazole-5-one,(172) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -3-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,(173) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -3-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,(174) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ cis -4-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,(175) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[ trans -4-methoxycycloheptyl]amino]-1 H -Imidazole-5-one,(176) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-2-methoxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,(177) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 S )-2-methoxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one,(178) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(2 R )-2-hydroxy-2-phenyl-ethyl]amino]-1 H -Imidazole-5-one,(179) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(2 S )-2-hydroxy-2-phenyl-ethyl]amino]-1 H -Imidazole-5-one,(180) (4 Z )-2-[[(1 R )-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride,(181) (4 Z )-2-[[(1 S )-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride,(182) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R )-quinuclidein-3-yl]amino]-1 H -Imidazole-5-one,(183) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S )-quinuclidein-3-yl]amino]-1 H -Imidazole-5-one,(184) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(tetrahydrothiopyran-3-ylamino)-1 H -Imidazole-5-one,(185) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-(1,4-dioxephane-6-ylamino)-1 H -Imidazole-5-one,(186) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(2-oxopyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,(187) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1-methyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,(188) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(4,4-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,(189) (3 R )-3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]piperidin-2-one,(190) (±)-3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-methyl-piperidin-2-one,(191) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-methyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,(192) (±)-(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(1,3-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazole-5-one,(192A) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-1,3-dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1 H -Imidazole-5-one,(192B) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 R ) / (3 S )-1,3-dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1 H -Imidazole-5-one,(193) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(3 S ,4 S )-4-hydroxytetrahydropyran-3-yl]amino]-1 H -Imidazole-5-one,(194) (4 Z )-2-(3-noradamantylamino)-4-(1,3-benzothiazole-6-ylmethylene)-1 H -Imidazole-5-one,(195) [3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl] N - tert -butylcarbamate,(196) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-1 H -Imidazole-5-one,(197) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-( tert -butoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(198) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-2- tert -butoxy-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one, (199) N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]acetamide, (200) N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]cyclopropanecarboxamide, (201) N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]methanesulfonamide, (202) N -[3-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]-1-adamantyl]cyclopropanesulfonamide,(203) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[3-(dimethylamino)-1-adamantyl]amino]-1 H -Imidazole-5-one,(204)methyl 2-[[(4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-5-oxo-1 H -imidazole-2-yl]amino]adamantan-2-carboxylate,(205) (4 Z )-2-(cyclohexylamino)-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,(206) (4 Z )-2-(cycloheptylamino)-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,(207) (4 Z )-2-[[(1 R )-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,(208) (4 Z )-2-[[(1 R )-2-methoxy-1-phenyl-ethyl]amino]-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,(209) (4 Z )-2-(1-adamantylamino)-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one, and (210) (4 Z )-2-[(3-hydroxy-1-adamantyl)amino]-4-[(2-methyl-1,3-benzothiazole-6-yl)methylene]-1 H -Imidazole-5-one,(211) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,5-dihydroxy-1-adamantyl)amino]-1 H -Imidazole-5-one,(212) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[(3,5,7-trifluoro-1-adamantyl)amino]-1 H -Imidazole-5-one,(213) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(ethoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(214) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(benzyloxymethyl)-3-methyl-butyl]amino]-1 H -Imidazole-5-one,(215) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-[(4-fluorophenyl)methoxymethyl]-3-methyl-butyl]amino]-1 H -Imidazole-5-one, and (216) (4 Z )-4-(1,3-benzothiazole-6-ylmethylene)-2-[[(1 R )-1-(cyclopropoxymethyl)-3-methyl-butyl]amino]-1 H - A compound of formula (I) selected from imidazole-5-one, or any pharmaceutically acceptable salt thereof. Claim 13 A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 11 or any pharmaceutically acceptable salt thereof, or at least one compound as defined in claim 12 or any pharmaceutically acceptable salt thereof, wherein the composition relates to: cognitive deficit associated with Down syndrome; Alzheimer's disease; dementia; tauopathy; and other neurodegenerative diseases; CDKL5 deficiency disorder; McDermid syndrome; autism; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis; Duchenne muscular dystrophy; a number of cancers; viral infections; neuroinflammation; anemia; infections caused by single-celled parasites; A pharmaceutical composition for use in the treatment and / or prevention of cattle disease selected from cattle disease caused by unicellular pathogens, or for thermoregulation. Claim 14 In claim 13, the pharmaceutical composition is for cognitive deficits associated with Down syndrome; Alzheimer's disease; dementia; tauopathies; Parkinson's disease; Pick disease; CDKL5 deficiency disorder; McDermid syndrome; autism; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; knee osteoarthritis; Duchenne muscular dystrophy; Brain cancer, leukemia, head and neck squamous cell carcinoma, pancreatic cancer, prostate cancer, gastrointestinal cancer, breast cancer, tissue cancer, Hedgehog / GLI-dependent cancer, liver cancer, and Human immunodeficiency virus type 1 (HIV-1), Human cytomegalovirus (HCMV), Influenza A, Herpes virus, Rhesus macaque cytomegalovirus, Varicella-zoster virus, Herpes simplex virus (HSV), Hepatitis C virus, Chikungunya virus, Dengue virus, Influenza virus, Severe acute respiratory syndrome (SARS), Viral infections caused by coronavirus, cytomegalovirus, and human papillomavirus; neuroinflammation; anemia; infections caused by malaria, leishmaniasis, Chagas, and sleeping sickness;A pharmaceutical composition selected from cattle disease caused by unicellular pathogens.; Claim 15 A synthesis process for producing a compound of formula (I) as defined in any one of claims 1 to 11 or any pharmaceutically acceptable salt thereof, or a compound of formula (I) as defined in claim 12 or any pharmaceutically acceptable salt thereof, wherein at least a compound of formula (II) is used in formula R 1 Synthesis process comprising a step of coupling NH2 with an amine: [In the formula, Alk is a (C1-C5)alkyl, and R 1 and R 2 [is as defined in any one of paragraphs 1 through 11]. Claim 16 Synthetic intermediate of the following chemical formula (II): [In the formula, Alk is a (C1-C5)alkyl, and R 2 [is as defined in any one of paragraphs 1 through 11]. Claim 17 A pharmaceutical composition for use in the treatment and / or prevention of Down syndrome, Alzheimer's disease, dementia, tauopathy, Parkinson's disease, Niemann-Pick type C disease, CDKL5 deficiency disorder and Phelan-McDiarmid syndrome and associated cognitive and motor conditions, and a disease selected from type 1 and type 2 diabetes. Claim 18 delete

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