New imidazolinone derivatives as inhibitors of protein kinases, in particular DYRK1A, CLK1 and / or CLK4

Abstract

This invention relates to compounds of formula (I) wherein R 1 Indicates (C1-C6) alkyl, spiro(C5 ... 11 Bicyclic, fused phenyl, substituted phenyl, R'-L- group, where L is a single bond or (C1-C3) alkyl diel, and R' represents (C3-C8) cycloalkyl, bridged (C6-C8) cycloalkyl, or fused phenyl. 10 The group may be a cycloalkyl, (C3-C8) heterocycloalkyl, or (C3-C8) heteroaryl, or an R'-L- group, wherein L is a (C1-C3) alkyldiyl and R' is an optionally substituted phenyl group, and wherein R... 2 The term represents any one of a hydrogen atom or a (C1-C3) alkyl group or a pharmaceutically acceptable salt thereof. The invention further relates to compositions comprising compounds of formula (I) and methods for preparing said compounds and their synthetic intermediates. The invention also relates to drugs for use as medicines, particularly for treating and / or preventing: cognitive deficits associated with Down syndrome; Alzheimer's disease; dementia; tau proteinosis; Parkinson's disease; CDKL5 deficiency disorder; Phelan-McDermid syndrome; autism; type 1 and type 2 diabetes; abnormal folic acid and methionine metabolism; osteoarthritis; Duchenne muscular dystrophy; several cancers; neuroinflammation, anemia, and viral and single-cell infections; and said compounds for regulating body temperature.

Description

Invention Field

[0001] This invention relates to leucettinib, a new class of compounds used as medicines. These new compounds are particularly used as kinase inhibitors, and even 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; Tau proteinosis; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency disorders; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis; Duchenne muscular dystrophy; several cancers and leukemias; viral infections; and for regulating body temperature.

[0002] Some of the compounds are additional inhibitors of other kinases, namely other DYRKs (DYRK1B, 2, 3, 4) and closely related cdc2-like kinases (CLKs) (CLK2, 3, 4). The compounds can then be further used effectively to treat and / or prevent Phelan-McDermid syndrome; autism; viral infections, cancer, neuroinflammation, anemia, and infections caused by single-celled parasites.

[0003] The present invention further relates to pharmaceutical compositions containing the novel compounds and chemical synthesis methods for obtaining them.

[0004] background

[0005] The DYRK and CLK kinase family belongs to the CMGC kinase group, which also 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 crucial roles in mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle, differentiation, homocysteine / methionine / folate regulation, endocytosis, neuronal development and function, and synaptic plasticity.

[0006] DYRK1A and Down Syndrome (DS)

[0007] The gene encoding DYRK1A is located on chromosome 21, specifically in the Down Syndrome Critical Region (DSCR), and its triploidy is the cause of most DS-related defects. There is considerable genetic and pharmacological evidence that overexpression of DYRK1A by only 1.5 times is the cause of most cognitive deficits, particularly memory and learning deficits, observed in patients with DS (Rueda N et al., 2020. Translational validity and implications of pharmacothepases in preclinical models of Down syndrome. Prog Brain Res 251, 245). Pharmacological or genetic normalization of DYRK1A levels leads to the restoration of 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).

[0008] DYRK1A and Alzheimer's disease (AD), Tau proteinosis

[0009] Mounting evidence suggests a role for DYRK1A in the onset of Alzheimer's disease (AD). DYRK1A phosphorylates key substrates involved in AD and dementia: Tau, septin 4, amyloid precursor protein (APP), presenilin 1, enkephalin, Munc18-1, α-synuclein, RCAN1, and β-tubulin. Evidence suggests aberrant expression and post-translational modifications of DYRK1A in AD. By modulating alternative splicing of exon 10, DYRK1A favors the production of the 3R-Tau splice isoform (a hallmark of DS / AD / tau proteinopathy) relative to the normal 4R-Tau isoform. DYRK1A inhibits promotion of autophagy, which can counteract the autophagy defects observed in AD.

[0010] DYRK1A and Parkinson's disease (PD) and Pick's disease

[0011] 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 PD factors such as Parkinson's, septin 4, and α-synuclein. Upregulation of PD-specific microRNAs targets 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). Further evidence suggests increased DYRK1A expression in PD. DYRK1A is overexpressed in Pick's disease.

[0012] DYRK1A and other diseases (viral infections, type 1 and type 2 diabetes, cancer)

[0013] DYRK1A and DYRK1B are utilized during HCMV placental replication. Inhibition of DYRK1A prevents the replication of various viruses, including herpesviruses, 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 (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). Numerous studies have linked DYRK1A to cancer. The most prominent examples are megakaryocyte leukemia, acute lymphoblastic leukemia, pancreatic cancer, and brain tumors (glioblastoma).

[0014] Therefore, abnormal DYRK1A dosage is associated with cognitive impairment observed in Down syndrome and Alzheimer's disease. DYRK1A is a risk factor for Parkinson's disease. Inhibition of DYRK1A also triggers the proliferation of insulin-secreting β-cells in the pancreas. Therefore, DYRK1A inhibitors can be used for the prevention and / or treatment of DS, AD, and other Tau protein disorders, dementia, PD, Niemann-Pick disease type C, CDKL5 deficiency, type 1 and type 2 diabetes, viral infections, several cancers (leukemia, pancreatic cancer, glioblastoma), osteoarthritis, infections caused by single-celled parasites, and for regulating body temperature.

[0015] Other DYRK and human diseases

[0016] DYRK1B is involved in the replication of various viruses, including hepatitis C virus, chikungunya virus, dengue virus, SARS coronavirus, cytomegalovirus, and human papillomavirus. Like DYRK1A, DYRK1B inhibits the proliferation of insulin-secreting β-cells in the pancreas. DYRK1B is also involved in neuroinflammation. Targeting DYRK1B provides a novel fundamental principle for treating various cancers such as liposarcoma or breast cancer.

[0017] DYRK2 and GSK-3β jointly regulate neuronal morphogenesis. DYRK2 participates in cancer development in various ways.

[0018] DYRK3 promotes hepatocellular carcinoma. DYRK3 couples the coagulation / dissolution of stress granules with mTORC1 signaling. DYRK3 regulates the phase transition of non-membranous organelles during mitosis. DYRK3 and DYRK4 are involved in the regulation of cytoskeleton organization and extracellular growth in neurons.

[0019] DYRK1A reduces axonal growth, DYRK3 and DYRK4 increase dendritic branching, and DYRK2 simultaneously reduces both axonal and dendritic growth and branching.

[0020] CLK and Human Diseases

[0021] Note that CLK is a confusing abbreviation because it has the following meanings: (a) monooxygenase CLK-1 (human homolog COQ7); (b) collagen lectin-K1 (CL-K1, or CL-11), a multifunctional Ca(2+)-dependent lectin; (c) the MAPK gene of Clk1 in the maize pathogen Curvularia lunata; (d) mitochondrial membrane-binding enzyme Clock-1 (CLK-1); and (e) kinase 1 (clk1) in Colletotrichum lindemuthianum.

[0022] CLK plays a fundamental role in alternative splicing. As a body temperature sensor, CLK globally controls alternative splicing and gene expression. CLK activity is actually highly responsive to changes in physiological temperature, which is conferred by structural rearrangements within the kinase activation region (Haltenhof T et al., 2020. A conserved kinase-based body-temperature sensor globally controls alternative splicing and gene expression. Mol Cell 78, 57).

[0023] CLK1 and Human Diseases

[0024] CLK1 triggers periodic alternative splicing during the cell division cycle. CLK1 regulates influenza A virus mRNA splicing, and its inhibition prevents viral replication. CLK1 and CLK2 also regulate HIV-1 gene expression. CLK1 is an inducer of autophagy. CLK1 inhibition can prevent chemoresistance in gliomas, and TG693 inhibition of CLK1 allows skipping of the mutated exon 31 of the dystrophin gene in Duchenne muscular dystrophy.

[0025] Other CLKs and human diseases

[0026] Inhibition of CLK2 has been proposed as a way to improve neuronal function and combat intellectual disability and autism in Phelan-McDermead syndrome (PMDS). Dual inhibition of CLK2 and DYRK1A by Lorecivivint is a potential disease-modulating approach for knee osteoarthritis. CLK2 inhibition damages MYC-driven breast tumors, triple-negative breast cancer, and glioblastoma. CLK2 inhibition improves autistic features in Phelan-McDermead syndrome (PMDS). Alternative splicing of Tau exon 10 is regulated by CLK2 and other CLKs, leading to altered 3R / 4R isotype ratios and neurodegeneration in sporadic AD. Inhibition of CLK2, CLK3, and CLK4 blocks HIV-1 production. By modulating alternative splicing, CLKs regulate the balance between pro-apoptotic and anti-apoptotic regulatory proteins, and therefore, CLK inhibition could be used in the treatment of various cancers.

[0027] CLK3 contributes to hepatocellular carcinoma and prostate cancer.

[0028] Table 1 below summarizes the significance of DYRK and CLK kinases in various diseases.

[0029] Table 1

[0030]

[0031]

[0032] DYRK and CLK inhibitors

[0033] Several DYRK1A inhibitors have been reported in recent years. Most DYRK1A inhibitors also inhibit DYRK1B, 2, 3, and 4, as well as the closely related CLK1, 2, 3, and 4, exhibiting several possible inhibitory properties.

[0034] WO2009 / 050352 discloses several imidazolinone derivatives (hereinafter referred to as Leucettine) as kinase inhibitors, and more specifically as inhibitors of DYRK1A kinase.

[0035] There is still a need to identify new compounds for the treatment and / or prevention of the diseases described above, and in particular by inhibition of DYRK1A, other DYRK and related CLK kinases, and especially by selective inhibition. Invention Overview

[0037] It has been found that compounds defined in formula (I) below can be used to treat and / or prevent diseases selected from: cognitive deficits associated with Down syndrome; Alzheimer's disease and related diseases; dementia; Tau proteinosis; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency disorder; Phelan-McDermid syndrome; autism; type 1 and type 2 diabetes; abnormal folic acid and methionine metabolism; osteoarthritis; several types of cancer and leukemia; neuroinflammation, anemia, infections caused by single-celled parasites, viral infections, and for regulating body temperature.

[0038] Therefore, the present invention relates to compounds of formula (I) as defined below.

[0039] The present invention further relates to compounds of formula (I) as defined below, which are used as pharmaceuticals.

[0040] The present invention further relates to compounds of formula (I) as defined below for the treatment and / or prevention of diseases selected from: cognitive deficits associated with Down syndrome; Alzheimer's disease and related diseases; dementia; Tau proteinosis; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency disorder; Phelan-McDermid syndrome; autism; type 1 and type 2 diabetes; abnormal folic acid and methionine metabolism; osteoarthritis; several cancers and leukemias; neuroinflammation; anemia; infections caused by single-celled parasites; viral infections; and for the regulation of body temperature.

[0041] The present invention further relates to pharmaceutical compositions comprising the same and methods for preparing the same.

[0042] Finally, this invention relates to synthetic intermediates of formula (II) as defined below.

[0043] definition

[0044] As used herein, the term “patient” means an animal that has or is likely to have one or more of the diseases and conditions described herein, such as valuable animals for breeding, corporate or conservation purposes, or preferably a human or human child.

[0045] In particular, as used in this application, the term "patient" refers to a mammal, such as a rodent, cat, dog, primate, or human, preferably a human and also extended to birds.

[0046] The determination of those patients who require treatment for the diseases and conditions described herein is entirely within the competence and knowledge of those skilled in the art. Veterinarians or physicians in this field can readily determine those patients who require this treatment by using clinical tests, physical examinations, medical / family history, or biological and diagnostic tests.

[0047] In the context of this invention, as used herein, the term “treating” or “treatment” means the prevention, reversal, mitigation, or inhibition of the progression of a disease and its cognitive, motor, or metabolic alterations, or the prevention of a disease and its cognitive, motor, or metabolic alterations caused by high expression and activity of DYRK1A kinase and / or CLK1, and optionally associated with abnormalities in other DYRKs (DYRK1B, 2, 3, 4) and closely related additional cdc2-like kinases (CLKs) (CLK2, 3, 4), and more specifically with diseases described below in the paragraph “Pathology”.

[0048] Therefore, the term "treating" or "treatment" within the scope of this invention covers the improvement of medical conditions in patients suffering from diseases described below in the paragraph "Pathology," diseases associated with high expression and activity of either DYRK1A or CLK1 kinases, and optionally with abnormalities in other DYRKs (DYRK1B, 2, 3, 4) and closely related cdc2-like kinases (CLKs) (CLK2, 3, 4).

[0049] As used herein, "effective amount" means the amount of the compound of the present invention that is effective in preventing, reducing, eliminating, treating or controlling the symptoms of the diseases and conditions described herein.

[0050] The term “control” refers to all processes that can slow, interrupt, stop or halt the progression of the diseases and conditions described herein, but does not necessarily mean the complete elimination of all symptoms of the diseases and conditions, and is intended to include preventative treatment.

[0051] The term "effective dose" includes both "preventive effective dose" and "therapeutic effective dose".

[0052] As used herein, the term “prevention” means reducing the risk of or slowing the occurrence of a given phenomenon (i.e., in this invention, a disease caused by abnormal DYRK / CLK kinase activity, particularly DYRK1A kinase activity).

[0053] As used in this article, “prevention” also includes “reducing the likelihood of occurrence” or “reducing the likelihood of recurrence”.

[0054] The term "preventive effective amount" refers to the concentration of the compound of the present invention that effectively inhibits, prevents, or reduces the likelihood of any of the diseases described above.

[0055] Similarly, the term "therapeutic effective dose" refers to the concentration of a compound that is effective in treating the disease described above, for example, when administered after the disease has occurred, resulting in a decrease or normalization of DYRK1A and / or CLK1 kinase activity after examination, and usually optionally additionally resulting in a decrease or normalization of DYRK / CLK kinase activity.

[0056] As used herein, the term “pharmaceutically acceptable” means those compounds, materials, excipients, compositions, or dosage forms that, to a reasonable extent of medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problematic complications commensurate with a reasonable benefit / risk ratio. Invention Details

[0058] The inventors have unexpectedly discovered that compounds of formula (I) disclosed below inhibit DYRK1A, other DYRKs (DYRK1B, DYRK2, DYRK3, DYRK4), and CLKs (CLK1, CLK2, CLK3, CLK4). This assertion is based on data shown in the following examples and described in more detail below.

[0059] According to a first aspect, the subject matter of the present invention relates to compounds of formula (I).

[0060]

[0061] Where R 1 express:

[0062] (i) Selected by one or two from -COOR a A (C1-C6) alkyl group substituted with a group consisting of a hydroxyl group, a halogen atom, a (C1-C4) alkoxy group, or a benzyloxy group, wherein the benzyloxy group is optionally substituted with one to three halogen atoms on its phenyl group.

[0063] (ii). Screw (C5-C) 11 Double ring,

[0064] (iii) Fused phenyl groups selected from those fused with (C5-C6)cycloalkyl or (C5-C6)heteroalkyl rings, wherein the (C5-C6)cycloalkyl and (C5-C6)heteroalkyl rings optionally contain unsaturation and are optionally surrounded by (C1-C4) alkyl, hydroxyl, halogen atom, (C1-C3) alkoxy or -COR a Group substitution,

[0065] (iv) A phenyl group, which is substituted with one or two groups selected from (C1-C8) alkyl, (C1-C3) fluoroalkyl, fluoro(C1-C4) alkoxy, halogen atom, and (C4-C7) heterocyclic alkyl, wherein the (C4-C7) heterocyclic alkyl group is itself optionally substituted with (C1-C4) alkyl, or

[0066] (v) R'-L- group, wherein L is a single bond or (C1-C3) alkyl dienylate, optionally substituted with a group selected from hydroxyl and (C1-C3) alkoxy groups, and

[0067] R' means:

[0068] (v.1). (C3-C8)cycloalkyl groups, optionally substituted with one, two, or three groups selected from (C1-C4)alkyl, hydroxyl, halogen, and (C1-C3)alkoxy groups.

[0069] (v.2). Bridged (C6-C) 10 )cycloalkyl group, optionally surrounded by one to three atoms selected from (C1-C4)alkyl, (C1-C4)alkoxy, halogen atom, hydroxyl, -OC(O)-R d Group, -OC(O)-NHR d Groups and -NH-C(O)-R d Group, -SO2-R d Group, -N(R) e )2 group and -COOR a Group substitution of groups,

[0070] (v.3). (C3-C8) heterocyclic alkyl groups, optionally composed of one to three radicals selected from -COOR. a Group substitutions of radicals, hydroxyl groups, halogen atoms, (C1-C4) alkyl groups, and oxo groups.

[0071] (v.4). (C3-C8) heteroaryl, optionally substituted with one to three groups selected from halogen atoms, (C1-C4) alkyl, (C1-C4) alkoxy and N-methylpiperazinyl groups, or

[0072] (v.5). Bridged (C6-C) 10 Heterocyclic alkyl groups, or

[0073] (vi) R'-L- group, wherein L is a (C1-C3) alkyldiyl group, optionally selected from -NR b R c Groups, (C1-C4)alkoxy groups, hydroxyl groups, -COOR a Substitution of groups and halogen atoms, and

[0074] R' is a phenyl group, optionally substituted with one to three groups selected from the group consisting of (C1-C6) alkyl, fluoro(C1-C4) alkyl and fluoro(C1-C4) alkoxy, halogen atom and hydroxyl group.

[0075] R a Indicates (C1-C4) alkyl or hydrogen atom,

[0076] R b and R c Independently representing (C1-C6) alkyl or hydrogen atoms,

[0077] R d Indicates (C1-C4) alkyl or cyclopropyl.

[0078] R e Indicates (C1-C3) alkyl, and

[0079] R 2 Indicates a hydrogen atom or a (C1-C3) alkyl group.

[0080] Or any of its pharmaceutically acceptable salts.

[0081] The inventors unexpectedly discovered that, compared with their benzothiazole homologues (compounds according to the invention), compounds having the skeletons of the following formulas (A) to (F) exhibited significantly reduced kinase inhibitory activity against DYRK1A and other related kinases: IC 50 The values ​​decreased by 10 to 1000 times, and some compounds were completely inactive at the highest dose tested (10 μM).

[0082]

[0083] For example, by comparing compounds of formula (I) alone with compounds having skeletons of formulas (A) to (F) (where in both, R) 2 It is a hydrogen atom and R 1 Selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, and 2-methoxy-1-phenyl-ethyl, these significantly reduced kinase inhibitory activities have been confirmed.

[0084] According to a specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 express:

[0085] (i) Selected by one or two from -COOR a A (C2-C6) alkyl group substituted with a group consisting of a hydroxyl group, a halogen atom, a (C1-C4) alkoxy group, or a benzyloxy group, wherein the benzyloxy group is optionally substituted with one to three halogen atoms on its phenyl group.

[0086] (ii). Spiral (C7-C9) double ring,

[0087] (iii) Fused phenyl groups selected from those fused with a cyclopentyl or heterocyclopentyl group, wherein the cyclopentyl or heterocyclopentyl group optionally contains an unsaturation and is optionally surrounded by a (C1-C4) alkyl group, a hydroxyl group, a halogen atom, a (C1-C3) alkoxy group, or a -COR group. a Group substitution,

[0088] (iv) A phenyl group, which is substituted with one or two groups selected from (C1-C8) alkyl, (C1-C3) fluoroalkyl, fluoro(C1-C4) alkoxy, halogen atom, and (C4-C7) heterocyclic alkyl, wherein the (C4-C7) heterocyclic alkyl group is itself optionally substituted with (C1-C4) alkyl, or

[0089] (v).R'-L-group, wherein

[0090] ●L is a single bond or (C1-C3) alkyl dienylate, optionally substituted with a group selected from hydroxyl and (C1-C3) alkoxy groups, and

[0091] ●R' indicates:

[0092] (v.1). (C3-C8)cycloalkyl, optionally substituted with one, two, or three groups selected from (C1-C4)alkyl, hydroxyl, fluorine, and (C1-C3)alkoxy groups.

[0093] (v.2). Bridged (C7-C) 10 )cycloalkyl group, optionally surrounded by one to three atoms selected from (C1-C4)alkyl, (C1-C4)alkoxy, hydroxyl, halogen atom, -OC(O)-R d Group, -OC(O)-NHR d Group, -NH-C(O)-R d Group, -SO2-R d Group, -N(R) e )2 group and -COOR a Group substitution of groups,

[0094] (v.3). (C4-C7) heterocyclic alkyl groups, optionally composed of one to three radicals selected from -COOR. a Group substitutions of radicals, hydroxyl groups, halogen atoms, (C1-C4) alkyl groups, and oxo groups.

[0095] (v.4). A heteroaryl group, optionally substituted with one to three groups selected from a halogen atom, (C1-C4)alkyl, (C1-C4)alkoxy, N-methylpiperazinyl, or

[0096] (v.5). Bridged (C6-C) 10 Heterocyclic alkyl groups, or

[0097] (vi). R'-L-group, wherein

[0098] ●L is a (C1-C3) alkyldiyl group, which is optionally selected from -NR b R c Groups, (C1-C3)alkoxy groups, hydroxyl groups, -COOR a Substitution of groups and halogen atoms, and

[0099] ●R' is a phenyl group, optionally substituted with one to three groups selected from the group consisting of (C1-C6) alkyl, fluoro(C1-C4) alkyl and fluoro(C1-C4) alkoxy, hydroxyl and halogen atoms.

[0100] R a Indicates (C1-C4) alkyl or hydrogen atom,

[0101] R b and R c Independently representing (C1-C6) alkyl or hydrogen atoms,

[0102] R d Indicates (C1-C4) alkyl or cyclopropyl.

[0103] R e Indicates (C1-C3) alkyl, and

[0104] R 2 Indicates a hydrogen atom or a (C1-C3) alkyl group.

[0105] Or any of its pharmaceutically acceptable salts.

[0106] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 express:

[0107] (i) An (C2-C6) alkyl group substituted with one or two groups selected from -COOCH3, hydroxyl, fluorine atom, methoxy, ethoxy, tert-butoxy, cyclopropoxy, and benzyloxy, wherein the benzyloxy group is optionally substituted with a fluorine atom on its phenyl group.

[0108] (ii) Spiro(C7-C8) bicyclic, particularly spiro[3.3]heptyl, spiro[2.5]octyl, or 7-azaspiro[3.5]nonyl,

[0109] (iii) Fused phenyl groups selected from those fused with cyclopentyl or heterocyclopentyl groups, wherein the cyclopentyl or heterocyclopentyl groups optionally contain unsaturation and are optionally substituted with methyl, hydroxyl, methoxy, and -COCH3 groups.

[0110] (iv) A phenyl group, which is substituted with one or two groups selected from methyl, hexyl, trifluoromethyl, difluoromethoxy, halogen atom, especially fluorine atom, morpholino group and N-methylpiperazinyl, or

[0111] (v) R'-L- group, wherein L is a single bond or (C1-C3) alkyl dienylate, optionally substituted with a group selected from hydroxyl and (C1-C3) alkoxy groups.

[0112] And R' can be selected from the following groups:

[0113] (v.1). (C3-C8)cycloalkyl groups, particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, optionally substituted with one, two, or three groups selected from methyl, isopropyl, hydroxy, and methoxy groups.

[0114] (v.2). Bridged (C7-C) 10 )cycloalkyl, particularly adamantyl or bicyclic [3.1.1]heptyl, optionally substituted by one to three groups selected from: methyl, methoxy, hydroxyl, 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,

[0115] (v.3). (C5-C8) Heterocyclic alkyl groups, particularly tetrahydropyranyl, piperidinyl, oxetaneyl, tetrahydrofuranyl or oxetaneyl-heptyl, tetrahydrothiaranyl, pyrrolidinyl, dioxetaneyl-heptyl or piperidinyl, optionally composed of one, two or three groups selected from -COOR. f Group substitution of radicals, hydroxyl groups, methyl groups, and oxo groups, wherein R f Indicates ethyl or isopropyl.

[0116] (v.4). A heteroaryl group, particularly pyrimidinyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, furanyl, optionally substituted with one to three groups selected from methyl, methoxy, and N-methylpiperazinyl, or

[0117] (v.5). Bridged (C7-C) 10)cycloalkyl, especially quinine-3-yl, or

[0118] (vi) R'-L- group, wherein L is a (C1-C3) alkyldiyl group, optionally selected from -NR b R c Groups, (C1-C4)alkoxy groups, hydroxyl groups, -COOR a Substitution of groups and groups consisting of halogen atoms, especially fluorine atoms, and

[0119] R' is a phenyl group, which is optionally substituted with one or two groups selected from the group consisting of methyl, trifluoromethyl, and trifluoromethoxy groups.

[0120] R a Indicates (C1-C3) alkyl,

[0121] R b and R c Independently selected from methyl or hydrogen atoms, and

[0122] R 2 Indicates a hydrogen atom or a (C1-C3) alkyl group.

[0123] Or any of its pharmaceutically acceptable salts.

[0124] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 It is an R'-L- group, where L is selected from the following groups: -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)- The 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 -CH(CH2OC(CH3)3) group or any pharmaceutically acceptable salt thereof.

[0125] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 It is an R'-L- group, wherein:

[0126] (v.1). When R' is a (C3-C8) cycloalkyl group, L is selected from the group consisting of single bonds, -CH2- groups, -CH(CH3)- groups, -CH(CH2OH)-CH2- groups, -CH(CH2OH)- groups, -CH(CH2OCH3)- groups, -CH(OH)-CH2- groups, and -CH(OCH3)-CH2- groups.

[0127] (v.2). When R' is bridged (C7-C 10 In cycloalkyl groups, L is a single bond, a -CH2- group, or a -CH(CH3)- group.

[0128] (v.3). When R' is a (C5-C8) heterocyclic alkyl, including spiro(C3-C8) heterocyclic alkyl, L is a single bond or a -CH2- group.

[0129] (v.4). When R' is phenyl, L is selected from the group consisting of: 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.

[0130] (v.5). When R' is a heteroaryl group, L is selected from single bonds, -CH2- groups, -(CH2)3- groups and -(CH2)2- groups.

[0131] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 express:

[0132] -Adamantyl group, optionally substituted with one to three groups, and particularly substituted with one group, said groups being selected from methyl, methoxy, hydroxyl, fluorine, -OC(O)-CH3, -OC(O)-C(CH3)3, -OC(O)-NH-C(CH3)3, -NH-C(O)-CH3, -NH-C(O)-C3H4, -S(O)2-CH3, -S(O)2-C3H4, -N(CH3)2, and -C(O)-O-CH3 groups, wherein the adamantyl group is preferably unsubstituted; or

[0133] -R”-O-CH2(R”')- group, wherein:

[0134] "○R" is (C1-C4) alkyl, preferably methyl or ethyl, and

[0135] ○R”' is a (C1-C4) alkyl, particularly (C3-C4) alkyl, and preferably isopropylmethyl, or

[0136] ○R”' is a phenyl group, which is optionally substituted with one to three groups and particularly with one group selected from the group consisting of (C1-C6)alkyl, fluoro(C1-C4)alkyl, fluoro(C1-C4)alkoxy, halogen atom and hydroxyl group, wherein the phenyl group is preferably unsubstituted.

[0137] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 express:

[0138] -Selected by one or two -COOR a A (C1-C6) alkyl group substituted with a group consisting of a hydroxyl group, a fluorine atom, a (C1-C4) alkoxy group, or a benzyloxy group, wherein the benzyloxy group is optionally substituted with a halogen atom on its phenyl group.

[0139] -Screw (C5-C) 11 Double ring, or

[0140] -R'-L- group, in which

[0141] ○L is a single bond or (C1-C3) alkyl dienylate, optionally substituted with a group selected from hydroxyl and (C1-C3) alkoxy groups, and

[0142] ○R' can be selected from the following groups:

[0143] ■ (C3-C8)cycloalkyl groups, optionally substituted with one, two, or three groups selected from halogen atoms, (C1-C4)alkyl groups, hydroxyl groups, and (C1-C3)alkoxy groups, and

[0144] ■Bridged (C6-C) 10 )cycloalkyl group, optionally surrounded by one to three atoms selected from (C1-C4)alkyl, (C1-C4)alkoxy, halogen atom, hydroxyl, -OC(O)-R d Group, -OC(O)-NHR d Groups and -NH-C(O)-R d Group, -SO2-R d Group, -N(R) e )2 group and -COOR a Group substitution of groups,

[0145] R a R represents (C1-C4) alkyl. d It represents (C1-C4) alkyl or cyclopropyl and R e Indicates (C1-C3) alkyl, and

[0146] Where R 2 Indicates a hydrogen atom or a (C1-C3) alkyl group.

[0147] Or any of its pharmaceutically acceptable salts.

[0148] The compound subgroups are summarized under “A1” type compounds in Table 1 below.

[0149] Furthermore, according to the aforementioned implementation scheme, R 1More specifically, 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-trimethylnorpinen-3-yl, 6,6-dimethylnorpinen-2-yl, spiro[2,5]octane-2-yl, spiro[3,5]octane-2-yl.3] Hept-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)-CH OH-CH3, 3,3-difluorocyclopentyl, 4,4-difluorocyclohexyl, 3,3-difluorocyclohexyl, 2,2-difluorocyclohexyl, 3,3-difluorocycloheptyl, 3-acetoxy-1-adamantyl, 3-neopentyloxy-1-adamantyl, 3-methoxycyclohexyl, 4-hydroxycycloheptyl, 3-methoxycycloheptyl, 3-methoxycycloheptyl, 4-methoxycycloheptyl, 3-noradamantyl, 3-tert-butylcarbamoyloxy-1-adamantyl, 3-fluoro-1-adamantyl, 1-(tert-butoxymethyl)-3-methyl-butyl, 3-acetamido-1-adamantyl 3-(cyclopropanecarbonylamino)-1-adamantyl, 3-(methanesulfonylamino)-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.

[0150] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 express:

[0151] - Fused phenyl groups selected from phenyl groups fused with (C5-C6)cycloalkyl or (C5-C6)heteroalkyl groups, wherein the (C5-C6)cycloalkyl and (C5-C6)heteroalkyl groups optionally contain unsaturation and are optionally surrounded by (C1-C4) alkyl, hydroxyl, halogen atom, (C1-C3) alkoxy and -COR a Group substitution,

[0152] -Phenyl group, which is substituted with one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy, halogen atom, and (C4-C7)heteroalkyl groups, wherein the (C4-C7)heteroalkyl group is optionally substituted with (C1-C4) alkyl group itself, or

[0153] -R'-L- group, in which

[0154] ○L is a (C1-C3) alkyldiyl group, optionally selected from hydroxyl, (C1-C4) alkoxy, -NR b R c Group, -COOR a Substitution of groups and halogen atoms, and

[0155] ○R' is a phenyl group, optionally substituted with one to three groups selected from (C1-C6) alkyl, fluoro(C1-C4) alkyl and fluoro(C1-C4) alkoxy, halogen atom and hydroxyl group.

[0156] Where R a It is a (C1-C4) alkyl or hydrogen atom, and R b and R c Independently selected from (C1-C6) alkyl and hydrogen atoms, and

[0157] Where R 2 Indicates a hydrogen atom or a (C1-C3) alkyl group.

[0158] Or any pharmaceutically acceptable salt thereof.

[0159] The compound subgroups are summarized under the "A2" and "A5" type compounds in Table 1 below.

[0160] Furthermore, according to the aforementioned implementation scheme, R 1More specifically, 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-methylpiperazin-1-yl)phenyl, 3-(difluoromethoxy)phenyl, 1-acetylindoline-6-yl, 3-(trifluoromethyl)phenyl, indan-5-yl, 4-morpholinophenyl, 1-methylindazole-7-yl, or 2-tert-butoxy-1-phenyl-ethyl.

[0161] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 2 It represents a hydrogen atom or a methyl group.

[0162] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 Represents the R'-L- group, where:

[0163] -R' is a (C3-C8) heteroaryl group, optionally substituted with one to three groups selected from halogen atoms, (C1-C4) alkyl groups, (C1-C4) alkoxy groups, and N-methylpiperazinyl groups.

[0164] -L is a (C1-C3) alkyl dienyllium or a single bond, and

[0165] Where R 2 Represents a hydrogen atom.

[0166] Or any pharmaceutically acceptable salt thereof.

[0167] The compound subgroups are summarized under “A3” and “A6” type compounds in Table 1 below.

[0168] Furthermore, according to the aforementioned implementation scheme, R 1More specifically, (5-methylpyrazin-2-yl)methyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, (5-methyl-2-furanyl)methyl, (4-methylthiazolyl-2-yl)methyl, 3-imidazol-1-ylpropyl, 2-(2-pyridyl)ethyl, 1,3-benzothiazolyl-2-ylmethyl, 2-pyrimidinyl, 2-pyridyl, 1-methylpyrazol-3-yl, 2-methoxy-6-methyl-3-pyridyl , pyrimidin-5-yl, 3-pyridinyl, 1,3,4-thiadiazol-2-yl, 5-(4-methylpiperazin-1-yl)-2-pyridinyl, 6-(4-methylpiperazin-1-yl)-3-pyridinyl, 2-(4-methylpiperazin-1-yl)pyrimidin-5-yl, 5-(4-methylpiperazin-1-yl)pyrimidin-2-yl, 5-(4-methylpiperazin-1-yl)pyrazin-2-yl or 6-(4-methylpiperazin-1-yl)pyridazin-3-yl.

[0169] According to another specific embodiment, the present invention relates to compounds of formula (I) as defined above, wherein R 1 Represents the R'-L- group, where:

[0170] -R' is a (C3-C5) heterocyclic alkyl group, optionally surrounded by one to three groups selected from hydroxyl, (C1-C4) alkyl, oxo group and -COOR. a Group substitution of a group, where R a As defined above, and

[0171] -L is a methylene group or a single bond, and

[0172] Where R 2 Represents a hydrogen atom.

[0173] Or any pharmaceutically acceptable salt thereof.

[0174] The compound subgroups are summarized under compounds of type “A4” and “A7” in Table 1 below.

[0175] Furthermore, according to the aforementioned implementation scheme, R 1More specifically, it can represent (1-methyl-4-piperidinyl)methyl, tetrahydropyran-4-yl-methyl, 1-tert-butoxycarbonylpiperidin-4-yl-methyl, 7-methyl-7-azaspiro[3.5]non-2-yl, tetrahydropyran-4-yl, 1-tert-butoxycarbonylpiperidin-4-yl, 1-ethoxycarbonylpiperidin-4-yl, 1-methyl-4-piperidinyl, 1-methyl-3-piperidinyl, oxetane-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, 6,6-dimethyltetrahydropyran-3-yl, 4-hydroxy Tetrahydropyran-3-yl, oxetane-3-yl, 2-oxo-piperidin-3-yl, 2-oxo-piperidin-5-yl, quinine-3-yl, tetrahydrothiaran-3-yl, 1,4-dioxetane-6-yl, 2-oxo-pyrrolidine-3-yl, 1-methyl-2-oxo-pyrrolidine-3-yl, 4,4-dimethyl-2-oxo-pyrrolidine-3-yl, 1-methyl-2-oxo-piperidin-3-yl, 3-methyl-2-oxo-pyrrolidine-3-yl, or 1,3-dimethyl-2-oxo-pyrrolidine-3-yl.

[0176] In the context of this invention, the terminology is:

[0177] - "Halogen" should be understood to mean chlorine, fluorine, bromine, or iodine, especially chlorine, fluorine, or bromine.

[0178] -As used in this article, "(C1-C x "alkyl" refers to C1-C1 alkyl groups respectively. x A monovalent saturated hydrocarbon group, such as (C1-C6) alkyl. Examples include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.

[0179] As used herein, “(C1-C3) alkyldiyl” refers to a branched or straight-chain divalent saturated hydrocarbon group containing 1 to 3 carbon atoms, and more specifically methylene, ethylene, or propylene, such as straight-chain propylene or isopropylene, said alkyldiyl group may be substituted as will be apparent from the following description.

[0180] As used herein, “(C3-C8)cycloalkyl” refers to a 3 to 8 carbon atom-containing, saturated or partially unsaturated, unsubstituted or substituted cyclic saturated hydrocarbon group. Examples are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0181] As used herein, "(C3-C8) heterocyclic alkyl" refers to a (C3-C8) cycloalkyl group in which one or two carbon atoms are replaced by a heteroatom (such as oxygen, nitrogen, or sulfur, and more specifically, oxygen or nitrogen). Such heterocyclic alkyl groups may be saturated or partially saturated and may be unsubstituted or substituted. Examples are, but are not limited to, morpholinyl, piperazineyl, piperidinyl, pyrrolinic, aziridine propane, oxanyl, oxacyclobutane, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxacycloheptyl, diaziridine heptane, dioxacyclohexane, and tetrahydrothiaranyl, and more particularly piperidinyl and piperazine, and even more particularly piperazine.

[0182] -As used in this article, "(C1-C x "Alkoxy" refers to -O-(C1-C x )alkyl or -O-(C3-C x The cycloalkyl moiety, wherein the alkyl and cycloalkyl groups are as defined above, such as (C1-C6)alkoxy groups. Examples are, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, cyclopropoxy, butoxy, tert-butoxy, and pentoxy groups.

[0183] -“Screw (C5-C) 11 "Bicyclic" refers to two rings linked by a single defined common atom. Such spirobicyclic alkyl groups typically contain 5 to 11 carbon atoms and are called "spiro(C5-C6)". 11 "Bicycloalkyl". In specific embodiments, one or more carbon atoms of these rings are replaced by heteroatoms (such as oxygen, nitrogen, or sulfur, and more particularly nitrogen atoms) to form a spirocycloalkyl ring. 11 Bicyclic heteroalkyl groups. Such spirobicyclic groups can be unsubstituted or substituted, particularly substituted with at least one (C1-C3) alkyl group such as methyl. Examples are, but are not limited to, spiro[3.3]heptyl, spiro[2.5]octyl, and 7-azaspiro[3.5]nonyl.

[0184] -As used in this article, "bridged (C6-C)" 10 A “cycloalkyl” group refers to a bicyclic or tricyclic compound in which the rings are cycloalkyl groups, the rings share three or more atoms, and the bridge contains at least one atom, such as 1, 2, or 3 atoms. Such a bridged cycloalkyl group can be substituted with one or more C1-C3 alkyl groups. Examples are, 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.

[0185] -As used in this article, "bridged (C6-C)" 10"Heterocyclic alkyl" refers to a bridged (C6-C) alkyl group as defined above. 10 Cycloalkyl groups, wherein one or more carbon atoms of these rings are replaced by heteroatoms (such as oxygen, nitrogen, or sulfur, and more particularly nitrogen atoms). An example is, but is not limited to, quinine-3-yl.

[0186] - "Fused phenyl" refers to a bicyclic group containing a phenyl moiety that can be substituted. The fused phenyl group may be fused with a cycloalkyl or heterocycloalkyl group and bonded to the remainder of the molecule via its phenyl moiety or via the cycloalkyl or heterocycloalkyl group. Examples are, but are not limited to, indanyl, acetylindololinyl, methylindazole, hydroxyindanyl, benzothiazolyl, indolyl, indazole, methoxyindanyl, etc.

[0187] -As used in this article, (C5-C 11 A heteroaryl group refers to a monocyclic aromatic group or a bicyclic aromatic group, wherein at least one ring is aromatic, and one to three ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, or sulfur. Examples of heteroaryl groups include, but are not limited to: oxazoles, isoxazoles, pyridines, pyrimidines, pyridazines, triazines, pyrazines, oxadiazoles, furans, pyrazoles, thiazoles, isothiazoles, thiadiazoles, imidazoles, triazoles, etc. Within the scope of this invention, heteroaryl groups are advantageously pyridines, imidazoles, pyrazines, furans, thiazoles, pyrazoles, thiadiazoles, pyridazines, and pyrimidines.

[0188] According to Hückel's rule, aromatic rings refer to molecules that have 4n+2 π electrons.

[0189] -As used in this article, (C1-C x )Fluoroalkyl refers to (C1-C2) alkyl groups as defined above. x Alkyl groups, wherein one or more hydrogen atoms have been replaced by fluorine. In one embodiment, all hydrogen atoms are replaced by fluorine atoms, forming a perfluoroalkyl group, such as trifluoromethyl.

[0190] -As used in this article, (C1-C x )Fluoroalkoxy refers to (C1-C2) as defined above. x Alkoxy groups, in which one or more hydrogen atoms have been replaced by fluorine, such as trifluoromethoxy. In one embodiment, all hydrogen atoms are replaced by fluorine atoms, forming a perfluoroalkoxy group, such as trifluoromethoxy.

[0191] In the context of this invention, the terms "aromatic ring" and "heteroaryl" include all positional isomers.

[0192] The following compounds (1) through (216) were named according to the principles of the International Union of Pure and Applied Chemistry, using Accelrys Draw 4.1 SP1. To avoid any confusion, the symbol “(±)” is added to indicate racemic mixtures; the prefixes “cis” and “trans” are also used to specify the relative stereochemistry of two adjacent chiral centers.

[0193] According to a preferred embodiment of the present invention, the compound of formula (I) is selected from:

[0194] (1).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclopropylmethylamino)-1H-imidazol-5-one,

[0195] (2). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclopropylamino)-1H-imidazol-5-one,

[0196] (3).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclobutylamino)-1H-imidazol-5-one,

[0197] (4).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclopentylamino)-1H-imidazol-5-one,

[0198] (5).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclohexylmethylamino)-1H-imidazol-5-one,

[0199] (6).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one,

[0200] (7).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cycloheptylmethylamino)-1H-imidazol-5-one,

[0201] (8).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one,

[0202] (9).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclooctylamino)-1H-imidazol-5-one,

[0203] (10). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-hydroxy-2,2-dimethyl-propyl)amino]-1H-imidazol-5-one,

[0204] (11).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(2-benzyloxyethylamino)-1H-imidazol-5-one,

[0205] (12).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[cis-2-methylcyclohexyl]amino]-1H-imidazol-5-one,

[0206] (13).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-cyclohexylethyl]amino]-1H-imidazol-5-one,

[0207] (14). (4Z)-2-(1-adamantylmethylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1H-imidazol-5-one,

[0208] (15).(±)-(4Z)-2-[1-(1-adamantyl)ethylamino]-4-(1,3-benzothiazo-6-ylmethylene)-1H-imidazol-5-one,

[0209] (16). (4Z)-2-(1-adamantylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1H-imidazol-5-one,

[0210] (17). (4Z)-2-(2-adamantylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1H-imidazol-5-one,

[0211] (18). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[3,5-dimethyl-1-adamantyl]amino]-1H-imidazol-5-one,

[0212] (19). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(trans-5-hydroxy-2-adamantyl)amino]-1H-imidazol-5-one,

[0213] (20). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one,

[0214] (21). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1H-imidazol-5-one,

[0215] (22). (4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[(1R,2R,3R,5S)-2,6,6-trimethylnorpinen-3-yl]amino]-1H-imidazol-5-one,

[0216] (23). (4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[(1S,2S,3S,5R)-2,6,6-trimethylnorpinen-3-yl]amino]-1H-imidazol-5-one,

[0217] (24). (4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[(1R,2R,5R)-6,6-dimethylnorpinen-2-yl]methylamino]-1H-imidazol-5-one,

[0218] (25).(±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(spiro[2.5]oct-2-ylamino)-1H-imidazol-5-one,

[0219] (26). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(spiro[3.3]hept-2-ylamino)-1H-imidazol-5-one,

[0220] (27). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(2R)-1,7,7-trimethylnorbornen-2-yl]amino]-1H-imidazol-5-one,

[0221] (28).(±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(norbornane-2-ylamino)-1H-imidazol-5-one,

[0222] (29). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl]amino]-1H-imidazol-5-one,

[0223] (30). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(cyclohexylmethyl)-2-hydroxy-ethyl]amino]-1H-imidazol-5-one,

[0224] (31). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(cyclopentylmethyl)-2-hydroxy-ethyl]amino]-1H-imidazol-5-one,

[0225] (32). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(cyclobutylmethyl)-2-hydroxyethyl]amino]-1H-imidazol-5-one,

[0226] (33). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(cyclopropylmethyl)-2-hydroxyethyl]amino]-1H-imidazol-5-one,

[0227] (34). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0228] (35). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0229] (36). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0230] (37). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0231] (38). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)propyl]amino]-1H-imidazol-5-one,

[0232] (39). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S)-1-(hydroxymethyl)propyl]amino]-1H-imidazol-5-one,

[0233] (40).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0234] (41).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-cyclohexyl-2-hydroxy-ethyl)amino]-1H-imidazol-5-one,

[0235] (42).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-cyclohexyl-2-methoxy-ethyl)amino]-1H-imidazol-5-one,

[0236] (43).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(2-cyclohexyl-2-hydroxy-ethyl)amino]-1H-imidazol-5-one,

[0237] (44).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(2-cyclohexyl-2-methoxy-ethyl)amino]-1H-imidazol-5-one,

[0238] (45).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-2-hydroxycyclopentyl]amino]-1H-imidazol-5-one,

[0239] (46).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-2-hydroxycyclopentyl]amino]-1H-imidazol-5-one,

[0240] (47).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-2-methoxycyclopentyl]amino]-1H-imidazol-5-one,

[0241] (48).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-2-methoxycyclopentyl]amino]-1H-imidazol-5-one,

[0242] (49).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-2-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0243] (50).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-2-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0244] (51). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,2S)-2-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0245] (52). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S,2R)-2-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0246] (53). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,2R)-2-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0247] (54). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S,2S)-2-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0248] (55).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-3-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0249] (56).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[trans-3-hydroxycyclohexyl]amino]-1H-imidazol-5-one,

[0250] (57). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(trans-4-hydroxycyclohexyl)amino]-1H-imidazol-5-one,

[0251] (58).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-2-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0252] (59).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[trans-2-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0253] (60). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(trans-4-methoxycyclohexyl)amino]-1H-imidazol-5-one,

[0254] (61).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-2-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0255] (62).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-2-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0256] (63). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,2R)-2-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0257] (64). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S,2S)-2-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0258] (65).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[cis-3-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0259] (66).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[trans-3-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0260] (67).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-2-methoxycycloheptyl]amino]-1H-imidazol-5-one,

[0261] (68).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-2-methoxycycloheptyl]amino]-1H-imidazol-5-one,

[0262] (69). (2S)-2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-3-methyl-butyrate methyl ester,

[0263] (70). Methyl propionate of (2S)-2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]propionate,

[0264] (71). Methyl 2S)-2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-4-methyl-valerate,

[0265] (72). (2R)-2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-4-methyl-valerate,

[0266] (73). Methyl 3-hydroxybutyrate (2S)-2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-3-hydroxybutyrate

[0267] (74). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(benzylamino)-1H-imidazol-5-one,

[0268] (75). (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(indan-2-ylamino)-1H-imidazol-5-one,

[0269] (76). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,4-dimethylphenyl)methylamino]-1H-imidazol-5-one,

[0270] (77). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2,4-dimethylphenyl)methylamino]-1H-imidazol-5-one,

[0271] (78). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one,

[0272] (79). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[2-(trifluoromethoxy)phenyl]methylamino]-1H-imidazol-5-one,

[0273] (80).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[cis-2-hydroxyindane-1-yl]amino]-1H-imidazol-5-one,

[0274] (81).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-2-hydroxyindane-1-yl]amino]-1H-imidazol-5-one,

[0275] (82). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,2R)-2-hydroxyindane-1-yl]amino]-1H-imidazol-5-one,

[0276] (83). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S,2S)-2-hydroxyindane-1-yl]amino]-1H-imidazol-5-one,

[0277] (84).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[cis-2-methoxyindan-1-yl]amino]-1H-imidazol-5-one,

[0278] (85).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-2-methoxyindan-1-yl]amino]-1H-imidazol-5-one,

[0279] (86). Methyl (2S)-2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-3-phenyl-propionic acid,

[0280] (87). Methyl (2R)-2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-3-phenyl-propionic acid,

[0281] (88).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2-fluoro-1-phenyl-ethyl)amino]-1H-imidazol-5-one,

[0282] (89).(±)-(4Z)-2-[(2-amino-1-phenyl-ethyl)amino]-4-(1,3-benzothiazolyl-6-ylmethylene)-1H-imidazol-5-one dihydrochloride,

[0283] (90).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[2-(methylamino)-1-phenyl-ethyl]amino]-1H-imidazol-5-one dihydrochloride,

[0284] (91).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[2-(dimethylamino)-1-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0285] (92).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(1-benzyl-2-hydroxy-ethyl)amino]-1H-imidazol-5-one,

[0286] (93). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-benzyl-2-hydroxy-ethyl]amino]-1H-imidazol-5-one,

[0287] (94).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(1-benzyl-2-methoxy-ethyl)amino]-1H-imidazol-5-one,

[0288] (95).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1H-imidazol-5-one,

[0289] (96). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0290] (97). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0291] (98).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2-methoxy-1-phenyl-ethyl)amino]-1H-imidazol-5-one,

[0292] (99).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(2-hydroxy-2-phenyl-ethyl)amino]-1H-imidazol-5-one,

[0293] (100).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(2-methoxy-2-phenyl-ethyl)amino]-1H-imidazol-5-one,

[0294] (101).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(2-hydroxy-3-phenyl-propyl)amino]-1H-imidazol-5-one,

[0295] (102).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2-methoxy-3-phenyl-propyl)amino]-1H-imidazol-5-one,

[0296] (103). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(5-methylpyrazin-2-yl)methylamino]-1H-imidazol-5-one,

[0297] (104).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(2-pyridylmethylamino)-1H-imidazol-5-one,

[0298] (105). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(3-pyridylmethylamino)-1H-imidazol-5-one,

[0299] (106). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-pyridylmethylamino)-1H-imidazol-5-one,

[0300] (107). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(5-methyl-2-furanyl)methylamino]-1H-imidazol-5-one,

[0301] (108). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(4-methylthiazo-2-yl)methylamino]-1H-imidazol-5-one,

[0302] (109).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(3-imidazol-1-ylpropylamino)-1H-imidazol-5-one,

[0303] (110). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[2-(2-pyridyl)ethylamino]-1H-imidazol-5-one,

[0304] (111).(4Z)-2-(1,3-benzothiazol-2-ylmethylamino)-4-(1,3-benzothiazol-6-ylmethylene)-1H-imidazol-5-one,

[0305] (112). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-4-piperidinyl)methylamino]-1H-imidazol-5-one,

[0306] (113). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one,

[0307] (114). 4-[[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester,

[0308] (115). (4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[(7-methyl-7-azaspiro[3.5]non-2-yl)amino]-1H-imidazol-5-one,

[0309] (116). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(3-fluoro-4-methyl-aniline)-1H-imidazol-5-one,

[0310] (117). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-fluoroanilino)-1H-imidazol-5-one,

[0311] (118). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-hexylanilino)-1H-imidazol-5-one,

[0312] (119). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one,

[0313] (120). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[3-(difluoromethoxy)anilino]-1H-imidazol-5-one,

[0314] (121). (4Z)-2-[(1-acetylindoline-6-yl)amino]-4-(1,3-benzothiazo-6-ylmethylene)-1H-imidazol-5-one,

[0315] (122).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[3-(trifluoromethyl)anilino]-1H-imidazol-5-one,

[0316] (123).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(indan-5-ylamino)-1H-imidazol-5-one,

[0317] (124). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-morpholinoaniline)-1H-imidazol-5-one,

[0318] (125). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methylindazol-7-yl)amino]-1H-imidazol-5-one,

[0319] (126). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(pyrimidin-2-ylamino)-1H-imidazol-5-one,

[0320] (127). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(2-pyridylamino)-1H-imidazol-5-one,

[0321] (128). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methylpyrazol-3-yl)amino]-1H-imidazol-5-one,

[0322] (129). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2-methoxy-6-methyl-3-pyridinyl)amino]-1H-imidazol-5-one,

[0323] (130). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(pyrimidin-5-ylamino)-1H-imidazol-5-one,

[0324] (131). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(3-pyridylamino)-1H-imidazol-5-one,

[0325] (132). (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(1,3,4-thiadiazol-2-ylamino)-1H-imidazol-5-one,

[0326] (133). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[5-(4-methylpiperazin-1-yl)-2-pyridinyl]amino]-1H-imidazol-5-one,

[0327] (134). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[6-(4-methylpiperazin-1-yl)-3-pyridinyl]amino]-1H-imidazol-5-one,

[0328] (135). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino]-1H-imidazol-5-one,

[0329] (136). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino]-1H-imidazol-5-one,

[0330] (137). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]amino]-1H-imidazol-5-one,

[0331] (138). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino]-1H-imidazol-5-one,

[0332] (139). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(tetrahydropyran-4-ylamino)-1H-imidazol-5-one,

[0333] (140). 4-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]piperidine-1-carboxylic acid tert-butyl ester,

[0334] (141). Ethyl 4-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]piperidine-1-carboxylic acid ester,

[0335] (142). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-4-piperidinyl)amino]-1H-imidazol-5-one,

[0336] (143).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-3-piperidinyl)amino]-1H-imidazol-5-one,

[0337] (144). (4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-(oxetane-3-ylamino)-1H-imidazol-5-one

[0338] (145). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R)-tetrahydrofuran-3-yl]amino]-1H-imidazol-5-one,

[0339] (146). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3S)-tetrahydrofuran-3-yl]amino]-1H-imidazol-5-one,

[0340] (147). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one,

[0341] (148). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one,

[0342] (149).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-1H-imidazol-5-one,

[0343] (149A).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R) / (3S)-6,6-dimethyltetrahydropyran-3-yl]amino]-1H-imidazol-5-one,

[0344] (149B).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R) / (3S)-6,6-dimethyltetrahydropyran-3-yl]amino]-1H-imidazol-5-one,

[0345] (150). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one,

[0346] (151).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(oxepane-3-ylamino)-1H-imidazol-5-one,

[0347] (152).(±)-3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]piperidin-2-one,

[0348] (153). (3S)-3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]piperidin-2-one,

[0349] (154). (5S)-5-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]piperidin-2-one,

[0350] (155).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,3-difluorocyclopentyl)amino]-1H-imidazol-5-one,

[0351] (156). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(4,4-difluorocyclohexyl)amino]-1H-imidazol-5-one,

[0352] (157).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,3-difluorocyclohexyl)amino]-1H-imidazol-5-one,

[0353] (158).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2,2-difluorocyclohexyl)amino]-1H-imidazol-5-one,

[0354] (159).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,3-difluorocycloheptyl)amino]-1H-imidazol-5-one,

[0355] (160). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0356] (161). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0357] (162). Acetic acid [3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-1-adamantyl] ester,

[0358] (163). 2,2-Dimethylpropionic acid [3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-1-adamantyl ester,

[0359] (164). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one,

[0360] (165). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one,

[0361] (166). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0362] (167). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S,2S)-2-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0363] (168).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[cis-3-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0364] (169).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[trans-3-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0365] (169A).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,3R) / (1S,3S)-3-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0366] (169B).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,3R) / (1S,3S)-3-methoxycyclohexyl]amino]-1H-imidazol-5-one,

[0367] (170).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[cis-4-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0368] (171).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[trans-4-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0369] (171A).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,4R) / (1S,4S)-4-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0370] (171B).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R,4R) / (1S,4S)-4-hydroxycycloheptyl]amino]-1H-imidazol-5-one,

[0371] (172).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-3-methoxycycloheptyl]amino]-1H-imidazol-5-one,

[0372] (173).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-3-methoxycycloheptyl]amino]-1H-imidazol-5-one,

[0373] (174).(±)-(4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[cis-4-methoxycycloheptyl]amino]-1H-imidazol-5-one,

[0374] (175).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[trans-4-methoxycycloheptyl]amino]-1H-imidazol-5-one,

[0375] (176). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0376] (177). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1S)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0377] (178). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0378] (179). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(2S)-2-hydroxy-2-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0379] (180). (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazolyl-6-ylmethylene)-1H-imidazol-5-one dihydrochloride,

[0380] (181). (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazolyl-6-ylmethylene)-1H-imidazol-5-one dihydrochloride,

[0381] (182). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R)-quininecyclo-3-yl]amino]-1H-imidazol-5-one,

[0382] (183). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3S)-quininecyclo-3-yl]amino]-1H-imidazol-5-one,

[0383] (184).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(tetrahydrothiaran-3-ylamino)-1H-imidazol-5-one,

[0384] (185).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-(1,4-dioxane-6-ylamino)-1H-imidazol-5-one,

[0385] (186).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2-oxopyrrolidone-3-yl)amino]-1H-imidazol-5-one,

[0386] (187).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-2-oxo-pyrrolidone-3-yl)amino]-1H-imidazol-5-one,

[0387] (188).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(4,4-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1H-imidazol-5-one,

[0388] (189). (3R)-3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]piperidin-2-one,

[0389] (190).(±)-3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-1-methyl-piperidin-2-one,

[0390] (191).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-methyl-2-oxo-pyrrolidine-3-yl)amino]-1H-imidazol-5-one,

[0391] (192).(±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1,3-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1H-imidazol-5-one,

[0392] (192A).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R) / (3S)-1,3-dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1H-imidazol-5-one,

[0393] (192B).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3R) / (3S)-1,3-dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1H-imidazol-5-one,

[0394] (193). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3S,4S)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one,

[0395] (194). (4Z)-2-(3-noradamantylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1H-imidazol-5-one,

[0396] (195). N-tert-butylcarbamate [3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-1-adamantyl] ester

[0397] (196). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-1H-imidazol-5-one,

[0398] (197). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(tert-butoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0399] (198). (4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[(1R)-2-tert-butoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one,

[0400] (199).N-[3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazo-2-yl]amino]-1-adamantyl]acetamide,

[0401] (200).N-[3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-1-adamantyl]cyclopropaneformamide,

[0402] (201).N-[3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-1-adamantyl]methanesulfonamide,

[0403] (202).N-[3-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]-1-adamantyl]cyclopropanesulfonamide,

[0404] (203).(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[3-(dimethylamino)-1-adamantyl)amino]-1H-imidazol-5-one,

[0405] (204). Methyl 2-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1H-imidazol-2-yl]amino]adamantane-2-carboxylate,

[0406] (205).(4Z)-2-(cyclohexylamino)-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1H-imidazol-5-one,

[0407] (206).(4Z)-2-(cycloheptylamino)-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1H-imidazol-5-one,

[0408] (207). (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1H-imidazol-5-one,

[0409] (208). (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1H-imidazol-5-one,

[0410] (209). (4Z)-2-(1-adamantylamino)-4-[(2-methyl-1,3-benzothiazolyl-6-yl)methylene]-1H-imidazol-5-one, and

[0411] (210). (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1H-imidazol-5-one,

[0412] (211). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,5-dihydroxy-1-adamantyl)amino]-1H-imidazol-5-one,

[0413] (212). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,5,7-trifluoro-1-adamantyl)amino]-1H-imidazol-5-one,

[0414] (213). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(ethoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0415] (214). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(benzyloxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0416] (215). (4Z)-4-(1,3-benzothiazolyl-6-ylmethylene)-2-[[(1R)-1-[(4-fluorophenyl)methoxymethyl]-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0417] (216). (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(1R)-1-(cyclopropoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one,

[0418] Or any of their pharmaceutically acceptable salts.

[0419] According to an even more preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of: compounds (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), (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 their pharmaceutically acceptable salts.

[0420] According to an even more preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of: compounds (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), (1 60), (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), (197), (198), (199), (200), (201), (203), (204), (208) and their pharmaceutically acceptable salts.

[0421] According to an even more preferred embodiment of the invention, the compounds of formula (I) are 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 their pharmaceutically acceptable salts.

[0422] According to an alternative embodiment of the invention, the compound of formula (I) is selected from the group consisting of: compounds (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), (1 79), (180), (181), (182), (183), (184), (185), (191), (192), (192A), (192 B), (194), (195), (196), (197), (198), (199), (200), (201), (203), (208),(209), (210) and their pharmaceutically acceptable salts.

[0423] According to a preferred embodiment of the present invention, the compounds of formula (I) are selected from the group consisting of: compounds (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),(1 04), (105), (106), (108), (109), (113), (117), (119), (127), (128), (130), (131), (135), (139), (141), (146), (147), (148), (14 9), (149A), (149B), (150), (151), (155), (156), (157), (158), (159), (160), (161), (162), (163), (164), (165), (166), (167), (16 8), (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 their pharmaceutically acceptable salts.

[0424] According to an even more preferred embodiment of the invention, the compounds of formula (I) are 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 their pharmaceutically acceptable salts.

[0425] According to another embodiment of the invention, the compound of formula (I) is selected from the group consisting of: 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), (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), (15 6), (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 their pharmaceutically acceptable salts.

[0426] The group of compounds defined and specifically identified as the most effective kinase inhibitors and multi-target kinase inhibitors by the list of compounds determined in Tables 4A to 4F of Examples 4 below also constitutes part of this invention.

[0427] According to another aspect, the subject matter of the present invention relates to any one of the compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, used as medicines, or at least any one of compounds (1) to (216) or pharmaceutically acceptable salts thereof.

[0428] "Pharmaceutical acceptable salts" refer to acid addition salts formed with inorganic acids (such as hydrochloric acid and hydrobromic acid) and salts formed with organic acids such as acetic acid, tartaric acid, and succinic acid.

[0429] Suitable physiologically acceptable acid addition salts of compounds of formula (I) include hydrobromide, tartrate, hydrochloride, succinate, and acetate.

[0430] Compounds of formula (I) and any of compounds (1) to (216) or any of their pharmaceutically acceptable salts can form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0431] The terms "hydrate" and "solvent" simply mean that the compound (I) according to the invention can be in the form of a hydrate or a solvate, i.e., combined or associated with one or more water or solvent molecules. This is merely a chemical characteristic of such compounds, which can be applied to all organic compounds of this type.

[0432] Compounds of formula (I) may contain one or more asymmetric carbon atoms. Therefore, they may exist as enantiomers or diastereomers. These enantiomers, diastereomers, and mixtures thereof, including racemic mixtures, are included within the scope of this invention.

[0433] The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below represent general methods that can be used to prepare the compounds of the present invention and are not intended to limit the scope or utility.

[0434] List of abbreviations:

[0435]

[0436]

[0437] Compounds of general formula (I) can be prepared according to Scheme 1 below. Scheme 1: Synthetic route:

[0438]

[0439] The synthesis of compounds according to the present invention is based on compounds of formula (II) and R. 1 NH2 (of which R) 1Amine functionalization (as defined above) follows General Scheme 3 (GP3) as described below.

[0440] According to GP3, compounds of formula (II) can be placed in aprotic solvents such as THF or dioxane, or a mixture of both. Compounds of formula R... 1 The amine of NH2 is added, for example, in a molar ratio of 2 to 6, particularly 4, relative to the compound of formula (II). The reaction mixture can be placed in a sealed tube and can receive energy, such as from a heating block or from a microwave. When the reaction is complete, the mixture can be brought back to room temperature.

[0441] In the embodiment named GP3-A, the reaction mixture can be stirred at a temperature of -10°C to 10°C, for example at 0°C, for a duration of 30 minutes to 2 hours, for example, 1 hour. Depending on the state of the obtained product (solid, precipitate), purification methods well known to those skilled in the art can be performed, such as filtration, washing, grinding, vacuum drying, rapid chromatography, precipitation, and reflux.

[0442] In an embodiment where the product fails to precipitate, designated GP3-B, the reaction mixture can be concentrated, particularly under vacuum, and purified, particularly by rapid chromatography. A second purification step can be performed, particularly selected from reprecipitation, grinding, and recrystallization.

[0443] In another embodiment, in which the product fails to precipitate and is named GP3-C, the reaction mixture can be concentrated, particularly in a vacuum, and the resulting crude product can be purified by grinding in a proton-polar solvent such as ethanol. The grinding can be carried out at a temperature from 20°C to 100°C, particularly at room temperature. A second purification step can be performed, particularly selected from reprecipitation, grinding, and recrystallization.

[0444] As defined above, compounds of formula (II) can be derived from compounds of formula (III) (where R...). 2 As defined above, Alk is obtained by S-alkylation of (C1-C5) alkyl groups.

[0445] According to the general scheme GP2, the compound of formula (III) can be placed in a polar aprotic solvent such as dimethylformamide (DMF). Then, an alkyl halide of formula Alk-Hal, wherein Hal is a halogen such as iodine or bromine, can be added dropwise, for example, in the presence of an inorganic base such as K₂CO₃ at a molar ratio of 0.7 to 1.50, particularly 1.05, relative to the compound of formula (III). The reaction mixture can be stirred during the addition of the alkyl halide.

[0446] In a specific implementation, the resulting mixture can then be stirred at room temperature for, for example, 8 to 16 hours, particularly 12 hours.

[0447] In another embodiment, the resulting mixture can be stirred at a temperature of -10°C to 10°C, particularly at 0°C, for example, for 2 to 8 hours, particularly for 6 hours.

[0448] Compounds of formula (III) as defined above can be derived from R according to the general scheme GP1. 2 Compounds of formula (IV) as defined above are obtained.

[0449] According to GP1, the compound of formula (IV) can be placed in a protic solvent such as ethanol in the presence of, for example, 0.85 to 1.15, particularly 1, molar ratio of 2-thiohydantoin relative to the compound of formula (IV), in the presence of an organic base such as piperidine in the presence of, for example, 0.85 to 1.15, particularly 1, molar ratio of acetic acid relative to the compound of formula (II), and in the presence of, for example, an organic acid such as acetic acid in the presence of, for example, 0.85 to 1.15, particularly 1, molar ratio still relative to the compound of formula (IV). The reaction mixture can be placed in a sealed tube and stirred and heated at a temperature of, for example, 60°C to 130°C, particularly 80°C, for a duration of 10 to 100 minutes, particularly 15 to 90 minutes. The reaction mixture can be irradiated, for example, by microwave.

[0450] Therefore, the present invention further relates to a synthetic method for preparing novel compounds of formula (I) as defined above, which includes at least the step of substituting a compound of formula (II) with a primary amine. The present invention relates to a synthetic method for preparing any one of compounds of formula (I) as defined above or any pharmaceutically acceptable salt thereof, or any one of compounds (1) to (216) as defined above or any pharmaceutically acceptable salt thereof, which includes at least the step of reacting a compound of formula (II) with formula R. 1 Amines of NH2 (where R) 1 and R 2 As defined above, the steps of coupling,

[0451]

[0452] Alk is a (C1-C5) alkyl group.

[0453] The present invention further relates to the synthetic intermediate of formula (II) below.

[0454]

[0455] Where Alk is a (C1-C5) alkyl group, specifically selected from the group consisting of ethyl and methyl groups, and R 2 As defined above.

[0456] The chemical structures, analytical and spectroscopic data of some compounds of formula (I) of the present invention are shown in Tables 2 and 3 below.

[0457] The reaction was carried out in oven-dried glassware under an inert argon atmosphere. Unless otherwise specified, all reagent-grade chemicals and solvents were obtained from commercial suppliers and used as is. The reaction was monitored by thin-layer chromatography on aluminum plates (0.25 mm) pre-coated with silica gel 60F254. Visualization was performed under UV light at 254 nm or 312 nm, or with appropriate TLC staining, including but not limited to: phosphomolybdic acid, KMnO4, ninhydrin, CAM, vanillin, and p-anisaldehyde.

[0458] Anton Paar Monowave Microwave experiments were conducted in a microwave reactor. Experiments were performed in a single-mode cavity with a power delivery range of 0W to 850W, allowing pressurized reactions (0 to 30 bar) in sealed glass vials (4 mL to 30 mL) equipped with snap-caps and silicone diaphragms. Temperature (0°C to 300°C) was monitored using a non-contact infrared sensor and calibrated with a ruby ​​thermometer. Temperature, pressure, and power curves were edited and monitored via a touchscreen control panel. The times indicated in various schemes are the measurements taken when the mixture reaches the programmed temperature after a 3-minute heating period.

[0459] Chromatographic purification of the compounds was performed on an automated Interchim Puriflash XS420 equipped with a pre-packed column filled with 30 μm spherical silica as the stationary phase.

[0460] Some of the compounds of the present invention are described in Table 2 below with their structures, which are illustrative only and do not limit the scope of the invention.

[0461] Table 2: Structures of compounds (1) through (216). Using Perkin Elmer's... Version 17.1.0.105: Generic formulas and molecular weights.

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479] Table 3 below describes the analytical and spectroscopic data of the compounds described in Table 2.

[0480] Record using a Bruker ULTRASHIELD 500 or 400 spectrometer 1 H NMR analysis (400 or 500 MHz) and 13 CNMR spectra (101 MHz). Spectral processing and analysis were performed using MestReNova. Data are presented in the following order: chemical shifts in ppm, involving internal solvent signal, multiplicity, proton number, and coupling constant J in Hertz.

[0481] Reversed-phase HPLC / MS analysis was performed using a Waters Alliance 2795 HPLC system equipped with an autosampler, inline membrane degasser, column oven (T = 45°C), UV detector, and ZQ quadrupole mass detector operating in ionization electrospray mode. The compound (0.1 mg to 0.3 mg) was dissolved in a minimal amount of DMSO and brought to a final volume (V) with acetonitrile. 总计 =1 mL). Standard analytical parameters: flow rate: 1 mL / min, V 进样 =5μL.

[0482] - 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, from 95 / 5 to 0 / 100, over 18.5 min.

[0483] - Alkaline conditions: Waters Xbridge C18 column (3.5 μm, 2.1 x 50 mm). Gradient: (H₂O + 0.06% v / v NH₄) 3(水溶液) (10mM)) / ACN, from 95 / 5 to 0 / 100, within 18.5 min.

[0484] The enantiomers of racemic products (149), (169), (171), and (192) were separated by preparative chiral SFC according to Reach Separations (Bio City, Pennyfoot St., Nottingham, NG1 1GF, UK. www.reachseparations.com). In short: the racemic products were dissolved in MeOH and purified by preparative SFC (conditions in Table 3). The combined fractions containing the first eluted enantiomers were then evaporated to near dryness using a rotary evaporator, transferred to a final container with DCM (which was removed at 35°C on a Biotage V10), and stored in a vacuum oven at 35°C and 5 mbar until constant weight to obtain pure enantiomers. The fractions containing the second eluted enantiomers were combined, concentrated, and purified again as described above. The optical purity of each enantiomer relative to the racemic product was controlled by analytical chiral SFC (conditions in Table 3). Chemical purity of each enantiomer was controlled by analytical UHPLC on an 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, from 98 / 2 to 0 / 100 in 2.02 min.

[0485] Table 3. Spectroscopic and analytical characterization of compounds (1) to (216)

[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] Pathology

[0546] Compounds of formula (I) can be used to treat and / or prevent diseases selected from: cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tau proteinosis; and other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick type C); CDKL5 deficiency disorders; McDermead syndrome; autism; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; several cancers, such as brain cancer, including glioblastoma; leukemia, including megakaryocytic leukemia, acute lymphoblastic leukemia; squamous cell carcinoma of the head and neck; pancreatic cancer, including pancreatic ductal adenocarcinoma; prostate cancer; gastrointestinal cancer; breast cancer, such as triple-negative breast cancer. Cancer (TNBC), tissue cancer, including liposarcoma, Hedgehog / GLI-dependent carcinoma, liver cancer, including hepatocellular carcinoma; and viral infections, such as those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpesvirus, rhesus monkey 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; infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), and bovine diseases caused by single-celled pathogens; and those used to regulate body temperature.

[0547] According to specific embodiments, the compounds of formula (I) of the present invention can be used to treat and / or prevent diseases selected from: cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tau proteinosis; other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick type C disease); CDKL5 deficiency disorders; type 1 and type 2 diabetes; abnormal folic acid and methionine metabolism; osteoarthritis, especially knee osteoarthritis; Duchenne muscular dystrophy; and several cancers, such as brain cancer. This includes glioblastoma, leukemia, including megakaryocytic leukemia and acute lymphoblastic leukemia, squamous cell carcinoma of the head and neck, pancreatic cancer, including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer, and breast cancer, such as triple-negative breast cancer (TNBC); and viral infections, such as those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpesvirus, rhesus monkey cytomegalovirus, varicella-zoster virus, and herpes simplex virus (HSV); and diseases related to the regulation of body temperature. These diseases are more specifically associated with abnormal doses of DYRK1A and / or CLK1.

[0548] According to this specific embodiment, the compound of formula (I) of the present invention can be used to treat and / or prevent diseases selected from: Down syndrome, Alzheimer's disease, dementia, tau protein disease, Parkinson's disease, Niemann-Pick type C disease, CDKL5 deficiency disorder and Ferenc-McDermid syndrome and related cognitive and motor symptoms, and more particularly diseases caused by high expression and activity of DYRK1A.

[0549] According to this specific embodiment, the compound of formula (I) of the present invention can be used to treat and / or prevent diseases selected from: Down syndrome, Alzheimer's disease and related Tau protein disorders, Parkinson's disease, related cognitive / motor impairments, or one or more symptoms of such diseases. Typical symptoms of such diseases are a decline in learning and memory as well as social interaction.

[0550] According to this specific embodiment, the compound of formula (I) of the present invention can be used to combat cognitive decline associated with Down syndrome (trisomy 21), cognitive decline in learning and memory, and especially cognitive decline associated with cognitive or neurodegenerative disorders as mentioned above.

[0551] According to this specific embodiment, the compound of formula (I) of the present invention can be used to treat and / or prevent type 1 and type 2 diabetes.

[0552] The compounds of formula (I) of the present invention can be used to treat and / or prevent type 1 and type 2 diabetes by directly treating diabetic patients or by treating pancreatic islets or β-cells prior to transplantation into diabetic patients.

[0553] According to this specific embodiment, the compounds of formula (I) of the present invention can be used to treat and / or prevent viral infections, particularly those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpesvirus, rhesus monkey cytomegalovirus, varicella-zoster virus, and herpes simplex virus (HSV), and especially those caused by herpes, coronaviruses, cytomegalovirus, and influenza. These infections may be associated with high expression and activity of DYRK1A and / or CLK1, and optionally additionally with dual inhibitors of CLK / DYRKS.

[0554] Acute respiratory illness has recently been caused by a novel coronavirus (SARS-CoV-2, formerly known as 2019-nCoV), belonging to the family Coronaviridae, and also referred to herein as coronavirus 2019 (COVID-19). The compound of formula (I) according to the invention can also treat said infection caused by the SARS-CoV-2 virus.

[0555] According to this specific embodiment, the compounds of formula (I) of the present invention can be used to treat and / or prevent cancers such as brain cancer, including glioblastoma, leukemia, including megakaryocytic 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 optionally additionally with dual inhibitors of CLK / DYRKS.

[0556] According to this specific embodiment, the compounds of formula (I) of the present invention can be used to treat and / or prevent osteoarthritis. Osteoarthritis can be associated with high expression and activity of DYRK1A and / or CLK2.

[0557] According to this specific embodiment, the compounds of formula (I) of the present invention can be used to treat and / or prevent infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease, and sleeping sickness (Trypanosoma sp.), as well as bovine diseases caused by single-celled pathogens. The parasitic infection can be correlated with the expression and activity of DYRK / CLK.

[0558] According to this specific embodiment, the compound of formula (I) of the present invention can be used for thermoregulation. The thermoregulation may be related to the expression and activity of CLK.

[0559] According to another specific embodiment, the compounds of formula (I) of the present invention can be used to treat and / or prevent diseases selected from: Ferenc-McDermid syndrome; autism; additional viral infections, such as those caused by hepatitis C virus, chikungunya virus, dengue virus, influenza virus, and severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus, and human papillomavirus; additional cancers, such as tissue cancers, including liposarcoma, Hedgehog / GLI-dependent carcinoma, liver cancer, including hepatocellular carcinoma; neuroinflammation; anemia; infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease, and sleeping sickness (Trypanosoma sp.); and bovine diseases caused by single-celled pathogens. These diseases are more particularly associated with abnormalities in other DYRKs (DYR1B, 2, 3, 4) and closely related additional cdc2-like kinases (CLKs) (CLK 2, 3, 4).

[0560] The following examples are provided for illustrative purposes and are in no way intended to limit the scope of the invention.

[0561] The following examples illustrate in detail the preparation of some compounds according to the present invention. The structures of the obtained products have been confirmed by NMR analysis and mass spectrometry.

[0562] Example 1 Synthesis of general scheme 1-(5Z)-5-heteroaryl-2-thio-imidazolidine-4-one

[0563]

[0564] In the above scheme, R 2 Represents a hydrogen atom or a (C1-C3) alkyl group, specifically, R 2 It represents a hydrogen atom or a methyl group.

[0565] GP1: A stirred solution (c = 0.3 M) of 2-thiohydantoin (1 equivalent), appropriate heteroarylformaldehyde (1 equivalent), piperidine (1 equivalent), and AcOH (1 equivalent) in EtOH is heated in a sealed tube in a microwave oven (Anton Paar) at the specified temperature for an appropriate time. After completion (after aldehyde consumption on TLC), the reaction medium is cooled and added dropwise to water. The precipitated solid is stirred for 30 min, filtered through a sintered glass funnel, thoroughly dried, and can be used for the next step without further purification. If necessary, final grinding in EtOH can help remove trace impurities without significant yield loss.

[0566] Example 1.1: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-thio-imidazolidine-4-one (1.1)

[0567]

[0568] According to GP1, compound (1.1) was synthesized as follows: The reaction was carried out in a 4.2 mmol scale with 2-thiohydantoin, benzothiazole-6-carboxaldehyde, AcOH, and piperidine. Reaction temperature: 110 °C, time: 90 min. After filtration, the yellow solid was ground in EtOH. Yellow solid, 89% (978 mg). 1 H NMR (400MHz, DMSO-d6)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 C NMR (101MHz, DMSO-d6)δ C 179.3,165.7,158.0,153.1,134.4,129.8,128.9,128.1,123.7,123.1,110.9. MS(ESI + ):[M+H] + 262.1.

[0569] Example 1.2: Synthesis of (5Z)-5-[(2-methyl-1,3-benzothiazolyl-6-yl)methylene]-2-thio-imidazolidine-4-one (1.2)

[0570]

[0571] According to GP1, compound (1.2) was synthesized: the reaction was carried out on 7.34 mmol of 2-thiohydantoin, 2-methyl-1,3-benzothiazol-6-carboxaldehyde, AcOH, and piperidine. Reaction temperature: 110 °C, time: 90 min. After filtration, the yellow solid was ground in EtOH. Yellow solid, 94% (1,898 g). 1 H NMR (400MHz, DMSO-d6)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 C NMR (101MHz, DMSO-d6)δ C179.2,169.1,165.7,153.1,136.0,129.0,128.8,127.7,123.0,122.0,111.1,20.0. MS(ESI + ):[M+H] + 275.9.

[0572] Example 2 S-alkylation of general scheme 2-(5Z)-5-heteroaryl-2-thio-imidazolidine-4-one

[0573]

[0574] In the above scheme, Hal represents a halogen atom, specifically selected from iodine and bromine atoms, Alk is a (C1-C5) alkyl group, and R 2 Represents a hydrogen atom or a (C1-C3) alkyl group, particularly R 2 It represents a hydrogen atom or a methyl group.

[0575] GP2: At an appropriate temperature, an appropriate amount of alkyl iodine (1.05 equivalents) was added dropwise to a stirred solution (5Z)-5-heteroaryl-2-thio-imidazolidine-4-one (1 equivalent) and K2CO3 (1 equivalent) in DMF (c = 0.3 M). The resulting mixture was stirred at the specified temperature for an appropriate time. After completion (TLC), the mixture was poured into water. The precipitated solid was stirred for 30 min and filtered through a sintered glass funnel, dried thoroughly, and could be used for the next step without further purification. Trace impurities resulting from dialkylation could be removed by FC: elution: cyclohexane / AcOEt 7 / 3 to 3 / 7 or by grinding.

[0576] Example 2.1: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-ethylthioalkyl-1H-imidazol-5-one (2.1)

[0577]

[0578] According to GP2, compound (2.1) was synthesized by reacting (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-thio-imidazolidine-4-one (7.69 mmol) with EtI at room temperature for 12 h. Yellow solid, 89% (978 mg). 1 H NMR (400MHz, DMSO-d6)δ H11.85 (br s, 1H, NH, D2O exchange), 9.46 (s, 1H), 8.90 (s, 1H), 8.45 (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 C NMR (101MHz, DMSO-d6)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. MS(ESI + ):[M+H] + 289.9.

[0579] Example 2.2: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-methylthioalkyl-1H-imidazol-5-one (2.2)

[0580] According to GP2, compound (2.2) was synthesized by reacting (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-thio-imidazolidine-4-one (3.83 mmol) with MeI at 0 °C for 6 h. After filtration, the yellow solid was ground in DCM. Yellow solid, 83% (879 mg). 1 H NMR (400MHz, DMSO-d6)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 C NMR (101MHz, DMSO-d6) δ171.1,166.1,158.3,153.7,140.0,134.6,132.4,129.8,125.9,123.5,120.4,12.8. MS(ESI + ):[M+H] + 275.9.

[0581] Example 2.3: Synthesis of (4Z)-2-ethylthioalkyl-4-[(2-methyl-1,3-benzothiazolyl-6-yl)methylene]-1H-imidazol-5-one (2.3)

[0582]

[0583] According to GP2, compound (2.3) was synthesized by reacting (5Z)-5-[(2-methyl-1,3-benzothiazol-6-yl)methylene]-2-thio-imidazolidine-4-one (1.45 mmol) with EtI at room temperature for 12 h. Yellow solid, 84% (368 mg). 1 H NMR (400MHz, DMSO-d6)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 C NMR (101MHz, DMSO-d6)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. MS(ESI + ):[M+H] + 303.9.

[0584] Example 2.4: Synthesis of (4Z)-4-[(2-methyl-1,3-benzothiazolyl-6-yl)methylene]-2-methylthioalkyl-1H-imidazol-5-one (2.4)

[0585]

[0586] According to GP2, compound (2.4) was synthesized by reacting (5Z)-5-[(2-methyl-1,3-benzothiazol-6-yl)methylene]-2-thio-imidazolidine-4-one (3.63 mmol) with MeI at room temperature for 6 h. After filtration, the yellow solid was ground in DCM. Yellow solid, 92% (962 mg). 1 H NMR (400MHz, DMSO-d6)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 C NMR (101MHz, DMSO-d6)δ C170.6,169.0,165.3,153.3,139.2,135.7,131.2,129.3,124.9,121.9,120.2,19.9,12.3. MS(ESI + ):[M+H] + 290.1.

[0587] Example 3: General Scheme 3 - Adding aliphatic and aromatic amines to (4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-alkylthioalkyl-1H-imidazol-5-one

[0588]

[0589] In the above scheme, Alk is a (C1-C5) alkyl group and R 2 Represents a hydrogen atom or a (C1-C3) alkyl group, specifically, R 2 It represents a hydrogen atom or a methyl group.

[0590] In a sealed tube (heating block or μw), place an appropriate amount of amine (a) (x equivalents) added to (4Z)-4-heteroaryl-2-alkylthioalkyl-1H-imidazol-5-one (b) (1 equivalent) in a stirred suspension (c = 0.3 M) in a suitable solvent mixture. Thoroughly purge the mixture with a vacuum / argon circulation and heat at a suitable temperature (μW or heating block) for the specified time. After completion (after isothiourea is consumed on TLC), allow the mixture to return to room temperature.

[0591] -GP3-A: Direct precipitation of the desired product: Stir the reaction medium at 0°C for 1 hour. Filter the precipitated solid through a sintered glass funnel. High purity can be obtained after filtration by washing, reprecipitation, grinding, or recrystallization.

[0592] -GP3-B: Product failed to precipitate: The reaction mixture was concentrated under vacuum, adsorbed onto silica, and purified by FC. High purity can be obtained after filtration by reprecipitation, grinding, or recrystallization.

[0593] -GP3-C: Product failed to precipitate: The reaction mixture was concentrated under vacuum. The resulting crude product was ground in EtOH (at room temperature or under reflux) and filtered through a sintered glass funnel. High purity can be obtained after filtration by purification, reprecipitation, grinding, or recrystallization.

[0594] (a) When using amine hydrochloride, quench it in situ with TEA or DIPEA.

[0595] (b) It may require activation with AcOH, depending on the amine.

[0596] Selected embodiments from subgroup A1:

[0597] Example 3.1: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one (6)

[0598] According to GP3-A, 2.73 mmol of (2.1) was reacted with 4 equivalents of cyclohexylamine in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. The product was directly precipitated in the reaction medium and separated after filtration, washing with cold THF, and then washing with pentane. Separation yield: 34%.

[0599] Example 3.2: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(cycloheptylmethylamino)-1H-imidazol-5-one (7)

[0600] According to GP3-B, 1.01 mmol of (2.1) was reacted with 4 equivalents of cycloheptamethylamine in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 23%.

[0601] Example 3.3: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one (8)

[0602] According to GP3-A, 4.84 mmol of (2.1) reacted with 4 equivalents of cycloheptanine in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. The product was directly precipitated in the reaction medium and separated after filtration, washing with cold THF, and then washing with pentane. Separation yield: 49%.

[0603] Example 3.4: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(cyclooctylamino)-1H-imidazol-5-one (9)

[0604] According to GP3-A, 2.73 mmol of (2.1) and 4 equivalents of cyclooctylamine were reacted in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. The product was directly precipitated in the reaction medium and separated after filtration, washing with cold THF, and then washing with pentane. Separation yield: 58%.

[0605] Example 3.5: Synthesis of (4Z)-2-(1-adamantylamino)-4-(1,3-benzothiazol-6-ylmethylene)-1H-imidazol-5-one (16)

[0606] According to GP3-B, 2.54 mmol of (2.2) was reacted with 3 equivalents of 1-adamantylamine and 15 equivalents of AcOH in THF (0.3 M) at 160 °C (sealed tube, heating block) for 24 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required two consecutive millings in refluxed EtOH. Separation yield: 61%.

[0607] Example 3.6: Synthesis of (4Z)-2-(2-adamantylamino)-4-(1,3-benzothiazol-6-ylmethylene)-1H-imidazol-5-one (17)

[0608] According to GP3-B, 746 μmol of (2.2) was reacted with 4 equivalents of 2-adamantylamine and 15 equivalents of AcOH in THF (0.3 M) at 170 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in EtOH at 0 °C. Separation yield: 44%.

[0609] Example 3.7: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(trans-5-hydroxy-2-adamantyl)amino]-1H-imidazol-5-one (19)

[0610] According to GP3-B, 746 μmol of (2.2) was reacted with 4 equivalents of trans-4-aminoadamantane-1-ol and 15 equivalents of AcOH in THF (0.3 M) at 170 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in EtOH at 0 °C. Separation yield: 27%.

[0611] Example 3.8: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one (20)

[0612] According to GP3-B, 746 μmol of (2.2) was reacted with 4 equivalents of 3-amino-1-adamantaneol and 15 equivalents of AcOH in THF (0.3 M) at 160 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in EtOH at 0 °C. Separation yield: 59%.

[0613] Example 3.9: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R,2R,3R,5S)-2,6,6-trimethylnorpinen-3-yl]amino]-1H-imidazol-5-one (22)

[0614] According to GP3-B, 746 μmol of (2.1) was reacted with 4 equivalents of (1R,2R,3R,5S)-3-pinenamine in THF (0.3 M) at 120 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 60%.

[0615] Example 3.10: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(spiro[2.5]oct-2-ylamino)-1H-imidazol-5-one (25)

[0616] According to GP3-B, in THF (0.3 M), 773 μmol of (2.1) was reacted with 2 equivalents of (±)-spiro[2.5]octyl-2-amine hydrochloride and 2 equivalents of TEA at 110 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 61%.

[0617] Example 3.11: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(2R)-1,7,7-trimethylnorbornen-2-yl]amino]-1H-imidazol-5-one (27)

[0618] According to GP3-B, 746 μmol of (2.1) was reacted with 3 equivalents of (R)-(+)-borneolamine in THF (0.3 M) at 150 °C (sealed tube, heating block) for 8 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 34%.

[0619] Example 3.12: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (34)

[0620] According to GP3-B, 746 μmol of (2.1) was reacted with 4 equivalents of D-leucine in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 39%.

[0621] Example 3.13: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (35)

[0622] According to GP3-B, 2.91 mmol of (2.2) was reacted with 2.5 equivalents of (2R)-1-methoxy-4-methyl-pentane-2-amine in THF (0.3 M) at 120 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 74%.

[0623] Example 3.14: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (36)

[0624] According to GP3-B, 746 μmol of (2.1) was reacted with 4 equivalents of L-leucine in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 39%.

[0625] Example 3.15: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (40)

[0626] According to GP3-B, 908 μmol of (2.2) was reacted with 1.2 equivalents of (±)-1-fluoro-4-methyl-pentane-2-amine in THF (0.3 M) at 150 °C (sealed tube, heating block) for 96 h. Purification was achieved by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7) followed by PTLC. Yield: 8%.

[0627] Example 3.16: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[trans-2-methoxycyclopentyl]amino]-1H-imidazol-5-one (48)

[0628] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-trans-2-methoxycyclopentanamine hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 120 °C (sealed tube, heating block) for 7 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in refluxed EtOH. Separation yield: 81%.

[0629] Example 3.17: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[cis-3-hydroxycyclohexyl]amino]-1H-imidazol-5-one (55)

[0630] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-cis-3-aminocyclohexanol hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 120 °C (sealed tube, heating block) for 24 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Separate yield: 82%.

[0631] Example 3.18: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[trans-3-hydroxycyclohexyl]amino]-1H-imidazol-5-one (56)

[0632] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-trans-3-aminocyclohexanol hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 120 °C (sealed tube, heating block) for 24 h. Purification was achieved by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7) followed by PTLC. The isolated yield was 82%.

[0633] Example 3.19: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[trans-2-methoxycyclohexyl]amino]-1H-imidazol-5-one (59)

[0634] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-trans-2-methoxycyclohexylamine hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 120 °C (sealed tube, heating block) for 28 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Separate yield: 82%.

[0635] Example 3.20: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[cis-2-hydroxycycloheptyl]amino]-1H-imidazol-5-one (61)

[0636] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-cis-2-aminocycloheptanol hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 120 °C (sealed tube, heating block) for 28 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in refluxed EtOH. Separation yield: 56%.

[0637] Example 3.21: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[trans-2-hydroxycycloheptyl]amino]-1H-imidazol-5-one (62)

[0638] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-trans-2-aminocycloheptanol in THF (0.3 M) at 120 °C (sealed tube, heating block) for 6 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in refluxed EtOH. Separation yield: 31%.

[0639] Example 3.22: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R,2R)-2-hydroxycycloheptyl]amino]-1H-imidazol-5-one (63)

[0640] According to GP3-B, 746 μmol of (2.1) was reacted with 3 equivalents of (1R,2R)-2-aminocycloheptanol in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 49%.

[0641] Example 3.23: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[cis-3-hydroxycycloheptyl]amino]-1H-imidazol-5-one (65)

[0642] According to GP3-B, in THF (0.3 M), 218 μmol of (2.2) was reacted with 3 equivalents of (±)-cis-3-aminocycloheptanol hydrochloride and 4 equivalents of DIPEA at 150 °C (sealed tube, μw) for 6 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Separate yield: 46%.

[0643] Example 3.24: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[trans-3-hydroxycycloheptyl]amino]-1H-imidazol-5-one (66)

[0644] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-trans-3-aminocycloheptanol hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 120 °C (sealed tube, heating block) for 31 h. Purification was achieved by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7) followed by PTLC. The isolated yield was 67%.

[0645] Example 3.25: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[trans-2-methoxycycloheptyl]amino]-1H-imidazol-5-one (68) According to GP3-B, in THF (0.3 M), 272 μmol of (2.2) was reacted with 3 equivalents of (±)-trans-2-methoxycycloheptylamine at 120 °C (sealed tube, heating block) for 24 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Separate yield: 79%.

[0646] Selected embodiments from subgroup A2:

[0647] Example 3.26: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(benzylamino)-1H-imidazol-5-one (74)

[0648] According to GP3-A, 1.38 mmol of (2.1) was reacted with 4 equivalents of benzylamine in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. The product was directly precipitated in the reaction medium and separated after filtration, washing with cold THF, and then washing with pentane. Separation yield: 80%.

[0649] Example 3.27: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one (78)

[0650] According to GP3-A, 272 μmol of (2.2) was reacted with 3 equivalents of [2-(trifluoromethyl)phenyl]methylamine in THF (0.3 M) at 120 °C (sealed tube, heating block) for 24 h. The product was directly precipitated in the reaction medium and separated after filtration and washing with cold THF. The final product was ground in refluxed EtOH. Separation yield: 72%.

[0651] Example 3.28: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[trans-2-hydroxyindan-1-yl]amino]-1H-imidazol-5-one (81)

[0652] According to GP3-A, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-trans-1-aminoindan-2-ol in THF (0.3 M) at 120 °C (sealed tube, heating block) for 30 h. The product was directly precipitated in the reaction medium and separated after filtration and washing with cold THF. The final product was then ground in EtOH at room temperature. Separation yield: 56%.

[0653] Example 3.29: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-1H-imidazol-5-one (83)

[0654] According to GP3-A, 272 μmol of (2.2) was reacted with 3 equivalents of (1S,2S)-1-aminoindan-2-ol in THF (0.3 M) at 120 °C (sealed tube, heating block) for 40 h. The product was directly precipitated in the reaction medium and separated after filtration and washing with cold THF. The final product was then ground in EtOH at room temperature. Separation yield: 62%.

[0655] Example 3.30: Synthesis of (±)-(4Z)-2-[(2-amino-1-phenyl-ethyl)amino]-4-(1,3-benzothiazol-6-ylmethylene)-1H-imidazol-5-one dihydrochloride (89)

[0656] According to GP3-B, in THF (0.3 M), 363 μmol of (2.2) was reacted with 3 equivalents of (±)-N-(2-amino-2-phenyl-ethyl)carbamate tert-butyl ester at 120 °C (sealed tube, heating block) for 48 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7), followed by deprotection with HCl (4 M, in dioxane). Separate yield: 63%.

[0657] Example 3.31: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1H-imidazol-5-one (95)

[0658] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-2-phenylglycine in THF (0.3 M) at 150 °C (sealed tube, heating block) for 8 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in refluxed EtOH. Separation yield: 37%.

[0659] Example 3.32: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-methoxy-1-phenyl-ethyl)amino]-1H-imidazol-5-one (98)

[0660] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-2-methoxy-1-phenyl-ethylamine in THF (0.3 M) at 120 °C (sealed tube, heating block) for 48 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in refluxed EtOH. Separation yield: 41%.

[0661] Example 3.33: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1H-imidazol-5-one (99)

[0662] According to GP3-B, 272 μmol of (2.2) was reacted with 3 equivalents of (±)-2-amino-1-phenyl-ethanol hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 120 °C (sealed tube, heating block) for 2.5 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in refluxed EtOH. Separation yield: 41%.

[0663] Example 3.34: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one (176)

[0664] According to GP3-A, 12.71 mmol of (2.2) was reacted with 3 equivalents of (1R)-2-methoxy-1-phenyl-ethylamine in THF (0.3 M) at 140 °C (sealed tube, heating block) for 24 h. The product was precipitated directly in the reaction medium and separated after filtration and washing with cold THF. The final product was ground in refluxed EtOH. Separation yield: 51%.

[0665] Selected embodiments from subgroup A3:

[0666] Example 3.35: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(5-methylpyrazin-2-yl)methylamino]-1H-imidazol-5-one (103)

[0667] According to GP3-B, 182 μmol of (2,2) was reacted with 3 equivalents of (5-methylpyrazin-2-yl)methylamine in THF (0.3 M) at 80 °C (sealed tube, heating block) for 16 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The isolated yield was 47%.

[0668] Example 3.36: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one (108)

[0669] According to GP3-B, 182 μmol of (2.2) was reacted with 3 equivalents of (4-methylthiazolyl-2-yl)methylamine in THF (0.3 M) at 120 °C (sealed tube, heating block) for 24 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product was ground in refluxed EtOH. Separation yield: 40%.

[0670] Selected embodiments from subgroup A4:

[0671] Example 3.37: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one (113)

[0672] According to GP3-B, 182 μmol of (2.2) was reacted with 3 equivalents of tetrahydropyran-4-ylmethylamine in THF (0.3 M) at 120 °C (sealed tube, heating block) for 2 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Separate yield: 51%.

[0673] Selected embodiments from subgroup A5:

[0674] Example 3.38: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one (119)

[0675] According to GP3-A, 182 μmol of (2.1) was reacted with 5 equivalents of 4-(4-methylpiperazin-1-yl)aniline in THF (0.3 M) at 150 °C (sealed tube, μw) for 3 h. The product was directly precipitated in the reaction medium and separated after filtration. The final product required two consecutive millings in refluxed EtOH. Separation yield: 65%.

[0676] Example 3.39: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-methylindazole-7-yl)amino]-1H-imidazol-5-one (125)

[0677] According to GP3-A, 182 μmol of (2.2) was reacted with 5 equivalents of 1-methylindazole-7-amine and 15 equivalents of AcOH in THF (0.3 M) at 130 °C (sealed tube, heating block) for 5 h. The product was directly precipitated in the reaction medium and separated after filtration. The final product was then ground in EtOH at room temperature. Separation yield: 52%.

[0678] Selected embodiments from subgroup A6:

[0679] Example 3.40: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(2-pyridylamino)-1H-imidazol-5-one (127)

[0680] According to GP3-A, 1.05 mmol of (2.2) was reacted with 5 equivalents of pyridine-2-amine and 15 equivalents of AcOH in THF (0.3 M) at 150 °C (sealed tube, μw) for 2 h. The product was precipitated directly in the reaction medium and separated after filtration. The final product was ground in refluxed EtOH. Separation yield: 41%.

[0681] Example 3.41: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-methylpyrazol-3-yl)amino]-1H-imidazol-5-one (128)

[0682] According to GP3-A, 182 μmol of (2.2) was reacted with 5 equivalents of 1-methylpyrazole-3-amine in THF (0.3 M) at 150 °C (sealed tube, μw) for 3 h. The product was directly precipitated in the reaction medium and separated after filtration. The final product was then ground in EtOH at room temperature. Separation yield: 71%.

[0683] Selected embodiments from subgroup A7:

[0684] Example 3.42: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(3S)-tetrahydrofuran-3-yl]amino]-1H-imidazol-5-one (146)

[0685] According to GP3-B, 746 μmol of (2.2) was reacted with 3 equivalents of (3S)-tetrahydrofuran-3-amine in THF (0.3 M) at 120 °C (sealed tube, heating block) for 12 h. The product was directly precipitated in the reaction medium and separated after filtration. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 51%.

[0686] Example 3.43: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(3R)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one (147)

[0687] According to GP3-B, 1.04 mmol of (2.1) was reacted with 4 equivalents of (3R)-tetrahydropyran-3-amine hydrochloride and 6 equivalents of TEA in THF (0.3 M) at 110 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 60%.

[0688] Example 3.44: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one (148)

[0689] According to GP3-B, 746 μmol of (2.2) was reacted with 3 equivalents of (3S)-tetrahydropyran-3-amine hydrochloride and 4 equivalents of DIPEA in THF (0.3 M) at 130 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 62%.

[0690] Example 3.45: Synthesis of (4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one (150)

[0691] According to GP3-B, in THF (0.3 M), 746 μmol of (2.2) was reacted with 3 equivalents of (3R,4R)-3-aminotetrahydropyran-4-ol at 130 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Separation yield: 35%.

[0692] Example 3.46: Synthesis of (±)-(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-2-(oxepane-3-ylamino)-1H-imidazol-5-one (151)

[0693] According to GP3-B, in THF (0.3 M), 272 μmol of (2.2) was reacted with 1.2 equivalents of (±)-oxetane-3-amine at 130 °C (sealed tube, heating block) for 12 h. Purification was performed by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Separate yield: 33%.

[0694] Example 4: Bioactivity

[0695] Materials and methods

[0696] Protein kinase assay

[0697] 1. Overview

[0698] The assays were performed by ProQinase GmbH (Engesserstr. 4, D-79108 Freiburg, Germany. www.proqinase.com) (now Reaction Biology; https: / / www.reactionbiology.com / ). The IC50 values ​​of all compounds were determined using 12 protein kinases (CDK5 / p25, CK1ε, CLK1, 2, 3, 4, DYRK1A, 1B, 2, 3, 4, GSK3β). 50 Characteristics. IC50 was measured by testing each compound at 10 concentrations (10 μM to 30 nM) in a single assay. 50 value.

[0699] 2. Testing compounds

[0700] The compounds were provided as a 1 μM stock solution in 100% DMSO. Prior to testing, the 1 μM stock solution was subjected to sequential semi-logarithmic dilutions using 100% DMSO as the solvent. This yielded 10 different concentrations, with the dilution endpoint at 3 × 10 nM / 100% DMSO, with 100% DMSO serving as a control. During this process, 90 μL of H₂O was added to each well of each compound dilution plate. To minimize potential precipitation, H₂O was added to each plate only a few minutes before transferring the compound solution to the assay plate. The plates were shaken thoroughly to obtain the compound dilution plate / 10% DMSO.

[0701] For the assay (see below), transfer 5 μL of the solution from the compound dilution plate / 10% DMSO to each well into the assay plate. The final assay volume is 50 μL. All compounds were tested at 10 final assay concentrations ranging from 10 μM to 30 nM. In all cases, the final DMSO concentration in the reaction mixture was 1%.

[0702] 3. Recombinant protein kinase

[0703] All protein kinases provided by ProQinase were expressed as recombinant GST-fusion proteins or His-tagged proteins in Sf9 insect cells or in E. coli, as full-length or enzyme-active fragments. All kinases were generated from human cDNA and purified by GSH affinity chromatography or immobilized metals. Affinity tags were removed from many kinases during purification. The purity of the protein kinases was examined by SDS-PAGE / Coomassie staining, and identity was checked by mass spectrometry.

[0704] 4. Protein kinase assay

[0705] The protein kinase assay (33Pan) was performed using a radiometric method. The Activity Assay was used to measure the kinase activity of 12 protein kinases. All kinase assays were performed in 50 μL reaction volumes using 96-well FlashPlates™ from PerkinElmer (Boston, MA, USA). The reaction mixture was pipetted in four steps in the following order:

[0706] ● 25 μL of assay buffer (standard buffer / [γ-) 33 [P-ATP),

[0707] ●10 μL of ATP (in H2O),

[0708] ●5 μL of the test compound (in 10% DMSO),

[0709] ● 10 μL of enzyme / substrate mixture.

[0710] All protein kinase assays contained 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, corresponding to the apparent ATP-Km of each kinase), [γ- 33 P-ATP (approximately 6.5 x 10⁻⁵ cpm / well), protein kinase (variable), and substrate (variable). Incubate the reaction mixture at 30 °C for 60 min. Terminate the reaction with 50 μL of 2% (v / v) H₃PO₄, aspirate the plate, and wash twice with 200 μL of 0.9% (w / v) NaCl. Determine the reaction time using a microplate scintillation counter (Microbeta, Wallac). 33 Pi incorporation. IC50 values ​​for all compounds were calculated from dose-response curves. 50 value.

[0711] 5. Quality Control

[0712] As a parameter for assay quality, the Z′-factors of the low and high controls for each assay plate (n=8) were used (Zhang et al., J. Biomol. Screen. 2:67-73, 1999). The ProQinase standard for replicate assay plates was a Z′-factor below 0.4 (Iversen et al., J. Biomol. Screen. 3:247-252, 2006).

[0713] Their activity has been classified according to two criteria: kinase inhibitory titer and kinase selectivity.

[0714] According to IC 50 Kinase inhibitory titers are classified according to the following ranges:

[0715] Some compounds have IC50 values ​​that vary from above 0.050 μM. 50 Activity. These compounds correspond to category E above. Some compounds have IC50 values ​​varying from 0.025 μM to 0.050 μM. 50 Activity. These compounds correspond to category D above. Some compounds of the present invention have IC50 values ​​ranging from 0.010 μM to 0.025 μM. 50 Activity. These compounds correspond to category C above. Other specific compounds have IC50 values ​​varying from 0.005 μM to 0.010 μM. 50 Activity. These compounds correspond to category B above. Even more preferred are those with an IC50 of less than 0.005 μM. 50 The active compounds of the present invention. These compounds correspond to Category A above. This classification applies to CLK1 and DYRK1A. The activity / efficacy of the compounds of the present invention in Tables 4, 4A and 4B below are cited using the letters A to E.

[0716] Kinase-selective classification is based on the IC50 of DYRK1A. 50 Value of IC CLK1 50 Value or IC of DYRK1B 50 Values ​​are compared. Classification is based on the following range of values: I: IC for CLK1 or DYRK1B 50 IC with DYRK1A 50 The ratios are as follows: I: ≥10-fold (most DYRK1A-selective compounds); II: 2-10-fold; III: 0.5-2-fold; IV: 0.1-0.5-fold; V: ≥0.1-fold (most CLK1- or DYRK1B-selective compounds). The relative selectivity of the compounds of the present invention is cited in the table below using the numbers I through V.

[0717] Table 4.The kinase inhibitory activity of compounds (1) to (216) tested against 12 kinases was evaluated. IC50 was calculated from dose-response curves. 50 The compounds were further classified based on their efficacy against CLK1 or DYRK1A (reduced efficacy range: A to E) and their relative selectivity (reduced selectivity range: I to V).

[0718]

[0719]

[0720]

[0721] Table 4A. The most effective CLK1 inhibitor (IC) 50 ≤10nM). Kinase inhibitory titer category IC 50 Values: A≤0.005μM; B≤0.010μM; C≤0.025μM; D≤0.050μM; E>0.050μM. Based on DYRK1A Kinase Selective Classes Category I (>10-fold selectivity), Category II (2-10-fold selectivity), Category III (0.5-2-fold selectivity = valence). Compared to DYRK1A, some compounds showed better selectivity for CLK1 or DYRK1B. These compounds correspond to Category IV (2-10-fold selectivity) or Category V (>10-fold selectivity) as described above.

[0722]

[0723] IC with less than or equal to 10 nM 50 The most effective CLK2 inhibitors are compounds (9), (16), (20), (21), (22), (24), (25), (81), (83), (89), (95), (96), (159), (181), (194), (196), (199), (200), (201), (202) and (203).

[0724] IC with less than or equal to 100 nM 50 The most effective CLK3 inhibitors are compounds (48), (89), (90), (159), (164), (165), (169), (169B), (178) and (181).

[0725] IC with less than or equal to 10 nM 50The most effective CLK4 inhibitors 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).

[0726] Table 4B The most effective DYRK1A inhibitor (IC) 50 (≤10 nM). Kinase inhibitory efficacy category and kinase selectivity category are described in Table 4A.

[0727]

[0728]

[0729] IC with less than or equal to 10 nM 50 The most effective DYRK1B inhibitors 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).

[0730] IC with less than or equal to 100 nM 50 The most effective DYRK2 inhibitors are compounds (16), (20), (21), (48), (89), (90), (99), (119), (158), (159), (169), (179), (194), (196), (199), (200), (201), (203) and (210).

[0731] IC with less than or equal to 100 nM 50 The most effective DYRK3 inhibitors are compounds (16), (20), (21), (89), (90), (119), (162), (159), (181), (194), (196), (199), (200), (201) and (203).

[0732] IC with less than or equal to 100 nM 50 The most effective DYRK4 inhibitors are compounds (20) and (48), (164), (194) and (196).

[0733] Table 4C Most DYRK1A selective inhibitors compared to CLK1. Kinase selectivity categories are described in Table 4A.

[0734]

[0735] Table 4D Most CLK1 selective inhibitors compared to DYRK1A. Kinase selectivity categories are described in Table 4A.

[0736]

[0737] Table 4E Most DYRK1A selective inhibitors compared to DYRK1B. Kinase selectivity categories are described in Table 4A.

[0738]

[0739]

[0740] Table 4F Most DYRK1B selective inhibitors compared to DYRK1A. Kinase selectivity categories are described in Table 4A.

[0741]

[0742] result

[0743] Most of the compounds of this invention exhibit IC50 values ​​of less than 2 μM for CLK or DYRK. 50 Activity. All compounds are inhibitors of DYRK1A and CLK1 (Table 4).

[0744] The compounds preferably have inhibitory effects on CLK1 (Table 4A), CLK4, DYRK1A (Table 4B) and DYRK1B.

[0745] Some compounds are most selective for DYRK1A relative to CLK1 (Table 4C), DYRK1A relative to DYRK1B (Table 4E), DYRK1B relative to DYRK1A (Table 4F), or CLK1 relative to DYRK1A (Table 4D). Some compounds show better selectivity for DYRK1A compared to CLK1 or DYRK1B. These compounds correspond to Category I (>10-fold selectivity) or Category II (2 to 10-fold selectivity) as described above. Some compounds are equivalent. These compounds correspond to Category III (0.5 to 2-fold selectivity) as described above. Some compounds show better selectivity for CLK1 or DYRK1B compared to DYRK1A. These compounds correspond to Category IV (2 to 10-fold selectivity) or Category V (>10-fold selectivity) as described above.

[0746] in conclusion

[0747] Based on previous results, it can be concluded that the compound of formula (I) is a suitable compound for the prevention and / or treatment of the following: cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related disorders; dementia; tau proteinosis; other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick type C disease); CDKL5 deficiency disorders; type 1 and type 2 diabetes; abnormal folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; several cancers, such as brain cancer, including glioblastoma; leukemia, including megakaryocytic leukemia and acute lymphoblastic leukemia; squamous cell carcinoma of the head and neck; pancreatic cancer, including pancreatic ductal adenocarcinoma; prostate cancer; gastrointestinal cancer and breast cancer, such as triple-negative breast cancer (TNBC); malaria; leishmaniasis; Chagas disease; and sleeping sickness (Treatrozoa). sp.)) and bovine diseases caused by single-celled pathogens, viral infections such as those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpesvirus, rhesus monkey cytomegalovirus, varicella-zoster virus and herpes simplex virus (HSV); and suitable compounds for regulating body temperature.

[0748] It can be further concluded that some compounds of formula (I) are further applicable to the treatment and / or prevention of Ferenc-McDermid syndrome; autism; additional viral infections, such as those caused by hepatitis C virus, chikungunya virus, dengue virus, influenza virus and severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus and human papillomavirus; additional cancers, such as tissue cancers, including liposarcoma, Hedgehog / GLI-dependent cancer, liver cancer, including hepatocellular carcinoma, neuroinflammation, anemia, infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), and bovine diseases caused by single-celled pathogens.

[0749] Compared to the reference compound, Leucettinib showed a significantly increased efficacy (down to submicromolar and single-digit micromolar IC50). 50 (Values). They also show broad selectivity for DYRK1A or CLK1. Moreover, some products equivalent to CLK and DYRK can also be found as bispecific inhibitors.

[0750] The present invention further relates to pharmaceutical compositions 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 at least one pharmaceutically acceptable excipient.

[0751] The pharmaceutical compositions of the present invention may contain one or more compounds of the present invention in any form as described herein.

[0752] Another object of the present invention comprises the use of at least one compound of formula (I) as defined above and one of compounds (1) to (216) as defined above or their pharmaceutically acceptable salts according to the present invention for the preparation of a medicament for the prevention and / or treatment of diseases selected from: cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tau proteinosis; and other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick type C disease); CDKL5 deficiency disorder; McDermead syndrome; autism; type 1 and type 2 diabetes; regulation of folic acid and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; several cancers, such as brain cancer, including glioblastoma, leukemia, including megakaryocytic leukemia, squamous cell carcinoma of the head and neck, 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, such as those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpesvirus, rhesus monkey 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; infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease, and sleeping sickness (Trypanosoma sp.), as well as bovine diseases caused by single-celled pathogens, and for thermoregulation.

[0753] Another object of the present invention comprises the use of at least one compound of formula (I) as defined above and one of compounds (1) to (216) as defined above or their pharmaceutically acceptable salts according to the present invention for the preparation of a medicament for the prevention and / or treatment of diseases selected from: cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tau proteinosis; other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick type C disease); CDKL5 Deficiency disorders; type 1 and type 2 diabetes; regulation of folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; several cancers, such as brain cancer, including glioblastoma, leukemia, including megakaryocytic leukemia, squamous cell carcinoma of the head and neck, pancreatic cancer, including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer, and breast cancer, such as triple-negative breast cancer (TNBC); infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease, and sleeping sickness (Trypanosoma sp.), as well as bovine diseases caused by single-celled pathogens, and viral infections, such as those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpesvirus, rhesus monkey cytomegalovirus, varicella-zoster virus, and herpes simplex virus (HSV); and for the purpose of regulating body temperature.

[0754] Another object of the present invention comprises the use of at least one of the compounds of formula (I) as defined above and one of the compounds (1) to (216) as defined above or their pharmaceutically acceptable salts, according to the present invention, in the preparation of a medicament for combating diseases selected from: type 1 and type 2 diabetes, viral infections (especially as mentioned above), osteoarthritis, cancer (especially as mentioned above), infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), and bovine diseases caused by single-celled pathogens, and for the purpose of regulating body temperature.

[0755] Depending on the specific implementation plan, the treatment may be continuous or discontinuous.

[0756] "Continuous treatment" means long-term treatment that can be administered at various frequencies, such as once a day, once every three days, once a week, or once every two weeks, or once a month, or delivered via a transdermal patch.

[0757] According to one embodiment, any one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof is administered in a dose varying from 0.1 mg to 1000 mg, particularly from 1 mg to 500 mg, or for example from 5 mg to 100 mg.

[0758] Another object of the present invention relates to a treatment for the treatment and / or prevention of diseases selected from those of patients in need, including: cognitive deficits associated with Down syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tau proteinosis; and other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick type C disease); CDKL5 deficiency disorder; McDermead syndrome; autism; type 1 and type 2 diabetes; regulation of folate and methionine metabolism; osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; several cancers, such as brain cancer, including glioblastoma, leukemia, including megakaryocytic leukemia, squamous cell carcinoma of the head and neck, 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 carcinoma, liver cancer, including hepatocellular carcinoma, and viral infections such as those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpesvirus, rhesus monkey 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; infections caused by single-celled parasites such as malaria, leishmaniasis, Chagas disease, and sleeping sickness (Trypanosoma sp.), and bovine diseases caused by single-celled pathogens, and treatments for regulating body temperature, which include 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 one of their acceptable salts.

[0759] In specific embodiments, the present invention provides the use of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof or a pharmaceutically active derivative thereof, or a method according to the invention, wherein the compound of formula (I) is administered in combination with a co-agent that can be used for any of the diseases mentioned above.

[0760] The compound can be administered via any route of administration, such as, for example, intramuscular, intravenous, intranasal, or oral routes, transdermal patches, etc.

[0761] The compositions 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 are described in particular in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition" (multiple editors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994, Williams & Wilkins).

[0762] The aforementioned excipients are selected based on the dosage form and the desired route of administration.

[0763] The compositions of the present invention can be administered in any manner, including but not limited to oral, parenteral, sublingual, transdermal, vaginal, rectal, transmucosal, topical, intranasal via inhalation, buccal or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intra-articular administration. The compositions of the present invention can also be administered in the form of implants that allow for slow release of the composition, and in the form of slow, controlled intravenous infusion.

[0764] For example, compounds of formula (I) may be present with suitable excipients in any pharmaceutical form suitable for intravenous or parenteral administration, such as uncoated or coated tablets, hard gelatin, soft-shell capsules and other capsules, suppositories, or drinkable forms (such as suspensions, syrups), or injectable solutions or suspensions.

[0765] In a specific implementation, the compound of formula (I) according to the invention is administered orally.

[0766] In terms of prevention or treatment according to the present invention, oral administration is particularly preferred.

Claims

1. A compound of formula (I), or any of its pharmaceutically acceptable salts, Where R 1 express: (i) Selected by one or two from -COOR a A (C2-C6) alkyl group substituted with a group, hydroxyl group, halogen atom, (C1-C4) alkoxy group, or benzyloxy group, wherein the benzyloxy group is optionally substituted with one to three halogen atoms on its phenyl group. (ii). Double-ringed screw (C7-C9), (iii) A fused phenyl group selected from phenyl groups fused with a cyclopentyl or heterocyclopentyl group, wherein the heterocyclopentyl group comprises one or two nitrogen atoms, and the cyclopentyl and heterocyclopentyl groups optionally contain unsaturation and are optionally surrounded by (C1-C4)alkyl, hydroxyl, (C1-C3)alkoxy, or -COR groups. a Group substitution, (iv). A phenyl group, which is substituted with one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy, halogen atom, piperazine, and morpholinyl, wherein the piperazine group itself is optionally substituted with a (C1-C4)alkyl group, or (v). R'-L-group, wherein L is a single bond or (C1-C3) alkyl dienylate, optionally substituted with a group selected from hydroxyl and (C1-C3) alkoxy groups, and R' represents: (v.1) (C3-C8) cycloalkyl, optionally substituted with one, two, or three groups selected from (C1-C4) alkyl, hydroxyl, fluorine, and (C1-C3) alkoxy groups. (v.2) Bridged (C7-C) 10 )cycloalkyl group, optionally surrounded by one to three atoms selected from (C1-C4)alkyl, (C1-C4)alkoxy, halogen atom, hydroxyl, -OC(O)-R d Group, -OC(O)-NHR d Group, -NH-C(O)-R d Group, -SO2-R d Group, -N(R) e )2 group and -COOR a Group substitution of groups, (v.3) (C4-C7) heterocyclic alkyl group selected from tetrahydropyranyl, piperidinyl, oxetane, tetrahydrofuranyl, oxetane, tetrahydrothiaranyl, pyrrolidinyl, dioxetane, and piperidinyl, optionally composed of one to three groups selected from -COOR. a Group substitutions of radicals, hydroxyl groups, (C1-C4)alkyl groups, and oxo groups. (v.4) (C5-C 11 Heteroaryl groups selected from pyrimidinyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, and furanyl groups, optionally surrounded by one to three groups selected from (C1-C4) alkyl, (C1-C4) alkoxy, and... N -Methylpiperazine group substitution, or (v.5) Quinine ring-3-base, or (vi). R'-L- group, wherein L is a (C1-C3) alkyldiyl group, optionally selected from -NR. b R c Groups, (C1-C4)alkoxy groups, hydroxyl groups, -COOR a Substitution of groups and halogen atoms, and R' is a phenyl group, optionally substituted with one to three groups selected from the group consisting of (C1-C6) alkyl, fluoro(C1-C4) alkyl, and fluoro(C1-C4) alkoxy groups. R a Indicates (C1-C4) alkyl or hydrogen atom, R b and R c Independently representing (C1-C6) alkyl or hydrogen atoms, R d Indicates (C1-C4) alkyl or cyclopropyl. R e Indicates (C1-C3) alkyl, and R 2 Indicates a hydrogen atom or a (C1-C3) alkyl group. The following compounds are not included: , , , , , and .

2. Any one of the compounds of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 express: (i) An (C2-C6) alkyl group substituted with one or two groups selected from -COOCH3, hydroxyl, fluorine atom, methoxy, ethoxy, tert-butoxy, cyclopropoxy, and benzyloxy, wherein the benzyloxy group is optionally substituted with a fluorine atom on its phenyl group. (ii). Spiral (C7-C8) double ring, (iii) Fused phenyl groups selected from those fused with cyclopentyl or heterocyclopentyl groups, wherein the heterocyclopentyl group comprises one or two nitrogen atoms, and the cyclopentyl and heterocyclopentyl groups optionally contain unsaturation and are optionally substituted with methyl, hydroxyl, methoxy, and -COCH3 groups. (iv) A phenyl group, wherein the radical is selected from one or two groups chosen from methyl, hexyl, trifluoromethyl, difluoromethoxy, halogen atom, morpholino group and N -Methylpiperazine group substitution, or (v) An R'-L- group, wherein L is a single bond or a (C1-C3) alkyl dienyllium group, optionally substituted with a group selected from hydroxyl and (C1-C3) alkoxy groups. And R' can be selected from the following groups: (v.1). (C3-C8)cycloalkyl, optionally substituted with one, two, or three groups selected from methyl, isopropyl, hydroxy, and methoxy groups. (v.2). Bridged (C7-C) 10 ) cycloalkyl groups, optionally substituted by one to three groups selected from the following: methyl, methoxy, hydroxyl, fluorine, -OC(O)-CH3, -OC(O)-C(CH3)3, -OC(O)-NH-C(CH3)3, -NH-C(O)-CH3, -NH-C(O)-C3H5, -S(O)2-CH3, -S(O)2-C3H5, -N(CH3)2, and -C(O)-O-CH3. (v.3). (C5-C7) Heterocyclic alkyl group selected from tetrahydropyranyl, piperidinyl, oxetane, tetrahydrofuranyl, oxetane, tetrahydrothiaranyl, pyrrolidinyl, dioxetane, and piperidinyl, optionally composed of one, two, or three groups selected from -COOR. a Group substitution of radicals, hydroxyl groups, methyl groups, and oxo groups, wherein R a Indicates ethyl or isopropyl. (v.4). (C5-C 11 () heteroaryl group, selected from pyrimidinyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, pyridazinyl, and furanyl, optionally surrounded by one to three groups selected from methyl, methoxy, and N -Methylpiperazine group substitution, or (v.5). Quinine ring-3-base, or (vi). R'-L- group, wherein L is a (C1-C3) alkyldiyl group, optionally selected from -NR b R c Groups, (C1-C4)alkoxy groups, hydroxyl groups, -COOR a Group substitution of groups and halogen atoms in a group, and R' is a phenyl group, which is optionally substituted with one or two groups selected from the group consisting of methyl, trifluoromethyl, and trifluoromethoxy groups. R a Indicates (C1-C3) alkyl, R b and R c Independently selected from methyl or hydrogen atoms, and R 2 It represents a hydrogen atom or a (C1-C3) alkyl group.

3. The compound of formula (I) according to claim 1 or 2, or any pharmaceutically acceptable salt thereof, wherein 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(COOCH3)- group, -C H(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 -CH(CH2OC(CH3)3) group.

4. Any compound of formula (I) according to any one of the preceding claims, or any pharmaceutically acceptable salt thereof, wherein: (v.1). When R' is a (C3-C8) cycloalkyl group, L is selected from the group consisting of single bonds, -CH2- groups, -CH(CH3)- groups, -CH(CH2OH)-CH2- groups, -CH(CH2OH)- groups, -CH(CH2OCH3)- groups, -CH(OH)-CH2- groups, and -CH(OCH3)-CH2- groups. (v.2). When R' is bridged (C7-C 10 In cycloalkyl groups, L is a single bond, a -CH2- group, or a -CH(CH3)- group. (v.3). When R' is a (C5-C7) heterocyclic alkyl group selected from tetrahydropyranyl, piperidinyl, oxetane, tetrahydrofuranyl, oxetane, tetrahydrothiaranyl, pyrrolidinyl, dioxetane, and piperidinyl, including spiro(C3-C8) heterocyclic alkyl groups, L is a single bond or a -CH2- group. (v.4). When R' is phenyl, L is selected from: -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. (v.5). When R' is selected from pyrimidinyl, pyridinyl, thiazolyl, imidazolel, pyrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, and furanyl (C5-C5). 11 When L is a heteroaryl group, it is selected from the group containing a single bond, a -CH2- group, a -(CH2)3- group, and a -(CH2)2- group. (v.6). When R' is bridged (C7-C) 10 In heterocyclic alkyl groups, L is a single bond.

5. Any compound of formula (I) according to any one of the preceding claims, or any pharmaceutically acceptable salt thereof, wherein R 1 express: - Adamantyl group, optionally substituted with one to three groups selected from methyl, methoxy, hydroxyl, fluorine, -OC(O)-CH3, -OC(O)-C(CH3)3, -OC(O)-NH-C(CH3)3, -NH-C(O)-CH3, -NH-C(O)-C3H5, -S(O)2-CH3, -S(O)2-C3H5, -N(CH3)2, and -C(O)-O-CH3.

6. Any one of the compounds of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 express: - Selected by one or two from -COOR a A (C2-C6) alkyl group substituted with a group consisting of a hydroxyl group, a fluorine atom, a (C1-C4) alkoxy group, or a benzyloxy group, wherein the benzyloxy group is optionally substituted with a halogen atom on its phenyl group. - Double-ringed screw (C7-C9), or - R'-L- group, in which o L is a single bond or (C1-C3) alkyl dienylate, optionally substituted with a group selected from hydroxyl and (C1-C3) alkoxy groups, and o R' selects from the following groups: (C3-C8)cycloalkyl groups, optionally substituted with one, two, or three groups selected from fluorine atoms, (C1-C4)alkyl groups, hydroxyl groups, and (C1-C3)alkoxy groups, and Bridged (C7-C) 10 )cycloalkyl group, optionally surrounded by one to three atoms selected from (C1-C4)alkyl, (C1-C4)alkoxy, halogen atom, hydroxyl, -OC(O)-R d Group, -OC(O)-NHR d Group, -NH-C(O)-R d Group, -SO2-R d Group, -N(R) e )2 group and -COOR a Group substitution of groups, R a R represents (C1-C4) alkyl. d It represents (C1-C4) alkyl or cyclopropyl, and R e Indicates (C1-C3) alkyl, and Where R 2 It represents a hydrogen atom or a (C1-C3) alkyl group.

7. The compound of formula (I) according to claim 1, or any pharmaceutically acceptable salt thereof, wherein R 1 express: - Fused phenyl groups selected from phenyl groups fused with cyclopentyl or heterocyclopentyl groups, wherein the heterocyclopentyl group comprises one or two nitrogen atoms, and the cyclopentyl and heterocyclopentyl groups optionally contain unsaturation and are optionally surrounded by (C1-C4)alkyl, hydroxyl, (C1-C3)alkoxy, and -COR groups. a Group substitution, - Phenyl, which is substituted with one or two groups selected from (C1-C8)alkyl, (C1-C3)fluoroalkyl, fluoro(C1-C4)alkoxy, halogen atom, piperazine, and morpholinyl, wherein the piperazine itself is optionally substituted with (C1-C4)alkyl, or - R'-L- group, in which o L is a (C1-C3) alkyldiyl group, optionally selected from hydroxyl, (C1-C4) alkoxy, -NR b R c Group, -COOR a Substitution of groups and halogen atoms, and o R' is a phenyl group, which is optionally substituted with one to three groups selected from the group consisting of (C1-C6) alkyl, fluoro(C1-C4) alkyl, and fluoro(C1-C4) alkoxy groups. Where R a It is a (C1-C4) alkyl or hydrogen atom, and R b and R c Independently selected from (C1-C6) alkyl and hydrogen atoms, and Where R 2 It represents a hydrogen atom or a (C1-C3) alkyl group.

8. A compound of formula (I) according to any one of the preceding claims, or any pharmaceutically acceptable salt thereof, wherein R 2 It represents a hydrogen atom or a methyl group.

9. The compound of formula (I) according to claim 1, or any pharmaceutically acceptable salt thereof, wherein R 1 Represents the R'-L- group, where - R' is (C5-C 11 Heteroaryl groups selected from pyrimidinyl, pyridinyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, and furanyl groups, optionally surrounded by one to three groups selected from (C1-C4) alkyl, (C1-C4) alkoxy, and... N -Methylpiperazine group substitution, and - L is a (C1-C3) alkyl dienylon or a single bond, and Where R 2 It represents a hydrogen atom.

10. A compound of formula (I) according to claim 1, or any pharmaceutically acceptable salt thereof, wherein R 1 Represents the R'-L- group, where - R' is a (C3-C5) heterocyclic alkyl group selected from tetrahydropyranyl, piperidinyl, oxetane, tetrahydrofuranyl, oxetane, tetrahydrothiaranyl, pyrrolidinyl, dioxetane, and piperidinyl, optionally surrounded by one to three groups selected from hydroxyl, (C1-C4) alkyl, oxo group, and -COOR. a Group substitution of a group, wherein R a As defined in claim 1, and -L is a methylene group or a single bond, and Where R 2 It represents a hydrogen atom.

11. Compounds selected from: (twenty four Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(cyclopropylamino)-1 H -Imidazol-5-one, (3) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(cyclobutylamino)-1 H -Imidazol-5-one, (4) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(cyclopentylamino)-1 H -Imidazol-5-one, (5) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(cyclohexylmethylamino)-1 H -Imidazol-5-one, (6) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(cyclohexylamino)-1 H -Imidazol-5-one, (7) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(cycloheptylmethylamino)-1 H -Imidazol-5-one, (8) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(cycloheptylamino)-1 H -Imidazol-5-one, (9) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(cyclooctylamino)-1 H -Imidazol-5-one, (10) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(3-hydroxy-2,2-dimethyl-propyl)amino]-1 H -Imidazol-5-one, (11) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(2-benzyloxyethylamino)-1 H -Imidazol-5-one, (12) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-Methylcyclohexyl]amino]-1 H -Imidazol-5-one, (13) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-Cyclohexylethyl]amino]-1 H -Imidazol-5-one, (14) (4 Z )-2-(1-adamantylmethylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1 H -Imidazol-5-one, (15) (±)-(4 Z )-2-[1-(1-adamantyl)ethylamino]-4-(1,3-benzothiazo-6-ylmethylene)-1 H -Imidazol-5-one, (16) (4 Z )-2-(1-adamantylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1 H -Imidazol-5-one, (17) (4 Z )-2-(2-adamantylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1 H -Imidazol-5-one, (18) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[3,5-dimethyl-1-adamantyl]amino]-1 H -Imidazol-5-one, (19) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[( trans [-5-hydroxy-2-adamantyl)amino]-1 H -Imidazol-5-one, (20) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1 H -Imidazol-5-one, (21) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1 H -Imidazol-5-one, (22) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 R ,3 R 5 S )-2,6,6-Trimethylnorpinen-3-yl]amino]-1 H -Imidazol-5-one, (23) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S ,2 S ,3 S 5 R )-2,6,6-Trimethylnorpinen-3-yl]amino]-1 H -Imidazol-5-one, (24) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 R 5 R )-6,6-dimethylnorpinen-2-yl]methylamino]-1 H -Imidazol-5-one, (25) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(spiro[2.5]oct-2-ylamino)-1 H -Imidazol-5-one, (26) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(spiro[3.3]hept-2-ylamino)-1 H -Imidazol-5-one, (27) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(2 R )-1,7,7-Trimethylnorbornene-2-yl]amino]-1 H -Imidazol-5-one, (28) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(norbornene-2-ylamino)-1 H -Imidazol-5-one, (29) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 S 5 R )-2-Isopropyl-5-methyl-cyclohexyl]amino]-1 H -Imidazol-5-one, (30) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(cyclohexylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazol-5-one, (31) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(cyclopentylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazol-5-one, (32) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(cyclobutylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazol-5-one, (33) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(cyclopropylmethyl)-2-hydroxy-ethyl]amino]-1 H -Imidazol-5-one, (34) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (35) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(methoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (36) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S )-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (37) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S )-1-(methoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (38) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(hydroxymethyl)propyl]amino]-1 H -Imidazol-5-one, (39) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S )-1-(hydroxymethyl)propyl]amino]-1 H -Imidazol-5-one, (40) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (41) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-cyclohexyl-2-hydroxy-ethyl)amino]-1 H -Imidazol-5-one, (42) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-cyclohexyl-2-methoxy-ethyl)amino]-1 H -Imidazol-5-one, (43) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-cyclohexyl-2-hydroxy-ethyl)amino]-1 H -Imidazol-5-one, (44) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-cyclohexyl-2-methoxy-ethyl)amino]-1 H -Imidazol-5-one, (45) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-hydroxycyclopentyl]amino]-1 H -Imidazol-5-one, (46) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-hydroxycyclopentyl]amino]-1 H -Imidazol-5-one, (47) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-Methoxycyclopentyl]amino]-1 H -Imidazol-5-one, (48) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-Methoxycyclopentyl]amino]-1 H -Imidazol-5-one, (49) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (50) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (51) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 S )-2-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (52) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S ,2 R )-2-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (53) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (54) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (55) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -3-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (56) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -3-hydroxycyclohexyl]amino]-1 H -Imidazol-5-one, (57) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[( trans [-4-hydroxycyclohexyl)amino]-1 H -Imidazol-5-one, (58) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-Methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (59) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-Methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (60) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[( trans -4-Methoxycyclohexyl)amino]-1 H -Imidazol-5-one, (61) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-Hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (62) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-Hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (63) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (64) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (65) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -3-hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (66) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -3-hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (67) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-Methoxycycloheptyl]amino]-1 H -Imidazol-5-one, (68) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-Methoxycycloheptyl]amino]-1 H -Imidazol-5-one, (69) (2 S )-2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H Methyl methyl imidazolium-2-yl]amino]-3-methyl-butyrate (70) (2 S )-2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H Methyl imidazole-2-yl]amino]propionate (71) (2 S )-2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H Methyl 2-imidazolium-2-yl]amino]-4-methylvalerate (72) (2 R )-2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H Methyl 2-imidazolium-2-yl]amino]-4-methylvalerate (73) (2 S )-2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H Methyl methyl imidazole-2-yl]amino]-3-hydroxy-butyrate (75) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(indan-2-ylamino)-1 H -Imidazol-5-one, (76) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,4-dimethylphenyl)methylamino]-1 H -Imidazol-5-one, (77) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2,4-dimethylphenyl)methylamino]-1 H -Imidazol-5-one, (78) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1 H -Imidazol-5-one, (79) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[2-(trifluoromethoxy)phenyl]methylamino]-1 H -Imidazol-5-one, (80) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-hydroxyindene-1-yl]amino]-1 H -Imidazol-5-one, (81) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-hydroxyindene-1-yl]amino]-1 H -Imidazol-5-one, (82) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 R )-2-hydroxyindene-1-yl]amino]-1 H -Imidazol-5-one, (83) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S ,2 S )-2-hydroxyindene-1-yl]amino]-1 H -Imidazol-5-one, (84) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -2-Methoxyindane-1-yl]amino]-1 H -Imidazol-5-one, (85) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -2-Methoxyindane-1-yl]amino]-1 H -Imidazol-5-one, (86) (2 S )-2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H Methyl imidazolium-2-yl]amino]-3-phenyl-propionate (87) (2 R )-2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H Methyl imidazolium-2-yl]amino]-3-phenyl-propionate (88) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-fluoro-1-phenyl-ethyl)amino]-1 H -Imidazol-5-one, (89) (±)-(4 Z )-2-[(2-amino-1-phenyl-ethyl)amino]-4-(1,3-benzothiazolyl-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride, (90) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[2-(methylamino)-1-phenyl-ethyl]amino]-1 H -Imidazole-5-one dihydrochloride, (91) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[2-(dimethylamino)-1-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (92) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-benzyl-2-hydroxy-ethyl)amino]-1 H -Imidazol-5-one, (93) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-Benzyl-2-hydroxy-ethyl]amino]-1 H -Imidazol-5-one, (94) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-benzyl-2-methoxy-ethyl)amino]-1 H -Imidazol-5-one, (95) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-hydroxy-1-phenyl-ethyl)amino]-1 H -Imidazol-5-one, (96) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-2-hydroxy-1-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (97) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S )-2-hydroxy-1-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (98) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-methoxy-1-phenyl-ethyl)amino]-1 H -Imidazol-5-one, (99) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-hydroxy-2-phenyl-ethyl)amino]-1 H -Imidazol-5-one, (100) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-methoxy-2-phenyl-ethyl)amino]-1 H -Imidazol-5-one, (101) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-hydroxy-3-phenyl-propyl)amino]-1 H -Imidazol-5-one, (102) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-methoxy-3-phenyl-propyl)amino]-1 H -Imidazol-5-one, (103) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(5-methylpyrazine-2-yl)methylamino]-1 H -Imidazol-5-one, (104) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(2-pyridylmethylamino)-1 H -Imidazol-5-one, (105) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(3-pyridylmethylamino)-1 H -Imidazol-5-one, (106) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-pyridylmethylamino)-1 H -Imidazol-5-one, (107) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(5-methyl-2-furanyl)methylamino]-1 H -Imidazol-5-one, (108) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(4-methylthiazol-2-yl)methylamino]-1 H -Imidazol-5-one, (109) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(3-imidazol-1-ylpropylamino)-1 H -Imidazol-5-one, (110) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[2-(2-pyridyl)ethylamino]-1 H -Imidazol-5-one, (111) (4 Z )-2-(1,3-benzothiazol-2-ylmethylamino)-4-(1,3-benzothiazol-6-ylmethylene)-1 H -Imidazol-5-one, (112) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-4-piperidinyl)methylamino]-1 H -Imidazol-5-one, (113) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1 H -Imidazol-5-one, (114) 4-[[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H tert-butyl [imidazol-2-yl]amino]methyl]piperidine-1-carboxylate (115) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(7-methyl-7-azaspiro[3.5]non-2-yl)amino]-1 H -Imidazol-5-one, (116) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(3-fluoro-4-methyl-aniline)-1 H -Imidazol-5-one, (117) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-fluoroaniline)-1 H -Imidazol-5-one, (118) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-hexylaniline)-1 H -Imidazol-5-one, (119) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1 H -Imidazol-5-one, (120) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[3-(difluoromethoxy)anilino]-1 H -Imidazol-5-one, (121) (4 Z )-2-[(1-acetylindoline-6-yl)amino]-4-(1,3-benzothiazo-6-ylmethylene)-1 H -Imidazol-5-one, (122) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[3-(trifluoromethyl)aniline]-1 H -Imidazol-5-one, (123) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(inden-5-ylamino)-1 H -Imidazol-5-one, (124) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(4-morpholinoaniline)-1 H -Imidazol-5-one, (125) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-methylindazol-7-yl)amino]-1 H -Imidazol-5-one, (126) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(pyrimidin-2-ylamino)-1 H -Imidazol-5-one, (127) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(2-pyridylamino)-1 H -Imidazol-5-one, (128) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(1-methylpyrazol-3-yl)amino]-1 H -Imidazol-5-one, (129) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2-methoxy-6-methyl-3-pyridyl)amino]-1 H -Imidazol-5-one, (130) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(pyrimidin-5-ylamino)-1 H -Imidazol-5-one, (131) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(3-pyridylamino)-1 H -Imidazol-5-one, (132) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(1,3,4-thiadiazol-2-ylamino)-1 H -Imidazol-5-one, (133) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[5-(4-methylpiperazin-1-yl)-2-pyridyl]amino]-1 H -Imidazol-5-one, (134) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[6-(4-methylpiperazin-1-yl)-3-pyridyl]amino]-1 H -Imidazol-5-one, (135) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]amino]-1 H -Imidazol-5-one, (136) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino]-1 H -Imidazol-5-one, (137) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]amino]-1 H -Imidazol-5-one, (138) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino]-1 H -Imidazol-5-one, (139) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(tetrahydropyran-4-ylamino)-1 H -Imidazol-5-one, (140) 4-[[(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H tert-butyl 1-imidazol-2-yl]amino]piperidine-1-carboxylate (141) 4-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H ethyl imidazol-2-yl]amino]piperidine-1-carboxylate (142) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-4-piperidinyl)amino]-1 H -Imidazol-5-one, (143) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-3-piperidinyl)amino]-1 H -Imidazol-5-one, (144) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(oxecyclobutane-3-ylamino)-1 H -Imidazol-5-one, (145) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R )-Tetrahydrofuran-3-yl]amino]-1 H -Imidazol-5-one, (146) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 S )-Tetrahydrofuran-3-yl]amino]-1 H -Imidazol-5-one, (147) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R )-Tetrahydropyran-3-yl]amino]-1 H -Imidazol-5-one, (148) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 S )-Tetrahydropyran-3-yl]amino]-1 H -Imidazol-5-one, (149) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-1 H -Imidazol-5-one, (149A). (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R ) / (3 S )-6,6-dimethyltetrahydropyran-3-yl]amino]-1 H -Imidazol-5-one, (149B). (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R ) / (3 S )-6,6-dimethyltetrahydropyran-3-yl]amino]-1 H -Imidazol-5-one, (150) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R 4 R )-4-hydroxytetrahydropyran-3-yl]amino]-1 H -Imidazol-5-one, (151) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(oxecycloheptane-3-ylamino)-1 H -Imidazol-5-one, (152) (±)-3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]piperidin-2-one (153) (3 S )-3-[[(4Z)-4-(1,3-benzothiazol-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]piperidin-2-one (154) (5 S )-5-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]piperidin-2-one (155) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,3-difluorocyclopentyl)amino]-1 H -Imidazol-5-one, (156) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(4,4-difluorocyclohexyl)amino]-1 H -Imidazol-5-one, (157) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(3,3-difluorocyclohexyl)amino]-1 H -Imidazol-5-one, (158) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[(2,2-difluorocyclohexyl)amino]-1 H -Imidazol-5-one, (159) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,3-difluorocycloheptyl)amino]-1 H -Imidazol-5-one, (160) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (161) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S )-1-(fluoromethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (162) Acetic acid [3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H [-imidazol-2-yl]amino]-1-adamantyl] ester, (163) 2,2-Dimethylpropionic acid [3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H [-imidazol-2-yl]amino]-1-adamantyl] ester, (164) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 R )-2-methoxycyclopentyl]amino]-1 H -Imidazol-5-one, (165) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S ,2 S )-2-methoxycyclopentyl]amino]-1 H -Imidazol-5-one, (166) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,2 R )-2-methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (167) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S ,2 S )-2-methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (168) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -3-Methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (169) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -3-Methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (169A). (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,3 R ) / (1 S ,3 S )-3-methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (169B). (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R ,3 R ) / (1 S ,3 S )-3-methoxycyclohexyl]amino]-1 H -Imidazol-5-one, (170) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -4-Hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (171) (±)-(4Z)-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -4-Hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (171A). (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R 4 R ) / (1 S 4 S )-4-hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (171B). (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R 4 R ) / (1 S 4 S )-4-hydroxycycloheptyl]amino]-1 H -Imidazol-5-one, (172) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -3-Methoxycycloheptyl]amino]-1 H -Imidazol-5-one, (173) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -3-Methoxycycloheptyl]amino]-1 H -Imidazol-5-one, (174) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ Cis -4-Methoxycycloheptyl]amino]-1 H -Imidazol-5-one, (175) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[ trans -4-Methoxycycloheptyl]amino]-1 H -Imidazol-5-one, (176) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-2-methoxy-1-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (177) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 S )-2-methoxy-1-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (178) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(2 R )-2-hydroxy-2-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (179) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(2 S )-2-hydroxy-2-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (180) (4 Z )-2-[[(1 R [-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazolyl-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride, (181) (4 Z )-2-[[(1 S [-2-amino-1-phenyl-ethyl]amino]-4-(1,3-benzothiazolyl-6-ylmethylene)-1 H -Imidazole-5-one dihydrochloride, (182) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R )-quinine ring-3-yl]amino]-1 H -Imidazol-5-one, (183) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 S )-quinine ring-3-yl]amino]-1 H -Imidazol-5-one, (184) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-(tetrahydrothiaran-3-ylamino)-1 H -Imidazol-5-one, (185) (±)-(4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-(1,4-dioxane-6-ylamino)-1 H -Imidazol-5-one, (186) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(2-oxopyrrolidine-3-yl)amino]-1 H -Imidazol-5-one, (187) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1-methyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazol-5-one, (188) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(4,4-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazol-5-one, (189) (3 R )-3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]piperidin-2-one (190) (±)-3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]-1-methyl-piperidin-2-one, (191) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-methyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazol-5-one, (192) (±)-(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(1,3-dimethyl-2-oxo-pyrrolidine-3-yl)amino]-1 H -Imidazol-5-one, (192A). (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R ) / (3 S )-1,3-Dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1 H -Imidazol-5-one, (192B). (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 R ) / (3 S )-1,3-Dimethyl-2-oxo-pyrrolidine-3-yl]amino]-1 H -Imidazol-5-one, (193) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[(3 S 4 S )-4-hydroxytetrahydropyran-3-yl]amino]-1 H -Imidazol-5-one, (194) (4 Z )-2-(3-noradamantylamino)-4-(1,3-benzothiazo-6-ylmethylene)-1 H -Imidazol-5-one, (195) N -tert-butylcarbamate[3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H [-imidazol-2-yl]amino]-1-adamantyl] ester, (196) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-1 H -Imidazol-5-one, (197) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(tert-butoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (198) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-2-tert-butoxy-1-phenyl-ethyl]amino]-1 H -Imidazol-5-one, (199) N -[3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]-1-adamantyl]acetamide, (200) N -[3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]-1-adamantyl]cyclopropaneformamide, (201) N -[3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]-1-adamantyl]methanesulfonamide, (202) N -[3-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H -imidazol-2-yl]amino]-1-adamantyl]cyclopropanesulfonamide, (203) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[[3-(dimethylamino)-1-adamantyl)amino]-1 H -Imidazol-5-one, (204) 2-[[(4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-5-oxo-1 H methyl imidazol-2-yl]amino]adamantane-2-carboxylate (205) (4 Z )-2-(cyclohexylamino)-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1 H -Imidazol-5-one, (206) (4 Z )-2-(cycloheptylamino)-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1 H -Imidazol-5-one, (207) (4 Z )-2-[[(1 R )-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1 H -Imidazol-5-one, (208) (4 Z )-2-[[(1 R [(2-methyl-1,3-benzothiazo-6-yl)methylene]-1 H -Imidazol-5-one, (209) (4 Z )-2-(1-adamantylamino)-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1 H -imidazol-5-one, and (210) (4 Z )-2-[(3-hydroxy-1-adamantyl)amino]-4-[(2-methyl-1,3-benzothiazo-6-yl)methylene]-1 H -Imidazol-5-one, (211) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,5-dihydroxy-1-adamantyl)amino]-1 H -Imidazol-5-one, (212) (4 Z )-4-(1,3-benzothiazo-6-ylmethylene)-2-[(3,5,7-trifluoro-1-adamantyl)amino]-1 H -Imidazol-5-one, (213) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(ethoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (214) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(benzyloxymethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (215) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-[(4-fluorophenyl)methoxymethyl]-3-methyl-butyl]amino]-1 H -Imidazol-5-one, (216) (4 Z )-4-(1,3-benzothiazol-6-ylmethylene)-2-[[(1 R )-1-(cyclopropoxymethyl)-3-methyl-butyl]amino]-1 H -Imidazol-5-one, Or any of their pharmaceutically acceptable salts.

12. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a compound as defined in claim 11 or a pharmaceutically acceptable salt thereof.

13. A method of synthesis for preparing any one of the compounds of formula (I) as defined in any one of claims 1 to 10 or any one of the pharmaceutically acceptable salts thereof, or any one of the compounds of formula (II) as defined in claim 11 or any one of the pharmaceutically acceptable salts thereof, comprising at least causing a compound of formula (II) to react with formula R. 1 The steps of amine coupling of NH2, Where Alk is a (C1-C5) alkyl group, Where R 1 and R 2 As defined in any one of claims 1 to 10.

14. A synthetic intermediate of formula (II) Alk is a (C1-C5) alkyl group, which does not include any compounds. And R 2 As defined in any one of claims 1 to 10.

15. Use of any compound of formula (I) as defined in any one of claims 1 to 10, or at least any compound as defined in claim 11, or any pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment and / or prevention of diseases selected from: cognitive deficits associated with Down syndrome; Alzheimer's disease and related diseases; dementia; tau proteinosis; Parkinson's disease; Pick's disease; CDKL5 deficiency disorder; McDermead syndrome; autism; type 1 and type 2 diabetes; abnormal folic acid and methionine metabolism; osteoarthritis; Duchenne muscular dystrophy; cancer; viral infections; neuroinflammation; anemia; infections caused by single-celled parasites and bovine diseases caused by single-celled pathogens; and for the regulation of body temperature.

16. Use of any compound of formula (I) as defined in any one of claims 1 to 10, or at least any compound as defined in claim 11, or any pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment and / or prevention of diseases selected from: cognitive deficits associated with Down syndrome; Alzheimer's disease and related diseases; dementia; tau proteinosis; Parkinson's disease; Pick's disease; CDKL5 deficiency disorder; McDermead syndrome; autism; type 1 and type 2 diabetes; abnormal folic acid and methionine metabolism; knee osteoarthritis; Duchenne muscular dystrophy; brain cancer. Leukemia, squamous cell carcinoma of the head and neck, pancreatic cancer, prostate cancer, gastrointestinal cancer, breast cancer, tissue cancer, Hedgehog / GLI-dependent cancer, liver cancer, and viral infections caused by human immunodeficiency virus type 1, human cytomegalovirus, influenza A, herpesvirus, rhesus monkey cytomegalovirus, varicella-zoster virus, herpes simplex virus, hepatitis C virus, chikungunya virus, dengue virus, influenza virus and severe acute respiratory syndrome coronavirus, cytomegalovirus and human papillomavirus; neuroinflammation; anemia; malaria, leishmaniasis, Chagas disease and sleeping sickness, and bovine diseases caused by single-celled pathogens; and for regulating body temperature.

17. Use of any compound of formula (I) according to any one of claims 1 to 10 or any pharmaceutically acceptable salt thereof, or at least any compound as defined in claim 11 or any pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment and / or prevention of diseases selected from: Down syndrome, Alzheimer's disease, dementia, tau protein disease, Parkinson's disease, Niemann-Pick type C disease, CDKL5 deficiency disorder, and Ferenc-McDermid syndrome and related cognitive and motor disorders, as well as type 1 and type 2 diabetes.

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