Imidazolone Derivatives as Inhibitors of Protein Kinases, Particularly DYRK1A, CLK1 and / or CLK4

Abstract

The present invention relates to a compound of formula (I) below, or any one of its pharma- ceutically acceptable salts: [Formula 1] JPEG2024540217000251.jpg24170, where R 1 is a (C4-C6) alkyl group, a (C3-C8) cycloalkyl group, a bridged C6-C 10 ) a cycloalkyl group, a fused phenyl group, a substituted phenyl group, an R'-L- group (wherein L is either a single bond or a (C1-C3)alkanediyl group, and R' represents a (C3-C8)heterocycloalkyl group or a (C3-C8)heteroaryl group), or an R''-L- group (wherein L is a (C1-C3)alkanediyl group, and R'' may be a substituted phenyl group); R 2 is selected from the group consisting of a hydrogen atom and a (C1-C3) alkyl group; R 5 represents a hydrogen atom, a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group. The present invention further relates to compositions comprising the compounds of formula (I) and to processes for producing said compounds, as well as to synthetic intermediates thereof. The present invention also relates to said compounds for use as medicines, in particular for use in the treatment and / or prevention of cognitive disorders and neuroinflammation associated with Down's syndrome; Alzheimer's disease; dementia; tauopathies; Parkinson's disease; CDKL5 deficiency; Phelan-McDermid syndrome; autism; type 1 and type 2 diabetes; folate and methionine metabolic disorders; osteoarthritis and tendinopathy; Duchenne muscular dystrophy; cancer and leukemia; neuroinflammation, anemia, infections caused by single-cell parasites, viral infections, and for thermoregulation.

Description

[Technical field]

[0001] The present invention relates to a class of novel compounds useful as pharmaceuticals, Leucettinib. The novel compounds are particularly useful as kinase inhibitors, more particularly as inhibitors of DYRK1A and / or CLK1 and / or CLK4. The novel compounds are effective for treating and / or preventing cognitive impairment associated with Down's syndrome; Alzheimer's disease and related diseases; dementia; tauopathies; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency; diabetes mellitus type 1 and type 2; folate and methionine metabolic disorders; osteoarthritis and tendon disorders; Duchenne muscular dystrophy; some cancers and leukemias; viral infections; and for regulating body temperature. [Background technology]

[0002] Some of the above compounds are further inhibitors of other kinases, namely other DYRKs (DYRK1B, 2, 3, 4) and the closely related cdc2-like kinases (CLKs) (CLKs 2, 3, 4).The above compounds may then be further effective for treating and / or preventing Phelan-McDermid syndrome; autism; viral infections, cancer, neuroinflammation, anemia, and infections caused by single-cell parasites.

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

[0004] The DYRK and CLK kinase families belong to the CMGC kinase group, which includes mitogen-activated protein kinases (MAPKs), cyclin-dependent kinases (CDKs), and glycogen synthase kinase-3 (GSK-3). They phosphorylate many substrates involved in signal transduction pathways. DYRKs and CLKs play important 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 (for review, see Lindberg, M. and Meijer, L., 2021. Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) in human disease, an overview. Internat. J. Mol. Sci. 22, 6047).

[0005] DYRK1A and Down syndrome (DS)

[0006] The gene encoding DYRK1A is located on chromosome 21, specifically in the "Down syndrome critical region" (DSCR), and its triploidy is responsible for most of the disorders associated with DS. There is considerable genetic and pharmacological evidence indicating that a mere 1.5-fold overexpression of DYRK1A is causative for most of the cognitive impairments observed in DS patients, particularly memory and learning disorders (Feki, A., Hibaoui, Y., 2018. DYRK1A protein, a promising therapeutic target to improve cognitive deficits in Down syndrome. Brain Sci. 8, 187; Rueda N et al., 2020. Translational validity and implications of pharmacotherapies in preclinical models of Down syndrome. Prog Brain Res 251, 245). Pharmacological or genetic normalization of DYRK1A levels restores cognitive function (Nguyen TL et al., 2017. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature. Expert Opin. Ther. Pat. 27, 1183-1199; Nguyen TL et al., 2018. Correction of cognitive deficits in mouse models of Down syndrome by pharmacological inhibitor of DYRK1A. Dis. Model Mech. 11, dmm035634).

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

[0008] Increasing evidence implicates DYRK1A in the pathogenesis of AD. DYRK1A phosphorylates key substrates involved in AD and dementia: Tau, septin 4, amyloid precursor protein (APP), presenilin 1, neprilysin, Munc18-1, α-synuclein, RCAN1, and β-tubulin. There is evidence for aberrant expression and post-translational modification of DYRK1A in AD. By regulating alternative splicing of exon 10, DYRK1A promotes the production of 3R-tau isoforms (characteristic for DS / AD / tauopathy) over normal 4R-tau isoforms. Inhibition of DYRK1A promotes autophagy and may counteract the autophagy defects seen in AD. There is a clear association between AD and DS (Fortea J. et al., 2021. Alzheimer's disease associated with Down syndrome: a genetic form of dementia. The Lancet 20, 930-942): Most DS patients show AD neuropathology early (in their 40s) and a high prevalence of dementia in later stages (over 60 years of age).

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

[0010] GWAS studies have revealed that DYRK1A is a risk factor for PD (Nalls MA et al.,2019. Identification of novel risk loci, causal insights,and heritable risk for Parkinson's disease:a meta-analysis of genome-wide association studies. Lancet Neurol 18,1091). DYRK1A phosphorylates key factors for PD, such as Parkin, 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). There is further evidence that DYRK1A expression is increased in PD. DYRK1A is overexpressed in Pick's disease.

[0011] DYRK1A and viral infections

[0012] DYRK1A and DYRK1B are utilized during placental replication of HCMV. Inhibition of DYRK blocks the replication of various viruses, including those mentioned above, including herpesvirus, cytomegalovirus, and HIV-1.

[0013] DYRK1A and Type 1 and Type 2 Diabetes

[0014] DYRK1A inhibitors stimulate the proliferation of insulin-producing beta cells in the pancreas. This is a promising approach for both type 1 diabetes (low number of beta cells) and type 2 diabetes (beta cell mass halved) (Ackeifi C et al.,2020.Pharmacologic and genetic approaches define human pancreatic beta cell mitogenic targets of DYRK1A inhibitors.JCI Insight 5,e132594;Kumar K et al.,2021.DYRK1A inhibitors as potential therapeutics for beta-cell regeneration for diabetes.J Med Chem 64,2901-2922.Barzowska A,et al.,2021.DYRK1A kinase inhibitors promote beta-cell survival and insulin homeostasis.Cells.10,2263;Wang P et al.,2021.Human beta cell regenerative drug therapy for diabetes: past achievements and future challenges.Front Endocrinol 12,671946). Besides being administered directly to diabetic patients, DYRK1A inhibitors could potentially be administered to stimulate β-cell proliferation in vitro or ex vivo to increase β-cell mass prior to transplantation.

[0015] DYRK1A, Cancer and Leukemia

[0016] There is a wealth of literature linking DYRK1A to cancer, most notably in megakaryoblastic leukemia (Malinge S et al.,2012. Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.J Clin Invest 122,948-962), acute lymphoblastic leukemia (Bhansali RS et al.,2021. DYRK1A regulates B cell Acute Lymphoblastic Leukemia through phosphorylation of FOXO1 and STAT3.J Clin Investig,131,e135937), pancreatic cancer, and brain tumors (glioblastoma) (see above, review in Lindberg and Meijer,2021).

[0017] Thus, abnormalities in DYRK1A dosage are associated with cognitive impairments observed in Down's syndrome and Alzheimer's disease. DYRK1A is a risk factor for Parkinson's disease. Inhibition of DYRK1A also triggers the proliferation of insulin-producing β-cells in the pancreas. Thus, DYRK1A inhibitors may find application in the prevention and / or treatment of DS, AD and other tauopathies (particularly the cognitive impairments associated with these conditions), dementia, PD, Niemann-Pick disease type C, CDKL5 deficiency, type 1 and type 2 diabetes, viral infections, some cancers (leukemia, pancreatic cancer, glioblastoma), tendon disorders and osteoarthritis, infections caused by single-cell parasites, and for thermoregulation.

[0018] Other DYRKs and Human Diseases

[0019] DYRK1B is involved in the replication of various viruses, including the above-mentioned various viruses, including Hepatitis C virus, Chikungunya virus, Dengue virus, SARS coronavirus, cytomegalovirus and human papillomavirus.Similar to DYRK1A, inhibition of DYRK1B leads to proliferation of insulin-producing beta cells in the pancreas.DYRK1B is involved in neuroinflammation.Targeting DYRK1B provides a new rationale for the treatment of various cancers, such as liposarcoma or breast cancer.

[0020] DYRK2 regulates neuronal morphogenesis in association with GSK-3β, and is involved in various ways in cancer progression.

[0021] DYRK3 promotes hepatocellular carcinoma. DYRK3 links stress granule condensation / dissolution to mTORC1 signaling. DYRK3 controls the phase transition of membrane-free organelles in mitosis. DYRK3 and DYRK4 are involved in the regulation of cytoskeletal organization and process outgrowth in neurons.

[0022] DYRK1A reduces axonal growth, DYRK3 and DYRK4 increase dendritic branching, and DYRK2 reduces both axonal and dendritic growth and branching.

[0023] CLK and human diseases

[0024] It should be noted that CLK is a confusing abbreviation because it represents: (a) the monooxygenase CLK-1 (human homolog COQ7); (b) the multifunctional Ca(2+)-dependent lectin Collectin-K1 (CL-K1 or CL-11); (c) the MAPK gene Clk1 of the corn pathogen Curvularia lunata; (d) the mitochondrial membrane-bound enzyme Clock-1 (CLK-1); and (e) Colletotrichum lindemuthianum kinase 1 (clk1).

[0025] CLK plays an important role in alternative splicing. CLK acts as a body temperature sensor that globally controls alternative splicing and gene expression. CLK activity is in fact highly sensitive to physiological temperature changes, which is brought about by structural changes within the kinase activation segment (Haltenhof T et al.,2020. A conserved kinase-based body-temperature sensor globally controls alternative splicing and gene expression.Mol Cell 78,57).

[0026] CLK1 and human diseases

[0027] CLK1 triggers cyclic alternative splicing during the cell division cycle. CLK1 controls influenza A virus mRNA splicing, and its inhibition blocks viral replication. CLK1 and CLK2 also control HIV-1 gene expression. CLK1 is an autophagy inducer. Inhibition of CLK1 may prevent chemotherapy resistance in gliomas, and inhibition of CLK1 by TG693 allows skipping of the mutated exon 31 of the dystrophin gene in Duchenne Muscular Dystrophy.

[0028] Other CLKs and human diseases

[0029] Inhibition of CLK2 has been proposed as a way to improve neurological function and combat intellectual disability and autism in Phelan-McDermid syndrome (PMDS). Dual inhibition of CLK2 and DYRK1A with Lorecivivint is a potential disease-modifying approach for knee osteoarthritis. CLK2 inhibition exacerbates MYC-driven breast cancer, triple-negative breast cancer and glioblastoma. Inhibition of CLK2 ameliorates autistic features in Phelan-McDermid syndrome (PMDS). Alternative splicing of tau exon 10 is regulated by CLK2 and other CLKs, leading to changes in the 3R / 4R isoform ratio and neurodegeneration in sporadic AD. Inhibition of CLK2, CLK3 and CLK4 inhibits HIV-1 production. By controlling alternative splicing, CLKs regulate the balance between pro- and anti-apoptotic regulators, and inhibition of CLKs may find application in the treatment of many cancers, particularly prostate and hepatocellular carcinoma.

[0030] Table 1 below summarizes the involvement of DYRK and CLK kinases in various diseases.

[0031] [Table 1] JPEG2024540217000003.jpg104170

[0032] DYRK and CLK inhibitors

[0033] Several DYRK1A inhibitors have been reported in recent years, and most of them also inhibit DYRK1B, 2, 3, and 4, as well as the closely related CLK1, 2, 3, and 4, allowing for several possible inhibitory profiles.

[0034] Certain imidazolone derivatives, named infra as Leucettines, have been disclosed in WO 2009 / 050352 as kinase inhibitors, more particularly as inhibitors of DYRK1A kinase.

[0035] WO2021 / 114314 and WO2021 / 115489 disclose useful compounds having cardiomyocyte proliferation activity for the treatment of cardiac diseases. However, these documents are exemplified in a very partial manner and include a very wide range of compounds focusing on benzothiazole derivatives (i.e., in the context of the present invention, A= =C- and B= -S-). In other words, none of the disclosed compounds can be considered to include the formula (I) of the present invention. Moreover, the compounds disclosed in these applications do not have optimized activity with respect to DYRK1A and CLK1 and are not directed to the pathologies defined hereinafter. Summary of the Invention [Problem to be solved by the invention]

[0036] There remains a need to identify novel compounds for treating and / or preventing such diseases, particularly through inhibition, particularly selective inhibition, of DYRK1A, other DYRK and related CLK kinases. Example 13 herein further provides comparative biological data showing the superiority of the biological activity of the claimed compounds with respect to the closest compounds (C1-C5) of WO2021 / 114314. [Means for solving the problem]

[0037] The compounds defined herein below as formula (I) have been found to be useful in the treatment and / or prevention of diseases selected from cognitive impairment and neuroinflammation associated with Down's syndrome, Alzheimer's disease and related diseases, dementias and tauopathies; Parkinson's disease; and other neurodegenerative diseases; CDKL5 deficiency; Phelan-McDermid syndrome; autism; type 1 and type 2 diabetes; folate and methionine metabolic disorders; osteoarthritis and tendon disorders; some cancers and leukemias, neuroinflammation, anemia, infections caused by single-celled parasites, viral infections and for thermoregulation.

[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 for use as a medicament.

[0040] The present invention further relates to compounds of formula (I) for use in the treatment and / or prevention of diseases selected from cognitive impairment and neuroinflammation associated with Down's syndrome, Alzheimer's disease and related diseases, dementia or tauopathies; Parkinson's disease; other neurodegenerative diseases; CDKL5 deficiency; Phelan-McDermid syndrome; autism; type 1 and type 2 diabetes; folate and methionine metabolism disorders; osteoarthritis and tendon disorders; some cancers and leukemias, neuroinflammation, anemia, infections caused by single-celled parasites, viral infections, and for thermoregulation.

[0041] The present invention further relates to pharmaceutical compositions comprising the compounds of formula (I) and processes for preparing the compounds of formula (I).

[0042] The invention finally describes synthesis intermediates of formula (III) and formula (IX) as defined below, as well as relates to a synthesis intermediate of formula (XI) as defined below.

[0043] definition

[0044] As used herein, the term "patient" refers to either an animal, e.g., a valuable animal for breeding, mating or conservation purposes, or, preferably, a human or human child, suffering from or susceptible to one or more of the diseases and conditions described herein.

[0045] In particular, as used herein, the term "patient" refers to a mammal, such as a rodent, cat, dog, primate, or human, preferably the subject is a human, and also extends to birds.

[0046] Identification of those patients in need of treatment for the diseases and conditions described herein is within the ability and knowledge of one of ordinary skill in the art. A veterinarian or physician of ordinary skill in the art can readily identify patients in need of such treatment through clinical tests, physical examination, medical / family history, or the use of biological and diagnostic tests.

[0047] In the context of the present invention, the term "treat" or "treatment", as used herein, means the prevention, reversal, mitigation, slowing of progression, or prevention of diseases and their cognitive, motor or metabolic changes resulting from high expression and activity of DYRK1A kinase and / or CLK1, optionally associated with abnormalities in other DYRKs (DYRK1B, 2, 3, 4) and further closely related cdc2-like kinases (CLKs) (CLK2, 3, 4), more particularly associated with diseases described in the "Pathological Conditions" paragraph and following herein.

[0048] Therefore, the term "treat" or "treatment", within the framework of the present invention, includes the improvement of the pathology of patients suffering from diseases associated with high expression and activity of either DYRK1A and CLK1 kinases, and optionally with abnormalities of other DYRKs (DYRK1B, 2, 3, 4) and further closely related cdc2-like kinases (CLKs) (CLK2, 3, 4), as described herein starting from the paragraph "Pathological Conditions".

[0049] As used herein, "effective amount" refers to an amount of a compound of the present invention that is effective in preventing, alleviating, eliminating, treating or controlling the diseases and conditions described herein.

[0050] The term "control" is intended to refer to any process that may slow, interrupt, halt or stop the progression of the diseases and conditions described herein, but does not necessarily indicate the complete elimination of all disease and condition symptoms, and is intended to encompass preventative treatment.

[0051] The term "effective amount" encompasses a "prophylactically effective amount" and a "therapeutically effective amount."

[0052] As used herein, the term "prevent" means reducing the risk of developing or delaying the onset of a disease caused by a given phenomenon, i.e., in this invention, abnormal DYRK / CLK kinase activity, in particular DYRK1A kinase activity.

[0053] As used herein, the term "prevention" also encompasses "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0054] The term "prophylactically effective amount" refers to a concentration of a compound of the present invention effective in inhibiting, preventing, or reducing the likelihood of any of the diseases listed above.

[0055] Similarly, the term "therapeutically effective amount" refers to a concentration of a compound that is effective in treating the above-mentioned diseases, e.g., when administered after the disease has developed, results in a reduction or normalization of DYRK1A and / or CLK1 kinase activity, and optionally, DYRK / CLK kinase activity in general, after testing.

[0056] As used herein, the term "pharmaceutical acceptable" refers to compounds, materials, excipients, compositions or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit / risk ratio. Effect of the Invention

[0057] The present inventors have surprisingly found that compounds of formula (I) disclosed herein below inhibit DYRK1A, other DYRKs (DYRK1B, DYRK2, DYRK3, DYRK4) and CLKs (CLK1, CLK2, CLK3, CLK4), and this assertion is based on the data presented in the Examples below and in more detail hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] According to a first aspect, the subject of the present invention relates to a compound of formula (I) below, or any one of its pharma- ceutically acceptable salts, [ka] Where: A is =CH-, -N= and -NR 3 - selected from the group consisting of B is -O-, ═CH-, ═N-, -NH-, -S-, or -NR 4 - selected from the group consisting of At least one of A and B is ═CH— or —S—; A and B cannot both represent =CH-; R 2 is selected from the group consisting of a hydrogen atom and a (C1-C3) alkyl group, or R 2 When the nitrogen atom to which R is bonded is -N=, 2 does not exist, R 3 and R 4 are independently selected from (C1-C3) alkyl groups; R 5represents a hydrogen atom, a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, and When A represents =CH- and B represents =N- or -NH-, R 2 each represents a hydrogen atom or is absent, and Here, R 1 represents the following (i), (ii), (iii), (iv), (v), (vi) or (vii): (i) a (C4-C6) alkyl group substituted by a group selected from a hydroxy group, a halogen atom, and a (C1-C3) alkoxy group; (ii) a (C3-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; (iii) a bridged (C6-C 10 ) a cycloalkyl group, (iv) a fused phenyl group selected from a phenyl group fused with a (C5-C6)cycloalkyl, wherein the (C5-C6)cycloalkyl is optionally substituted by a hydroxy group; (v) a phenyl group substituted by a (C4-C7)heterocycloalkyl group, wherein the (C4-C7)heterocycloalkyl group may itself be substituted by a (C1-C4)alkyl group; Or, (vi) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3)alkoxy group; and R' represents the following (vi.1) or (vi.2): (vi.1) a (C3-C8) heterocycloalkyl group optionally substituted by one or two groups selected from a hydroxy group and a (C1-C4) alkyl group, or (vi.2) a (C3-C8) heteroaryl group optionally substituted by a (C1-C4) alkyl group, Or, (vii) R″-L- group, where L is -NR b R c a (C1-C3)alkanediyl group optionally substituted by a group selected from a group, a (C1-C3)alkoxy group, and a hydroxy group, and R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group; Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0059] The expression "at least one of A and B is =CH--, and A and B cannot both represent =CH--" means that only one of A and B can be =CH--.

[0060] Expression “R 2 "does not exist" is R 2 This means that it is a lone pair.

[0061] The present inventors have surprisingly discovered that compounds having the following scaffolds (A) to (J) exhibit significantly reduced kinase inhibitory activity against DYRK1A and other related kinases compared to their congeners (compounds according to the present invention): IC 50 Values ​​were reduced 10- to 1000-fold, with some compounds being completely inactive at the highest dose tested (10 μM). [ka]

[0062] These significantly reduced kinase inhibitory activities have been verified, for example, by individual comparisons of compounds of formula (I) and compounds having scaffolds of formulas (A) through (J), where in both cases R 1is selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, 1-(hydroxymethyl)-3-methyl-butyl, 1-(methoxymethyl)-3-methyl-butyl, 2-methoxy-1-phenyl-ethyl, 3-noradamantyl, 1-adamantyl, 3-hydroxy-1-adamantyl, 3-fluoro-1-adamantyl; R 5 is selected from the group consisting of a methyl group or a hydrogen atom.

[0063] According to a particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the following (i), (ii), (iii), (iv), (v) or (vi): (i) a (C5-C6) alkyl group substituted by a group selected from a hydroxy group, a halogen atom, and a (C1-C3) alkoxy group; (ii) a (C5-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; (iii) a bridged (C9-C 10 ) a cycloalkyl group, (iv) a phenyl group fused to a cyclopentyl, the cyclopentyl being optionally substituted by a hydroxy group; (v) a phenyl group substituted by a (C4-C7)heterocycloalkyl group, wherein the (C4-C7)heterocycloalkyl group may itself be substituted by a (C1-C4)alkyl group; Or, (vi) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3)alkoxy group, and R' represents the following (vi.1) or (vi.2): (vi.1) a (C6-C7) heterocycloalkyl group optionally substituted by one or two groups selected from a hydroxy group and a (C1-C4) alkyl group, or (vi.2) a (C3-C8) heteroaryl group optionally substituted by a (C1-C4) alkyl group, Or, (vi) R″-L- group, where L is -NR b R c a (C1-C3)alkanediyl group optionally substituted by a group selected from a group, a (C1-C3)alkoxy group, and a hydroxy group, and R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group, and Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0064] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the following (i), (ii), (iii), (iv), (v), (vi) or (vii): (i) a (C5-C6) alkyl group substituted by a group selected from a hydroxy group, a fluorine atom, and a methoxy group; (ii) a (C5-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a methoxy group, in particular, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; (iii) a crosslinked (C9 to C12) alkyl group optionally substituted with a group selected from a methoxy group, a fluorine atom, and a hydroxy group; 10 ) cycloalkyl groups, in particular adamantyl or noradamantyl, (iv) a phenyl group fused to a cyclopentyl, wherein the cyclopentyl is substituted by a hydroxy group. (v) a phenyl group substituted by an N-methylpiperazinyl group; Or, (vi) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group optionally substituted by a group selected from a hydroxy group and a methoxy group; and R' is selected from the group consisting of (vi.1) and (vi.2) below: (vi.1) (C6-C7) heterocycloalkyl groups which may be substituted by one or two groups selected from a hydroxy group and a methyl group, in particular tetrahydropyranyl or oxepanyl, (vi.2) (C3-C8) heteroaryl groups optionally substituted by methyl groups, in particular pyridinyl or thiazolyl, Or, (vii) R″-L- group, where L is a -NH2 group, a methoxy group, a hydroxy group, a -COOR a a (C1-C3)alkanediyl group optionally substituted by a group selected from the group consisting of a group and a halogen atom, particularly a fluorine atom; and R'' is a phenyl group optionally substituted by a trifluoromethyl group.

[0065] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of its pharma- ceutically acceptable salts, wherein L is selected from the group consisting of the -CH-, -CH(CHOH)-, -CH(CHOCH)-, -CH(OH)-CH- and -CH(CHNH)- groups.

[0066] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of its pharma- ceutically acceptable salts, wherein (vi.1) when R' is a (C5-C8) heterocycloalkyl group, L is a -CH2- group, (vi.2) when R' is phenyl, L is selected from the group consisting of -CH-, -CH(CHOH)-, -CH(CHOCH)-, -CH(OH)-CH- and -CH(CHNH)- groups; (vi.3) When R' is a (C3-C8) heteroaryl group, L is a -CH2- group.

[0067] According to another particular embodiment, the present invention relates to a compound selected from the following compounds, or any one of their pharma- ceutically acceptable salts: [ka] Here, R 1 , R 2 , R 3 , R 4 and R 5 is as defined above.

[0068] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, in which R 1 represents the following (i), (ii), (iii), (iv) or (v): (i) a (C4-C6) alkyl group substituted by a group selected from a hydroxy group, a halogen atom, and a (C1-C3) alkoxy group; (ii) a (C3-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; (iii) a bridged (C6-C 10 ) a cycloalkyl group, Or, (iv) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3)alkoxy group; and R′ represents the following (iv.1) or (iv.2): (iv.1) a (C3-C8) heterocycloalkyl group optionally substituted by one or two groups selected from a hydroxy group and a (C1-C4) alkyl group, or (iv.2) a (C3-C8) heteroaryl group optionally substituted by a (C1-C4) alkyl group, Or, (v) R″-L- group, where L is -NR b R c a (C1-C3)alkanediyl group optionally substituted by a group selected from a group, a (C1-C3)alkoxy group, and a hydroxy group, and R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group; Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0069] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the following (i), (ii), (iii), (iv) or (v): (i) a (C4-C6) alkyl group substituted by a group selected from a hydroxy group, a halogen atom, and a (C1-C3) alkoxy group; (ii) a (C3-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; (iii) a bridged (C6-C 10 ) a cycloalkyl group, Or, (iv) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3)alkoxy group; and R′ represents the following (iv.1) or (iv.2): (iv.1) a (C3-C8) heterocycloalkyl group optionally substituted by one or two groups selected from a hydroxy group and a (C1-C4) alkyl group, or (iv.2) a (C3-C8) heteroaryl group optionally substituted by a (C1-C4) alkyl group, Or, (v) R″-L- group, where L is -NR b R c a (C1-C3)alkanediyl group optionally substituted by a group selected from a group, a (C1-C3)alkoxy group, and a hydroxy group, and R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group; Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0070] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the following (i), (ii), (iii), (iv) or (v): (i) a (C4-C6) alkyl group substituted by a group selected from a hydroxy group, a halogen atom, and a (C1-C3) alkoxy group; (ii) a (C3-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; (iii) a bridged (C6-C 10 ) a cycloalkyl group, Or, (iv) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3)alkoxy group; and R′ represents the following (iv.1) or (iv.2): (iv.1) a (C3-C8) heterocycloalkyl group optionally substituted by one or two groups selected from a hydroxy group and a (C1-C4) alkyl group, or (iv.2) a (C3-C8) heteroaryl group optionally substituted by a (C1-C4) alkyl group, Or, (v) R″-L- group, where L is -NR b R c a (C1-C3)alkanediyl group optionally substituted by a group selected from a group, a (C1-C3)alkoxy group, and a hydroxy group, and R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group; Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0071] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 5 represents a hydrogen atom or a (C1-C4) alkyl group.

[0072] According to another particular embodiment, the present invention relates to a compound of formula (Ia) below, or any one of its pharma- ceutically acceptable salts, [ka] Here, R 1 represents the following group: a (C5-C6) alkyl group substituted by a group selected from a hydroxy group and a methoxy group; (C5-C8) cycloalkyl groups optionally substituted by a group selected from a hydroxy group and a methoxy group, in particular cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; an adamantyl group optionally substituted by a group selected from a methoxy group and a hydroxy group; a phenyl group fused to a cyclopentyl, wherein the cyclopentyl is substituted by a hydroxy group; a phenyl group substituted by an N-methylpiperazinyl group; R'-L-group, where L is either a single bond or a methylene group, and R' is selected from the group consisting of: (C6-C7)heterocycloalkyl groups optionally substituted by one or two groups selected from a hydroxy group and a methyl group, in particular tetrahydropyranyl or oxepanyl, and (C3-C8) heteroaryl groups optionally substituted by methyl groups, particularly pyridyl or thiazolyl Or, R″-L-group, where L is a (C1-C2)alkanediyl group optionally substituted by a group selected from a hydroxy group and a methoxy group, and R″ is a phenyl group optionally substituted by trifluoromethyl, and R 5 is as defined above.

[0073] According to another particular embodiment, the present invention relates to a compound of formula (Ib) below, or any one of its pharma- ceutically acceptable salts, [ka] Here, R 1 represents the following group: a (C5-C6) alkyl group substituted by a group selected from a hydroxy group and a methoxy group; -cyclohexyl group, -adamantyl radical, a phenyl group substituted by an N-methylpiperazinyl group, or R″-L-group, where L is a methoxymethylmethylene group, and R″ is a phenyl group, and R 5 is as defined above.

[0074] According to another particular embodiment, the present invention relates to a compound of formula (Ic) below, or any one of its pharma- ceutically acceptable salts, [ka] Here, R 1 represents the following group: a (C5-C6) alkyl group substituted by a group selected from a hydroxy group and a methoxy group; cyclohexyl group, an adamantyl group optionally substituted by a group selected from a halogen atom and a hydroxy group; Or, R″-L-group, where L is a methoxymethylmethylene group, and R'' is a phenyl group; and, R 3 represents a methyl group, and R 5 is as defined above.

[0075] According to another particular embodiment, the present invention relates to a compound of formula (Id) below, or any one of its pharma- ceutically acceptable salts, [ka] Here, R 1 represents the following group: a (C5-C6) alkyl group substituted by a group selected from a hydroxy group, a methoxy group, and a fluorine atom; (C5-C8) cycloalkyl groups optionally substituted by a group selected from a hydroxy group and a methoxy group, in particular a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group; an adamantyl group optionally substituted by a group selected from a methoxy group, a hydroxy group, and a fluorine atom; a phenyl group fused to a cyclopentyl, wherein the cyclopentyl is substituted by a hydroxy group; Phenyl group substituted with N-methylpiperazinyl group, R'-L-group, where L is either a single bond or a methylene group, and R' is selected from the group consisting of (C6-C7)heterocycloalkyl groups optionally substituted by one or two groups selected from a hydroxy group and a methyl group, in particular tetrahydropyranyl or oxepanyl, and a (C3-C8)heteroaryl group optionally substituted by a methyl group, in particular a pyridyl group or a thiazolyl group; Or, R″-L-group, where L is a (C1-C2)alkanediyl group optionally substituted by a group selected from a hydroxy group, a methoxy group, and a -NH2 group, and R″ is a phenyl group optionally substituted by trifluoromethyl; And, here, R 2 represents a methyl group, and R 5is as defined above.

[0076] According to another particular embodiment, the present invention relates to a compound of formula (Ie) below, or any one of its pharma- ceutically acceptable salts, [ka] Here, R 1 represents the following group: a (C5-C6) alkyl group substituted by a group selected from a hydroxy group, a methoxy group, and a fluorine atom; (C5-C8) cycloalkyl groups optionally substituted by a group selected from a hydroxy group and a methoxy group, in particular cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; A crosslinked (C9-C 10 ) cycloalkyl groups, in particular adamantyl or noradamantyl, a phenyl group fused to a cyclopentyl, wherein the cyclopentyl is substituted by a hydroxy group; Phenyl group substituted with N-methylpiperazinyl group, R'-L-group, where L is either a single bond or a methylene group, and R' is selected from the group consisting of: (C6-C7)heterocycloalkyl groups optionally substituted by hydroxy groups, in particular tetrahydropyranyl or oxepanyl, and a (C3-C8)heteroaryl group optionally substituted by a methyl group, in particular a pyridinyl group or a thiazolyl group; Or, R″-L-group, where L is a (C1-C2)alkanediyl group optionally substituted by the group consisting of a hydroxy group, a methoxy group, and a -NH2 group, and R″ is a phenyl group optionally substituted by trifluoromethyl; and, R 5 is as defined above.

[0077] According to another particular embodiment, the present invention relates to a compound of formula (If) below, or any one of its pharma- ceutically acceptable salts, [ka] Here, R 1 represents the following group: a (C5-C6) alkyl group substituted by a group selected from a hydroxy group, a methoxy group, and a fluorine atom; (C6-C8) cycloalkyl groups, in particular cyclohexyl, cycloheptyl or cyclooctyl; A crosslinked (C9-C 10 ) cycloalkyl groups, in particular adamantyl or noradamantyl, - a phenyl group fused to a cyclopentyl, wherein the cyclopentyl is substituted by a hydroxy group, a phenyl group substituted by an N-methylpiperazinyl group; R'-L-group, where L is either a single bond or a methylene group, and R' is a (C3-C8) heteroaryl group optionally substituted by a methyl group, in particular pyridyl or thiazolyl; R a '-L- group, where L is a methylene group, and R a ' is a tetrahydropyranyl group, Or, R″-L-group, where L is a (C1-C2)alkanediyl group optionally substituted by a group selected from a hydroxy group, a methoxy group, and a -NH2 group, and R'' is a phenyl group optionally substituted by trifluoromethyl. And, here, R4 represents a methyl group, and R 5 is as defined above.

[0078] According to another particular embodiment, the present invention relates to a compound of formula (Ig) below, or any one of its pharma- ceutically acceptable salts, [ka] Here, R 1 represents the following group: (C5 to C6) substituted with a group selected from a hydroxy group, a methoxy group, and a fluorine atom; (C6-C8) cycloalkyl groups, in particular cyclohexyl or cycloheptyl; A crosslinked (C9-C 10 ) a cycloalkyl group, in particular adamantyl or noradamantyl.

[0079] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the following group: a (C4-C6) alkyl group substituted with a group selected from a hydroxy group, a halogen atom, and a (C1-C3) alkoxy; or a (C3-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; A bridged (C6-C 10 ) cycloalkyl groups.

[0080] This subgroup of compounds is collected under "A1" type compounds in Table 2 herein below.

[0081] Still according to this embodiment, R 1 may more particularly represent cyclohexyl, cycloheptyl, cyclooctyl, 1-adamantyl, 3-hydroxy-1-adamantyl, 3-methoxy-1-adamantyl, 1-(hydroxymethyl)-3-methyl-butyl, 1-(methoxymethyl)-3-methyl-butyl, 1-(fluoromethyl)-3-methyl-butyl, 2-methoxycyclopentyl, 4-hydroxycycloheptyl, 3-methoxycycloheptyl, 4-methoxycycloheptyl, 3-noradamantyl, 3-fluoro-1-adamantyl.

[0082] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the following group: a fused phenyl group selected from a phenyl group fused with a (C5-C6)cycloalkyl, wherein the (C5-C6)cycloalkyl is optionally substituted by a hydroxy group; a phenyl group substituted by a (C4-C7)heterocycloalkyl group, wherein the (C4-C7)heterocycloalkyl group may itself be substituted by a (C1-C4)alkyl group; Or, R″-L-group, where L is a hydroxy group, a (C1-C3) alkoxy group, or -NR b R c is a (C1-C3)alkanediyl group optionally substituted by a group selected from the group consisting of: R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group; Here, R b and R c are independently selected from (C1-C6) alkyl and a hydrogen atom.

[0083] The subgroups of compounds are collected under "A2" and "A5" type compounds in Table 2 herein below.

[0084] Still according to this embodiment, R 1 may more particularly represent [2-(trifluoromethyl)phenyl]methyl, 2-hydroxyindan-1-yl, 2-amino-1-phenyl-ethyl, 2-hydroxy-1-phenyl-ethyl, 2-methoxy-1-phenyl-ethyl, 2-hydroxy-2-phenyl-ethyl, 4-(4-methylpiperazin-1-yl)phenyl.

[0085] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the R'-L-group, where -R' is a (C3-C8) heteroaryl group optionally substituted by a (C1-C4) alkyl group, and -L is a (C1-C3)alkanediyl or a single bond.

[0086] The subgroups of compounds are collected under "A3" and "A6" type compounds in Table 2 herein below.

[0087] Still according to this embodiment, R 1 may more particularly represent (4-methylthiazol-2-yl)methyl or 2-pyridyl.

[0088] There is further provided herein a compound of formula (I) as defined above, wherein R 1 represents the following group: a (C4-C6) alkyl group substituted by a group selected from a hydroxy group, a halogen atom, and a (C1-C3) alkoxy group; A bridged (C6-C 10 ) a cycloalkyl group, or R″-L-group, where L is -NR b R c a (C1-C3)alkanediyl group optionally substituted by a group selected from a group, a (C1-C3)alkoxy group, and a hydroxy group, and R'' is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group.

[0089] According to another particular embodiment, the present invention relates to a compound of formula (I) as defined hereinabove, or any one of their pharma- ceutically acceptable salts, Here, R 1 represents the R'-L-group, where R' is a (C3-C8)heterocycloalkyl group optionally substituted by one or two groups selected from a hydroxy group and a (C1-C4)alkyl group, and L is a (C1-C3)alkanediyl or a single bond.

[0090] The subgroups of compounds are collected under "A4" and "A7" type compounds in Table 2 herein below.

[0091] Still according to this embodiment, R 1 may more particularly represent tetrahydropyran-4-yl-methyl, tetrahydropyran-3-yl, 6,6-dimethyltetrahydropyran-3-yl, 4-hydroxytetrahydropyran-3-yl or oxepan-3-yl.

[0092] In the context of the present invention the following terms are used:

[0093] The term "halogen atom" means chlorine, fluorine, bromine, and iodine atoms, and in particular refers to chlorine, fluorine, and bromine atoms.

[0094] As used herein, the term "(C x ~C y ) alkyl" are C x ~Cy "alkyl" refers to a primary, secondary, or tertiary monovalent saturated hydrocarbon radical, 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.

[0095] As used herein, the term "(C1-C3)alkanediyl" refers to a divalent saturated hydrocarbon radical, branched or straight chain, containing 1 to 3 carbon atoms, more particularly methylene, ethylene or propylene, e.g., straight chain propylene or isopropylene, wherein the alkanediyl may be optionally substituted as will be apparent from the description below.

[0096] As used herein, the term "(C3-C8)cycloalkyl" refers to a cyclic saturated hydrocarbon having from 3 to 8 carbon atoms, which is saturated or partially unsaturated, and unsubstituted or substituted. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0097] As used herein, the term "(C3-C8)heterocycloalkyl group" refers to a (C3-C8)cycloalkyl group in which one or two carbon atoms are replaced with a heteroatom, such as an oxygen atom, a nitrogen atom, or a sulfur atom, more particularly an oxygen atom or a nitrogen atom. Such heterocycloalkyl groups may be saturated or partially saturated, and may be unsubstituted or substituted. Examples include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, and tetrahydrothiopyranyl, more particularly piperidinyl and piperazinyl, and even more particularly piperazinyl.

[0098] As used herein, the term "(C1-C x )alkoxy" is -O-(C1-C x ) alkyl moiety or -O-(C3-C x ) cycloalkyl moieties, where alkyl and cycloalkyl are as defined above, such as (C1-C6)alkoxy. Examples include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, cyclopropoxy, butoxy, tert-butoxy, and pentoxy.

[0099] As used herein, “bridged (C6-C 10 A "cycloalkyl" group refers to a bicyclic or tricyclic compound where the rings are cycloalkyl, the rings share three or more atoms, and the bridge contains at least one atom, e.g., one, two, or three atoms. Such bridged cycloalkyl groups may be substituted with one or more C1-C3 alkyl groups. Examples include, but are not limited to, adamantyl and noradamantyl.

[0100] "Fused phenyl group" refers to a bicyclic radical that contains a phenyl moiety and may be substituted. The fused phenyl group may be fused to a cycloalkyl or to a heterocycloalkyl and may be attached to the remainder of the molecule through the phenyl moiety or through the cycloalkyl or heterocycloalkyl. Examples include, but are not limited to, indanyl, acetylindolinyl, methylindazolyl, hydroxyindanyl, benzothiazolyl, indolyl, indazolyl, methoxyindanyl, and the like.

[0101] As used herein, the term "(C3-C8)heteroaryl group" refers to a monocyclic aromatic group in which at least one of the rings is aromatic and 1 to 3 ring carbon atoms are replaced by nitrogen, a heteroatom, such as an oxygen atom or a sulfur atom. As examples of (C3-C8)heteroaryl groups, mention may be made of, but is not limited to, oxazole, isoxazole, pyridine, pyrimidine, pyridazine, triazine, pyrazine, oxadiazole, furan, pyrazole, thiazole, isothiazole, thiadiazole, imidazole, triazole, etc. In the framework of the present invention, (C3-C8)heteroaryl is advantageously pyridine, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine and pyrimidine.

[0102] "Aromatic ring" means that the molecule has 4n+2 pi electrons according to Hückel's rule.

[0103] As used herein, the term "(C1-C x The term "fluoroalkyl group" refers to a group having a C1-C x ) alkyl, in which one or more hydrogen atoms are replaced by fluorine. In one embodiment, all hydrogen atoms are replaced by fluorine atoms to form a perfluoroalkyl group, such as trifluoromethyl.

[0104] In the context of the present invention, the terms "aromatic ring" and "heteroaryl" include all positional isomers.

[0105] The nomenclature of compounds (1)-(271) below was generated using Accelrys Draw 4.1 SP1 and in accordance with the principles of the International Union of Pure and Applied Chemistry. To avoid any confusion, the "(±)" symbol was added to indicate a racemic mixture. The prefixes "cis" and "trans" were also used to assign the relative stereochemistry of two adjacent chiral centers.

[0106] According to a preferred embodiment of the present invention, the compound of formula (I) above is selected from the following compounds and their pharma- ceutically acceptable salts: (1) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one, (2) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one, (3) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cyclooctylamino)-1H-imidazol-5-one, (4) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (5) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (6) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one, (7) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one, (8) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[trans-4-hydroxycycloheptyl]amino]-1H-imidazol-5-one, (9) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[trans-4-methoxycycloheptyl]amino]-1H-imidazol-5-one, (10) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[cis-3-methoxycycloheptyl]amino]-1H-imidazol-5-one, (11) (4Z)-2-(1-adamantylamino)-4-(1,3-benzoxazol-6-ylmethylene)-1H-imidazol-5-one, (12) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one, (13) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1H-imidazol-5-one. (14) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (15) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-1H-imidazol-5-one, (16) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (17) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (18) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (19) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (20) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (21) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (22) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(2-pyridylamino)-1H-imidazol-5-one, (23) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-1H-imidazol-5-one. (24) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (25) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(oxepan-3-ylamino)-1H-imidazol-5-one, (26) (4Z)-2-(cyclohexylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (27) (4Z)-2-(cycloheptylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (28) (4Z)-2-(cyclooctylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (29) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (30) (4Z)-4-(1H-indazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (31) (4Z)-2-(1-adamantylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (32) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (33) (4Z)-4-(1H-indazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (34) (4Z)-2-(cyclohexylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (35) (4Z)-2-(cycloheptylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (36) (4Z)-2-(cyclooctylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (37) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (38) (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (39) (4Z)-2-(1-adamantylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (40) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (41) (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (42) (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (43) (4Z)-2-(cyclohexylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (44) (4Z)-2-(cycloheptylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (45) (4Z)-2-(cyclooctylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (46) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (47) (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (48) (4Z)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (49) (4Z)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (50) (4Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (51) (4Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (52) (±)-(4Z)-2-[[trans-4-hydroxycycloheptyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (53) (±)-(4Z)-2-[[trans-4-methoxycycloheptyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (54) (±)-(4Z)-2-[[cis-3-methoxycycloheptyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (55) (4Z)-2-(1-adamantylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (56) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (57) (4Z)-2-[(3-methoxy-1-adamantyl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (58) (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (59) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (60) (4Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (61) (4Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one. (62) (4Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (63) (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (64) (4Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (65) (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (66) (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (67) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (68) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (69) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (70) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-(2-pyridylamino)-1H-imidazol-5-one, (71) (4Z)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (72) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (73) (4Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (74) (±)-(4Z)-4-[(1-methylindazol-5-yl)methylene]-2-(oxepan-3-ylamino)-1H-imidazol-5-one, (75) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one, (76) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one. (77) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(cyclooctylamino)-1H-imidazol-5-one, (78) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (79) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (80) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (81) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (82) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one, (83) (4Z)-2-(3-noradamantylamino)-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one, (84) (4Z)-2-(1-adamantylamino)-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one, (85) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one, (86) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1H-imidazol-5-one, (87) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-1H-imidazol-5-one, (88) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (89) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-1H-imidazol-5-one, (90) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (91) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (92) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (93) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-1H-imidazol-5-one, (94) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(2S)-2-hydroxy-2-phenyl-ethyl]amino]-1H-imidazol-5-one, (95) (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one dihydrochloride, (96) (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one dihydrochloride, (97) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (98) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (99) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (100) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(2-pyridylamino)-1H-imidazol-5-one, (101) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (102) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (103) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3S,4S)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (104) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(oxepan-3-ylamino)-1H-imidazol-5-one, (105) (4Z)-2-(cyclohexylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (106) (4Z)-2-(cycloheptylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (107) (4Z)-2-(cyclooctylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (108) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (109) (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (110) (4Z)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (111) (4Z)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (112) (4Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (113) (4Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (114) (4Z)-2-(3-noradamantylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (115) (4Z)-2-(1-adamantylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (116) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (117) (4Z)-2-[(3-methoxy-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (118) (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (119) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (120) (4Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (121) (4Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (122) (4Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (123) (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (124) (4Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (125) (4Z)-2-[[(2S)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (126) (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (127) (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (128) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (129) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (130) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (131) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-(2-pyridylamino)-1H-imidazol-5-one, (132) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-(cyclohexylamino)-3-methyl-imidazol-4-one, (133) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-(cyclooctylamino)-3-methyl-imidazol-4-one, (134) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (135) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (136) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1SR,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (137) (5Z)-2-(3-noradamantylamino)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-imidazol-4-one, (138) (5Z)-2-(1-adamantylamino)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-imidazol-4-one, (139) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (140) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (141) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-imidazol-4-one, (142) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (143) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (144) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (145) (5Z)-2-(cyclohexylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (146) (5Z)-2-(cycloheptylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (147) (5Z)-2-(cyclooctylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (148) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (149) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (150) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (151) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (152) (5Z)-2-(3-noradamantylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (153) (5Z)-2-(1-adamantylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (154) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (155) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (156) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (157) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (158) (5Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (159) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (160) (5Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (161) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (162) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (163) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one dihydrochloride, (164) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (165) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (166) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (167) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-(2-pyridylamino)imidazol-4-one, (168) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[[(3S)-tetrahydropyran-3-yl]amino]imidazol-4-one, (169) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (170) (5Z)-2-(cyclohexylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (171) (5Z)-2-(cycloheptylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (172) (5Z)-2-(cyclooctylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (173) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (174) (5Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (175) (5Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (176) (5Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (177) (5Z)-2-(3-noradamantylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (178) (5Z)-2-(1-adamantylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (179) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (180) (5Z)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (181) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (182) (5Z)-3-Methyl-5-[(2-methylindazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (183) (5Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (184) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (185) (5Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (186) (5Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (187) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (188) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one dihydrochloride, (189) (5Z)-3-Methyl-5-[(2-methylindazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (190) (5Z)-3-Methyl-5-[(2-methylindazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (191) (5Z)-3-Methyl-5-[(2-methylindazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (192) (5Z)-3-Methyl-5-[(2-methylindazol-5-yl)methylene]-2-(2-pyridylamino)imidazol-4-one, (193) (5Z)-3-Methyl-5-[(2-methylindazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl]amino]imidazol-4-one, (194) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (195) (5Z)-2-(cyclohexylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (196) (5Z)-2-(cycloheptylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (197) (5Z)-2-(cyclooctylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (198) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (199) (5Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (200) (5Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (201) (5Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (202) (5Z)-2-(3-noradamantylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (203) (5Z)-2-(1-adamantylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (204) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (205) (5Z)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (206) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (207) (5Z)-3-Methyl-5-[(1-methylindazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (208) (5Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (209) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (210) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (211) (5Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (212) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (213) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one dihydrochloride, (214) (5Z)-3-Methyl-5-[(1-methylindazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (215) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (216) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (217) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-(2-pyridylamino)imidazol-4-one, (218) (5Z)-3-Methyl-5-[(1-methylindazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl]amino]imidazol-4-one, (219) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (220) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-(cyclohexylamino)-3-methyl-imidazol-4-one, (221) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-(cycloheptylamino)-3-methyl-imidazol-4-one, (222) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-(cyclooctylamino)-3-methyl-imidazol-4-one, (223) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (224) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (225) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (226) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (227) (5Z)-2-(3-noradamantylamino)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-imidazol-4-one, (228) (5Z)-2-(1-adamantylamino)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-imidazol-4-one, (229) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (230) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (231) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-imidazol-4-one, (232) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (233) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-imidazol-4-one, (234) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (235) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (236) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (237) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (238) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (239) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (240) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (241) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-(2-pyridylamino)imidazol-4-one, (242) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[[(3S)-tetrahydropyran-3-yl]amino]imidazol-4-one, (243) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-imidazol-4-one, (244) (5Z)-2-(cyclohexylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (245) (5Z)-2-(cycloheptylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (246) (5Z)-2-(cyclooctylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (247) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (248) (5Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (249) (5Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (250) (5Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (251) (5Z)-2-(3-noradamantylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (252) (5Z)-2-(1-adamantylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (253) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (254) (5Z)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (255) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (256) (5Z)-3-Methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (257) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (258) (5Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (259) (5Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (260) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (261) (5Z)-3-Methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (262) (5Z)-3-Methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (263) (5Z)-3-Methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (264) (5Z)-3-Methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-(2-pyridylamino)imidazol-4-one, (265) (5Z)-3-Methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl]amino]imidazol-4-one, (266) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (267) (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one, (268) (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one, (269) (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (270) (4Z)-2-(1-adamantylamino)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-1H-imidazol-5-one, (271) (4Z)-4-(indazol-5-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)aniline]-1H-imidazol-5-one.

[0107] According to a further preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (21), (22), (23), (24), (25), (27), (28), (29), (30), (31), (32), (35), (36), (37), (38), (39), (40), (41), (44), (45), (46), (47), (48), (51), (52), (53), (55), (56), (57), (58), (60), (69), (72), (76), (77), (78), (79), (80), (83), (84), (85), (86), (87), (88), (89), (90), (96), (99), (100), (101) , (105), (106), (107), (108), (109), (110), (112), (113), (114), (115), (116), (117), (118), (120), (121), (130), (132), (133), (134), (135), (136), (137), (138), (139), (140), (141), (142), (143), (152), (154), (156) ), (166), (172), (173), (174), (177), (178), (179), (180), (181), (183), (196), (198), (223), (225), (227), (228), (229), (230), (231), (247), (251), (252), (253), (255), (263), (271) and pharma- ceutically acceptable salts thereof.

[0108] According to a further preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (6 ), (24), (25), (27), (28), (29), (31), (32), (36), (37), (38), (39), (40), (41), (44), (45), (46), (48), (51), (56), (57), (58), (72), (78), (80), (83), (84), ( 85), (86), (87), (88), (89), (90), (108), (110), (114), (115), (116), (117), (118), (120), (130), (133), (134), (135), (137), (138), (139), (140), (141), (1 42), (156), (173), (177), (178), (179), (180), (181), (227), (228), (229), (231), (247), (251), (252), (253), (255), (271), and pharma- ceutically acceptable salts thereof.

[0109] According to a further preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (3), (4), (5), (6), (7), (10), (11), (12), (13), (15), (16), (18), (21), (32), (39), (40), (41), (46), (58), (83), (84), (85), (86), (87), (114), (115), (116), (118), (137), (138), (139), (140), (141), (181), (231) and pharma- ceutically acceptable salts thereof.

[0110] According to an alternative embodiment of the present invention, the compound of formula (I) above is selected from the group consisting of compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (28), (29), (31), (32), (35), (36), (37), (39), (40), (41), (42), (46), (58), (60), (75), (76), (77), (78), (80), ( 81), (83), (84), (85), (86), (87), (88), (89), (90), (91), (92), (93), (94), (95), (96), (97), (99), (100), (101), (102), (104), (105), (106), (107), (108), (109), (110), (111), (112), (113), (114), (115), (116), (117), (118), (119), (120), (121), (122), (123), (124), (125), (126), (127 ), (128), (129), (130), (131), (132), (133), (134), (135), (136), (137), (138), (139), (140), (141), (142), (143), (144), (147), (148), (150), (151), (152), (153), (154), (155), (156), (158), (172), (173), (177), (178), (179), (180), (181), (183), (184), (208), (220), (221), (222), (2 23), (225), (226), (227), (228), (229), (230), (231), (232), (233), (234), (235), (236), (237), (238), (239), (240), (241), (242), (243), (244), (245), (246), (247), (248), (249), (250), (251), (252), (253), (254), (255), (256), (257), (259), (260), (261), (262), (263), (264), (265),(266) and pharma- ceutically acceptable salts thereof.

[0111] According to a preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (28), (29), (31), (32), (36), (39), (40), (41), (46), (76), (77), (78), (80), (83), (84), (85), (86), (87), (88), (89), (90), (92), (93), (95), (96), (97), (99), (100), (101), (104), (105), (106), (107), (108), (109), (110), (111), (112), (113), (114), (115), (116), (117), (118), (119), (120), (121), (123), (124), ( 125), (126), (127), (128), (129), (130), (131), (132), (133), (134), (135), (136), (137), (138), (139), (140), (141), (142), (143), (144), (152), (153), (154), (155), (156), (158), (177), (179), (180), (181), (183), (184), (208), (221), (222) , (223), (226), (227), (229), (230), (231), (232), (233), (234), (237), (242), (244), (245), (246), (247), (248), (249), (250), (251), (252), (253), (254), (255), (256), (257), (260), (262), (263), (265), (266) and pharma- ceutically acceptable salts thereof.

[0112] According to a further preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (7), (11), (12), (13), (15), (16), (31), (39), (40), (41), (83), (84), (85), (86), (87), (90), (107), (108), (114), (115), (116), (118), (136), (137), (139), (140), (156), (229), (230), (231), (245), (246), (247), (251), (253), (255) and pharma- ceutically acceptable salts thereof.

[0113] According to a further embodiment of the present invention, the compound of formula (I) above is selected from the group consisting of compounds (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (18), (19), (21), (22), (23), (24), (25), (31), (39), (40), (41), (76), (77), (78), (80), (83), (84), (85), (86), (87), (88), (89), (90), (92), (95), (100), (101), (104), (105), (106), (107), , (108), (110), (111), (112), (113), (114), (115), (116), (117), (118), (119), (120), (121), (124), (128), (129), (130), (131), (137), (139), (140), (141), (142), (156), (227), (229), (230), (231), (246), (247), (251), (252), (253), (254), (255), (257), (260), and pharma- ceutically acceptable salts thereof.

[0114] The group of compounds defined by the list of compounds identified in Example 4 below through Tables 4A to 4F and specifically identified as the most potent kinase inhibitors and multi-targeted kinase inhibitors also form part of the present invention.

[0115] According to another aspect, a subject of the invention relates to a compound of formula (I) as defined above or any of its pharma- ceutically acceptable salts, or at least any of the compounds (1) to (271) or any of their pharma-ceutically acceptable salts, for use as a medicament.

[0116] "Pharmaceutically acceptable salts thereof" refers to acid addition salts formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, and salts formed with organic acids such as acetic acid, tartaric acid, and succinic acid.

[0117] Suitable physiologically acceptable acid addition salts of compounds of formula (I) include the hydrobromide, tartrate, hydrochloride, succinate and acetate salts.

[0118] The compound of formula (I), and any one of the compounds (1) to (271), or a pharma- ceutically acceptable salt thereof, may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0119] The terms "hydrate" and "solvate" simply mean that the compound (i) according to the invention can be in the form of a hydrate or solvate, i.e. can be combined or associated with one or more water or solvent molecules. This is merely a chemical characteristic of such compounds and can be applied to all organic compounds of this type.

[0120] The compounds of formula (I) may contain one or more asymmetric carbon atoms. Thus, the compounds of formula (I) may exist in the form of enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof (including racemic mixtures) are included within the scope of the present invention. In particular, the stereoisomers (Z) and (E) form part of the present invention.

[0121] The compounds of the present invention can be prepared by conventional organic synthesis methods practiced by one of ordinary skill in the art. The general reaction sequences outlined below are intended to illustrate general methods useful for preparing the compounds of the present invention and are not meant to limit their scope or usefulness.

[0122] [Table 1-1] JPEG2024540217000015.jpg146170

[0123] Compounds of general formula (I) can be prepared according to the following schemes 1-2'.

[0124] [ka]

[0125] [ka]

[0126] Route 1

[0127] The synthesis is based on the late-stage Knoevenagel reaction between N2-substituted 1,4-dihydroimidazolone of formula (II) and heteroarylcarboxaldehyde of formula (III), according to General Protocol 10 (GP10) described later in the specification, where R 2 , A and B are as defined above.

[0128] GP10 can be divided into two pathways, GP10-A and GP10-B, as described in more detail in Example 11 below.

[0129] According to GP10-A, compound (II) and compound (III) are placed in a protic solvent, for example ethanol. Compound (II) and compound (III) can be introduced, for example, in the presence of an ammonium carboxylate, for example ammonium formate, in a molar ratio to compound (II) ranging from 1 to 5, for example 1.2, for example, in a molar ratio of compound (III) to compound (II) ranging from 1 to 5, for example 1.2. The mixture can be irradiated, for example, by microwaves, for example, for a period ranging from 1 to 5 hours, in particular for 3 hours. The mixture can also be heated, for example, at a temperature ranging from 100° C. to 140° C., for example, from 110° C. to 130° C., and allowed to return to room temperature upon completion of the reaction.

[0130] According to GP6-B, compound (II) and compound (III) are placed in acetic acid. Compound (II) and compound (III) can be introduced, for example, in the presence of potassium acetate in a molar ratio to compound (II) ranging from 2 to 6, for example 4, for example, in a molar ratio of compound (III) to compound (II) ranging from 1 to 5, for example 1.2. The mixture can be irradiated, for example, by microwaves, for example, in the range of 1 to 5 hours, in particular for 3 hours. The mixture can also be heated, for example, at a temperature ranging from 100 to 140° C., for example in the range of 110 to 130° C., and returned to room temperature upon completion of the reaction. Compounds of formula (II) as defined above include aliphatic or aromatic amines, which can be prepared by reacting potassium acetate with a amine of formula R according to General Protocol 1 (GP1) described hereinbelow. 1 NH2 (wherein, R 1 can be obtained by addition of an amine (as defined above for 2-alkylsulfanyl-1,4-dihydroimidazol-5-one).

[0131] According to GP1, 2-alkylsulfanyl-1,4-dihydroimidazol-5-one can be placed in an aprotic solvent, tetrahydrofuran (THF), and then a compound of formula R 1An amine such as NH2 may be added in a molar ratio ranging from 1.2 to 6 relative to the 2-alkylsulfanyl-1,4-dihydroimidazol-5-one. Acetic acid may be added to the reaction mixture in a molar ratio ranging from 2 to 5. The reaction mixture may be placed in a sealed tube, stirred, and heated to a temperature ranging from 90°C to 150°C, for example 120°C. Upon completion of the reaction, the mixture may be allowed to return to room temperature and a solid may be allowed to crystallize. The mixture may then be stirred at a temperature ranging from -10°C to 10°C, for example 0°C, for a period ranging from 30 minutes to 90 minutes, for example 60 minutes.

[0132] Route 2

[0133] The synthesis may be carried out by reacting R of a compound of formula (IX) according to general protocols 11 or 12 (GP11 and GP12) described later in this specification. 1 It is based on the late-stage functionalization of NH2 with amines, where Alk, R 2 , R 5 , A and B are as defined above.

[0134] According to GP11, the compound of formula (IX) may be placed in an aprotic solvent, such as THF or dioxane, or a mixture of both. 1 An amine such as NH2 may be added, for example in a molar ratio ranging from 2 to 6, particularly 4, relative to the compound of formula (IX). Acetic acid may be added to the reaction mixture, for example in a molar ratio ranging from 4 to 8, relative to the compound of formula (IX). The reaction mixture may be placed in a sealed tube and may receive energy, for example from a heating block or from a microwave. Upon completion of the reaction, the mixture may be allowed to return to room temperature.

[0135] In an embodiment designated GP11-A, the reaction mixture may be stirred at a temperature ranging from -10°C to 10°C, such as 0°C, for a period ranging from 30 minutes to 2 hours, such as 1 hour.

[0136] Depending on the state of the product obtained (solid, precipitate), purification methods well known by a person skilled in the art may be performed, such as filtration, washing, grinding, vacuum drying, flash chromatography, precipitation and refluxing.

[0137] According to GP12, the compound of formula (IXa) (wherein A is a =C-group, B is an -O-group, and Alk and R 5 is as defined above) in an aprotic solvent, such as tetrahydrofuran (THF), 1 NH (in the formula, R 1 where R is as defined above) may be added together with an amine having a molar ratio in the range of, for example, 4 to 8, in particular 6. The reaction mixture may be heated, for example in a sealed tube, at a temperature in the range of, for example, 90° C. to 130° C., in particular 110° C. After completion, the reaction is returned to a temperature in the range of, for example, 15° C. to 30° C., in particular room temperature, and isolated to give a compound of formula (XI) (where R 1 and R 5 is as defined above).

[0138] In the second step of GP12, a compound of formula (XI) may be placed in a solvent, such as toluene, together with triethyl orthoformate, for example in a molar ratio of triethyl orthoformate to compound of formula (XI) in the range of from 15 to 35, particularly 25. The reaction mixture may be heated, for example in a sealed tube, at a temperature in the range of from 100° C. to 200° C., particularly 150° C., for example for a period in the range of from 30 minutes to 90 minutes, particularly 60 minutes.

[0139] Compounds of formula (IX) as defined above may be obtained by S-alkylation of compounds of formula (X), according to General Protocol 9 (GP9), where R 2 , R 5 , A and B are as defined above.

[0140] According to GP9, the compound of formula (X) may be placed in a polar aprotic solvent, for example dimethylformamide (DMF). An alkyl halide of formula Alk-Hal, where Hal is a halide, for example iodine or bromine, and Alk is a (C1-C5) alkyl, for example methyl or ethyl, may then be added, for example in the presence of an inorganic base, for example K2CO3, in a molar ratio in the range of 0.7-1.5, in particular 1, relative to the compound of formula (X). The reaction mixture may be stirred while the alkyl halide is being added. The resulting mixture may then be stirred, for example for 8-16 hours, in particular 12 hours, at a temperature in the range of -10°C to 30°C, in particular at 0°C when Alk is methyl, or at room temperature when Alk is ethyl.

[0141] Compounds of formula (X) as defined above can be obtained from compounds of formula (III) according to General Protocol 8 (GP8), in which R 2 , A and B are as defined above.

[0142] According to GP8, the compound of formula (III) may be placed in a protic solvent, such as ethanol, in the presence of 2-thiohydantoin, for example in a molar ratio in the range of 0.85 to 1.15, particularly 1, relative to the compound of formula (III), in the presence of an organic base, for example piperidine or ethanolamine, for example in a molar ratio in the range of 0.85 to 1.15, particularly 1, relative to the compound of formula (III), in the presence of an organic acid, for example acetic acid, for example in a molar ratio in the range of 0.85 to 1.15, particularly 1, relative to the compound of formula (III). The reaction mixture may be placed in a sealed tube, stirred and heated, for example at a temperature in the range of 60° C. to 130° C., particularly 80° C., for a period of 10 to 100 minutes, particularly 15 to 90 minutes. The reaction mixture may be irradiated, for example by microwaves.

[0143] In both synthetic routes described herein above, a compound of formula (III) as described above, or a heteroaryl carboxaldehyde may be prepared.

[0144] Compounds of formula (III) can be obtained by vinylation of heteroaryl bromides of formula (V), according to general protocol 5 (GP5), followed by at least one step of Lemieux-Johnson oxidation, according to general protocol 6 (GP6), in which R 2 , R 3 , R 4 , A and B are as defined above, and X is a halogen atom.

[0145] According to one embodiment, GP5 performs the palladium-catalyzed vinylation of heteroaryl bromides. A compound of formula (V) can be placed in a solvent mixture containing at least an inorganic base, such as Cs2CO3, together with potassium vinyltrifluoroborate, and a solvent capable of stabilizing the cation, such as dioxane, in the presence of a source of Pd[0]. Protocol GP5 encompasses two options.

[0146] According to a first option of GP5 (named GP5-A), the palladium source is tetrakis(triphenylphosphine)palladium(0) (Pd(Ph3)4). In this embodiment, the compound of formula (V) can be mixed with potassium vinyltrifluoroborate in a molar ratio in the range of 1 to 1.4, in particular 1.2, relative to the compound of formula (V), in the presence of an inorganic base, for example Cs2CO3, in a molar ratio in the range of 1 to 5, in particular 2, relative to the compound of formula (V), in the presence of Pd(PPh3)4 in an amount in the range of 2 to 10 mol%, in particular 5 mol%, relative to the total amount of the compound of formula (V), in a solvent mixture comprising at least a solvent capable of stabilizing cations, for example dioxane. The mixture can be refluxed and heated for example for 6 to 18 hours, in particular 12 hours.

[0147] According to a second option of GP5 (named GP5-B), the palladium source is pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI), for example PEPPSI-iPr. The reaction mixture may comprise a compound of formula (V) and vinyltrifluoroborate in a molar ratio ranging from 1.5 to 2.5, for example 2, relative to the compound of formula (V), in a solvent mixture comprising at least a solvent capable of stabilizing cations in the presence of a PEPPSI catalyst, for example PEPPSI-iPr, in an amount ranging from 10 to 20 mol %, in particular 15 mol %, relative to the total amount of the compound of formula (V), for example dioxane, in the presence of an inorganic base, for example Cs2CO3, in a molar ratio ranging from 1 to 5, for example 3, relative to the compound of formula (V). The reaction mixture may be irradiated, for example by microwaves, for example for 2 to 6 hours, in particular for 4 hours, and heated at a temperature in the range of 120° C. to 170° C., for example 150° C. After completion of the reaction, the mixture may be cooled to room temperature and optionally purified.

[0148] According to the general protocol GP6, vinyl heteroaryls (IV) (wherein R 2 A, B and C) can be placed in a solvent mixture containing at least a solvent capable of stabilizing the cation, for example dioxane. An oxidizing agent, for example a periodate, can then be added in the presence of an osmium compound, for example osmium tetroxide (OsO4), in an amount of 1-10 mol %, particularly 5 mol %, relative to the total amount of vinylheteroaryl (IV) obtained from GP5, in the presence of a non-nucleophilic base, for example 2,6-lutidine, in a molar ratio ranging from 2 to 6, particularly 4, relative to the vinylheteroaryl (IV) obtained from GP5. The reaction mixture can be stirred and maintained, for example, at a temperature ranging from -5°C to 5°C, particularly 0°C, for example, for a period ranging from 30 minutes to 2 hours.

[0149] Alternatively, heteroarylcarboxaldehydes of formula (III) as defined above can be converted to heteroarylcarbonitriles of formula (V), where R 2 , A and B are as defined above, and X is a cyanide group.

[0150] According to GP7, compound (v) may be placed in a solvent mixture containing at least a protic solvent, such as formic acid. Adam's catalyst (platinum dioxide) may be added to the mixture, for example in an amount ranging from 15 mol % to 30 mol %, in particular 23 mol %. The reaction mixture may be refluxed, for example, for a period of 24 hours to 72 hours, in particular 48 hours. After completion of the reaction, compound (III) may be isolated and purified.

[0151] Compounds of formula (V) as defined above can be obtained by cyclization of 2-aminobromophenol or of compounds of formula (VI), where X is selected from the group consisting of halogen atoms and cyanidinium groups and Y is a hydroxy group and -NHR 4 groups, where R 4 is as defined above.

[0152] According to the first option of GP4 (named GP4-A), commercially available 2-aminobromophenol, where Y is a hydroxy group and X is a halogen atom, in particular a bromine atom, can be placed in a solvent, such as toluene, and triethyl orthoformate, where the molar ratio of triethyl orthoformate to 2-amino-bromo-phenol is, for example, in the range of 1.5 to 3, in particular 2. The reaction mixture can be irradiated, for example, at a temperature in the range of 100° C. to 200° C., in particular 130° C., for example, in the range of 1 hour to 3 hours, in particular 2 hours. After completion of the reaction, the mixture can be cooled to room temperature.

[0153] According to a second option of GP4 (designated GP4-B), X is a halogen atom, in particular a bromine atom, and Y is -NHR 4 is a group and R 4 The compound of formula (VI), where is as defined above, may be placed in a solvent, for example toluene, and triethyl orthoformate, where the molar ratio of triethyl orthoformate to the compound of formula (VI) is, for example, in the range of 1.5 to 3, in particular 2. The solution may also contain paratoluenesulfonic acid, for example in an amount of 1 mol % to 10 mol %, in particular 5 mol %. The reaction mixture may be irradiated, for example at a temperature in the range of 100° C. to 200° C., in particular 130° C., for example in the range of 1 hour to 3 hours, in particular 2 hours.

[0154] According to the third option of GP4 (designated GP4-C), X is a cyanide group and Y is -NHR 4 is a group and R 4 A compound of formula (VI), wherein is as defined above, may be refluxed in a protic solvent, such as formic acid. The reaction may be carried out for a period ranging from 2 to 6 hours, in particular 4 hours. After completion of the reaction, the mixture may be cooled to room temperature.

[0155] Compounds of formula (VI) as defined above can be obtained from compounds of formula (VII) according to General Protocol 3 (GP3), in which R 4 is as defined above, and X is selected from the group consisting of halogen atoms and cyanidinium groups.

[0156] According to the first option of GP3 (named GP3-A), R 4A compound of formula (VII), where X is as defined above and X is a halogen atom, in particular a bromine atom, may be placed in a solution comprising at least an aprotic solvent, such as tetrahydrofuran (THF), and a polar protic solvent, such as methanol, in a solvent ratio, for example, ranging from 2 / 1 to 1 / 2, in particular 1 / 1. The solution may also comprise zinc dust, for example, in a molar ratio, for example, ranging from 5 to 5, in particular 10. A hydrogen donor, such as NH4Cl, may be added to the reaction mixture, for example, in a range from 15 minutes to 60 minutes, in particular 30 minutes. The reaction mixture may be maintained at a temperature, for example, ranging from -10°C to 10°C, in particular 0°C, for a total time, for example, ranging from 45 minutes to 120 minutes, in particular 90 minutes. The reaction mixture may then be stirred, for example, at a temperature, for example, ranging from 15°C to 30°C, in particular at room temperature, for a time ranging from 3 hours to 12 hours, in particular 6 hours.

[0157] According to the second option of GP3 (named GP3-B), R 4 The compound of formula (VII), where X is as defined above and X is a cyanidide group, may be placed in a polar protic solvent, such as methanol, containing ammonium formate, where the molar ratio of ammonium formate to the compound of formula (VII) is, for example, in the range of 5 to 15, in particular 10. A hydrogenolysis catalyst on carbon, such as palladium, may be added to the reaction mixture, for example in a content in the range of 5% to 15% by weight, in particular 10% by weight, relative to the total weight of the compound of formula (VII). The reaction mixture may be refluxed for 3 hours to 12 hours, in particular 6 hours.

[0158] Compounds of formula (VII) as defined above can be obtained from o-fluoronitrobenzenes of formula (VIII) as described in scheme 1, where X is selected from the group consisting of halogen atoms and cyanidinium groups, according to General Protocol 2 (GP2).

[0159] The o-fluoronitrobenzene of formula (VIII) may be placed in a polar protic solvent, such as ethanol, and reacted with a compound of formula R 4 NH2 (wherein, R 4(wherein is as defined above) may be added to the reaction mixture in a molar ratio to o-fluoronitrobenzene of formula (VIII) in the range of, for example, 1.5 to 5, in particular 3. The reaction mixture may be maintained at a temperature in the range of, for example, -10°C to 10°C, in particular 0°C, for a time in the range of, for example, 30 minutes to 90 minutes. The reaction mixture may then be brought to a temperature in the range of, for example, 15°C to 30°C, in particular room temperature, for example in the range of, for example, 6 hours to 24 hours, in particular 12 hours.

[0160] Therefore, the present invention further relates to a synthetic process for preparing the novel compounds of formula (I) as defined above, comprising at least the step of coupling a compound of formula (III) with a compound of formula (II).

[0161] The present invention relates to a synthesis process for producing a compound of formula (I) as defined above or one of its pharma- ceutically acceptable salts, or any one of the compounds (1) to (271) as defined above or one of their pharma-ceutically acceptable salts, comprising the steps of: [ka] Here, R 1 and R 5 is as defined above, with a compound of formula (III) [ka] Here, R 2 , A and B are as defined above; The present invention relates to the above synthesis method, which comprises at least a step of coupling with

[0162] The present invention further relates to a synthetic intermediate of formula (II) [ka] Here, R 1 and R 5 is as defined above.

[0163] The present invention further relates to a synthetic intermediate of formula (III): [ka] Here, R 2 , A and B are as defined above.

[0164] Therefore, the present invention further relates to a synthetic process for preparing the novel compounds of formula (I) as defined above, comprising at least the step of substituting a compound of formula (IX) with a primary amine.

[0165] The present invention relates to a synthesis process for producing a compound of formula (I) as defined above or one of its pharma- ceutically acceptable salts, or any one of the compounds (1) to (271) as defined above or one of its pharma- ceutically acceptable salts, comprising the steps of: (i) reacting a compound of formula (IX) [ka] Here, R 2 , R 5 vA and B are as defined above, and Alk is (C1-C5) alkyl; Formula R 1 NH2 (wherein, R 1 wherein R is as defined above with an amine of

[0166] The present invention further relates to a synthetic intermediate of formula (XI) [ka] Here, R 1 and R 5 is as defined above.

[0167] The present invention further relates to a synthetic intermediate selected from [ka] where Alk is (C1-C5) alkyl, in particular Alk is selected from the group consisting of ethyl and methyl, and where R 1 , R 2 , R 5 , A and B are as defined above.

[0168] The chemical structures, analytical data and spectroscopic data of some compounds of formula (I) of the present invention are shown in Tables 2 and 3 below, respectively.

[0169] Reactions were carried out using oven-dried glassware under an inert atmosphere of argon. All reagent grade chemicals and solvents were obtained from commercial suppliers and used as received unless otherwise noted. Reactions were monitored by thin layer chromatography using aluminum plates (0.25 mm) precoated with silica gel 60 F254. Visualization was performed under UV irradiation at 254 nm or 312 nm or with a suitable TLC stain, such as those listed above, including but not limited to phosphomolybdic acid, KMnO4, ninhydrin, CAM, vanillin, p-anisaldehyde.

[0170] Microwave experiments performed on the Anton Paar Monowave 400 登録商標 The experiments were carried out in a microwave reactor. Experiments were carried out in a monomode cavity with a power range of 0-850 W and pressurized reactions (0-30 bar) were carried out in sealed glass vials (4-30 mL) equipped with snap caps and silicon septas. Temperatures (0-300 °C) were monitored with non-contact infrared sensors and calibrated with ruby ​​thermometers. Temperature, pressure and power profiles were compiled and monitored through a touch screen control panel. Times indicated in the various protocols are the times measured when the mixtures reached the programmed temperatures after a 3 min ramp period.

[0171] Chromatographic purification of the compounds was performed on an automated Interchim Puriflash XS420 equipped with a 30 μm spherical silica prepacked column as stationary phase.

[0172] Some compounds of the present invention are listed below in Table 2 together with their structures, which are merely illustrative and do not limit the scope of the present invention.

[0173] [Table 2] JPEG2024540217000026.jpg226170JPEG2024540217000027.jpg233170JPEG2024540217000028.jpg23 2170JPEG2024540217000029.jpg235170JPEG2024540217000030.jpg233170JPEG2024540217000031.j pg230170JPEG2024540217000032.jpg231170JPEG2024540217000033.jpg240170JPEG20245402170000 34.jpg236170JPEG2024540217000035.jpg237170JPEG2024540217000036.jpg235170JPEG2024540217 000037.jpg236170JPEG2024540217000038.jpg232170JPEG2024540217000039.jpg237170JPEG202454 0217000040.jpg231170JPEG2024540217000041.jpg242170JPEG2024540217000042.jpg241170JPEG20 24540217000043.jpg236170JPEG2024540217000044.jpg242170JPEG2024540217000045.jpg239170JP EG2024540217000046.jpg240170JPEG2024540217000047.jpg237170JPEG2024540217000048.jpg79170

[0174] Table 3 below lists analytical and spectroscopic data for the compounds presented in Table 2 above.

[0175] 1 H NMR analysis (400 or 500 MHz) 13 C NMR spectra (101 MHz) were recorded using a Bruker ULTRASHIELD 500 or 400 spectrometer. Spectral processing and analysis was performed using MestReNova. Data are presented in the following order: chemical shift in ppm relative to the internal solvent signal, multiplicity, number of protons, and coupling constant J in Hertz.

[0176] Reversed-phase HPLC / MS analysis was performed using a Waters Alliance 2795 HPLC equipped with an autosampler, an in-line membrane degasser, a column oven (T = 4 °C), a UV detector, and a ZQ quadrupole mass detector operated in ionization electrospray mode. Compounds (0.1–0.3 mg) were dissolved in acetonitrile (V 合計 Dissolved in a minimum amount of DMSO (1 mL). Standard analytical parameters: Flow rate: 1 mL / min, V 注入量 : 5μL. Acidic conditions: Waters XSelect CSH C18 column (3.5 μm, 2.1 x 50 mm). Gradient: (H2O + 0.04% v / v HCOOH (10 mM)) / ACN 95 / 5 to 0 / 100, 18.5 min. Alkaline conditions: Waters Xbridge C18 column (3.5 μm, 2.1 x 50 mm). Gradient: (H2O + 0.06% v / v NH 3(水性) (10mM) / ACN 95 / 5~0 / 100, 18.5 min.

[0177] [Table 3] JPEG2024540217000050.jpg255155JPEG2024540217000051.jpg255149JPEG2024540217000052.jpg255136JPEG2024540217000053.jpg255143JPEG2024540217000054.jpg255160JPEG2024540217000055.jpg255135JPEG2024540217000056.jpg255138JPEG2024540217000057.jpg255138JPEG2024540217000058.jpg255144JPEG2024540217000059.jpg255139JPEG2024540217000060.jpg255122JPEG2024540217000061.jpg255140JPEG2024540217000062.jpg255134JPEG2024540217000063.jpg255142JPEG2024540217000064.jpg255154JPEG2024540217000065.jpg255141JPEG2024540217000066.jpg255138JPEG2024540217000067.jpg255133JPEG2024540217000068.jpg255140JPEG2024540217000069.jpg255153JPEG2024540217000070.jpg255139JPEG2024540217000071.jpg255160JPEG2024540217000072.jpg255151JPEG2024540217000073.jpg255148JPEG2024540217000074.jpg255152JPEG2024540217000075.jpg255147JPEG2024540217000076.jpg255158JPEG2024540217000077.jpg255152JPEG2024540217000078.jpg255149JPEG2024540217000079.jpg255156JPEG2024540217000080.jpg255149JPEG2024540217000081.jpg255142JPEG2024540217000082.jpg255155JPEG2024540217000083.jpg255150JPEG2024540217000084.jpg255157JPEG2024540217000085.jpg255149JPEG2024540217000086.jpg255151JPEG2024540217000087.jpg255145JPEG2024540217000088.jpg255157JPEG2024540217000089.jpg255157JPEG2024540217000090.jpg255170JPEG2024540217000091.jpg255139JPEG2024540217000092.jpg255148JPEG2024540217000093.jpg255158JPEG2024540217000094.jpg255140JPEG2024540217000095.jpg255158JPEG2024540217000096.jpg255137JPEG2024540217000097.jpg255139JPEG2024540217000098.jpg255159JPEG2024540217000099.jpg255140JPEG2024540217000100.jpg255135JPEG2024540217000101.jpg255149JPEG2024540217000102.jpg255159JPEG2024540217000103.jpg255146JPEG2024540217000104.jpg255147JPEG2024540217000105.jpg255150JPEG2024540217000106.jpg255156JPEG2024540217000107.jpg255158JPEG2024540217000108.jpg255139JPEG2024540217000109.jpg255157JPEG2024540217000110.jpg255154JPEG2024540217000111.jpg255135JPEG2024540217000112.jpg255144JPEG2024540217000113.jpg255152JPEG2024540217000114.jpg255149JPEG2024540217000115.jpg255150JPEG2024540217000116.jpg255145JPEG2024540217000117.jpg255145JPEG2024540217000118.jpg255158JPEG2024540217000119.jpg255150JPEG2024540217000120.jpg255151JPEG2024540217000121.jpg255151JPEG2024540217000122.jpg255159JPEG2024540217000123.jpg255149JPEG2024540217000124.jpg255147JPEG2024540217000125.jpg255150JPEG2024540217000126.jpg255148JPEG2024540217000127.jpg255154JPEG2024540217000128.jpg255146JPEG2024540217000129.jpg255149JPEG2024540217000130.jpg255157JPEG2024540217000131.jpg255156JPEG2024540217000132.jpg255153JPEG2024540217000133.jpg255137JPEG2024540217000134.jpg255148JPEG2024540217000135.jpg255153JPEG2024540217000136.jpg255149JPEG2024540217000137.jpg255141JPEG2024540217000138.jpg255153JPEG2024540217000139.jpg255143.

[0178] pathology

[0179] The compounds of formula (I) may be used to treat cognitive impairment and neuroinflammation associated with Down's syndrome (Trisomy 21), Alzheimer's disease and related disorders, dementia; tauopathies; and other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick disease type C); CDKL5 deficiency; Phelan-McDermid syndrome; autism; type 1 and type 2 diabetes; folate and methionine metabolic disorders; tendon disorders and osteoarthritis, particularly knee osteoarthritis; Duchenne muscular dystrophy; cancer, for example brain tumors, including glioblastomas, leukemias, including megakaryoblastic leukemia and acute lymphoblastic leukemia, squamous cell carcinoma of the head and neck, pancreatic cancers, including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer, breast cancers, including triple-negative breast cancer (TNBC). cancer, 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, herpes virus, rhesus cytomegalovirus, varicella zoster virus, herpes simplex virus (HSV), hepatitis C virus, chikungunya virus, dengue virus, influenza virus, and Severe acute respiratory syndrome (SARS) coronavirus, cytomegalovirus, and human papillomavirus; neuroinflammation; anemia; infections caused by single-celled parasites such as malaria, leishmaniasis, Chagas disease, and sleeping sickness (Trypanosoma spp. sp.), bovine diseases caused by single-cell pathogens, and for thermoregulation.

[0180] According to a particular embodiment, the compounds of formula (I) of the present invention are useful for treating cognitive disorders and neuroinflammation associated with Down's syndrome (trisomy 21), Alzheimer's disease and related diseases, dementia or tauopathies; other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick disease type C); CDKL5 deficiency; diabetes mellitus type 1 and type 2; folate and methionine metabolic disorders; tendon disorders and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; cancer, including brain tumors, including glioblastoma, megakaryoblastic leukemia and acute lymphoblastic leukemia. The present invention may be useful in the treatment and / or prevention of diseases selected from leukemia, including head and neck squamous cell carcinoma, pancreatic cancer, including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer, and breast cancer, including 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, herpes virus, rhesus cytomegalovirus, varicella zoster virus, and herpes simplex virus (HSV), as well as for thermoregulation. The above diseases are particularly associated with abnormalities in the dosage of DYRK1A and / or CLK1.

[0181] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of diseases selected from Down's syndrome, Alzheimer's disease, dementia, tauopathies, Parkinson's disease, Niemann-Pick disease type C, CDKL5 deficiency and Phelan-McDermid syndrome, and their associated cognitive and motor conditions, more particularly diseases caused by high expression and activity of DYRK1A.

[0182] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of diseases selected from Down's syndrome, Alzheimer's disease and related tauopathies, Parkinson's disease, their associated cognitive / movement disorders or one or more symptoms of such diseases, typical symptoms of which include a decline in learning and memory and social interaction.

[0183] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in combating the cognitive decline associated with Down's syndrome (trisomy 21), the cognitive decline in learning and memory, in particular the cognitive decline associated with cognitive disorders or neurodegenerative disorders as described above.

[0184] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of type 1 diabetes and type 2 diabetes.

[0185] The compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of type 1 and type 2 diabetes, either by directly treating diabetic patients or by treating isolated / cultured pancreatic islets or pancreatic beta cells in vitro or ex vivo prior to transplantation into a diabetic patient.

[0186] Further provided herein is a method for treating type 1 and type 2 diabetes in a patient in need of such treatment, said method comprising administering a compound of formula (I) as defined above.

[0187] Further provided herein is a method for treating type 1 and type 2 diabetes in a patient in need thereof, comprising treating isolated or cultured pancreatic islets or pancreatic beta cells in vitro or ex vivo prior to transplantation into the patient with a compound of formula (I) as defined above.

[0188] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in treating and / or preventing viral infections, in particular those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), in particular those caused by herpes virus, coronavirus, cytomegalovirus and influenza virus, which may be associated with high expression and activity of DYRK1A and / or CLK1, and optionally further associated with dual inhibitors of CLK / DYRKS.

[0189] Acute respiratory diseases have recently been caused by a new coronavirus (SARS-CoV-2, previously known as 2019-nCoV), belonging to the family Coronaviridae, also known herein as coronavirus 2019 (COVID-19). Compounds of formula (I) according to the present invention can also treat infections caused by the SARS-CoV-2 virus.

[0190] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of cancers, such as brain tumors including glioblastomas, leukemias including megakaryoblastic leukemia and acute lymphocytic leukemia, head and neck squamous cell carcinoma, pancreatic cancers including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer and breast cancers including triple-negative breast cancer (TNBC), which may be associated with high expression and activity of DYRK1A and / or CLK1, and may optionally be further associated with dual inhibitors of CLK / DYRKS.

[0191] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of tendonopathy and osteoarthritis, which may be associated with high expression and activity of DYRK1A and / or CLK2.

[0192] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of infections caused by unicellular parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), as well as bovine diseases caused by unicellular pathogens. Said parasitic infections may be associated with the expression and activity of DYRK / CLK.

[0193] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in regulating body temperature, said body temperature regulation being linked to the expression and activity of CLKs.

[0194] According to another particular embodiment, the compounds of formula (I) of the present invention may be useful in the treatment and / or prevention of diseases selected from Phelan-McDermid syndrome; autism; further 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; further cancers, such as tissue cancers including liposarcoma, Hedgehog / GLI-dependent cancers, liver cancers including hepatocellular carcinoma, neuroinflammation, anemia, infections caused by single-cell parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), and bovine diseases caused by single-cell pathogens. The above diseases are more particularly associated with abnormalities in other DYRKs (DYR1B, 2, 3, 4) and closely related further cdc2-like kinases (CLKs) (CLK2, 3, 4).

[0195] The following examples are offered by way of illustration and are not intended to limit the scope of the invention in any way.

[0196] The following examples detail the preparation of some compounds according to the invention. The structures of the products obtained were confirmed by NMR and mass spectrometry.

[0197] Example 1: S-Alkylation of 2-thiohydantoin

[0198] Example 1.1: Synthesis of 2-methylsulfanyl-1,4-dihydroimidazol-5-one (1.1) [ka]

[0199] MeI (51.4 mL, 0.827 mol, 4 eq) was slowly added dropwise to a stirred suspension of 2-thiohydantoin (24 g, 206.6 mmol, 1 eq), DIPEA (72 mL, 413.2 mmol, 2 eq) and DMAP (10.096 g, 82.64 mmol, 0.4 eq) in DCM (413 mL) kept at 0 °C. The resulting mixture was stirred at 0 °C for 6 h. A precipitate gradually appeared. After completion (TLC), the precipitate was filtered through a fritted glass funnel. The resulting solid was adsorbed onto silica and purified by FC on silica gel (eluent: cyclohexane / AcOEt / DCM 70 / 30 / 3 to 0 / 60 / 40). The volume of the collected fractions was reduced to approximately one eighth of its initial volume until yellow crystals started to appear. The mixture was stirred at 0° C. for 30 min and the solid was collected by filtration on a fritted glass funnel to give 2-methylsulfanyl-1,4-dihydroimidazol-5-one (15.368 g, 118.1 mmol, 57%) in analytically pure form as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6, 300K) δ H 11.24(br s,1H,NH,D2O exchange),4.01(s,2H),2.47(s,3H). MS(ESI + ):[M+H] + 131.0.

[0200] Example 1.2: Synthesis of 1-methyl-2-methylsulfanyl-4H-imidazol-5-one (1.2) [ka]

[0201] MeO3BF4 (6.818 g, 46.1 mmol, 1.5 eq) was added in portions to a stirred solution of 3-methyl-2-thiohydantoin (4 g, 30.73 mmol, 1 eq) in DCM. The reaction medium was stirred at room temperature for 12 hours. After completion (TLC), the resulting mixture was washed with saturated Na2CO 3(水性) The mixture was quenched with 100 mL of ethyl acetate. The aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, adsorbed onto silica and purified by FC on silica gel (eluent: cyclohexane / AcOEt / DCM: 92 / 5 / 3 to 50 / 47 / 3) to give the desired isothiourea in analytically pure form (3.797 g, 26.33 mmol, 85%). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 4.11(s,2H),2.93(s,3H),2.51(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 179.6,162.6,58.3,25.9,11.8. MS(ESI + ):[M+H] + 145.0.

[0202] Example 2 :General Protocol 1 - Addition of Aliphatic and Aromatic Amines to 2-Alkylsulfanyl-1,4-dihydroimidazol-5-ones - Route 1 [ka]

[0203] In the above scheme, R 1 and R 5 is as defined above, and Alk is (C1-C5) alkyl.

[0204] GP1: The appropriate amine (x eq) is reacted with the appropriate 2-alkylsulfanyl-1,4-dihydroimidazol-5-one in dry THF (C=0.3M / isothiourea) in a sealed tube or sealed round flask (heat block). (a) (1 eq) of 1,2-dichlorophenyl 2,4-dichlorophenyl 2,5-dichlorophenyl 2,6-dichlorophenyl 2,7 ...

[0205] -GP1-A: Direct precipitation of the desired product: The reaction medium was stirred for 1 h at 0° C. The precipitated solid was filtered through a fritted glass funnel. High purity can be achieved after filtration by washing, reprecipitation, grinding, or recrystallization.

[0206] GP1-B: No product precipitated: The reaction mixture was poured onto EtO maintained at 0° C. The precipitated solid was filtered through a fritted glass funnel. High purity can be achieved after filtration by washing, reprecipitation, trituration, or recrystallization.

[0207] GP1-C: No product precipitated: The reaction mixture was concentrated in vacuum, adsorbed onto silica, and purified by FC. After purification, higher purity can be achieved by washing, reprecipitation, trituration, or recrystallization.

[0208] -(a) Depending on the amine, activation with AcOH may be necessary (see below for details).

[0209] Example 2.1: Synthesis of 2-(cyclohexylamino)-1,4-dihydroimidazol-5-one (2.1) [ka]

[0210] Compound (2.1) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (8.91 mmol) and 4 eq of cyclohexylamine in THF at 120° C. (heating block) for 12 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Off-white solid, 35% (571 mg). The main tautomer 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.41(br s,1H,NH,D2O exchange),6.95(br s,1H,NH,D2O exchange),3.61(s,2H),3.39-3.23(m,1H),1.88-1.75(m,2H),1.74-1.62(m,2H),1.61-1.51(m,1H),1.33-1.03(m,5H). MS(ESI + ):[M+H] + 182.0.

[0211] Example 2.2: Synthesis of 2-(cycloheptylamino)-1,4-dihydroimidazol-5-one (2.2) [ka]

[0212] Compound (2.2) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (11.52 mmol) and 4 eq of cycloheptylamine in THF at 120° C. (sealed tube, heating block) for 12 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Off-white solid, 64% (1.429 g). The yield of the main tautomer was 1.0. 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.42(br s,1H,NH,D2O exchange),6.88(br s,1H,NH,D2O exchange),3.86-3.68(m,1H),3.59(s,2H),1.89-1.76(m,2H),1.70-1.32(m,10H). MS(ESI + ):[M+H] + 196.0.

[0213] Example 2.3: Synthesis of 2-(cyclooctylamino)-1,4-dihydroimidazol-5-one (2.3) [ka]

[0214] Compound (2.3) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (11.52 mmol) and 4 eq of cyclooctylamine in THF at 120° C. (sealed tube, heating block) for 12 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Off-white solid, 72% (1.739 g). The main tautomer 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.43(br s,1H,NH,D2O exchange),6.86(br s,1H,NH,D2O exchange),3.89-3.74(m,1H),3.59(s,2H),1.90-1.27(m,14H). MS(ESI + ):[M+H] + 210.0.

[0215] Example 2.4: Synthesis of 2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1,4-dihydroimidazol-5-one (2.4) [ka]

[0216] Compound (2.4) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (16.90 mmol) and 2.5 eq of (D)-leucinol in THF at 125° C. for 4 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Pale beige solid, 52% (1.750 g). The main tautomer 1 H NMR (400MHz, DMSO-d6, 343K) δH 7.11(br s,2H,NH,D2O exchange),4.61(s,1H,OH,D2O exchange),3.91-3.70(m,1H),3.61(s,2H),3.46 -3.28(m,2H),1.70-1.56(m,1H),1.37(t,J=7.0Hz,2H),0.89(t,J=7.1Hz,6H). MS(ESI + ):[M+H] + 200.1.

[0217] Example 2.5: Synthesis of 2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1,4-dihydroimidazol-5-one (2.5) [ka]

[0218] Compound 2.5 was synthesized according to GP1-B: the reaction was carried out with intermediate 1.1 (11.52 mmol) with 2 eq of (2R)-1-methoxy-4-methyl-pentan-2-amine and 4 eq of AcOH in THF. Light beige solid, 39% (948 mg). 1 H NMR (400MHz, DMSO-d6, 343K) δ H 7.20(br s,1H,NH,D2O exchange),6.98(br s,1H,NH,D2O exchange),4.09-3.75(m,1H),3.61(s,2H),3.39-3.29(m,2H),3.27(s,3H),1.71-1.56(m,1H),1.47-1.27(m,2H),0.89(t,J=6.7Hz,6H). MS(ESI + ):[M+H] + 214.3.

[0219] Example 2.6: Preparation of 2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-1,4-dihydroimidazol-5-one (2.6) [ka]

[0220] Compound 2.6 was synthesized according to GP1-B: the reaction was carried out with intermediate 1.1 (4.088 mmol), 1.6 eq (2R)-1-fluoro-4-methyl-pentan-2-amine and 4 eq AcOH in THF at 120° C. (heating block) for 4 h. Beige solid, 32% (267 mg). 1 H NMR (400MHz, DMSO-d6, 343K) δ H 7.39(br s,1H,NH,D2O exchange),7.12(br s,1H,NH,D2O exchange),4.47-4.38(m,1H),4.36-4.26(m,1H),4.11-3.89(m,1H),3.63(s ,2H),1.73-1.59(m,1H),1.52-1.42(m,1H),1.40-1.29(m,1H),0.97-0.86(m,6H). MS(ESI + ):[M+H] + 202.1.

[0221] Example 2.7: Synthesis of 2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-1,4-dihydroimidazol-5-one (2.7) [ka]

[0222] Compound 2.7 was synthesized according to GP1-B: the reaction was carried out with intermediate 1.1 (4.088 mmol), 1.6 eq (2S)-1-fluoro-4-methyl-pentan-2-amine and 4 eq AcOH in THF at 120° C. (heating block) for 4 h. Beige solid, 44% (366 mg). 1 H NMR (400MHz, DMSO-d6, 343K) δ H7.39(br s,1H,NH,D2O exchange),7.12(br s,1H,NH,D2O exchange),4.47-4.38(m,1H),4.36-4.26(m,1H),4.11-3.89(m,1H),3.63(s ,2H),1.73-1.59(m,1H),1.52-1.42(m,1H),1.40-1.29(m,1H),0.97-0.86(m,6H). MS(ESI + ):[M+H] + 202.1.

[0223] Example 2.8: Synthesis of 2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1,4-dihydroimidazol-5-one (2.8) [ka]

[0224] Compound (2.8) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (868 μmol) and 3 eq of (1R,2R)-2-methoxycyclopentanamine in THF at 115° C. for 12 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Colorless solid, 74% (127 mg). The main tautomer 1 H NMR (400MHz, DMSO-d6, 343K) δ H 7.57(br s,1H,NH,D2O exchange),7.13(br s,1H,NH,D2O exchange),3.99-3.79(m,1H),3.69-3.63(m,1H),3.61(s,2H),3.25(s,3H),2.05-1.83(m,2H),1.73-1.40(m,4H). MS(ESI + ):[M+H] + 198.1.

[0225] Example 2.9: Synthesis of 2-[[(1S,2S)-2-methoxycyclopentyl]amino]-1,4-dihydroimidazol-5-one (2.9) [ka]

[0226] Compound (2.9) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (2.89 mmol) and 3 eq of (1SR,2S)-2-methoxycyclopentanamine in THF at 115° C. for 12 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Colorless solid, 71% (405 mg). The main tautomer 1 H NMR (400MHz, DMSO-d6, 343K) δ H 7.57(br s,1H,NH,D2O exchange),7.13(br s,1H,NH,D2O exchange),3.99-3.79(m,1H),3.69-3.63(m,1H),3.61(s,2H),3.25(s,3H),2.05-1.83(m,2H),1.73-1.40(m,4H). MS(ESI + ):[M+H] + 198.1.

[0227] Example 2.10: Synthesis of 2-(3-noradamantylamino)-1,4-dihydroimidazol-5-one (2.10) [ka]

[0228] Compound 2.10 was synthesized according to GP1-C: the reaction was carried out in dioxane with intermediate 1.1 (3.55 mmol), 3 eq 3-noradamantanamine and 4 eq AcOH in THF at 130° C. (heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 9 / 1). The final product required trituration in DCM at 0° C. Light beige solid, 65% (502 mg). 1 H NMR (400MHz, DMSO-d6, 343K) δ H7.47(br s,1H,NH,D2O exchange),6.64(br s,1H,NH,D2O exchange),3.56(s,2H),2.41(t,J=6.8Hz,1H),2.29-2.20(m,2H),2.10-1.90(m,6H),1.64-1.45(m,4H). MS(ESI + ):[M+H] + 220.2.

[0229] Example 2.11: Synthesis of 2-(1-adamantylamino)-1,4-dihydroimidazol-5-one (2.11) [ka]

[0230] Compound 2.11 was synthesized according to GP1-C: the reaction was carried out in dioxane with intermediate 1.1 (3.073 mmol), 3 eq adamantane-1-amine and 4 eq AcOH in THF at 150° C. (heating block) for 16 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 9 / 1). The final product required trituration in DCM at 0° C. Beige solid, 35% (254 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.18(br s,1H,NH,D2O exchange),6.73(br s,1H,NH,D2O exchange),3.52(s,2H),2.03(s,3H),1.96(s,6H),1.62(s,6H). MS(ESI + ):[M+H] + 234.2.

[0231] Example 2.12: Synthesis of 2-[(3-hydroxy-1-adamantyl)amino]-1,4-dihydroimidazol-5-one (2.12) [ka]

[0232] Compound 2.11 was synthesized according to GP1-C: the reaction was carried out in dioxane with intermediate 1.1 (9.22 mmol), 3 eq 3-aminoadamantan-1-ol and 4 eq AcOH in THF at 145 °C (heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required trituration in refluxing DCM. Beige solid, 58% (1.336 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.25(br s,1H,NH,D2O exchange),6.75(br s,1H,NH,D2O exchange),4.53(s,1H,OH,D2O exchange),3.53(s,2H),2.15(br s,2H),1.90-1.78(m,6H),1.60-1.35(m,6H). MS(ESI + ):[M+H] + 250.3.

[0233] Example 2.13: Synthesis of 2-[(3-methoxy-1-adamantyl)amino]-1,4-dihydroimidazol-5-one (2.13) [ka]

[0234] Compound 2.13 was synthesized according to GP1-C: the reaction was carried out in dioxane with intermediate 1.1 (768 μmol), 3 eq 3-methoxyadamantan-1-amine and 4 eq AcOH in THF at 150 °C (heating block) for 16 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 9 / 1). Brown solid, 50% (102 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.30(br s,1H,NH,D2O exchange),6.77(br s,1H,NH,D2O exchange),3.53(s,2H),3.12(s,3H),2.21(br s, 2H), 1.95-1.80 (m, 6H), 1.67-1.56 (m, 4H), 1.55-1.40 (m, 2H). MS(ESI+ ):[M+H] + 264.3.

[0235] Example 2.14: Synthesis of 2-[(3-fluoro-1-adamantyl)amino]-1,4-dihydroimidazol-5-one (2.14) [ka]

[0236] Compound 2.14 was synthesized according to GP1-C: the reaction was carried out in dioxane with intermediate 1.1 (3.073 mmol), 3 eq 3-fluoro-adamantan-1-amine and 4 eq AcOH in THF at 130° C. (heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required trituration in Et2O at 0° C. Beige solid, 44% (343 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.41(br s,1H,NH,D2O exchange),6.83(br s,1H,NH,D2O exchange),3.54(s,2H),2.35-2.24(m,2H),2.14(d,J=5.9Hz,2H),2.01-1.72(m,8H),1.56-1.43(m,2H). MS(ESI + ):[M+H] + 252.3.

[0237] Example 2.15: Synthesis of 2-[[(1R)-2-Methoxy-1-phenyl-ethyl]amino]-1,4-dihydroimidazol-5-one (2.15) [ka]

[0238] Compound (2.15) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (3.073 mmol), 3 eq (1R)-2-methoxy-1-phenyl-ethanamine and 4 eq AcOH in THF at 115° C. (sealed tube, heating block) for 12 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Beige solid, 58% (414 mg). 1 H NMR (400MHz, DMSO-d6, 343K) δ H 7.95(bs,1H,NH,D2O exchange),7.60-7.22(m,5H),7.17(bs,1H,NH,D2O exchange),5.09-4.85( m,1H),3.67-3.63(m,1H),3.62(s,2H),3.56(dd,J=10.2,5.2Hz,1H),3.29(s,3H). MS(ESI + ):[M+H] + 234.2.

[0239] Example 2.16: Synthesis of tert-butyl N-[(2R)-2-[(5-oxo-1,4-dihydroimidazol-2-yl)amino]-2-phenyl-ethyl]carbamate (2.16) [ka]

[0240] Compound (2.16) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (10.18 mmol), 1.5 eq of tert-butyl N-[(2R)-2-amino-2-phenyl-ethyl]carbamate and 2.3 eq of AcOH in THF at 115° C. (sealed tube, heating block) for 6 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Colorless solid, 40% (1.517 g). 1 H NMR (400MHz, DMSO-d6, 343K) δ H7.83(br s,1H,NH,D2O exchange),7.56-7.05(m,5H+NH,D2O exchange),6.63(br s,1H,NH,D2O exchange),4.91(br s,1H),3.59(s,2H),3.29(t,J=6.5Hz,2H),1.36(s,9H). MS(ESI + ):[M+H] + 319.2.

[0241] Example 2.17: Synthesis of tert-butyl N-[(2S)-2-[(5-oxo-1,4-dihydroimidazol-2-yl)amino]-2-phenyl-ethyl]carbamate (2.17) [ka]

[0242] Compound (2.17) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (10.92 mmol), 1.5 eq of tert-butyl N-[(2S)-2-amino-2-phenyl-ethyl]carbamate and 2.3 eq of AcOH in THF at 115° C. (heating block) for 6 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Colorless solid, 38% (1.306 g). 1 H NMR (400MHz, DMSO-d6, 343K) δ H 7.83(br s,1H,NH,D2O exchange),7.56-7.05(m,5H+NH,D2O exchange),6.63(br s,1H,NH,D2O exchange),4.91(br s,1H),3.59(s,2H),3.29(t,J=6.5Hz,2H),1.36(s,9H). MS(ESI + ):[M+H] + 319.3.

[0243] Example 2.18: Synthesis of 2-[(4-methylthiazol-2-yl)methylamino]-1,4-dihydroimidazol-5-one (2.18) [ka]

[0244] Compound (2.18) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (3.073 mmol), 2 eq of (4-methylthiazol-2-yl)methanamine and 3 eq of AcOH in THF at 110° C. (sealed tube, heating block) for 3 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Beige solid, 35% (248 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.21(br s,1H,NH,D2O exchange),7.59(br s,1H,NH,D2O exchange),7.17(s,1H),4.65(s,2H),3.69(s,2H),2.33(s,3H). MS(ESI + ):[M+H] + 211.1.

[0245] Example 2.19: Synthesis of 2-(tetrahydropyran-4-ylmethylamino)-1,4-dihydroimidazol-5-one (2.19) [ka]

[0246] Compound (2.19) was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (3.073 mmol) and 3 eq of tetrahydropyran-4-ylmethanamine in THF at 110° C. (sealed tube, heating block) for 16 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Beige solid, 70% (424 mg). 1 H NMR (400MHz, DMSO-d6, 343K) δ H7.47(br s,1H,NH,D2O exchange),7.22(br s,1H,NH,D2O exchange),3.90-3.80(m,2H),3.61(s,2H),3.28(td,J=11.6,2.0Hz,2H),3.1 1-3.05(m,2H),1.80-1.73(m,1H),1.64-1.52(m,2H),1.19(qd,J=11.8,4.4Hz,2H). MS(ESI + ):[M+H] + 198.1.

[0247] Example 2.20: Synthesis of 2-[4-(4-methylpiperazin-1-yl)anilino]-1,4-dihydroimidazol-5-one (2.20) [ka]

[0248] Compound 2.20 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.1 (4.61 mmol), 2 eq 4-(4-methylpiperazin-1-yl)aniline and 3 eq AcOH in THF at 130° C. (heating block) for 3 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required trituration in EtOH at 0° C. Beige solid, 59% (749 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 9.66(br s,1H,NH,D2O exchange),7.43(br s,1H,NH,D2O exchange),7.33-7.19(m,2H),6.91(d,J=8.9Hz,2H),3.67(s,2H),3.13-3.03(m,4H),2.47-2.41(m,4H),2.21(s,3H). MS(ESI + ):[M+H] + 274.2.

[0249] Example 2.21: Synthesis of 2-(2-pyridylamino)-1,4-dihydroimidazol-5-one (2.21) [ka]

[0250] Compound 2.21 was synthesized according to GP1-C: the reaction was carried out in dioxane with intermediate 1.1 (6.15 mmol), 2.5 eq 2-aminopyridine and 3 eq AcOH in THF at 130 °C (heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required trituration in DCM at room temperature. Light beige solid, 35% (384 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 10.99(bs,1H,NH,D2O exchange),9.20(bs,1H,NH,D2O exchange),8.30-8.22(m,1H),7.79- 7.73(m,1H),7.15(d,J=8.3Hz,1H),7.05(dd,J=7.3,5.0Hz,1H),3.91(s,2H). MS(ESI + ):[M+H] + 177.2.

[0251] Example 2.22: Synthesis of (±)-2-(oxepan-3-ylamino)-1,4-dihydroimidazol-5-one (2.22) [ka]

[0252] Compound 2.22 was synthesized according to GP1-A: the reaction was carried out with intermediate (1.1) (851 μmol) and 2.5 eq of oxepan-3-amine in THF at 110° C. (heating block) for 12 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Light beige solid, 73% (122 mg). 1 H NMR (400MHz, DMSO-d6, 343K) δ H7.33(br s,1H,NH,D2O exchange),7.05(br s,1H,NH,D2O exchange),3.96-3.79(m,1H),3.76-3.62(m,3H),3.61(s,2H),3.5 6-3.46(m,1H),1.91-1.77(m,1H),1.77-1.60(m,4H),1.59-1.46(m,1H). MS(ESI + ):[M+H] + 198.1.

[0253] Example 2.23: Synthesis of 2-(cyclohexylamino)-1-methyl-4H-imidazol-5-one (2.23) [ka]

[0254] Compound 2.23 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq cyclohexylamine and 5 eq AcOH in dioxane at 150° C. (heating block) for 3 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Brown solid, 44% (89 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 6.64(br s,1H,NH,D2O exchange),3.81(s,2H),3.48-3.37(m,1H),2.88(s,3H),1.87-1.55(m,4H),1.34-1.07(m,6H). MS(ESI + ):[M+H] + 196.3.

[0255] Example 2.24: Synthesis of 2-(cyclooctylamino)-1-methyl-4H-imidazol-5-one (2.24) [ka]

[0256] Compound 2.24 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq cyclooctylamine and 5 eq AcOH in dioxane at 150° C. (heating block) for 3 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Brown oil, 41% (105 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 6.71(br s,1H,NH,D2O exchange),3.84(s,2H),3.70(br s,1H),2.89(s,3H),1.78-1.41(m,14H). MS(ESI + ):[M+H] + 224.3.

[0257] Example 2.25: Synthesis of 2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1-methyl-4H-imidazol-5-one (2.25) [ka]

[0258] Compound 2.25 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq (2R)-1-methoxy-4-methyl-pentan-2-amine and 3 eq AcOH in dioxane at 150° C. (heating block) for 3 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Brown oil, 41% (97 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H nd. MS(ESI + ) [M+H] + 228.3.

[0259] Example 2.26: Synthesis of 2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1-methyl-4H-imidazol-5-one (2.26) [ka]

[0260] Compound (2.26) was synthesized according to GP1-C: the reaction was carried out with intermediate (1.04 mmol), 3 eq (1R,2R)-2-methoxycyclopentanamine and 5 eq AcOH in dioxane at 130° C. (heating block) for 3 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Brown oil, 47% (130 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.07(br s,1H,NH,D2O exchange),3.83(s,2H),3.76(br s,1H),3.60(br s,1H),3.22(s,3H),2.86(s,3H),1.98-1.82(m,2H),1.69-1.47(m,3H),1.43-1.33(m,1H). MS(ESI + ):[M+H] + 212.3.

[0261] Example 2.27: Synthesis of 2-[[(1S,2S)-2-methoxycyclopentyl]amino]-1-methyl-4H-imidazol-5-one (2.27) [ka]

[0262] Compound (2.26) was synthesized according to GP1-C: the reaction was carried out with intermediate (1.04 mmol), 3 eq (1S,2S)-2-methoxycyclopentanamine and 5 eq AcOH in dioxane at 130° C. (heating block) for 3 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Brown oil, 33% (96 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.07(br s,1H,NH,D2O exchange),3.83(s,2H),3.76(br s,1H),3.60(br s,1H),3.22(s,3H),2.86(s,3H),1.98-1.82(m,2H),1.69-1.47(m,3H),1.43-1.33(m,1H). MS(ESI+ ):[M+H] + 212.3.

[0263] Example 2.28: Synthesis of 2-(3-noradamantylamino)-1-methyl-4H-imidazol-5-one (2.28) [ka]

[0264] Compound (2.28) was synthesized according to GP1-C: the reaction was carried out with intermediate (1.04 mmol), 3 eq of 3-noradamantanamine and 5 eq of AcOH in dioxane at 150 °C (heating block) for 6 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Beige solid, 37% (100 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 1 H NMR (400MHz, DMSO-d6, 300K) δ 6.33 (s, 1H, NH, D2O exchange), 3.84 (s, 2H), 2.92 (s, 3H), 2.26-2.09 (m, 3H), 2.01-1.84 (m, 6H), 1.61-1.43 (m, 4H). MS(ESI + ):[M+H] + 234.3.

[0265] Example 2.29: Synthesis of 2-(1-adamantylamino)-1-methyl-4H-imidazol-5-one (2.29) [ka]

[0266] Compound 2.29 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq adamantane-1-amine and 5 eq AcOH in dioxane at 150° C. (heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Brown solid, 7% (19 mg). 1H NMR (400MHz, DMSO-d6, 300K) δ H 5.58 (br s, 1H, NH, D2O exchange), 3.83 (s, 2H), 2.90 (s, 3H), 2.11-1.97 (m, 8H), 1.71-1.59 (m, 7H). MS(ESI + ):[M+H] + 248.3.

[0267] Example 2.30: Synthesis of 2-[(3-hydroxy-1-adamantyl)amino]-1-methyl-4H-imidazol-5-one (2.30) [ka]

[0268] Compound 2.30 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq 3-hydroxyadamantan-1-amine and 5 eq AcOH in dioxane at 150° C. (heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Beige solid, 11% (52 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 5.76(br s,1H,NH,D2O exchange),4.46(s,1H,OH,D2O exchange),3.85(s,2H),2.90(s,3H),2.15(s,2H),2.03-1.91(m,6H),1.60-1.39(m,6H). MS(ESI + ):[M+H] + 264.2.

[0269] Example 2.31: Synthesis of 2-[(3-methoxy-1-adamantyl)amino]-1-methyl-4H-imidazol-5-one (2.31) [ka]

[0270] Compound 2.31 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq 3-methoxyadamantan-1-amine and 5 eq AcOH in dioxane at 150° C. (heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Beige solid, 10% (36 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 5.75(br s,1H,NH,D2O exchange),3.84(s,2H),3.11(s,3H),2.89(br s,3H),2.20(br s,2H),2.09-1.91(m,6H),1.68-1.54(m,4H),1.54-1.41(m,2H). MS(ESI + ):[M+H] + 278.3.

[0271] Example 2.32: Synthesis of 2-[(3-fluoro-1-adamantyl)amino]-1-methyl-4H-imidazol-5-one (2.32) [ka]

[0272] Compound 2.32 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq 3-fluoroadamantan-1-amine and 5 eq AcOH in dioxane at 150° C. (heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Beige solid, 14% (64 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H nd. MS(ESI + ):[M+H] + 266.2.

[0273] Example 2.33: Synthesis of 1-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]-4H-imidazol-5-one (2.33) [ka]

[0274] Compound 2.33 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq [2-(trifluoromethyl)phenyl]methanamine and 5 eq AcOH in dioxane at 150° C. (heating block) for 1.5 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Brown oil, 33% (131 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.87-7.76(m,1H),7.72-7.61(m,2H),7.47-7.38(m,1H),7.25(br s,1H,NH,DO exchange),4.49(s,2H),3.86(s,2H),2.96(s,3H). MS(ESI + ):[M+H] + 272.2.

[0275] Example 2.34: Synthesis of 2-[[(1R)-2-Methoxy-1-phenyl-ethyl]amino]-1-methyl-4H-imidazol-5-one (2.34) [ka]

[0276] Compound 2.34 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq (1R)-2-methoxy-1-phenyl-ethanamine and 3 eq AcOH in dioxane at 150° C. (heating block) for 1.5 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Beige oil, 45% (195 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H7.40-7.36(m,2H),7.29(t,J=7.4Hz,2H),7.23-7.17(m,1H),6.96(br s,1H,NH,D2O exchange),4.60(br s,1H),3.88-3.70(m,2H),3.46(br s,2H),3.24(s,3H),2.92(br s,3H). MS(ESI + ):[M+H] + 248.2.

[0277] Example 2.35: Synthesis of 1-methyl-2-[(4-methylthiazol-2-yl)methylamino]-4H-imidazol-5-one (2.35) [ka]

[0278] Compound 2.35 was synthesized according to GP1-C: the reaction was carried out with intermediate 1.2 (1.04 mmol), 3 eq (4-methylthiazol-2-yl)methanamine and 5 eq AcOH in dioxane at 150° C. (heating block) for 1.5 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Beige solid, 39% (130 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 7.32 (bs, 1H, NH, D2O exchange), 7.06 (s, 1H), 4.46 (s, 2H), 3.89 (s, 2H), 2.92 (s, 3H), 2.32 (s, 3H). MS(ESI + ):[M+H] + 225.2.

[0279] Example 3 General Protocol 2: Synthesis of 4- and 5-Substituted N-Alkyl-2-nitro-anilines [ka]

[0280] In the above scheme, X is either a cyano group or a halogen atom, in particular a bromine atom, and R4 is (C1-C3) alkyl.

[0281] GP2: The appropriate amine (3 eq) was added dropwise to a stirred solution of appropriately substituted o-fluoronitrobenzene (1 eq) in EtOH (C=1M) maintained at 0° C. The resulting mixture was stirred at 0° C. for 1 h, allowed to warm to room temperature, and stirred for an additional 12 h. After completion (TLC), the mixture was partially concentrated in vacuo and poured onto water. The precipitated solid was filtered through a Büchner funnel and thoroughly dried in vacuo. The resulting light red / orange solid was reprecipitated from DCM / pentane at 0° C. and gave the desired product in analytically pure form.

[0282] Example 3.1: Synthesis of 5-bromo-N-methyl-2-nitro-aniline (3.1) [ka]

[0283] Compound 3.1 was synthesized according to GP2: the reaction was carried out with 4-bromo-2-fluoro-1-nitrobenzene (68.18 mmol) and MeNH2 (2 M solution in MeOH or 33% in EtOH, 3 eq). Light orange solid, 87% (13.763 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.30-8.20(m,1H,NH,D2O exchange),7.98(d,J=9.1Hz,1H),7.16(s,1H),6.82(d,J=9.1Hz,1H),2.94(d,J=5.0Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 146.3,130.9,130.1,127.9,117.7,116.4,29.8. MS(ESI + ):[M+H] + 232.8.

[0284] Example 3.2: Synthesis of 3-(methylamino)-4-nitro-benzonitrile (3.2) [ka]

[0285] Compound (3.2) was synthesized according to GP2: the reaction was carried out with 3-fluoro-4-nitro-benzonitrile (150.5 mmol) and MeNH2 (2 M solution in MeOH or 33% in EtOH, 3 eq). Light orange solid, 97% (25.917 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.25(d,J=5.3Hz,1H,NH,D2O exchange),8.18(d,J=8.7Hz,1H),7.51(s,1H),7.01(dd,J=8.8,1.7Hz,1H),2.97(d,J=5.0Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 145.2,132.9,127.4,119.4,118.1,117.7,116.4,29.9. MS(ESI + ):[M+H] + 178.0.

[0286] Example 4: General Protocol 3 - Synthesis of Substituted N1- and N2-Alkyl-Benzene-1,2-diamines [ka]

[0287] In the above scheme, X is either a cyano group or a halogen atom, particularly a bromine atom, and is (C1-C3) alkyl.

[0288] GP3-A (X=Br): NH4Cl (10 eq) was carefully added in portions over 30 min to a stirred solution of the appropriate bromo-N-alkyl-2-nitro-aniline (1 eq) and zinc dust (10 eq) in a THF / MeOH mixed solvent (1 / 1) (C=0.5 M) kept at 0° C. After the addition was complete, the mixture was stirred for another hour at 0° C. (until the orange color completely disappeared) and then allowed to warm slowly to room temperature. The reaction medium was stirred for another 6 hours at room temperature. After completion (TLC), the mixture was filtered on a pad of Celite. The Celite was rinsed with MeOH. The filtrate was concentrated in vacuum, adsorbed on silica and purified by FC on silica gel (eluent: cyclohexane / AcOEt: 8 / 2 to 1 / 1) to give the desired bromo-N-alkyl-benzene-1,2-diamine in analytically pure form.

[0289] Example 4.1: Synthesis of 4-Bromo-N2-methyl-benzene-1,2-diamine (4.1) [ka]

[0290] Compound 4.1 was synthesized according to GP3-A: the reaction was carried out with intermediate 3.1 (17.31 mmol). Brown oil, 81% (2.83 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 6.52(dd,J=8.1,2.2Hz,1H),6.44(d,J=8.1Hz,1H),6.40(d,J=2.2Hz,1H),4.88(bs,1H),4.61(bs,2H),2.68(d,J=3.8Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 138.8,134.4,118.4,114.6,110.9,108.8,29.9. MS(ESI + ):[M+H] + 201.1.

[0291] GP3-B (X=CN): 10% Pd / C (10% w / w) was carefully added portionwise to a stirred solution of the appropriate cyano-substituted N-alkyl-2-nitro-aniline (1 eq) and ammonium formate (10 eq) in MeOH (C=0.3 M). The resulting mixture was refluxed for 6 h. After completion (TLC), the mixture was filtered over a pad of Celite. The Celite was rinsed with MeOH. The filtrate was concentrated in vacuo and the resulting crude was purified by elution with AcOEt and saturated NaHCO 3(水性) The mixture was partitioned between 100 ml of ethyl acetate and 100 ml of ethyl acetate. The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was reprecipitated from DCM / pentane at 0° C. to give the desired product in analytically pure form.

[0292] Example 4.2: Synthesis of 4-amino-3-(methylamino)benzonitrile (4.2) [ka]

[0293] Compound 4.2 was synthesized according to GP3-B: the reaction was carried out with intermediate 3.2 (146.2 mmol). Beige solid, 87% (18.764 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 6.85(dd,J=8.0,1.8Hz,1H),6.61-6.52(m,2H),5.48(bs,2H,NH,D2O exchange),5.01 (q,J=5.0Hz,1H,NH,D2O exchange),2.72(d,J=4.9Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 140.4,136.4,122.2,121.4,112.2,110.4,97.3,29.9. MS(ESI + ):[M+H] + 148.1.

[0294] Example 5General Protocol 4: Cyclization of Brominated 2-Aminophenols and N2-Methylbenzene-1,2-diamines with Triethyl Orthoformate [ka]

[0295] In the above scheme, Y is an -OH group or -NHR 4 X is either a cyano group or a halogen atom, particularly a bromine atom, and R 4 is (C1-C3) alkyl.

[0296] GP4-A (Y=OH and X=Br): A solution of the appropriate 2-aminobromophenol (1 eq) and (EtO)3CH (2 eq) in toluene (C=0.5 M) was irradiated for 2 h at 130° C. After completion (TLC), the mixture was cooled to room temperature, adsorbed directly onto silica, and purified by FC on silica gel using the appropriate solvent gradient (eluent: cyclohexane / AcOEt: 1 / 0 to 6 / 4) to give the desired bromo-1,3-benzoxazole in analytically pure form.

[0297] Example 5.1: Synthesis of 6-bromo-1,3-benzoxazole (5.1) [ka]

[0298] Compound 5.1 was synthesized according to GP4-A: the reaction was carried out with 2-amino-5-bromophenol (21.27 mmol). Light beige solid, 89% (3.745 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.79(s,1H),8.12(s,1H),7.77(d,J=8.4Hz,1H),7.58(d,J=8.5Hz,1H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C154.8,150.0,139.1,127.8,121.5,117.7,114.5. MS(ESI + ):[M+H] + 199.7.

[0299] GP4-B(Y=NHR 4 and X=Br): A solution of the appropriate 4-bromo-N-methyl-benzene-1,2-diamine (1 eq), (EtO)3CH (2 eq) and APTS.HO (5 mol%) in toluene (C=0.5 M) was irradiated at 130 °C for 2 h. After completion (TLC), the mixture was washed with AcOEt and saturated NaHCO 3(水性) The mixture was partitioned between 1,2-dichloromethane and 1,2-dichloromethane. The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was dissolved in DCM / pentane at 0° C. and precipitated from pentane. The precipitated light beige solid was filtered on a Buchner funnel, rinsed thoroughly with pentane, and dried in vacuo to give the desired bromo-1-methyl-benzimidazole in analytically pure form.

[0300] Example 5.2.: 6-Bromo-1-methyl-benzimidazole (5.2) [ka]

[0301] Compound 5.2 was synthesized according to GP4-B: the reaction was carried out with intermediate 4.1 (10.94 mmol). Light beige solid, 79% (1.815 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.21(s,1H),7.86(s,1H),7.60(d,J=8.5Hz,1H),7.33(d,J=8.4Hz,1H),3.83(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C145.6,142.4,135.8,124.3,121.0,114.7,113.3,30.8. MS(ESI + ):[M+H] + 212.8.

[0302] GP4-C(Y=NHR 4 and X=CN): A solution of cyano-substituted N2-methylbenzene-1,2-diamine (1 eq) was refluxed in HCOOH (C=0.4 M) for 4 h. After completion (TLC), the mixture was allowed to warm to room temperature and concentrated in vacuo. The resulting crude was dissolved in saturated NaHCO 3(水性) The precipitated solid was filtered off using a Buchner funnel. The solid was dissolved in DCM and water, saturated NaHCO 3(水性) The solid was washed with hexane, dried over MgSO4, filtered, and concentrated in vacuo to give the desired solid in analytically pure form. Higher purity can be obtained by reprecipitation from DCM / pentane at 0°C.

[0303] Example 5.3: Synthesis of 3-methylbenzimidazole-5-carbonitrile (5.3) [ka]

[0304] Compound 5.3 was synthesized according to GP4-C: the reaction was carried out with intermediate 4.2 (127.5 mmol). Beige solid, 94% (18.829 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.46(s,1H),8.24(s,1H),7.82(d,J=8.4Hz,1H),7.59(dd,J=8.3,1.6Hz,1H),3.90(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 148.1,146.2,134.3,124.8,120.4,119.9,115.9,104.0,31.1. MS(ESI + ):[M+H] + 158.1.

[0305] Example 6: General Protocol 5 - Palladium-Catalyzed Vinylation of Heteroaryl Bromides [ka]

[0306] In the above scheme, A, B and R 2 is as defined above.

[0307] GP5-A: A mixture of the appropriate heteroaryl bromide (1 eq), potassium vinyltrifluoroborate (1.2 eq), CsCO (2 eq) and Pd(PPh) (5 mol%) in dioxane / HO (95 / 5) (C=0.4 M) was thoroughly purged with vacuum / argon cycles. The mixture was refluxed and heated for 12 h. After completion ( 1 H NMR), the mixture was partitioned between HO and AcOEt. The aqueous layer was extracted three times with AcOEt. The combined organic layers were dried over MgSO, filtered, concentrated in vacuo, adsorbed onto silica, and purified by FC on silica gel using the appropriate solvent gradient (see below for details for each compound) to give the desired vinylheteroaryls in analytically pure form.

[0308] Example 6.1: Synthesis of 6-vinyl-1,3-benzoxazole (6.1) [ka]

[0309] Compound 6.1 was synthesized according to GP5-A: the reaction was carried out with intermediate 5.1 (40.70 mmol). Purification by FC: elution: cyclohexane / AcOEt: 99 / 1-8 / 2. Brown oil, 74% (4.345 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H8.73(s,1H),7.90(s,1H),7.75(d,J=8.3Hz,1H),7.53(d,J=8.2Hz,2H),6.8 6(dd,J=17.7,11.0Hz,1H),5.94(d,J=17.6Hz,1H),5.33(d,J=10.9Hz,1H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 154.7,149.9,139.5,136.2,135.3,123.2,119.9,115.0,108.4. MS(ESI + ):[M+H] + 145.9. (NB: (6.1) showed almost the same Rf as the starting material (5.1) in cyclohexane / AcOEt:8 / 2.

[0310] GP5-B: In a sealed tube thoroughly purged with vacuum / argon cycles, the appropriate heteroaryl bromide (1 eq), potassium vinyltrifluoroborate (2 eq), CsCO (3 eq) and PEPPSI-iPr (15 mol%) in dioxane / HO (95 / 5) (C=0.4 M) were irradiated at the appropriate temperature for 4 h (see below for details on each compound). 1 1 H NMR), the mixture was cooled to room temperature, adsorbed directly onto silica, and purified by FC on silica gel using the appropriate solvent gradient (see below for details for each compound) to give the desired vinyl heteroaryls in analytically pure form.

[0311] Example 6.2: Synthesis of 1-methyl-6-vinyl-benzimidazole (6.2) [ka]

[0312] Compound 6.2 was synthesized according to GP5-B: the reaction was carried out with intermediate 5.2 (4.26 mmol). Purification by FC: elution: DCM / MeOH: 99 / 1 to 94 / 6. Brown oil, 82% (551 mg). 1 H NMR (400MHz, CDCl3, 300K) δH 7.87(s,1H),7.74(d,J=8.3Hz,1H),7.49-7.33(m,2H),6.86(dd,J=17.5, 10.9Hz, 1H), 5.79 (d, J=17.5Hz, 1H), 5.26 (d, J=10.9Hz, 1H), 3.85 (s, 3H). 13 C NMR (101MHz, CDCl3) δ C 144.2,143.8,137.3,135.0,133.2,120.8,120.2,113.2,107.3,31.1. MS(ESI + ):[M+H] + 159.1.

[0313] Example 6.3: Synthesis of 6-vinyl-1,2,3-benzothiadiazole (6.3) [ka]

[0314] Compound (6.3) was synthesized according to GP5-B: the reaction was carried out with 6-bromo-1,2,3-benzothiadiazole (15.38 mmol). Purification by FC: elution: cyclohexane / AcOEt: 98 / 2 to 8 / 2. Brown oil, 59% (1.466 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.66(d,J=8.7Hz,1H),8.45(s,1H),7.93(d,J=8.7Hz,1H),6.97(dd,J=17.6,10.9Hz,1H),6.13(d,J=17.6Hz,1H),5.55(d,J=10.9Hz,1H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C ,157.4,141.4,138.3,135.5,125.5,123.3,118.5,117.8. MS(ESI + ):[M+H] + 163.1.

[0315] Example 7:General Protocol 6 - Synthesis of Heteroarylcarbaldehydes from Vinyl Heteroaryls - Osmium-Catalyzed Lemieux-Johnson Oxidation [ka]

[0316] In the above scheme, A, B and R 2 is as defined above.

[0317] GP6: NaIO4 (4 eq) was added portionwise to a stirred solution of the appropriate vinyl heteroaryl (1 eq), 2,6-lutidine (2 eq), and OsO4 (4% w / w H2O solvent, 5 mol%) in dioxane / H2O (1 / 1) (C=0.2 M) maintained at 0°C. The reaction mixture was stirred vigorously at 0°C for 1 h, allowed to warm to room temperature, and stirred for an additional 4 h. After completion (TLC), the mixture was partitioned between AcOEt and H2O. The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with saturated NH4Cl (水性) , saturated NaHCO 3(水性) The mixture was washed with hexane, dried over MgSO4, filtered, and concentrated in vacuo (trace amounts of 2,6-lutidine were removed by coevaporation with toluene). The solid residue was adsorbed onto silica and purified by FC on silica gel using the appropriate solvent gradient (see below for details on each compound).

[0318] Example 7.1: Synthesis of 1,3-benzoxazole-6-carbaldehyde (7.1) [ka]

[0319] Compound 7.1 was synthesized according to GP6: the reaction was carried out with intermediate 6.1 (20.66 mmol). Purification by FC: elution: cyclohexane / AcOEt: 99 / 1-7 / 3. Light beige solid, 87% (2.654 g). 1H NMR (400MHz, DMSO-d6, 300K) δ H 10.12(s,1H),9.01(s,1H),8.34(s,1H),8.16-7.91(m,2H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 192.1,157.5,149.5,144.6,134.0,126.0,120.7,112.6. MS(ESI + ):[M+H] + 147.9.

[0320] Example 7.2: Synthesis of 3-methylbenzimidazole-5-carbaldehyde (7.2) [ka]

[0321] Compound 7.2 was synthesized according to GP6: the reaction was carried out with intermediate 6.2 (3.48 mmol). Purification by FC: elution: DCM / MeOH: 99 / 1 to 94 / 6. Colorless solid, 54% (300 mg). 1 H NMR (400MHz, CDCl3, 300K) δ H 10.12(s,1H),8.39-8.22(m,1H),8.02(s,1H),7.95(d,J=8.4Hz,1H),7.87(d,J=8.3Hz,1H),3.98(s,3H). 13 C NMR (101MHz, CDCl3, 300K) δ C 192.1,148.5,147.0,134.9,132.1,124.7,120.9,111.4,31.5. MS(ESI + ):[M+H] + 161.1.

[0322] Example 7.3: Synthesis of 1,2,3-benzothiadiazole-6-carbaldehyde (7.3) [ka]

[0323] Compound 7.3 was synthesized according to GP6: the reaction was carried out with intermediate 6.3 (9.04 mmol). Purification by FC: elution: cyclohexane / AcOEt: 95 / 5 to 80 / 20. Colorless solid, 41% (609 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 10.27(s,1H),9.03(s,1H),8.89(d,J=8.6Hz,1H),8.20(dd,J=8.6,1.5Hz,1H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 192.9,159.4,141.1,135.5,126.5,124.1,124.1. MS(ESI + ):[M+H] + 165.0.

[0324] Example 8: General Protocol 7 - Synthesis of Heteroarylcarbaldehydes from Heteroarylcarbonitriles - Adam's catalyst-mediated oxidation [ka]

[0325] In the above scheme, A, B and R 2 is as defined above.

[0326] GP7: Adam's catalyst (23 mol%) was carefully added portionwise to a stirred solution of the appropriate carbonitrile (1 eq) in HCOOH / HO solution (9 / 1) (C=0.3 M). The resulting mixture was refluxed for 48 h. After completion (TLC), the mixture was allowed to warm to room temperature and filtered over a pad of Celite. The Celite was rinsed with HCOOH. The filtrate was concentrated in vacuo and then washed with DCM and saturated NaHCO 3(水性) The aqueous layer was extracted three times with DCM. The combined organic layers were washed with saturated NaHCO 3(水性)The extract was then concentrated in vacuo, washed with water, dried over MgSO4, filtered, concentrated in vacuo, adsorbed onto silica, and purified by FC on silica gel (see below for details).

[0327] Example 8.1: Synthesis of 3-methylbenzimidazole-5-carbaldehyde (7.2)

[0328] Compound 7.2 was synthesized from intermediate 5.3 (30.32 mmol) according to GP7. Purification by FC: elution: DCM / MeOH: 99 / 1 to 94 / 6. Colorless solid, 61% (2.986 g). The final product required reprecipitation from DCM / pentane at 0° C. The spectroscopic and analytical data were the same as those previously described in Example 7.2.

[0329] Example 9: General Protocol 8 - Knoevenagel condensation of thiohydantoins with heteroarylcarbaldehydes (Route 2) [ka]

[0330] In the above scheme, A, B, R 2 and R 5 is as defined above.

[0331] GP8: A stirred solution of thiohydantoin (1 eq), appropriate heteroarylcarbaldehyde (1 eq), organic base (1 eq) and AcOH (1 eq) in EtOH (C=0.3M) was heated in a sealed tube in a microwave oven (Anton Paar) at the appropriate temperature for the indicated time (see below for details for each compound). Upon completion (after the heteroarylcarbaldehyde was consumed on TLC), the reaction medium was cooled and added to stirred water. The precipitated solid was stirred for 30 minutes and then filtered through a fritted glass funnel, thoroughly dried and could be used in the next step without further purification. Higher purity could be obtained by trituration.

[0332] Example 9.1: Synthesis of (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-thioxo-imidazolidin-4-one (9.1) [ka]

[0333] Compound 9.1 was synthesized according to GP8: the reaction was carried out with 2-thiohydantoin (2.72 mmol), intermediate (7.1), AcOH and ethanolamine as organic base. Reaction temperature: 80° C., time: 15 min. The final product required trituration. Yellow solid, 72% (483 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.33(bs,2H,NH,D2O exchange),8.84(s,1H),8.25(s,1H),7.82(d,J=8.3Hz,1H),7.75(d,J=8.4Hz,1H),6.64(s,1H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 179.4,165.8,155.7,149.8,140.3,130.2,128.0,127.7,120.2,112.2,111.1. MS(ESI + ):[M+H] + 245.8.

[0334] Example 9.2: Synthesis of (5Z)-5-(1H-indazol-5-ylmethylene)-2-thioxo-imidazolidin-4-one (9.2) [ka]

[0335] Compound (9.2) was synthesized according to GP8: the reaction was carried out with 2-thiohydantoin (4.42 mmol), indazole-5-carbaldehyde, AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 89% (742 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 13.24(bs,1H,NH,D2O exchange),12.33(bs,1H,NH,D2O exchange),12.19(bs,1H,NH,D2O exchange),8. 27(s,1H),8.14(s,1H),7.70(d,J=8.7Hz,1H),7.55(d,J=8.7Hz,1H),6.64(s,1H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 179.2,166.3,140.1,135.0,129.0,126.8,125.2,123.8,113.6,111.0. MS(ESI + ):[M+H] + 244.9.

[0336] Example 9.3: Synthesis of (5Z)-5-[(2-methylindazol-5-yl)methylene]-2-thioxo-imidazolidin-4-one (9.3) [ka]

[0337] Compound (9.3) was synthesized according to GP8: the reaction was carried out with 2-thiohydantoin (2.12 mmol), 2-methylindazole-5-carbaldehyde, AcOH, piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 89% (485 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.31(bs,1H,NH,D2O exchange),12.16(bs,1H,NH,D2O exchange),8.44(s,1H),8.22(s,1H),7.62-7.54(m,2H),6.58(s,1H),4.19(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.6,165.8,147.7,127.5,126.3,126.1,125.2,123.9,121.9,117.0,113.3,39.9. MS(ESI + ):[M+H] + 259.1.

[0338] Example 9.4: Synthesis of (5Z)-5-[(1-methylindazol-5-yl)methylene]-2-thioxo-imidazolidin-4-one (9.4) [ka]

[0339] Compound (9.4) was synthesized according to GP8: the reaction was carried out with 2-thiohydantoin (1.72 mmol), 1-methylindazole-5-carbaldehyde, AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 92% (408 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H12.33(bs,1H,NH,D2O exchange),12.20(bs,1H,NH,D2O exchange),8.24(s,1H),8.11(d,J=0.9Hz ,1H),7.75(dd,J=8.9,1.4Hz,1H),7.67(d,J=8.8Hz,1H),6.64(s,1H),4.06(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.8,165.8,139.4,133.5,128.4,126.4,124.8,123.9,123.6,112.9,110.1,35.5. MS(ESI + ):[M+H] + 244.9.

[0340] Example 9.5: Synthesis of (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-thioxo-imidazolidin-4-one (9.5) [ka]

[0341] Compound (9.5) was synthesized according to GP8: the reaction was carried out with 2-thiohydantoin (4.2 mmol), 1H-benzimidazole-5-carbaldehyde, AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 95% (975 mg). The main tautomer 1 H NMR (400MHz, DMSO-d6, 343K) δ H 12.42 (bs, 1H, NH, D2O exchange), 12.03 (bs, 2H, NH, D2O exchange), 8.25 (s, 1H), 8.03 (br s, 1H), 7.69-7.51 (m, 2H), 6.64 (s, 1H). MS(ESI + ):[M+H] + 245.8.

[0342] Example 9.6: Synthesis of (5Z)-5-[(3-methylbenzimidazol-5-yl)methylene]-2-thioxo-imidazolidin-4-one (9.6) [ka]

[0343] Compound (9.6) was synthesized according to GP8: the reaction was carried out with 2-thiohydantoin (4.37 mmol), intermediate (7.2), AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 76% (858 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.38(bs,1H,NH,D2O exchange),12.24(bs,1H,NH,D2O exchange),8.29(s,1H),8.02(s,1 H),7.66(d,J=8.4Hz,1H),7.52(d,J=8.2Hz,1H),6.65(s,1H),3.92(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.8,165.8,146.6,144.3,135.1,126.5,126.4,125.4,119.6,113.2,111.6,31.2. MS(ESI + ):[M+H] + 259.1.

[0344] Example 9.7: Synthesis of (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-2-thioxo-imidazolidin-4-one (9.7) [ka]

[0345] Compound (9.7) was synthesized according to GP8: the reaction was carried out with 3-methyl-2-thiohydantoin (13.83 mmol), intermediate (7.1), AcOH, and ethanolamine as organic base. Reaction temperature: 80° C., time: 20 min. The final product required trituration. Yellow solid, 80% (2.90 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H12.46(bs,1H,NH,D2O exchange),8.83(s,1H),8.25(s,1H),7.82(d,J=8.3Hz,1H),7.78-7.73(m,1H),6.76(s,1H),3.21(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 179.2,164.1,155.7,149.8,140.5,130.0,127.7,126.5,120.2,112.3,112.2,27.3. MS(ESI + ):[M+H] + 260.1.

[0346] Example 9.8: Synthesis of (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-thioxo-imidazolidin-4-one (9.8) [ka]

[0347] Compound (9.8) was synthesized according to GP8: the reaction was carried out with 3-methyl-2-thiohydantoin (13.67 mmol), indazole-5-carbaldehyde, AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 92% (3.25 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 13.25(bs,1H,NH,D2O exchange),12.38(bs,1H,NH,D2O exchange),8.30(s,1H),8.15(s,1H) ,7.72(dd,J=8.8,1.7Hz,1H),7.56(d,J=8.7Hz,1H),6.78(s,1H),3.21(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.7,164.1,139.7,134.6,128.6,124.9,124.7,123.6,123.4,114.3,110.5,27.2. MS(ESI + ):[M+H] + 259.1.

[0348] Example 9.9: Synthesis of (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-thioxo-imidazolidin-4-one (9.9) [ka]

[0349] Compound (9.9) was synthesized according to GP8: the reaction was carried out with 3-methyl-2-thiohydantoin (8.07 mmol), 2-methylindazole-5-carbaldehyde, AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 92% (2.01 g). 1 H NMR(400MHz,DMSO-d6) δ H 1 H NMR (400MHz, DMSO-d6, 300K) δ 12.35 (bs, 1H, NH, D2O exchange), 8.45 (s, 1H), 8.25 (s, 1H), 7.63-7.57 (m, 2H), 6.72 (s, 1H), 4.19 (s, 3H), 3.21 (s, 3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.5,164.2,147.8,127.6,126.2,125.2,124.8,124.2,121.9,117.1,114.5,40.1,27.2. MS(ESI + ):[M+H] + 273.1.

[0350] Example 9.10: Synthesis of (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-thioxo-imidazolidin-4-one (9.10) [ka]

[0351] Compound (9.9) was synthesized according to GP8: the reaction was carried out with 3-methyl-2-thiohydantoin (14.90 mmol), 1-methylindazole-5-carbaldehyde, AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 96% (3.90 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.39(bs,1H,NH,D2O exchange),8.27(s,1H),8.12(d,J=0.9Hz,1H),7.78(dd,J=8. 8,1.7Hz,1H),7.67(d,J=8.9Hz,1H),6.78(s,1H),4.07(s,3H),3.21(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.7,164.1,139.4,133.5,128.5,124.9,124.8,123.9,123.8,114.1,110.1,35.5,27.2. MS(ESI + ):[M+H] + 273.1.

[0352] Example 9.11: Synthesis of (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-thioxo-imidazolidin-4-one (9.11) [ka]

[0353] Compound (9.11) was synthesized according to GP8: the reaction was carried out with 3-methyl-2-thiohydantoin (8.07 mmol), 1H-benzimidazole-5-carbaldehyde, AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 90% (1.88 g). The main tautomer was 1 H NMR (400MHz, DMSO-d6, 300K) δ H12.63(bs,1H,NH,D2O exchange),12.42(bs,1H,NH,D2O exchange),8.32(s,1H),8.08(s,1H),7.62(s,2H),6.80(s,1H),3.21(s,3H). MS(ESI + ):[M+H] + 259.1.

[0354] Example 9.12: Synthesis of (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-thioxo-imidazolidin-4-one (9.11) [ka]

[0355] Compound (9.12) was synthesized according to GP8: the reaction was carried out with 3-methyl-2-thiohydantoin (8.53 mmol), intermediate (7.2), AcOH and piperidine as organic base. Reaction temperature: 110° C., time: 60 min. The final product required trituration. Yellow solid, 95% (2.21 g). 1 H NMR(400MHz,CF3COOD,300K) δ H 9.03(s,1H),8.03(d,J=1.5Hz,1H),7.89(d,J=8.7Hz,1H),7.82(dd,J=8.8,1.5Hz,1H),7.10(s,1H),4.22(s,3H),3.40(s,3H). 13 C NMR(101MHz,CF3COOD,300K) δ C 182.5,168.1,143.2,134.6,134.1,133.2,132.7,129.4,117.9,117.4,114.8,35.0,29.1. MS(ESI + ):[M+H] + 273.1.

[0356] Example 10 General Protocol 9 - S-Alkylation of (5Z)-5-Heteroarylmethylene-2-thioxo-imidazolidin-4-ones (Route 2) [ka]

[0357] In the above scheme, A, B, R 2 and R 5 is as defined above, and Alk is (C1-C5) alkyl.

[0358] GP9: The appropriate alkyl iodide (1.05 eq) was added dropwise to a stirred solution of the appropriate 5-heteroaryl-2-thioxo-imidazolidin-4-one (1 eq) and K2CO3 (1 eq) in DMF (C=0.3 M) at a suitable temperature (see below for details). The resulting mixture was stirred at a suitable temperature for the indicated time. After completion (TLC), the mixture was poured onto water. The precipitated solid was stirred for 30 min and then filtered on a fritted glass funnel, thoroughly dried and could be used in the next step without further purification. Trace impurities resulting from N3-alkylation could be removed by trituration or FC.

[0359] Example 10.1: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-ethylsulfanyl-1H-imidazol-5-one (10.1) [ka]

[0360] Compound 10.1 was synthesized according to GP9: the reaction was carried out with intermediate 9.1 (1.97 mmol) and EtI at room temperature for 12 h. Yellow solid, 76% (411 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 11.85(bs,1H,NH,D2O exchange),8.82(s,1H),8.69(s,1H),8.16(d,J=8.4Hz,1H),7 .83(d,J=8.3Hz,1H),6.90(s,1H),3.33-3.27(m,2H),1.45(t,J=7.3Hz,3H). 13C NMR (101MHz, DMSO-d6, 300K) δ C 170.4,165.0,155.7,149.6,140.6,139.4,132.3,128.6,120.1,120.0,113.1,24.4,14.5. MS(ESI + ):[M+H] + 273.9.

[0361] Example 10.2: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-methylsulfanyl-1H-imidazol-5-one (10.2) [ka]

[0362] Compound 10.2 was synthesized according to GP9: the reaction was carried out with intermediate 9.1 (11.89 mmol) and MeI at 0° C. for 6 h and then at room temperature for 12 h. The final product required trituration in DCM. Yellow solid, 91% (2.805 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 11.88(bs,1H,NH,D2O exchange),8.82(s,1H),8.69(s,1H),8.19(d,J=8.4Hz,1H),7.83(d,J=8.3Hz,1H),6.91(s,1H),2.71(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 170.5,165.7,155.7,149.6,140.6,139.4,132.3,128.6,120.2,120.0,113.3,12.3. MS(ESI + ):[M+H] + 260.2.

[0363] Example 10.3: Synthesis of (4Z)-2-ethylsulfanyl-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one (10.3) [ka]

[0364] Compound 10.3 was synthesized according to GP9: the reaction was carried out with intermediate 9.2 (2.05 mmol) and EtI at room temperature for 12 h. Yellow solid, 86% (481 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 13.24(bs,1H,NH,D2O exchange),11.71(bs,1H,NH,D2O exchange),8.52(s,1H),8.36(d,J=8.9Hz,1H),8 .16(s,1H),7.58(d,J=8.8Hz,1H),6.88(s,1H),3.58-3.03(m,2H),1.44(t,J=7.3Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 170.6,162.8,139.9,137.8,134.8,129.0,127.1,125.2,123.3,122.2,110.4,24.2,14.6. MS(ESI + ):[M+H] + 272.9.

[0365] Example 10.4: Synthesis of (4Z)-2-ethylsulfanyl-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (10.4) [ka]

[0366] Compound 10.4 was synthesized according to GP9: the reaction was carried out with intermediate 9.3 (1.87 mmol) and EtI at room temperature for 12 h. Yellow solid, 88% (471 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H11.70(bs,1H,NH,D2O exchange),8.46(s,1H),8.40(s,1H),8.31(d,J=9.1Hz,1H),7.60(d ,J=9.1Hz,1H),6.83(s,1H),4.17(s,3H),3.32-3.26(m,2H),1.44(t,J=7.3Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 170.6,162.6,148.0,137.7,127.8,127.7,126.4,126.0,122.4,121.9,116.9,39.9,24.2,14.6. MS(ESI + ):[M+H] + 287.9.

[0367] Example 10.5: (4Z)-2-Ethylsulfanyl-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (10.5) [ka]

[0368] Compound 10.5 was synthesized according to GP9: the reaction was carried out with intermediate 9.4 (1.58 mmol) and EtI at room temperature for 12 h. Yellow solid, 76% (344 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 11.73(bs,1H,NH,D2O exchange),8.50(s,1H),8.41(d,J=8.9Hz,1H),8.14(s,1H),7.69(d,J =9.0Hz,1H),6.89(s,1H),4.05(s,3H),3.31(q,J=7.3Hz,2H),1.45(t,J=7.3Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 170.6,163.0,139.5,137.9,133.7,128.9,127.1,125.3,123.8,122.0,110.0,35.5,24.3,14.6. MS(ESI + ):[M+H] + 287.9.

[0369] Example 10.6: (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-methylsulfanyl-1H-imidazol-5-one (10.6) [ka]

[0370] Compound 10.6 was synthesized according to GP9: the reaction was carried out with intermediate 9.4 (12.00 mmol) and MeI at 0° C. for 6 h and then at room temperature for 12 h. The final product required trituration in DCM. Yellow solid, 94% (3.060 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 11.75(bs,1H,NH,D2O exchange),8.53(s,1H),8.39(d,J=8.9Hz,1H),8.14(s,1H),7.69(d,J=8.9Hz,1H),6.89(s,1H),4.06(s,3H),2.70(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 170.7,163.7,139.5,137.9,133.7,129.1,127.1,125.3,123.8,122.0,109.9,35.4,12.2. MS(ESI + ):[M+H] + 273.2.

[0371] Example 10.7: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-ethylsulfanyl-1H-imidazol-5-one (10.7) [ka]

[0372] Compound 10.7 was synthesized according to GP9: the reaction was carried out with intermediate 9.5 (1.64 mmol) and EtI at room temperature for 12 h. Yellow solid, 61% (274 mg). 1H NMR (400MHz, DMSO-d6, 300K) δ H 12.85-12.51(brm,1H,NH,D2O exchange),11.71(br s,1H,NH,D2O exchange), 8.52(s,1H),8.29(s,1H),8.17-7.90(m,1H),7.74-7.48(m,1H),6.89(s,1H),3.38-3.29(m,2H),1.45(t,J=7.3Hz,3H). MS(ESI + ):[M+H] + 272.9.

[0373] Example 10.8: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-methylsulfanyl-1H-imidazol-5-one (10.8) [ka]

[0374] Compound (10.8) was synthesized according to GP9: the reaction was carried out with intermediate (9.5) (16.04 mmol) and MeI at 0° C. for 6 h and then at room temperature for 12 h. The final product required trituration in DCM. Yellow solid, 92% (3.827 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.64(br s,1H,NH,D2O exchange),11.75(br s,1H,NH,D2O exchange),8.53(s,1H),8.29(s,1H),8.05(br s,1H),7.72-7.53(m,1H),6.89(s,1H),2.71(s,3H). MS(ESI + ):[M+H] + 259.1.

[0375] Example 10.9: Synthesis of (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-methylsulfanyl-1H-imidazol-5-one (10.9) [ka]

[0376] Compound (10.9) was synthesized according to GP9: the reaction was carried out with intermediate (9.6) (12.99 mmol) and MeI at 0° C. for 6 h and then at room temperature for 12 h. The final product required trituration in DCM. Yellow solid, 96% (3.395 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 11.79(br s,1H,NH,D2O exchange),8.52(s,1H),8.28(s,1H),8.07(d,J=8.5Hz,1H),7.67(d,J=8.5Hz,1H),6.90(s,1H),3.86(s,3H),2.71(s,3H). MS(ESI + ):[M+H] + 273.1.

[0377] Example 10.10: Synthesis of (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-2-methylsulfanyl-imidazol-4-one (10.10) [ka]

[0378] Compound 10.10 was synthesized according to GP9: the reaction was carried out with intermediate 9.7 (11.18 mmol) and MeI at 0° C. for 30 min and then at room temperature for 12 h. Yellow solid, 96% (2.92 g). 1 H NMR (400MHz, CDCl3, 300K) δ H 8.66(s,1H),8.15(s,1H),7.98(dd,J=8.4,1.5Hz,1H),7.78(d,J=8.3Hz,1H),7.04(s,1H),3.19(s,3H),2.78(s,3H). 13 C NMR (101MHz, CDCl3, 300K) δ C 170.0,166.3,154.1,150.5,141.3,138.9,132.7,129.3,123.1,120.5,114.0,26.7,13.2. MS(ESI + ):[M+H] +274.1.

[0379] Example 10.11: Synthesis of (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-methylsulfanyl-imidazol-4-one (10.11) [ka]

[0380] Compound 10.11 was synthesized according to GP9: the reaction was carried out with intermediate 9.8 (12.27 mmol) and MeI at 0° C. for 30 min and then at room temperature for 12 h. Yellow solid, 99% (3.30 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 13.25(br s,1H,NH,D2O exchange),8.57(s,1H),8.40(dd,J=8.9,1.5Hz,1H),8.17(s,1H),7.59(d,J=8.8Hz,1H),7.01(s,1H),3.09(s,3H),2.76(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 169.0,164.6,139.9,136.7,134.8,129.3,127.0,125.6,123.5,123.3,110.4,26.3,12.5. MS(ESI + ):[M+H] + 273.1.

[0381] Example 10.12: Synthesis of (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-methylsulfanyl-imidazol-4-one (10.12) [ka]

[0382] Compound (10.12) was synthesized according to GP9: the reaction was carried out with intermediate (9.9) (7.12 mmol) and MeI at 0° C. for 30 min and then at room temperature for 12 h. Yellow solid, 95% (1.93 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.47(s,1H),8.44(s,1H),8.35(d,J=1.7Hz,1H),7.61(d,J=9.1Hz,1H),6.96(s,1H),4.17(s,3H),3.09(s,3H),2.75(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 169.0,164.3,148.0,136.7,127.9,127.6,126.5,126.4,123.7,121.9,116.9,40.1,26.3,12.5. MS(ESI + ):[M+H] + 287.1.

[0383] Example 10.13: Synthesis of (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-methylsulfanyl-imidazol-4-one (10.13) [ka]

[0384] Compound 10.13 was synthesized according to GP9: the reaction was carried out with intermediate 9.10 (14.14 mmol) and MeI at 0° C. for 30 min and then at room temperature for 12 h. Yellow solid, 100% (4.05 g). 1 H NMR (400MHz, TFA-d, 300K) δ H 8.77(s,1H),8.30(s,1H),7.97(dd,J=9.2,1.6Hz,1H),7.78(d,J=9.1Hz,1H),7.67(s,1H),4.31(s,3H),3.40(s,3H),2.97(s,3H). 13 C NMR(101MHz,CF3COOD,300K) δ C177.0,164.0,142.6,136.8,133.4,130.6,129.7,129.5,127.5,122.9,114.0,36.8,29.4,15.0. MS(ESI + ):[M+H] + 287.1.

[0385] Example 10.14: Synthesis of (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-methylsulfanyl-imidazol-4-one (10.14) [ka]

[0386] Compound (10.14) was synthesized according to GP9: the reaction was carried out with intermediate (9.11) (7.24 mmol) and MeI at 0° C. for 30 min and then at room temperature for 12 h. Yellow solid, 81% (1.59 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.65(br s,1H,NH,D2O exchange),8.56(s,1H),8.30(s,1H),8.09(d,J=8.4Hz,1H),7.62(d,J=8.4Hz,1H),7.03(s,1H),3.10(s,3H),2.77(s,3H). MS(ESI + ):[M+H] + 273.1.

[0387] Example 10.15: Synthesis of (5Z)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-methylsulfanyl-imidazol-4-one (10.15) [ka]

[0388] Compound 10.15 was synthesized according to GP9: the reaction was carried out with intermediate 9.11 (7.93 mmol) and MeI at 0° C. for 30 min and then at room temperature for 12 h. Yellow solid, 95% (2.15 g).1 H NMR (400MHz, DMSO-d6, 300K) δ H 8.55(s,1H),8.29(s,1H),8.09(dd,J=8.5,1.5Hz,1H),7.67(d,J=8.5Hz,1H),7.02(s,1H),3.86(s,3H),3.10(s,3H),2.77(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 168.9,165.0,146.6,144.6,137.1,134.9,128.6,125.8,123.3,119.3,113.9,30.6,26.3,12.5. MS(ESI + ):[M+H] + 287.1.

[0389] Example 11: Synthesis of compounds of formula (I) according to general protocols 10 (GP10), 11 (GP11) and 12 (GP12)

[0390] General protocol 10 - Knoevenagel condensation of N2-functionalized 2-amino-1,4-dihydroimidazol-5-ones with heteroarylcarbaldehydes (route 1) [ka]

[0391] In the above scheme, A, B, R 1 , R 2 and R 5 is as defined above.

[0392] GP10-A: A stirred solution of the appropriate N2-functionalized 2-amino-1,4-dihydroimidazol-5-one (1 eq), heteroarylcarboxaldehyde (1.2 eq) and NH4HCOO (1.2 eq) in EtOH (C=0.3 M) was heated in a sealed tube in a microwave oven (Anton Paar) at 120° C. for 3 h. After completion (after consumption of the heteroarylcarboxaldehyde on TLC), the mixture was allowed to cool to room temperature, adsorbed onto silica and purified by FC (see below for details). After FC, higher purity can be achieved by reprecipitation, trituration or recrystallization (see below for details).

[0393] GP10-B: A stirred solution of the appropriate N2-functionalized 2-amino-1,4-dihydroimidazol-5-one (1 eq), heteroarylcarboxaldehyde (1.2 eq) and AcOK (4 eq) in AcOH (C=0.1 M) was heated in a sealed tube in a microwave oven (Anton Paar) at 120 °C for 3 h (see below for details on each compound). Upon completion (after consumption of the heteroarylcarboxaldehyde on TLC), the mixture was allowed to cool to room temperature and was washed with saturated Na2CO 3(水性) The precipitated solid was filtered through a fritted glass funnel, adsorbed onto silica, and purified by FC (see below for details). After FC, higher purity can be achieved by reprecipitation, trituration, or recrystallization (see below for details).

[0394] General Protocol 11 - Addition of Amines to (Z)-Heteroarylmethylene-2-alkylsulfanyl-1H-imidazol-5-ones (Route 2) [ka]

[0395] In the above scheme, A, B, R 1 , R2 and R 5 is as defined above, and Alk is (C1-C5) alkyl.

[0396] GP11: suitable amine (x eq), (4Z)-4-heteroaryl-2-alkylsulfanyl-1H-imidazol-5-one in suitable solvent (C=0.3M) (a) A stirred solution of (1 eq) was heated in a sealed tube (heating block). Upon completion (after the isothiourea had been consumed on TLC), the mixture was allowed to warm to room temperature.

[0397] GP11-A: Direct precipitation of the desired product: The reaction medium was stirred for 1 h at 0° C. The precipitated solid was filtered through a fritted glass funnel. High purity can be achieved after filtration by washing, reprecipitation, grinding, or recrystallization (see Table 3 for details).

[0398] GP11-B: No product precipitated: The reaction mixture was concentrated in vacuum, adsorbed onto silica, and purified by FC. High purity can be achieved by filtration followed by reprecipitation, trituration, or recrystallization.

[0399] GP11-C: No product precipitated: The reaction mixture was concentrated in vacuo. The resulting crude was triturated in EtOH (at room temperature or reflux) and filtered through a fritted glass funnel.

[0400] (a) Depending on the amine, activation with AcOH or TEA.HCl may be necessary (see below for details).

[0401] General Protocol 12 - Addition of Amines to (4Z)-4-(1,3-Benzoxazol-6-ylmethylene)-2-alkylsulfanyl-1H-imidazol-5-ones (Route 2') [ka]

[0402] In the above scheme, R 1 and R 5 is as defined above, and Alk is (C1-C5) alkyl.

[0403] GP12 - Step 1: A stirred solution of the appropriate amine (x eq), (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-alkylsulfanyl-1H-imidazol-5-one (1 eq) in THF (C=0.3M) was heated in a sealed tube (heating block). After completion (after consumption of isothiourea on TLC), the mixture was allowed to warm to room temperature. The precipitated red / brown solid was isolated by filtration, washed with ice-cold THF or dioxane, and dried.

[0404] GP12 - Step 2: A stirred solution of the previously isolated solid (1 eq) and HC(OEt)3 (25 eq) in toluene (C=0.3 M) was heated in a sealed tube in a microwave oven (Anton Paar) at 150° C. for 1 h. After completion, the mixture was adsorbed onto silica and purified by FC (see details below). Higher purity can be achieved by reprecipitation, trituration, or recrystallization (see details below).

[0405] Selected Examples from the Benzoxazole Subseries

[0406] Example 11.1: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one (1)

[0407] The reaction was carried out according to GP12-step 1 on a scale of 915 μmol of intermediate (10.1) in THF with 12 eq cyclohexylamine at 110 °C (sealed tube, heating block) for 12 h. The isolated aminophenol intermediate was cyclized according to GP12-step 2. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 34% (2 steps).

[0408] Example 11.2: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one (2)

[0409] The reaction was carried out according to GP12-step 1 on a scale of 695 μmol of intermediate (10.1) in THF with 12 eq cycloheptylamine at 110 °C (sealed tube, heating block) for 12 h. The isolated aminophenol intermediate was cyclized according to GP12-step 2. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 38% (2 steps).

[0410] Example 11.3: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (5)

[0411] The reaction was carried out according to GP12-step 1 with 5 eq (2R)-1-methoxy-4-methyl-pentan-2-amine in THF on a scale of 352 μmol of intermediate (10.2) at 120 °C (sealed tube, heating block) for 72 h. The isolated aminophenol intermediate was cyclized according to GP12-step 2. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Isolated yield: 39% (2 steps).

[0412] Example 11.4: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one (6)

[0413] The reaction was carried out according to GP12-step 1 on a scale of 386 μmol of intermediate (10.2) with 5 eq of (1R,2R)-2-methoxycyclopentan-1-amine in THF at 120° C. (sealed tube, heating block) for 28 h. The isolated aminophenol intermediate was cyclized according to GP12-step 2. Purification by PTLC (elution: DCM / MeOH: 97 / 3). Isolated yield: 39% (2 steps).

[0414] Example 11.5: Synthesis of (4Z)-2-(1-adamantylamino)-4-(1,3-benzoxazol-6-ylmethylene)-1H-imidazol-5-one (11)

[0415] The reaction was carried out with aldehyde (7.1) on a scale of 429 μmol of intermediate (2.11) according to GP10-A. Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 19%.

[0416] Example 11.6: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one (12)

[0417] The reaction was carried out with aldehyde (7.1) on a scale of 401 μmol of intermediate (2.12) according to GP10-A. Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 5%.

[0418] Example 11.7: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1H-imidazol-5-one (13)

[0419] The reaction was carried out with aldehyde (7.1) on a scale of 379 μmol of intermediate (2.13) according to GP10-A. Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 20%.

[0420] Example 11.8: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one (18)

[0421] The reaction was carried out according to GP12-step 1 on a scale of 386 μmol of intermediate (10.2) with 5 eq of (1R)-2-methoxy-1-phenyl-ethanamine in THF at 120 °C (sealed tube, heating block) for 96 h. The isolated aminophenol intermediate was cyclized according to GP12-step 2. Purification by PTLC (elution: DCM / MeOH: 96 / 4). Isolated yield: 23% (2 steps).

[0422] Example 11.9: Synthesis of (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one (24)

[0423] The reaction was carried out according to GP12-step 1 with 5 eq (3S)-tetrahydropyran-3-amine in THF on a scale of 386 μmol of intermediate (10.2) at 120 °C (sealed tube, heating block) for 24 h. The isolated aminophenol intermediate was cyclized according to GP12-step 2. Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 33% (2 steps).

[0424] Selected Examples from the Indazole Subseries

[0425] Example 11.10: Synthesis of (4Z)-2-(cyclohexylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one (26)

[0426] The reaction was carried out according to GP11-A on a scale of 734 μmol of intermediate (10.3) in THF with 6 eq of cyclohexylamine at 110° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Isolated yield: 54%.

[0427] Example 11.11: Synthesis of (4Z)-2-(cycloheptylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one (27)

[0428] The reaction was carried out according to GP11-A on a scale of 734 μmol of intermediate (10.3) in THF with 6 eq of cycloheptylamine at 110° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Isolated yield: 57%.

[0429] Example 11.12: Synthesis of (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one (29)

[0430] The reaction was carried out according to GP10-A using 1H-indazole-5-carbaldehyde on a scale of 427 μmol of intermediate (2.4). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required trituration in ACN at 0° C. Isolated yield: 32%.

[0431] Example 11.13: Synthesis of (4Z)-4-(1H-indazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (30)

[0432] The reaction was carried out according to GP10-A using 1H-indazole-5-carbaldehyde on a scale of 427 μmol of intermediate (2.5). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required precipitation from DCM / Et2O / pentane at 0 °C. Isolated yield: 28%.

[0433] Example 11.14: Synthesis of (4Z)-2-(1-adamantylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one (31)

[0434] The reaction was carried out according to GP10-A using 1H-indazole-5-carbaldehyde on a scale of 427 μmol of intermediate (2.11). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required trituration in EtOH at 0° C. Isolated yield: 36%.

[0435] Example 11.15: Synthesis of (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one (32)

[0436] The reaction was carried out according to GP10-A using 1H-indazole-5-carbaldehyde on a scale of 427 μmol of intermediate (2.11). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required trituration in EtOH at 0° C. Isolated yield: 50%.

[0437] Example 11.16: Synthesis of (4Z)-4-(1H-indazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one (33)

[0438] The reaction was carried out according to GP10-A using 1H-indazole-5-carbaldehyde on a scale of 427 μmol of intermediate (2.15). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 94 / 6). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 38%.

[0439] Selected Examples from the Subseries of N2-Methylindazoles

[0440] Example 11.17: Synthesis of (4Z)-2-(cyclohexylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (34)

[0441] The reaction was carried out according to GP11-A on a scale of 873 μmol of intermediate (10.4) in THF with 6 eq of cyclohexylamine at 110° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Isolated yield: 50%.

[0442] Example 11.18: Synthesis of (4Z)-2-(cycloheptylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (35)

[0443] The reaction was carried out according to GP11-A on a scale of 873 μmol of intermediate (10.4) in THF with 6 eq of cycloheptylamine at 110° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Isolated yield: 49%.

[0444] Example 11.19: Synthesis of (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (37)

[0445] The reaction was carried out according to GP10-A using 2-methylindazole-5-carbaldehyde on a scale of 427 μmol of intermediate (2.4). Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required trituration in ACN at 0° C. Isolated yield: 38%.

[0446] Example 11.20: Synthesis of (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (38)

[0447] The reaction was carried out according to GP10-A using 2-methylindazole-5-carbaldehyde on a scale of 427 μmol of intermediate (2.5). Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required trituration in ACN at 0° C. Isolated yield: 28%.

[0448] Example 11.21: Synthesis of (4Z)-2-(1-adamantylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (39)

[0449] The reaction was carried out according to GP10-A using 2-methylindazole-5-carbaldehyde on a scale of 321 μmol of intermediate (2.11). Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required trituration in EtOH at 0° C. Isolated yield: 27%.

[0450] Example 11.22: Synthesis of (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (41)

[0451] The reaction was carried out according to GP10-A using 2-methylindazole-5-carbaldehyde on a scale of 321 μmol of intermediate (2.14). Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required trituration in EtOH at 0° C. Isolated yield: 61%.

[0452] Example 11.23: Synthesis of (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one (42)

[0453] The reaction was carried out according to GP10-A using 2-methylindazole-5-carbaldehyde on a scale of 321 μmol of intermediate (2.15). Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 45%.

[0454] Selected Examples from N1-Methylindazole

[0455] Example 11.24: Synthesis of (4Z)-2-(cyclohexylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (43)

[0456] The reaction was carried out according to GP11-A on a scale of 698 μmol of intermediate (10.5) in THF with 6 eq of cyclohexylamine at 110° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Isolated yield: 39%.

[0457] Example 11.25: Synthesis of (4Z)-2-(cyclooctylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (45)

[0458] The reaction was carried out according to GP11-A on a scale of 275 μmol of intermediate (10.6) in THF with 3 eq of cyclooctylamine at 110° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. Isolated yield: 46%.

[0459] Example 11.26: Synthesis of (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (46)

[0460] The reaction was carried out according to GP11-B with 3 eq (R)-leucinol in THF on a scale of 275 μmol of intermediate (10.6) at 120 °C (sealed tube, heating block) for 30 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 88 / 12). Isolated yield: 55%.

[0461] Example 11.27: Synthesis of (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (47)

[0462] The reaction was carried out according to GP11-B on a scale of 275 μmol of intermediate (10.6) with 3 eq of (2R)-1-methoxy-4-methyl-pentan-2-amine in THF at 120 °C (sealed tube, heating block) for 72 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 88 / 12). Isolated yield: 52%.

[0463] Example 11.28: Synthesis of (4Z)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (48)

[0464] The reaction was carried out according to GP11-B on a scale of 275 μmol of intermediate (10.6) with 3 eq of (2R)-1-fluoro-4-methyl-pentan-2-amine in THF at 120° C. (sealed tube, heating block) for 120 h. Purification by PTLC (elution: DCM / MeOH: 98 / 2). Isolated yield: 32%.

[0465] Example 11.29: Synthesis of (4Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (51)

[0466] The reaction was carried out according to GP11-A with 3 eq of (1S,2S)-2-methoxycyclopentanamine in THF on a scale of 273 μmol of intermediate (10.6) at 120° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold EtOH and then with pentane. Isolated yield: 71%.

[0467] Example 11.30: Synthesis of (±)-(4Z)-2-[[cis-3-methoxycycloheptyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (54)

[0468] The reaction was carried out according to GP11-B on a scale of 273 μmol of intermediate (10.6) with 3 eq of (±)-cis-3-methoxycycloheptanamine in a mixture of THF / dioxane (2 / 1) at 120 °C (sealed tube, heating block) for 44 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Isolated yield: 77%.

[0469] Example 11.31: Synthesis of (4Z)-2-(1-adamantylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (55)

[0470] The reaction was carried out according to GP11-B on a scale of 273 μmol of intermediate (10.6) with 3 eq adamantane-1-amine and 9 eq AcOH in dioxane at 150 °C (sealed tube, heating block) for 72 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). The final product required trituration in EtOH. Isolated yield: 52%.

[0471] Example 11.32: Synthesis of (4Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (60)

[0472] The reaction was carried out according to GP11-A with 3 eq (1S,2S)-1-aminoindan-2-ol in THF on a scale of 275 μmol of intermediate (10.6) at 120° C. (sealed tube, heating block) for 52 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold EtOH and then with pentane. The final product required trituration in EtOH. Isolated yield: 62%.

[0473] Example 11.33: Synthesis of (4Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (61)

[0474] The reaction was carried out according to GP11-A on a scale of 275 μmol of intermediate (10.6) with 3 eq of (2R)-2-amino-2-phenyl-ethanol in THF at 120° C. (sealed tube, heating block) for 52 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold EtOH and then with pentane. The final product required trituration in EtOH. Isolated yield: 59%.

[0475] Example 11.34: Synthesis of ((4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (63)

[0476] The reaction was carried out according to GP11-B with 3 eq (1R)-2-methoxy-1-phenyl-ethanamine in THF on a scale of 275 μmol of intermediate (10.6) at 120 °C (sealed tube, heating block) for 44 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). Isolated yield: 47%.

[0477] Example 11.35: Synthesis of (4Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (64)

[0478] The reaction was carried out according to GP11-A on a scale of 273 μmol of intermediate (10.6) with 3 eq of (1R)-2-amino-1-phenyl-ethanol in THF at 120° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold EtOH and then with pentane. The final product required trituration in EtOH. Isolated yield: 94%.

[0479] Example 11.36: Synthesis of (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride (65)

[0480] The reaction was carried out according to GP11-Bon with 3 eq of tert-butyl N-[(1R)-2-amino-1-phenyl-ethyl]carbamate in THF on a scale of 275 μmol of intermediate (10.6) at 120 °C (sealed tube, heating block) for 48 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). The isolated carbamate was subjected to a final deprotection step with HCl (4M) in dioxane at 40 °C. Isolated yield: 56% (2 steps).

[0481] Example 11.37: Synthesis of (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride (66)

[0482] The reaction was carried out according to GP11-B with 3 eq of tert-butyl N-[(1S)-2-amino-1-phenyl-ethyl]carbamate in THF on a scale of 275 μmol of intermediate (10.6) at 120 °C (sealed tube, heating block) for 48 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). The isolated carbamate was subjected to a final deprotection step with HCl (4M) in dioxane at 40 °C. Isolated yield: 46% (2 steps).

[0483] Example 11.38: Synthesis of (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-(2-pyridylamino)-1H-imidazol-5-one (70)

[0484] The reaction was carried out according to GP11-A on a scale of 275 μmol of intermediate (10.6) with 5 eq 2-aminopyridine and 15 eq AcOH in dioxane at 150° C. (sealed tube, heating block) for 50 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold EtOH and then with pentane. The final product required trituration in EtOH. Isolated yield: 88%.

[0485] Example 11.39: Synthesis of (4Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (73)

[0486] The reaction was carried out according to GP11-B on a scale of 275 μmol of intermediate (10.6) with 3 eq (3R,4R)-3-aminotetrahydropyran-4-ol and 9 eq AcOH in THF at 120 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 9 / 1). The final product required trituration. Isolated yield: 53%.

[0487] Selected Examples from the Benzimidazole Subseries

[0488] Example 11.40: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(cyclooctylamino)-1H-imidazol-5-one (77)

[0489] The reaction was carried out according to GP11-B on a scale of 275 μmol of intermediate (10.8) with 3 eq cyclooctylamine and 15 eq AcOH in THF at 130 °C (sealed tube, heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 88 / 12). The final product required trituration in EtOH at 0 °C. Isolated yield: 21%.

[0490] Example 11.41: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (78)

[0491] The reaction was carried out according to GP11-B on a scale of 523 μmol of intermediate (10.8) with 3 eq (R)-leucinol and 6 eq AcOH in THF at 130 °C (sealed tube, heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 80 / 20). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 18%.

[0492] Example 11.42: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (79)

[0493] The reaction was carried out according to GP11-B with 3 eq (2R)-1-methoxy-4-methyl-pentan-2-amine in THF on a scale of 523 μmol of intermediate (10.8) at 130 °C (sealed tube, heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 30%.

[0494] Example 11.43: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (80)

[0495] The reaction was carried out according to GP10-A on a scale of 398 μmol of intermediate (2.6) using 1.2 eq of 1H-benzimidazole-5-carbaldehyde. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 47%.

[0496] Example 11.44: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (81)

[0497] The reaction was carried out according to GP10-A with 1.2 eq of 1H-benzimidazole-5-carbaldehyde on a scale of 398 μmol of intermediate (2.7). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 40%.

[0498] Example 11.45: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one (82)

[0499] The reaction was carried out according to GP11-B on a scale of 430 μmol of intermediate (10.8) with 3 eq (1R,2R)-2-methoxycyclopentan-1-amine and 6 eq AcOH in THF at 120 °C (sealed tube, heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 36%.

[0500] Example 11.46: Synthesis of (4Z)-2-(3-noradamantylamino)-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one (83)

[0501] The reaction was carried out according to GP10-A with 1.2 eq of 1H-benzimidazole-5-carbaldehyde on a scale of 321 μmol of intermediate (2.10). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required trituration in EtOH at 0° C. Isolated yield: 37%.

[0502] Example 11.47: Synthesis of (4Z)-2-(1-adamantylamino)-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one (84)

[0503] The reaction was carried out according to GP10-A with 1.2 eq of 1H-benzimidazole-5-carbaldehyde on a scale of 343 μmol of intermediate (2.11). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required trituration in EtOH at 0° C. Isolated yield: 19%.

[0504] Example 11.48: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one (85)

[0505] The reaction was carried out according to GP11-A on a scale of 542 μmol of intermediate (10.8) with 3 eq 3-aminoadamantan-1-ol and 6 eq AcOH in dioxane at 150 °C (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with EtOH and then with pentane. The final product required trituration in refluxing EtOH. Isolated yield: 46%.

[0506] Example 11.49: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-1H-imidazol-5-one (87)

[0507] The reaction was carried out according to GP10-A with 1.2 eq of 1H-benzimidazole-5-carbaldehyde on a scale of 321 μmol of intermediate (2.14). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required trituration in EtOH at 0° C. Isolated yield: 48%.

[0508] Example 11.50: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one (88)

[0509] The reaction was carried out according to GP11-B on a scale of 523 μmol of intermediate (10.8) with 3 eq [2-(trifluoromethyl)phenyl]methanamine and 6 eq AcOH in THF at 160 °C (sealed tube, heating block) for 12 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required reprecipitation from EtOH / Et2O / pentane at 0 °C. Isolated yield: 40%.

[0510] Example 11.51: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-1H-imidazol-5-one (89)

[0511] The reaction was carried out according to GP11-A with 3 eq (1S,2S)-1-aminoindan-2-ol in THF on a scale of 523 μmol of intermediate (10.8) at 130° C. (sealed tube, heating block) for 40 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with EtOH and then with pentane. The final product required trituration in ACN. Isolated yield: 16%.

[0512] Example 11.51: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one (90)

[0513] The reaction was carried out according to GP11-A on a scale of 542 μmol of intermediate (10.8) with 3 eq (2R)-2-amino-2-phenyl-ethanol and 6 eq AcOH in THF at 130° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtering and washing with EtOH and then with pentane. The final product required two successive triturations in MeOH. Isolated yield: 49%.

[0514] Example 11.52: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one (92)

[0515] The reaction was carried out according to GP10-A with 1.2 eq of 1H-benzimidazole-5-carbaldehyde on a scale of 429 μmol of intermediate (2.15). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 44%.

[0516] Example 11.53: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-1H-imidazol-5-one (93)

[0517] The reaction was carried out according to GP11-B on a scale of 542 μmol of intermediate (10.8) with 3 eq (1R)-2-amino-1-phenyl-ethanol and 6 eq AcOH in THF at 130 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 29%.

[0518] Example 11.54: Synthesis of (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one dihydrochloride (96)

[0519] The reaction was carried out according to GP10-A with 1.2 eq of 1H-benzimidazole-5-carbaldehyde on a scale of 855 μmol of intermediate (2.17). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The isolated carbamate was subjected to a final deprotection step with HCl (4M) in dioxane at 40 °C. Isolated yield: 40% (2 steps).

[0520] Example 11.55: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one (98)

[0521] The reaction was carried out according to GP10-A on a scale of 429 μmol of intermediate (2.19) using 1.2 eq of 1H-benzimidazole-5-carbaldehyde. Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required trituration in ACN. Isolated yield: 32%.

[0522] Example 11.56: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one (99)

[0523] The reaction was carried out according to GP10-A with 1.2 eq of 1H-benzimidazole-5-carbaldehyde on a scale of 366 μmol of intermediate (2.20). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 85 / 15). The final product required trituration in EtOH at 0° C. Isolated yield: 12%.

[0524] Example 11.57: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one (102)

[0525] The reaction was carried out according to GP11-A on a scale of 542 μmol of intermediate (10.8) with 3 eq of (3R,4R)-3-aminotetrahydropyran-4-ol and 6 eq of AcOH in THF at 130° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after being filtered and washed with EtOH and then with pentane. The final product required trituration in refluxing EtOH. Isolated yield: 35%.

[0526] Example 11.58: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3S,4S)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one (103)

[0527] The reaction was carried out according to GP11-A on a scale of 542 μmol of intermediate (10.8) with 3 eq of (3S,4S)-3-aminotetrahydropyran-4-ol and 6 eq of AcOH in THF at 130° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after being filtered and washed with EtOH and then with pentane. The final product required trituration in refluxing EtOH. Isolated yield: 40%.

[0528] Example 11.59: Synthesis of (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(oxepan-3-ylamino)-1H-imidazol-5-one (104)

[0529] The reaction was carried out according to GP11-B on a scale of 239 μmol of intermediate (10.8) with 4 eq oxepan-3-amine and 6 eq AcOH in a mixture of dioxane / EtOH (3 / 1) for 24 h at 140 °C (sealed tube, heating block). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 88 / 12). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 31%.

[0530] Selected Examples from the Subseries of N-Methylbenzimidazoles

[0531] Example 11.60: Synthesis of (4Z)-2-(cycloheptylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (106)

[0532] The reaction was carried out according to GP10-A on a scale of 562 μmol of intermediate (2.2) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 31%.

[0533] Example 11.61: Synthesis of (4Z)-2-(cyclooctylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (107)

[0534] The reaction was carried out according to GP10-A on a scale of 1.12 mmol of intermediate (2.3) using 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 64%.

[0535] Example 11.62: Synthesis of (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (108)

[0536] The reaction was carried out according to GP10-A with 1.2 eq of aldehyde (7.2) on a scale of 376 μmol of intermediate (2.4). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. The final product required trituration in EtOH at 0° C. Isolated yield: 31%.

[0537] Example 11.63: Synthesis of (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (109)

[0538] The reaction was carried out according to GP10-A with 1.2 eq of aldehyde (7.2) on a scale of 469 μmol of intermediate (2.5). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from EtOH / Et2O / pentane at 0 °C. Isolated yield: 27%.

[0539] Example 11.64: Synthesis of (4Z)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (110)

[0540] The reaction was carried out according to GP10-A on a scale of 398 μmol of intermediate (2.6) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 40%.

[0541] Example 11.65: Synthesis of (4Z)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (111)

[0542] The reaction was carried out according to GP10-A on a scale of 398 μmol of intermediate (2.7) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 36%.

[0543] Example 11.66: Synthesis of (4Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (112)

[0544] The reaction was carried out according to GP10-A on a scale of 355 μmol of intermediate (2.8) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 15%.

[0545] Example 11.67: Synthesis of (4Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (113)

[0546] The reaction was carried out according to GP10-A on a scale of 355 μmol of intermediate (2.9) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 90 / 10). The final product required reprecipitation from DCM / pentane at 0° C. Isolated yield: 26%.

[0547] Example 11.68: Synthesis of (4Z)-2-(3-noradamantylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (114)

[0548] The reaction was carried out according to GP10-A on a scale of 321 μmol of intermediate (2.10) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required trituration in EtOH at 0° C. Isolated yield: 20%.

[0549] Example 11.69: Synthesis of (4Z)-2-(1-adamantylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (115)

[0550] The reaction was carried out according to GP11-A on a scale of 551 μmol of intermediate (10.9) with 3 eq 1-adamantylamine and 10 eq AcOH in a mixture of THF / dioxane (1 / 1) at 160° C. (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. The final product required trituration in EtOH at 0° C. Isolated yield: 33%.

[0551] Example 11.70: Synthesis of (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (116)

[0552] The reaction was carried out according to GP11-A on a scale of 551 μmol of intermediate (10.9) with 3 eq of 3-aminoadamantan-1-ol and 15 eq of AcOH in a mixture of THF / dioxane (1 / 1) at 160 °C (sealed tube, heating block) for 6 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. The final product required two successive triturations in refluxing EtOH. Isolated yield: 44%.

[0553] Example 11.71: Synthesis of (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (118)

[0554] The reaction was carried out according to GP10-A with aldehyde (7.2) on a scale of 321 μmol of intermediate (2.10). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required trituration in EtOH at 0° C. Isolated yield: 29%.

[0555] Example 11.72: Synthesis of (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (123)

[0556] The reaction was carried out according to GP11-B on a scale of 551 μmol of intermediate (10.9) with 3 eq (1R)-2-methoxy-1-phenyl-ethanamine and 15 eq AcOH in a mixture of dioxane / THF (1 / 2) for 24 h at 140 °C (sealed tube, heating block). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 29%.

[0557] Example 11.73: Synthesis of (4Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (124)

[0558] The reaction was carried out according to GP11-A on a scale of 367 μmol of intermediate (10.9) with 3 eq of (1R)-2-amino-1-phenyl-ethanol in dioxane at 135° C. (sealed tube, heating block) for 48 h. The product precipitated directly in the reaction medium. It was isolated after filtration and washing with cold THF and then with pentane. The final product required trituration in EtOH at 0° C. Isolated yield: 44%.

[0559] Example 11.74: Synthesis of (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride (126)

[0560] The reaction was carried out according to GP10-A on a scale of 503 μmol of intermediate (2.16) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The isolated carbamate was subjected to a final deprotection step with HCl (4M) in dioxane at 40 °C. Isolated yield: 39% (2 steps).

[0561] Example 11.75: Synthesis of (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride (127)

[0562] The reaction was carried out according to GP10-A on a scale of 251 μmol of intermediate (2.17) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The isolated carbamate was subjected to a final deprotection step with HCl (4M) in dioxane at 40 °C. Isolated yield: 26% (2 steps).

[0563] Example 11.76: Synthesis of (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one (128)

[0564] The reaction was carried out according to GP10-A on a scale of 428 μmol of intermediate (2.18) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required trituration in EtOH at 0° C. Isolated yield: 17%.

[0565] Example 11.77: Synthesis of (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one (130)

[0566] The reaction was carried out according to GP10-A on a scale of 549 μmol of intermediate (2.20) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). Isolated yield: 37%.

[0567] Example 11.78: Synthesis of (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-(2-pyridylamino)-1H-imidazol-5-one (131)

[0568] The reaction was carried out according to GP10-A on a scale of 454 μmol of intermediate (2.21) with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 93 / 7). The final product required two successive triturations in refluxing MeOH. Isolated yield: 69%.

[0569] Selected Examples from the 1,2,3-Benzothiadiazole Subseries

[0570] Example 11.79: Synthesis of (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one (267)

[0571] The reaction was carried out according to GP10-B on a scale of 276 μmol of intermediate (2.1) with 1.2 eq of aldehyde (7.3). Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required trituration in ACN at 0° C. Isolated yield: 49%.

[0572] Example 11.80: Synthesis of (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one (268)

[0573] The reaction was carried out according to GP10-B on a scale of 276 μmol of intermediate (2.2) with 1.2 eq of aldehyde (7.3). Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). The final product required trituration in ACN at 0° C. Isolated yield: 26%.

[0574] Example 11.81: Synthesis of (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one (269)

[0575] The reaction was carried out according to GP10-B on a scale of 276 μmol of intermediate (2.5) with 1.2 eq of aldehyde (7.3). Purification by FC (elution: DCM / MeOH: 99 / 1 to 93 / 7). Isolated yield: 42%.

[0576] Example 11.82: Synthesis of (4Z)-2-(1-adamantylamino)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-1H-imidazol-5-one (270)

[0577] The reaction was carried out according to GP10-B on a scale of 276 μmol of intermediate (2.11) using 1.2 eq of aldehyde (7.3). 3(水性) Upon precipitation at 4° C. and drying, the pure product was isolated after trituration in refluxing EtOH. Isolated yield: 70%.

[0578] A compound of formula (I) 5 is a methyl group) (compounds (132) to (266)) were isolated using a similar procedure described above.

[0579] Example 12: biological activity

[0580] Materials and Methods

[0581] Protein kinase assays

[0582] 1. Overview Assays were performed by ProQinase GmbH (Engesserstr. 4, D-79108 Freiburg, Germany. www.proqinase.com). IC values ​​for all compounds were calculated using 12 protein kinases (CDK2 / cyclin E, CK1ε, CLK1, 2, 3, 4, DYRK1A, 1B, 2, 3, 4, GSK3β). 50 The profile was determined. IC 50 Values ​​were determined by testing ten concentrations (10 μM to 30 nM) of each compound at once.

[0583] 2. Test Compounds Compounds were provided as 1 μM stock solutions in 100% DMSO. Prior to testing, the 1 μM stock solutions were subjected to serial half-log dilutions using 100% DMSO as solvent. This resulted in 10 individual concentrations, with dilution end points of 3×10 nM / 100% DMSO, with 100% DMSO as control. In the process, 90 μl of H2O was added to each well of each compound dilution plate. To minimize the possibility of precipitation, H2O was added to each plate a few minutes before transferring compound solutions to assay plate. The plate was shaken thoroughly, resulting in compound dilution plate / 10% DMSO.

[0584] For the assay (see below), 5 μL of solution from each well of the compound dilution plate / 10% DMSO was transferred to the assay plate. The final volume of the assay was 50 μL. All compounds were tested at 10 final assay concentrations ranging from 10 μM to 30 nM. The final DMSO concentration in the reaction cocktail was 1% in all cases.

[0585] 3. Recombinant Protein Kinases All protein kinases provided by ProQinase were expressed in Sf9 insect cells or in E. coli as recombinant GST-fusion or His-tagged proteins, either full-length or as enzymatically active fragments. All kinases were produced from human cDNA and purified by either GSH affinity chromatography or immobilized metals. The affinity tags were removed from many kinases during purification. Purity of the protein kinases was examined by SDS-PAGE / Coomassie staining and identity was checked by mass spectrometry.

[0586] 4. Protein Kinase Assay Radioactive protein kinase assay (33PanQinase 登録商標 The Kinase Activity Assay (PKA) was used to measure the kinase activity of 12 protein kinases. All kinase assays were performed using 96-well FlashPlates (PerkinElmer, Boston, MA, USA). 商標 The reaction cocktail was pipetted in four steps in the following order: 25 μL of assay buffer (standard buffer / [γ- 33 P]-ATP), 10 μL of ATP solution (in HO), 5 μL of test compound (in 10% DMSO), · 10μL of enzyme / substrate mixture.

[0587] Assays for all protein kinases 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 concentrations, corresponding to the apparent ATP-Km of the respective kinase), [γ- 33 The reaction cocktail contained [P]-ATP (approximately 6.5x10-05 cpm per well), protein kinase (variable amounts), and substrate (variable amounts). The reaction cocktail was incubated for 60 minutes at 30°C. The reaction was stopped with 50 μL of 2% (v / v) H3PO4, the plate was aspirated, and washed twice with 200 μL of 0.9% (w / v) NaCl. 33 Pi incorporation was determined with a microplate scintillation counter (Microbeta, Wallac). IC 50 Values ​​were calculated from dose-response curves.

[0588] 5.Quality control The Z´-factors of the low and high controls of each assay plate (n=8) were used as assay quality parameters (Zhang et al., J. Biomol. Screen. 2:67-73, 1999). The ProQinase criterion for assay plate replication is a Z´-factor of less than 0.4 (Iversen et al., J. Biomol. Screen. 3:247-252, 2006).

[0589] Their activity has been classified according to two criteria: kinase inhibition potency and kinase selectivity.

[0590] Kinase inhibition potency is classified as follows: IC 50 was performed according to the range of values.

[0591] Several compounds have IC values ​​above 0.050 μM. 50 These compounds correspond to class E reported above. Some compounds have IC values ​​between 0.025 and 0.050 μM. 50 These compounds correspond to class D as reported above. Some compounds of the present invention have IC values ​​of 0.010-0.025 μM. 50 These compounds correspond to class C as reported above. Furthermore, some specific compounds have IC values ​​of 0.005-0.010 μM. 50 These compounds correspond to class B as reported above. More preferably, they have an IC 50 The compounds of the present invention have the activity. These compounds correspond to Class A reported above. This classification was applied to CLK1 and DYRK1A. In Tables 4, 4A and 4B below, the above letters A to E are used to refer to the activity / efficacy of the compounds of the present invention.

[0592] Kinase selectivity classification: IC of DYRK1A 50 Value of CLK1 IC 50Value and IC of DYRK1B 50 The classification was based on a comparison with the IC values ​​of DYRK1A. 50 IC of CLK1 or DYRK1B for value 50 Ratio of values ​​≧10-fold (mostly DYRK1A-selective compounds); II: ratio between 2-fold and 10-fold; III: ratio between 0.5-fold and 2-fold; IV: ratio between 0.1-fold and 0.5-fold; V: ratio >0.1-fold (mostly CLK1- or DYRK1B-selective compounds). In the table below, the numbers I to V above are used to refer to the relative selectivity of the compounds of the invention.

[0593] [Table 4] JPEG2024540217000230.jpg255166JPEG2024540217000231.jpg255165JPEG20245402170 00232.jpg255164JPEG2024540217000233.jpg255168JPEG2024540217000234.jpg255168

[0594] [Table 4A] JPEG2024540217000236.jpg52170

[0595] The most potent CLK1 inhibitors were IC 50 is 10 nM or less, for compounds (7), (11), (12), (13), (15), (16), (31), (39), (40), (41), (83), (84), (85), (86), (87), (90), (107), (108), (114), (115), (116), (118), (136), (137), (139), (140), (156), (247), (229), (230), (231), (245), (246), (251), (253), and (255).

[0596] The most potent CLK2 inhibitors were IC 50is 10 nM or less, for compounds (11), (15), (16), (83), (84), (87), (114), (115), (116), (118), (137), (138), (139), (140), (141), (156), (227), (228), (229), (231), (251), (252), (253), and (255).

[0597] The most potent CLK3 inhibitors were IC 50 is 250 nM or less, for compounds (24), (27), (29), (72), (100), (114), (134), (136), (152), and (168).

[0598] The most potent CLK4 inhibitors were IC 50 is 10 nM or less, and compounds (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (18), (19), (21), (22), (23), (24), (25), (31), (39), (40), (41), (76), (77), (78), (80), (83), (84), (85), (86), (87), (88), (89), (90), (92), (95), (100), (101), (104), (10 5), (106), (107), (108), (110), (111), (112), (113), (114), (115), (116), (117), (118), (119), (120), (121), (124), (128), (129), (130), (131), (137), (139), (140), (141), (156), (227), (229), (230), (231), (246), (247), (251), (252), (253), (254) and (255).

[0599] [Table 4B]

[0600] The most potent DYRK1A inhibitors are IC 50is 10 nM or less, for compounds (3), (4), (5), (6), (7), (10), (11), (12), (13), (15), (16), (18), (21), (32), (39), (40), (41), (46), (58), (83), (84), (85), (86), (87), (114), (115), (116), (118), (137), (138), (139), (140), (141), (181), and (231).

[0601] The most potent DYRK1B inhibitors are IC 50 is 10 nM or less, for compounds (4), (5), (6), (7), (10), (11), (12), (13), (15), (16), (32), (39), (40), (41), (83), (84), (85), (86), (87), (114), (116), (118), (134), (137), (138), (139), (140), (141), (177), (179), (181), (227), (229), (231), (251), (253), (255), and (271).

[0602] The most potent DYRK2 inhibitors are IC 50 is 25 nM or less, for compounds (118), (135), (137), (139), (140), (141), (154), (179), (229), (251), (252), and (253).

[0603] The most potent DYRK3 inhibitors are IC 50 is 25 nM or less, for compounds (41), (83), (84), (87), (114), (118), (137), (138), (139), (141), (181), (227), (228), (229), (231), (251), (252), and (255).

[0604] The most potent DYRK4 inhibitors are IC 50is less than 100 nM, for compounds (114), (115), (116), (118), (135), (137), (139), (140), (225), (227), (228), (229), (251), (252), (253), and (255).

[0605] [Table 4C]

[0606] [Table 4D]

[0607] [Table 4E]

[0608] [Table 4F]

[0609] Example 13: Comparison of biological activities of compounds (C1) to (C5) disclosed in International Publication No. WO2021 / 114314

[0610] (C1), (C2), (C3), (C4) and (C5) correspond to the compounds of Examples 26, 46, 75, 55 and 78 of International Publication No. WO2021 / 114314, respectively.

[0611] The synthesis of the above compounds (C1)-(C5) which are outside the scope of the present invention are reproduced and described hereinafter.

[0612] Example 13.1: Spectroscopic and analytical characterization of compounds (C1)-(C5)

[0613] [Table 5] JPEG2024540217000243.jpg185170

[0614] Example 13.2: Synthesis of (4Z)-2-anilino-4-(3H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one (C1)

[0615] The reaction was carried out according to GP10-A with 1H-benzimidazole-5-carbaldehyde on a scale of 285 μmol of 2-anilino-1,4-dihydroimidazol-5-one. The desired compound precipitated in the reaction medium. It was isolated after dilution with EtOH, stirring for 1 h and filtration. Isolated yield: 65%.

[0616] Example 13.3: Synthesis of (4Z)-2-anilino-4-[(3-methylbenzimidazol-5-yl)methylene)-1H-imidazol-5-one (C2)

[0617] The reaction was carried out according to GP10-A on a scale of 285 μmol of 2-anilino-1,4-dihydroimidazol-5-one with 1.2 eq of aldehyde (7.2). Purification by FC (elution: DCM / MeOH (7N NH3): 99 / 1 to 94 / 6). The final product required trituration. Isolated yield: 39%.

[0618] Example 13.4: Synthesis of (4Z)-2-(1,3-benzothiazole-6-amino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one (C3)

[0619] The reaction was carried out according to GP11-A on a scale of 294 μmol of intermediate (10.9) in anisole with 3 eq 1,3-benzothiazol-6-amine and 2 eq TEA.HCl at 145° C. (sealed tube, heating block) for 8 h. The product precipitated directly in the reaction medium. It was isolated after filtering and washing with EtOH and then with pentane. The final product required two successive triturations in refluxing MeOH. Isolated yield: 65%.

[0620] Example 13.5: Synthesis of (4Z)-2-anilino-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one (C4)

[0621] The reaction was carried out according to GP10-A on a scale of 285 μmol of 2-anilino-1,4-dihydroimidazol-5-one with 1.2 eq of 1H-indazole-5-carbaldehyde. The desired compound precipitated in the reaction medium. It was isolated after dilution with EtOH, stirring for 1 h and filtration. Isolated yield: 55%.

[0622] Example 13.6: Synthesis of (4Z)-2-(1,3-benzothiazole-6-amino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one (C5)

[0623] The reaction was carried out according to GP11-A on a scale of 367 μmol of intermediate (10.6) in anisole with 3 eq 1,3-benzothiazol-6-amine and 2 eq TEA.HCl at 150 °C (sealed tube, heating block) for 24 h. The product precipitated directly in the reaction medium. It was isolated after filtration, washed with EtOH and then with pentane. The final product required two successive triturations: one at reflux and one in refluxing MeOH (hot filtration). Isolated yield: 80%.

[0624] Example 13.7: Comparison of biological activity of the compounds of the present invention with compounds (C1) to (C5)

[0625] The biological activities of the compounds of the present invention were compared with those of the prior art compounds (C1) to (C5) above.

[0626] [Table 6]

[0627] Here, in the present invention, R 1 is necessarily substituted by a (C4-C7) heterocycloalkyl group, which may itself be substituted by a (C1-C4) alkyl group. 1 Another meaning of R being a bicyclic group is (iv) a fused phenyl group selected from a phenyl group fused with a (C5-C6)cycloalkyl, where the (C5-C6)cycloalkyl may be substituted by a hydroxy group. 1 is (vi) an R'-L- group, bicyclic groups are not encompassed within the claims.

[0628] The compounds described in the claims are clearly chemically different from the closest compounds found in International Publication No. WO2021 / 114314, and furthermore the biological activity of the compounds of the present invention is clearly superior to that of the comparative compounds.

[0629] result

[0630] Most of the compounds of the present invention have IC 50 All compounds exhibited activity below 2 μM and were inhibitors of DYRK1A and CLK1 (Table 4).

[0631] The compounds were preferably inhibitory against CLK1 (Table 4A), CLK4, DYRK1A (Table 4B), and DYRK1B.

[0632] Some are most selective for DYRK1A vs. CLK1 (Table 4C), DYRK1A vs. DYRK1B (Table 4E), DYRK1B vs. DYRK1A (Table 4F), or CLK1 vs. DYRK1A (Table 4D). Some compounds show better selectivity for DYRK1A compared to CLK1 or DYRK1B. These compounds correspond to Class I (>10-fold selectivity) or Class II (2-10-fold selectivity) reported above. Some compounds are equivalent. These compounds correspond to Class III (0.5-2-fold selectivity) reported above. Some compounds show better selectivity for CLK1 or DYRK1B compared to DYRK1A. These compounds correspond to Class IV (2-10-fold selectivity) or Class V (>10-fold selectivity) reported above.

[0633] conclusion

[0634] Based on the results to date, it is believed that the compounds of formula (I) may be useful in treating Down's syndrome neuroinflammation, cognitive impairment and neuroinflammation associated with Alzheimer's disease, Alzheimer's disease and related disorders, dementia and / or tauopathies; other neurodegenerative diseases (Parkinson's disease; Pick's disease, including Niemann-Pick disease type C); CDKL5 deficiency; diabetes mellitus type 1 and type 2; folate and methionine metabolic disorders; tendon disorders and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; some cancers, such as brain tumors, including glioblastomas, leukemias, including megakaryoblastic leukemia and acute lymphoblastic leukemia, squamous cell carcinoma of the head and neck, pancreatic cancers, including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancers and breast cancers, including triple negative breast cancer (TNBC), malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma spp. It can be concluded that the compounds of the present invention are suitable chemical compounds in the prevention and / or treatment of bovine diseases due to unicellular pathogens, viral infections, such as those caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza type A, herpes viruses, rhesus cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), and in the regulation of body temperature.

[0635] It may further be concluded that some compounds of formula (I) are further suitable for treating and / or preventing Phelan-McDermid syndrome; autism; further 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; further cancers, such as tissue cancers including liposarcoma, Hedgehog / GLI-dependent cancers, liver cancers 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 due to single-celled pathogens.

[0636] Leucettinibs show much increased potency (submicromolar and single-digit micromolar IC ) compared to reference compounds. 50 Leusetinib also shows broad selectivity against DYRK1A or CLK1 / CLK4. Some products also show equivalence to CLK and DYRK, and are also expected to be used as dual specific inhibitors.

[0637] The present invention further relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above or any of its pharma- ceutically acceptable salts, or at least any of the compounds (1) to (271) as defined above or any of their pharma- ceutically acceptable salts.

[0638] The present invention further relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above or any of its pharma- ceutically acceptable salts, or at least one of the compounds (1) to (271) as defined above or any of their pharma- ceutically acceptable salts, and also at least one pharma- ceutically acceptable excipient.

[0639] The pharmaceutical compositions of the present invention may contain one or more compounds of the present invention in any of the forms described herein.

[0640] A still further object of the present invention is to provide a method for treating cognitive impairment and neuroinflammation associated with Down's syndrome (trisomy 21), Alzheimer's disease and related diseases, dementia and / or tauopathies and other neurodegenerative diseases, such as Parkinson's disease and Pick's disease, in particular Niemann-Pick disease type C; CDKL5 deficiency; Phelan-McDermid syndrome; autism; type 1 diabetes and type 2 diabetes; folate and methionine metabolic disorders; tendon disorders and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; cancer, such as brain tumors including glioblastoma, leukemia including megakaryoblastic leukemia, head and neck squamous cell carcinoma, pancreatic ductal adenocar ... Cancers including pancreatic cancer, prostate cancer, gastrointestinal cancer, breast cancer including triple negative breast cancer (TNBC), tissue cancer including liposarcoma, Hedgehog / GLI-dependent cancer, liver cancer including hepatocellular carcinoma, and viral infections such as human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella zoster virus, herpes simplex virus (HSV), hepatitis C virus, chikungunya virus, dengue virus, influenza virus, and severe acute respiratory syndrome (SARS). 271) as defined above or one of their pharmaceutically acceptable salts for use in the treatment and / or prevention of diseases selected from: infections caused by coronaviruses, cytomegaloviruses and human papillomaviruses; neuroinflammation; anemia; infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), and bovine diseases due to single-celled pathogens, as well as for thermoregulation.

[0641] A still further object of the present invention is to provide a method for the treatment of cognitive disorders and neuroinflammation associated with Down's syndrome (trisomy 21), Alzheimer's disease and related diseases, dementia and / or tauopathies and other neurodegenerative diseases, such as Parkinson's disease; Pick's disease, including Niemann-Pick disease type C; CDKL5 deficiency; type 1 diabetes and type 2 diabetes; folate and methionine metabolic disorders; tendon disorders and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; cancer, such as brain tumors, including glioblastomas, leukemias, including megakaryoblastic leukemia, head and neck squamous cell carcinoma, pancreatic cancer, including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer and breast cancer, including triple negative breast cancer (TNBC), infectious diseases caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma species), sp.), and bovine diseases due to unicellular pathogens, and viral infections, such as infections caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes viruses, rhesus cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), and for thermoregulation, comprising a compound of formula (I) as defined above or one of its pharmaceutical acceptable salts, or a compound (1) to (271) as defined above or one of its pharmaceutical acceptable salts.

[0642] A still further object of the present invention consists of the compounds of formula (I) as defined above or one of their pharmaceutically acceptable salts, or of the compounds (1) to (271) as defined above or one of their pharmaceutically acceptable salts, for use in the treatment and / or prevention of diseases selected from type 1 and type 2 diabetes; viral infections, in particular the viral infections mentioned above; tendinopathies and osteoarthritis; cancer, in particular the cancers mentioned above; infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.); bovine diseases caused by single-celled pathogens, as well as for regulating body temperature.

[0643] A still further object of the present invention consists of a compound of formula (I) as defined above or one of their pharma- ceutically acceptable salts, or of compounds (1) to (271) as defined above or one of their pharma- ceutically acceptable salts, for use in the treatment and / or prevention of a disease selected from Down's syndrome, Alzheimer's disease, dementia, tauopathies, Parkinson's disease, Niemann-Pick disease type C, CDKL5 deficiency and Phelan-McDermid syndrome and their associated cognitive and motor conditions, and type 1 diabetes and type 2 diabetes.

[0644] It is still a further object of the present invention to treat cognitive impairment and neuroinflammation associated with Down's syndrome (trisomy 21); Alzheimer's disease and related diseases; dementia; tauopathies; and other neurodegenerative diseases, such as Parkinson's disease and Pick's disease, in particular Niemann-Pick disease type C; CDKL5 deficiency; Phelan-McDermid syndrome; autism; type 1 diabetes and type 2 diabetes; folate and methionine metabolic disorders; tendon disorders and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; cancer, such as brain tumors including glioblastoma, leukemias, such as megakaryoblastic leukemia, head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma. and cancers including pancreatic cancer, prostate cancer, gastrointestinal cancer, breast cancer including triple negative breast cancer (TNBC), tissue cancer including liposarcoma, hedgehog / GLI-dependent cancer, liver cancer including hepatocellular carcinoma, and viral infections such as human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella zoster virus, herpes simplex virus (HSV), hepatitis C virus, chikungunya virus, dengue virus, influenza virus, and severe acute respiratory syndrome (SARS). and / or a method according to the invention for the preparation of a medicament for the treatment and / or prevention of diseases selected from the group consisting of infections caused by coronaviruses, cytomegaloviruses and human papillomaviruses; neuroinflammation; anemia; infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), bovine diseases due to single-celled pathogens, and for thermoregulation, comprising the use of a compound of formula (I) as defined above or one of its pharmaceutical acceptable salts, or of the compounds (1) to (271) as defined above or one of their pharmaceutical acceptable salts, according to the invention.

[0645] A still further object of the present invention is to provide a method for treating cognitive disorders and neuroinflammation associated with Down's syndrome (trisomy 21), Alzheimer's disease and related diseases, dementia and / or tauopathies; other neurodegenerative diseases such as Parkinson's disease and Pick's disease, in particular Niemann-Pick disease type C; CDKL5 deficiency; type 1 diabetes and type 2 diabetes; folate and methionine metabolic disorders; tendon disorders and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; cancer, for example brain tumors including glioblastoma, leukemia including megakaryoblastic leukemia, head and neck squamous cell carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer and breast cancer including triple negative breast cancer (TNBC), infectious diseases caused by single cell parasites, for example malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma species sp.), bovine diseases due to unicellular pathogens, and viral infections, such as infections caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes viruses, rhesus cytomegalovirus, varicella zoster virus and herpes simplex virus (HSV), and for the preparation of a medicament for the regulation of body temperature, comprising the use of a compound of formula (I) as defined above or one of its pharmaceutical acceptable salts, or a compound (1) to (271) as defined above or one of its pharmaceutical acceptable salts, according to the invention.

[0646] A still further object of the present invention consists of the use of a compound of formula (I) as defined above or one of their pharmaceutically acceptable salts, or of compounds (1) to (271) as defined above or one of their pharmaceutically acceptable salts, according to the invention, for combating diseases selected from type 1 and type 2 diabetes, viral infections, in particular the viral infections mentioned above, osteoarthritis and tendon disorders, cancers and leukemias, in particular the cancers and leukemias mentioned above, infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), bovine diseases due to single-celled pathogens, as well as for thermoregulation.

[0647] Other objects of the invention are to treat and / or prevent the development of a range of disorders, including cognitive impairment and neuroinflammation associated with Down's syndrome (trisomy 21); Alzheimer's disease and related disorders; dementia; tauopathies; and other neurodegenerative diseases, such as Parkinson's disease; Pick's disease, in particular Niemann-Pick disease type C; CDKL5 deficiency; Phelan-McDermid syndrome; autism; diabetes mellitus type 1 and type 2; folate and methionine metabolic disorders; tendinopathy and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; cancer, such as brain tumors including glioblastoma, leukemia including megakaryoblastic leukemia, head and neck squamous cell carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer and breast cancer including triple negative breast cancer (TNBC), infectious diseases caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma species). sp.), and bovine diseases due to unicellular pathogens, and viral infections, such as infections caused by human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes viruses, rhesus cytomegalovirus, varicella zoster virus, and herpes simplex virus (HSV), as well as therapeutic methods for the treatment and / or prevention of diseases selected from these, and for thermoregulation.

[0648] Yet another object of the present invention consists of the use of a compound of formula (I) as defined above or one of their pharma- ceutically acceptable salts, or of compounds (1) to (271) as defined above or one of their pharma-ceutically acceptable salts, according to the invention, for preparing a medicament for combating diseases selected from type 1 and type 2 diabetes, viral infections, in particular the viral infections mentioned above, tendinopathies and osteoarthritis, cancer, in particular the cancers mentioned above, infections caused by unicellular parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), bovine diseases due to unicellular pathogens, and for thermoregulation.

[0649] According to a particular embodiment, the treatment is continuous or discontinuous.

[0650] "Continuous treatment" refers to chronic treatment, which can be performed with various administration frequencies, for example, once or twice daily, once every 3 days, once a week, once every 2 weeks, once a month, or treatment via a transdermal patch.

[0651] According to one embodiment, the compounds of formula (I), or any one of their pharma- ceutically acceptable salts, are administered in a dose of 0.1 to 1000 mg, in particular 0.5 to 500 mg, for example 5 to 100 mg.

[0652] Another object of the present invention is to provide a method for the treatment and / or prevention of the diseases mentioned below or for the regulation of body temperature in a patient in need thereof, including cognitive impairment and neuroinflammation associated with Down's syndrome (trisomy 21), Alzheimer's disease and related diseases, dementia and / or tauopathies and other neurodegenerative diseases, such as Parkinson's disease and Pick's disease, in particular Niemann-Pick disease type C; CDKL5 deficiency; Phelan-McDermid syndrome; autism; diabetes mellitus type 1 and type 2; folate and methionine metabolism disorders; tendinopathy and osteoarthritis, in particular knee osteoarthritis; Duchenne muscular dystrophy; cancer, including brain tumors, including glioblastoma, megakaryoblastic leukemia. and leukemia, head and neck squamous cell carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma, prostate cancer, gastrointestinal cancer, breast cancer including triple negative breast cancer (TNBC), tissue cancer including liposarcoma, hedgehog / GLI-dependent cancer, liver cancer including hepatocellular carcinoma, and viral infections, such as human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), influenza A, herpes virus, rhesus cytomegalovirus, varicella zoster virus, herpes simplex virus (HSV), hepatitis C virus, chikungunya virus, dengue virus, influenza virus, and severe acute respiratory syndrome (SARS). and / or prevention of diseases selected from the group consisting of infections caused by coronaviruses, cytomegaloviruses and human papillomaviruses; neuroinflammation; anemia; infections caused by single-celled parasites, such as malaria, leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), bovine diseases caused by single-celled pathogens, as well as for the regulation of body temperature, said method comprising at least the step of administering an effective amount of a compound of formula (I) or one of its pharmacologic acceptable salts, or of the compounds (1) to (271) as defined above or one of their pharmacologic acceptable salts.

[0653] In a particular embodiment, the present invention provides a method of use of a compound of formula (I) according to the present invention or a pharma- ceutically acceptable salt thereof or a pharma- ceutically active derivative thereof, or a method according to the present invention, comprising administering a compound of formula (I) in combination with a co-agent useful in any of the diseases described herein above.

[0654] The compounds can be administered by any mode of administration, including intramuscular, intravenous, intranasal or oral routes, transdermal patch, etc.

[0655] 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, inter alia, in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Ed." (various editors, 1989-1998, Marcel Dekker) and in "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al, 1994, WILLIAMS & WILKINS).

[0656] The aforementioned additives are selected according to the dosage form and the desired mode of administration.

[0657] The compositions of the present invention can be administered in any manner, including, but not limited to, oral, parenteral, sublingual, transdermal, vaginal, rectal, mucosal, topical, intranasal, via inhalation, intranasal via buccal or nasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular administration. The compositions of the present invention can also be administered in the form of an implant, which allows for sustained release of the composition and allows for slow, controlled intravenous (iv) infusion.

[0658] For example, the compounds of formula (I) may be present, in association with suitable excipients, in any pharmaceutical form suitable for enteral or parenteral administration, such as plain or coated tablets, hard gelatin, soft shell capsules and other capsules, suppositories, or drinks, such as suspensions, syrups, injection solutions or suspensions.

[0659] In a particular embodiment, the compounds of formula (I) according to the present invention are administered orally.

[0660] The oral administration route is particularly preferred in the prophylactic or therapeutic aspects of the present invention.

Claims

1. Any one of the compounds of formula (I) below, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 where: A is =CH-, -N= and -NR 3 - selected from the group consisting of B is —O—, ═CH—, ═N—, —NH—, —S—, or —NR 4 - selected from the group consisting of At least one of A and B is ═CH— or —S—; A and B cannot both represent =CH-; R 2 is hydrogen atoms and (C 1 ~C 3 ) alkyl groups, or R 2 When the nitrogen atom to which R is bonded is -N=, 2 does not exist, R 3 and R 4 are independent, (C 1 ~C 3 ) alkyl groups, R 5 is a hydrogen atom, (C 1 ~C 4 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group, and When A represents =CH- and B represents =N- or -NH-, R 2 represents a hydrogen atom or is absent, and where R 1 represents the following (i), (ii), (iii), (iv), (v), (vi) or (vii): (i) Hydroxy group, halogen atom and (C 1 ~C 3 ) alkoxy groups substituted by a group selected from (C 4 ~C 6 ) alkyl group, (ii) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 3 ~C 8 ) a cycloalkyl group, (iii) (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) a bridged (C) optionally substituted with a group selected from an alkoxy group, a halogen atom, and a hydroxy group; 6 ~C 10 ) a cycloalkyl group, (iv) (C 5 ~C 6 ) a fused phenyl group selected from a phenyl group fused with a cycloalkyl, wherein (C 5 ~C 6 ) cycloalkyl may be substituted by a hydroxy group; (v) (C 4 ~C 7 ) a phenyl group substituted by a heterocycloalkyl group, wherein (C 4 ~C 7 ) Heterocycloalkyl groups themselves are not (C 1 ~C 4 ) optionally substituted by an alkyl group; Or, (vi) R'-L- group, where: L is a single bond or a hydroxy group and (C 1 ~C 3 ) alkoxy groups (C 1 ~C 3 ) an alkanediyl group, and R' represents the following (vi.1) or (vi.2): (vi.1) Hydroxy group and (C 1 ~C 4 ) alkyl groups (C 3 ~C 8 ) a heterocycloalkyl group, or (vi.2) (C 1 ~C 4 ) optionally substituted by alkyl groups (C 3 ~C 8 ) heteroaryl groups, Or, (vii) R″-L- group, where: L is -NR b R c Group, (C 1 ~C 3 ) optionally substituted with a group selected from an alkoxy group and a hydroxy group (C 1 ~C 3 ) an alkanediyl group, and R” is fluoro(C 1 ~C 4 ) a phenyl group optionally substituted by an alkyl group; where R b and R c are independent, (C 1 ~C 6 ) represents an alkyl group or a hydrogen atom.

2. R 1 represents the following (i), (ii), (iii), (iv), (v), (vi) or (vii): (i) Hydroxy group, halogen atom and (C 1 ~C 3 ) alkoxy groups substituted by a group selected from (C 5 ~C 6 ) alkyl groups, (ii) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 5 ~C 8 ) a cycloalkyl group, (iii) (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) a bridged (C) optionally substituted with a group selected from an alkoxy group, a halogen atom, and a hydroxy group; 9 ~C 10 ) a cycloalkyl group, (iv) a phenyl group fused to a cyclopentyl, wherein the cyclopentyl is substituted by a hydroxy group; (v) (C 4 ~C 7 ) a phenyl group substituted by a heterocycloalkyl group, wherein (C 4 ~C 7 ) Heterocycloalkyl groups themselves are not (C 1 ~C 4 ) optionally substituted by an alkyl group; Or, (vi) R'-L- group, where: L is a single bond or a hydroxy group and (C 1 ~C 3 ) alkoxy groups (C 1 ~C 3 ) an alkanediyl group, and R' represents the following (vi.1) or (vi.2): (vi.1) Hydroxy group and (C 1 ~C 4 ) alkyl groups (C 6 ~C 7 ) a heterocycloalkyl group, or (vi.2) (C 1 ~C 4 ) optionally substituted by alkyl groups (C 3 ~C 8 ) heteroaryl groups, Or, (vii) R″-L- group, where: L is -NR b R c Group, (C 1 ~C 3 ) optionally substituted by a group selected from an alkoxy group and a hydroxy group (C 1 ~C 3 ) an alkanediyl group, and R” is fluoro(C 1 ~C 4 ) a phenyl group optionally substituted by an alkyl group, and where R b and R c are independent, (C 1 ~C 6 ) represents an alkyl group or a hydrogen atom; 10. A compound of formula (I) according to claim 1, or any one of its pharmaceutically acceptable salts.

3. R 1 represents the following (i), (ii), (iii), (iv), (v), (vi) or (vii): (i) (C) substituted with a group selected from a hydroxy group, a fluorine atom, and a methoxy group 5 ~C 6 ) alkyl groups, (ii) optionally substituted with a group selected from a hydroxy group and a methoxy group (C 5 ~C 8 ) a cycloalkyl group, (iii) a crosslinked (C 9 ~C 10 ) a cycloalkyl group, (iv) a phenyl group fused to a cyclopentyl, wherein the cyclopentyl is substituted by a hydroxy group; (v) a phenyl group substituted with an N-methylpiperazinyl group; Or, (vi) R'-L- group, where: L is a single bond or may be substituted with a group selected from a hydroxy group and a methoxy group (C 1 ~C 3 ) an alkanediyl group, and R' represents the following (vi.1) or (vi.2): (vi.1) optionally substituted with one or two groups selected from a hydroxy group and a methyl group (C 6 ~C 7 ) a heterocycloalkyl group, or (vi.2) optionally substituted with a methyl group (C 3 ~C 8 ) heteroaryl groups, Or, (vii) R″-L- group, where: L is -NH 2 group, methoxy group, hydroxy group, -COOR a and halogen atoms (C 1 ~C 3 ) an alkanediyl group, and R" is a phenyl group optionally substituted by a trifluoromethyl group; 3. A compound of formula (I) according to claim 1 or 2, or any one of its pharmaceutically acceptable salts.

4. L is -CH 2 - group, -CH(CH 2 -OH)- group, -CH(CH 2 OCH 3 )-group, -CH(OH)-CH 2 - group and -CH(CH 2 NH 2 3. The compound of claim 1, wherein the compound is selected from the group consisting of:

5. (vi.1) R' is (C 5 ~C 8 ) heterocycloalkyl group, L is -CH 2 - group, (vi.2) When R' is phenyl, L is -CH 2 - group, -CH(CH 2 -OH)- group, -CH(CH 2 OCH 3 )-group, -CH(OH)-CH 2 - group and -CH(CH 2 NH 2 )-groups, (vi.3) R' is (C 3 ~C 8 ) heteroaryl group, L is -CH 2 -based, 3. Any one of the compounds according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. 3. A compound of formula (I) according to claim 1 or 2, selected from the following compounds, or any one of their pharmaceutically acceptable salts: 【Chemistry 2】 where R 1 , R 2 , R 3 , R 4 and R 5 is as defined in claim 1 or 2.

7. the compound of formula (I) is selected from formula (Ib), formula (Id), formula (Ie) and formula (If); R 1 represents (i), (ii), (iii), (iv) or (v) below: (i) Hydroxy group, halogen atom and (C 1 ~C 3 ) alkoxy groups substituted by a group selected from (C 4 ~C 6 ) alkyl group, (ii) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 3 ~C 8 ) a cycloalkyl group, (iii) (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) a bridged (C) optionally substituted with a group selected from an alkoxy group, a halogen atom, and a hydroxy group; 6 ~C 10 ) a cycloalkyl group, Or, (iv) R'-L- group, where: L is a single bond or a hydroxy group and (C 1 ~C 3 ) alkoxy groups (C 1 ~C 3 ) an alkanediyl group, and R' represents the following (iv.1) or (iv.2): (iv.1) Hydroxy group and (C 1 ~C 4 ) alkyl groups (C 3 ~C 8 ) a heterocycloalkyl group, or (iv.2) (C 1 ~C 4 ) optionally substituted by alkyl groups (C 3 ~C 8 ) heteroaryl groups, Or, (v) R″-L- group, where: L is -NR b R c Group, (C 1 ~C 3 ) optionally substituted with a group selected from an alkoxy group and a hydroxy group (C 1 ~C 3 ) an alkanediyl group, and R” is fluoro(C 1 ~C 4 ) a phenyl group optionally substituted by an alkyl group; where R b and R c are independent, (C 1 ~C 6 ) represents an alkyl group or a hydrogen atom; 7. A compound of formula (I) according to claim 6, or any one of its pharmaceutically acceptable salts.

8. R 1 represents (i), (ii), (iii), (iv) or (v) below: (i) Hydroxy group, halogen atom and (C 1 ~C 3 ) alkoxy groups substituted by a group selected from (C 4 ~C 6 ) alkyl group, (ii) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 3 ~C 8 ) a cycloalkyl group, (iii) (C 1 ~C 4 ) alkyl group, (C 1 ~C 4 ) a bridged (C) optionally substituted with a group selected from an alkoxy group, a halogen atom, and a hydroxy group; 6 ~C 10 ) a cycloalkyl group, or (iv) R'-L- group, where: L is a single bond or a hydroxy group and (C 1 ~C 3 ) alkoxy groups (C 1 ~C 3 ) an alkanediyl group, and R' represents the following (iv.1) or (iv.2): (iv.1) Hydroxy group and (C 1 ~C 4 ) alkyl groups (C 3 ~C 8 ) a heterocycloalkyl group, or (iv.2) (C 1 ~C 4 ) optionally substituted by alkyl groups (C 3 ~C 8 ) heteroaryl groups, Or, (v) R″-L- group, where: L is -NR b R c Group, (C 1 ~C 3 ) optionally substituted with a group selected from an alkoxy group and a hydroxy group (C 1 ~C 3 ) an alkanediyl group, and R” is fluoro(C 1 ~C 4 ) a phenyl group optionally substituted by an alkyl group; where R b and R c are independent, (C 1 ~C 6 ) represents an alkyl group or a hydrogen atom; 3. A compound of formula (I) according to claim 1 or 2, or any one of its pharmaceutically acceptable salts.

9. R 5 is a hydrogen atom or (C 1 ~C 4 3. A compound of formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts, wherein R represents an alkyl group.

10. (1) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one, (2) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one, (3) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(cyclooctylamino)-1H-imidazol-5-one, (4) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (5) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (6) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one, (7) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one, (8) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[trans-4-hydroxycycloheptyl]amino]-1H-imidazol-5-one, (9) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[trans-4-methoxycycloheptyl]amino]-1H-imidazol-5-one, (10) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[cis-3-methoxycycloheptyl]amino]-1H-imidazol-5-one, (11) (4Z)-2-(1-adamantylamino)-4-(1,3-benzoxazol-6-ylmethylene)-1H-imidazol-5-one, (12) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one, (13) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1H-imidazol-5-one, (14) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (15) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-1H-imidazol-5-one, (16) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (17) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (18) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (19) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (20) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (21) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (22) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(2-pyridylamino)-1H-imidazol-5-one, (23) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-1H-imidazol-5-one, (24) (4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (25) (±)-(4Z)-4-(1,3-benzoxazol-6-ylmethylene)-2-(oxepan-3-ylamino)-1H-imidazol-5-one, (26) (4Z)-2-(cyclohexylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (27) (4Z)-2-(cycloheptylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (28) (4Z)-2-(cyclooctylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (29) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (30) (4Z)-4-(1H-indazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (31) (4Z)-2-(1-adamantylamino)-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (32) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-(1H-indazol-5-ylmethylene)-1H-imidazol-5-one, (33) (4Z)-4-(1H-indazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (34) (4Z)-2-(cyclohexylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (35) (4Z)-2-(cycloheptylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (36) (4Z)-2-(cyclooctylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (37) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (38) (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (39) (4Z)-2-(1-adamantylamino)-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (40) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (41) (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (42) (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(2-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (43) (4Z)-2-(cyclohexylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (44) (4Z)-2-(cycloheptylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (45) (4Z)-2-(cyclooctylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (46) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (47) (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (48) (4Z)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (49) (4Z)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (50) (4Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (51) (4Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (52) (±)-(4Z)-2-[[trans-4-hydroxycycloheptyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (53) (±)-(4Z)-2-[[trans-4-methoxycycloheptyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (54) (±)-(4Z)-2-[[cis-3-methoxycycloheptyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (55) (4Z)-2-(1-adamantylamino)-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (56) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (57) (4Z)-2-[(3-methoxy-1-adamantyl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (58) (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (59) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (60) (4Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (61) (4Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (62) (4Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (63) (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (64) (4Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (65) (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (66) (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (67) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (68) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (69) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (70) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-(2-pyridylamino)-1H-imidazol-5-one, (71) (4Z)-2-[(6,6-dimethyltetrahydropyran-3-yl)amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (72) (4Z)-4-[(1-methylindazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (73) (4Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-4-[(1-methylindazol-5-yl)methylene]-1H-imidazol-5-one, (74) (±)-(4Z)-4-[(1-methylindazol-5-yl)methylene]-2-(oxepan-3-ylamino)-1H-imidazol-5-one, (75) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one, (76) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one, (77) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(cyclooctylamino)-1H-imidazol-5-one, (78) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (79) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (80) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (81) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (82) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-1H-imidazol-5-one, (83) (4Z)-2-(3-noradamantylamino)-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one, (84) (4Z)-2-(1-adamantylamino)-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one, (85) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-1H-imidazol-5-one, (86) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-1H-imidazol-5-one, (87) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-1H-imidazol-5-one, (88) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (89) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-1H-imidazol-5-one, (90) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (91) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (92) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-1H-imidazol-5-one, (93) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-1H-imidazol-5-one, (94) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(2S)-2-hydroxy-2-phenyl-ethyl]amino]-1H-imidazol-5-one, (95) (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one dihydrochloride, (96) (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-(1H-benzimidazol-5-ylmethylene)-1H-imidazol-5-one dihydrochloride, (97) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (98) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (99) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (100) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(2-pyridylamino)-1H-imidazol-5-one, (101) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3S)-tetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (102) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (103) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-[[(3S,4S)-4-hydroxytetrahydropyran-3-yl]amino]-1H-imidazol-5-one, (104) (4Z)-4-(1H-benzimidazol-5-ylmethylene)-2-(oxepan-3-ylamino)-1H-imidazol-5-one, (105) (4Z)-2-(cyclohexylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (106) (4Z)-2-(cycloheptylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (107) (4Z)-2-(cyclooctylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (108) (4Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (109) (4Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (110) (4Z)-2-[[(1R)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (111) (4Z)-2-[[(1S)-1-(fluoromethyl)-3-methyl-butyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (112) (4Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (113) (4Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (114) (4Z)-2-(3-noradamantylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (115) (4Z)-2-(1-adamantylamino)-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (116) (4Z)-2-[(3-hydroxy-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (117) (4Z)-2-[(3-methoxy-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (118) (4Z)-2-[(3-fluoro-1-adamantyl)amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (119) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]-1H-imidazol-5-one, (120) (4Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (121) (4Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (122) (4Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (123) (4Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (124) (4Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (125) (4Z)-2-[[(2S)-2-hydroxy-2-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one, (126) (4Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (127) (4Z)-2-[[(1S)-2-amino-1-phenyl-ethyl]amino]-4-[(3-methylbenzimidazol-5-yl)methylene]-1H-imidazol-5-one dihydrochloride, (128) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]-1H-imidazol-5-one, (129) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)-1H-imidazol-5-one, (130) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]-1H-imidazol-5-one, (131) (4Z)-4-[(3-methylbenzimidazol-5-yl)methylene]-2-(2-pyridylamino)-1H-imidazol-5-one, (132) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-(cyclohexylamino)-3-methyl-imidazol-4-one, (133) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-(cyclooctylamino)-3-methyl-imidazol-4-one, (134) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (135) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (136) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1SR,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (137) (5Z)-2-(3-noradamantylamino)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-imidazol-4-one, (138) (5Z)-2-(1-adamantylamino)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-imidazol-4-one, (139) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (140) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (141) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-imidazol-4-one, (142) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (143) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (144) (5Z)-5-(1,3-benzoxazol-6-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (145) (5Z)-2-(cyclohexylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (146) (5Z)-2-(cycloheptylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (147) (5Z)-2-(cyclooctylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (148) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (149) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (150) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (151) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (152) (5Z)-2-(3-noradamantylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (153) (5Z)-2-(1-adamantylamino)-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (154) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (155) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (156) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (157) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (158) (5Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (159) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (160) (5Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (161) (5Z)-5-(1H-indazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (162) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (163) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one dihydrochloride, (164) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (165) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (166) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (167) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-(2-pyridylamino)imidazol-4-one, (168) (5Z)-5-(1H-indazol-5-ylmethylene)-3-methyl-2-[[(3S)-tetrahydropyran-3-yl ]amino]imidazol-4-one, (169) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-5-(1H-indazol-5-ylmethylene)-3-methyl-imidazol-4-one, (170) (5Z)-2-(cyclohexylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (171) (5Z)-2-(cycloheptylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (172) (5Z)-2-(cyclooctylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (173) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (174) (5Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (175) (5Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (176) (5Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (177) (5Z)-2-(3-noradamantylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (178) (5Z)-2-(1-adamantylamino)-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (179) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (180) (5Z)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (181) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (182) (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (183) (5Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (184) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (185) (5Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (186) (5Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (187) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (188) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one dihydrochloride, (189) (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (190) (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (191) (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (192) (5Z)-3-methyl-5-[(2-methylindazol-5-yl)methylene]-2-(2-pyridylamino)imidazol-4-one, (193) (5Z)-3-Methyl-5-[(2-methylindazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl ]amino]imidazol-4-one, (194) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-5-[(2-methylindazol-5-yl)methylene]imidazol-4-one, (195) (5Z)-2-(cyclohexylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (196) (5Z)-2-(cycloheptylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (197) (5Z)-2-(cyclooctylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (198) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (199) (5Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (200) (5Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (201) (5Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (202) (5Z)-2-(3-noradamantylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (203) (5Z)-2-(1-adamantylamino)-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (204) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (205) (5Z)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (206) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (207) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (208) (5Z)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (209) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (210) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (211) (5Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (212) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (213) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one dihydrochloride, (214) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (215) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (216) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (217) (5Z)-3-methyl-5-[(1-methylindazol-5-yl)methylene]-2-(2-pyridylamino)imidazol-4-one, (218) (5Z)-3-Methyl-5-[(1-methylindazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl ]amino]imidazol-4-one, (219) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-5-[(1-methylindazol-5-yl)methylene]imidazol-4-one, (220) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-(cyclohexylamino)-3-methyl-imidazol-4-one, (221) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-(cycloheptylamino)-3-methyl-imidazol-4-one, (222) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-(cyclooctylamino)-3-methyl-imidazol-4-one, (223) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (224) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (225) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (226) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (227) (5Z)-2-(3-noradamantylamino)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-imidazol-4-one, (228) (5Z)-2-(1-adamantylamino)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-imidazol-4-one, (229) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (230) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (231) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-imidazol-4-one, (232) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (233) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-imidazol-4-one, (234) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (235) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (236) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (237) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (238) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (239) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (240) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (241) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-(2-pyridylamino)imidazol-4-one, (242) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-3-methyl-2-[[(3S)-tetrahydropyran-3-yl ]amino]imidazol-4-one, (243) (5Z)-5-(1H-benzimidazol-5-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-imidazol-4-one, (244) (5Z)-2-(cyclohexylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (245) (5Z)-2-(cycloheptylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (246) (5Z)-2-(cyclooctylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (247) (5Z)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (248) (5Z)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (249) (5Z)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (250) (5Z)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (251) (5Z)-2-(3-noradamantylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (252) (5Z)-2-(1-adamantylamino)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (253) (5Z)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (254) (5Z)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (255) (5Z)-2-[(3-fluoro-1-adamantyl)amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (256) (5Z)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (257) (5Z)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (258) (5Z)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (259) (5Z)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (260) (5Z)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (261) (5Z)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (262) (5Z)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (263) (5Z)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (264) (5Z)-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-(2-pyridylamino)imidazol-4-one, (265) (5Z)-3-Methyl-5-[(3-methylbenzimidazol-5-yl)methylene]-2-[[(3S)-tetrahydropyran-3-yl ]amino]imidazol-4-one, (266) (5Z)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-5-[(3-methylbenzimidazol-5-yl)methylene]imidazol-4-one, (267) (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-(cyclohexylamino)-1H-imidazol-5-one, (268) (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-(cycloheptylamino)-1H-imidazol-5-one, (269) (4Z)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-1H-imidazol-5-one, (270) (4Z)-2-(1-adamantylamino)-4-(1,2,3-benzothiadiazol-6-ylmethylene)-1H-imidazol-5-one, (271) (4Z)-4-(indazol-5-ylmethylene)-2-[4-(4-methylpiperazin-1-yl)aniline]-1H-imidazol-5-one 2. The compound of formula (I) according to claim 1, selected from: or any one of their pharmaceutically acceptable salts.

11. A pharmaceutical composition comprising at least one compound as defined in claim 1 or any one of their pharmaceutically acceptable salts, or any one of the compounds (1) to (271) as defined in claim 10 or a pharmaceutically acceptable salt thereof.

12. 11. A synthetic process for preparing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, or a compound according to claim 10 or a pharmaceutically acceptable salt thereof, comprising: A compound of formula (IX) 【Chemistry 3】 where R 2 , R 5 , A and B are as defined in claim 1, and Alk is (C 1 ~C 5 ) alkyl, to the formula R 1 NH 2 where R 1 is as defined in claim 1, coupling with an amine of The method, comprising at least

13. 11. A synthetic process for producing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a compound according to claim 10 or a pharmaceutically acceptable salt thereof, comprising: A compound of formula (II) 【Chemistry 4】 where R 1 and R 5 is as defined in claim 1, with a compound of formula (III) 【Chemistry 5】 where R 2 , A and B are as defined in claim 1; coupling with a compound of The method, comprising at least

14. A synthetic intermediate represented by the following formula (XI): 【Chemistry 6】 where R 1 and R 5 is as set forth in claim 1 or 2.

15. A compound of formula (I) according to claim 1 or any one of its pharmaceutically acceptable salts, or at least any one of compounds (1) to (271) according to claim 10 or any one of its pharmaceutically acceptable salts, for use as a pharmaceutical.

16. A compound of formula (I) according to claim 1, or any one of its pharmaceutically acceptable salts, or at least one of compounds (1) to (271) according to claim 10, or any one of its pharmaceutically acceptable salts, for the treatment and / or prevention of a disease selected from cognitive impairment and neuroinflammation associated with Down syndrome; Alzheimer's disease and related diseases, dementia and / or tauopathies; and other neurodegenerative diseases; CDKL5 deficiency; Phelan-McDiarmid syndrome; autism; type 1 diabetes and type 2 diabetes; folate and methionine metabolism disorders; tendinopathy and osteoarthritis; Duchenne muscular dystrophy; cancer; and viral infections; neuroinflammation; anemia; infections caused by single-celled parasites, bovine diseases caused by single-celled pathogens, and for thermoregulation.

17. A compound of formula (I) according to claim 1, or any one of its pharmaceutically acceptable salts, or at least any one of compounds (1) to (271) according to claim 10, or any one of its pharmaceutically acceptable salts, for use in the treatment and / or prevention of a disease selected from Down syndrome, Alzheimer's disease, dementia, tauopathy, Parkinson's disease, Niemann-Pick disease type C, CDKL5 deficiency and Phelan-McDermid syndrome, and their associated cognitive and motor conditions, and type 1 diabetes and type 2 diabetes.

Images