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: JPEG2024540216000057.jpg40170, where R 2 is selected from the group consisting of a hydrogen atom and a (C1-C3) alkyl group; R 3 is a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, and 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, where 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, where L is a (C1-C3)alkanediyl group and R'' represents an optionally substituted phenyl group. The present invention further relates to compositions comprising the compounds of formula (I), and processes for producing said compounds, as well as synthetic intermediates thereof. The present invention also relates to said compounds for use as pharmaceuticals, 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; tendinopathies and osteoarthritis; 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, the leucettamines, that are useful as pharmaceuticals. 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 impairment 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 beta 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), 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] JPEG2024540216000003.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. In other words, none of the disclosed compounds includes or can be considered close to 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 new compounds for treating and / or preventing diseases such as those mentioned above, particularly through the inhibition, especially the selective inhibition, of DYRK1A, other DYRK and related CLK kinases. [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, dementia 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 tauopathy (in particular the cognitive impairment and neuroinflammation associated with these indications); 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 present invention finally describes a synthetic intermediate of formula (II) 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] 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.

[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: R 2 is selected from the group consisting of a hydrogen atom and a (C1-C3) alkyl group; R 3 is a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, 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 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) (C1-C4) 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; (vi) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl 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, for example, a (C6-C7) cycloalkyl group in which at least one carbon atom is substituted by an oxygen atom or a sulfur atom, 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; R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group, and wherein at least one of R″ and L is substituted; and Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0059] 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 1represents the following (i), (ii), (iii), (iv), (v), (vi), (vii) or (viii): (i) a (C5-C6) alkyl group, preferably a C6-alkyl group, substituted by a group selected from a hydroxy group 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) (C1-C4) bridged (C9-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 by a (C4-C7)heterocycloalkyl group, wherein the (C4-C7)heterocycloalkyl group may itself be substituted by a (C1-C4)alkyl group; (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, for example, a (C6-C7) cycloalkyl group in which at least one carbon atom is substituted by an oxygen atom or a sulfur atom, or (vi.2) a (C3-C8) heteroaryl group optionally substituted by a (C1-C4) alkyl group, Or, (viii) R″-L- group, wherein L is -NR b R ca (C1-C3)alkanediyl group optionally substituted by a group selected from a group, a (C1-C3)alkoxy group, and a hydroxy group; R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group, and wherein at least one of R″ and L is substituted; and Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0060] 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, preferably a C6-alkyl group, substituted by a group selected from a hydroxy group 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-C 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 with an N-methylpiperazinyl group, (vi) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group; and R' is selected from the group consisting of (vi.1) or (vi.2) below: (vi.1) (C6-C7) heterocycloalkyl groups optionally substituted by a hydroxy group, for example (C6-C7) cycloalkyl groups in which at least one carbon atom is substituted by an oxygen atom or a sulfur atom, in particular tetrahydropyranyl, or (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 (C1-C3)alkanediyl group optionally substituted by a group selected from the group consisting of an -NH2 group, a methoxy group, and a hydroxy group; R″ is a phenyl group optionally substituted by a trifluoromethyl group, and wherein at least one of R″ and L is substituted.

[0061] 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 is the R'-L- group, where L is selected from the group consisting of a single bond, a -CH2- group, a -CH(CH2OH)- group, a -CH(CH2OCH3)- group, a -CH(OH)-CH2- group, and a -CH(CH2NH2)- group.

[0062] 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, Where: (vi.1) when R' is a (C5-C8)heterocycloalkyl group, for example a (C5-C8)cycloalkyl group in which at least one carbon atom is replaced by an oxygen atom or a sulfur atom, L is a single bond or a -CH2- group, (vi.2) when R' is a (C3-C8) heteroaryl group, L is a single bond or a -CH2- group, (vi.3) When R″ is phenyl, L is selected from the group consisting of a single bond, a —CH2— group, a —CH(CH2OH)— group, a —CH(CH2OCH3)— group, a —CH(OH)—CH2— group and a —CH(CH2NH2)— group.

[0063] 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 and a (C1-C3) alkoxy group, or a (C3-C8) cycloalkyl group optionally substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; (C1-C4) alkoxy groups, halogen atoms, and hydroxy groups. 10 ) cycloalkyl groups.

[0064] This subgroup of compounds is collected under "A1" type compounds in Table 2 herein below.

[0065] Still according to the above embodiment, R 1 may more particularly represent a hydrogen atom, cyclohexyl, cycloheptyl, cyclooctyl, 1-(hydroxymethyl)-3-methyl-butyl, 1-(methoxymethyl)-3-methyl-butyl, 1-(ethoxymethyl)-3-methyl-butyl, 2-methoxycyclopentyl, 3-noradamantyl, 1-adamantyl, 3-hydroxy-1-adamantyl, 3-methoxy-1-adamantyl, 3-fluoro-1-adamantyl.

[0066] 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 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 R″ is a phenyl group optionally substituted by a fluoro(C1-C4)alkyl group, and wherein at least one of R″ and L is substituted; and Here, R b and R c are independently selected from (C1-C6) alkyl and a hydrogen atom.

[0067] The subgroups of compounds are collected under "A2" and "A5" type compounds in Table 2 herein below.

[0068] Still according to the above 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.

[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 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.

[0070] The subgroups of compounds are collected under "A3" and "A6" type compounds in Table 2 herein below.

[0071] Still according to the above embodiment, R 1 may more particularly represent (4-methylthiazol-2-yl)methyl or 2-pyridyl.

[0072] 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, for example a (C3-C8) cycloalkyl group, in which at least one carbon atom is replaced by an oxygen atom or a sulfur atom, and L is a (C1-C3)alkanediyl or a single bond.

[0073] The subgroups of compounds are collected under "A4" and "A7" type compounds in Table 2 herein below.

[0074] Still according to the above embodiment, R 1 may more particularly represent tetrahydropyran-4-yl-methyl, tetrahydropyran-3-yl or 4-hydroxytetrahydropyran-3-yl.

[0075] 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 1represents the following (i), (ii), (iii), (iv), (v) or (vi): (i) a (C4-C6) alkyl group substituted by a group selected from a hydroxy group 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) (C1-C4) bridged (C6-C 10 ) a cycloalkyl group, (iv) R'-L- group, where L is either a single bond or a (C1-C3)alkanediyl group; and R' represents the following (vi.1) or (vi.2): (iv.1) a tetrahydropyranyl 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 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; (vi) R″-L- group, wherein 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 substituted with a fluoro(C1-C4)alkyl group; Here, R b and R c each independently represents a (C1-C6) alkyl group or a hydrogen atom.

[0076] There is further provided herein a compound of formula (I) as defined herein above, wherein R 1 represents the following group: a (C4-C6) alkyl group substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group; (C1-C4) alkoxy groups, halogen atoms, and hydroxy groups. 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, and wherein at least one of R″ and L is substituted.

[0077] According to another particular embodiment, the present invention relates to compounds of formula (I) as defined above, in which R 3 is a (C1-C4) alkyl group, particularly a methyl group.

[0078] In the context of the present invention the following terms are used:

[0079] The term "halogen atom" means chlorine, fluorine, bromine, and iodine atoms, and in particular refers to chlorine, fluorine, and bromine atoms.

[0080] As used herein, the term "(C x ~C y ) alkyl" are C x ~C y"C4-C6" refers to a primary, secondary, or tertiary monovalent saturated hydrocarbon radical, such as (C4-C6) alkyl. Examples include, but are not limited to, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.

[0081] 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.

[0082] 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, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0083] 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 selected from oxygen and sulfur atoms, more particularly oxygen atoms. Such heterocycloalkyl groups may be saturated or partially saturated, and may be unsubstituted or substituted. Examples include, but are not limited to, oxanyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, oxepanyl, dioxanyl, and tetrahydrothiopyranyl, more particularly tetrahydropyranyl.

[0084] As used herein, the term "(C x ~C y )alkoxy" is -O-(C x ~C y ) alkyl moiety or -O-(C3-C y) 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, more particularly methoxy.

[0085] 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.

[0086] "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, more particularly indanyl.

[0087] 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, without being limited thereto, of 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 or thiazole.

[0088] "Aromatic ring" means that the molecule has 4n+2 pi electrons according to Hückel's rule.

[0089] 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.

[0090] In the context of the present invention, the terms "aromatic ring" and "heteroaryl" include all positional isomers.

[0091] The nomenclature of compounds (2)-(31) below was generated using Accelrys Draw 4.1 SP1 and following 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.

[0092] 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: (2) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cyclohexylamino)-3-methyl-imidazol-4-one, (3) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cycloheptylamino)-3-methyl-imidazol-4-one, (4) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cyclooctylamino)-3-methyl-imidazol-4-one, (5) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (6) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (7) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(ethoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (8) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (9) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (10) (5Z)-2-(3-noradamantylamino)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one, (11) (5Z)-2-(1-adamantylamino)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one, (12) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (13) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (14) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (15) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-imidazol-4-one, (16) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (17) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (18) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (19) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (20) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one dihydrochloride, (21) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (22) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (23) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (24) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-(2-pyridylamino)imidazol-4-one, (25) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[[(3S)-tetrahydropyran-3-yl]amino]imidazol-4-one, (26) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-imidazol-4-one, (27) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-ethyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (28) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclopropyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (29) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclobutyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (30) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclopentyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (31) (5Z)-5-(1,3-Benzothiazol-6-ylmethylene)-3-cyclohexyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one.

[0093] According to a further preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (19), (23), (25) and pharma- ceutically acceptable salts thereof.

[0094] 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), (8), (10), (11), (12), (13), (15), (16), (23), and pharma- ceutically acceptable salts thereof.

[0095] According to a further preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (4), (5), (6), (7), (10), (11), (12), (13), (15), (23) and pharma- ceutically acceptable salts thereof.

[0096] According to an alternative embodiment of the present invention, the compound of formula (I) above is selected from the group consisting of compounds (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (25), (26), (27) and pharma- ceutically acceptable salts thereof.

[0097] According to a preferred embodiment of the present invention, the compound of formula (I) is selected from the group consisting of compounds (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (25), (26) and pharma- ceutically acceptable salts thereof.

[0098] According to a further preferred embodiment of the present invention, the compound of formula (I) above is selected from the group consisting of compounds (8), (12), (15) and pharma- ceutically acceptable salts thereof.

[0099] According to a further embodiment of the present invention, the compound of formula (I) above is selected from the group consisting of compounds (5), (8), (9), (10), (12), (13), (15), (16), (18), (19), (23) and pharma- ceutically acceptable salts thereof.

[0100] 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.

[0101] 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 (2) to (31) or any of their pharma-ceutically acceptable salts, for use as a medicament.

[0102] "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.

[0103] Suitable physiologically acceptable acid addition salts of compounds of formula (I) include the hydrobromide, tartrate, hydrochloride, succinate and acetate salts.

[0104] The compound of formula (I), and any one of the compounds (2) to (31), or a pharma- ceutically acceptable salt thereof, may form solvates or hydrates, and the present invention includes all such solvates and hydrates.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] [Table 1-1] JPEG2024540216000006.jpg146170

[0109] Compounds of general formula (I) can be prepared according to Scheme 1 below. [ka]

[0110] The synthesis of the compounds according to the invention can be carried out according to General Protocol 3 (GP3) as described later in the specification, by reacting the compounds of formula (II) 2 and R 3 is as defined above) with a compound of formula R 1 NH2 (wherein, R 1is defined above) with an amine.

[0111] According to GP3, the compound of formula (II) can 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 (II). 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.

[0112] In an embodiment designated GP3-A, the reaction mixture may be stirred at a temperature ranging from -10°C to 10°C, for example at 0°C, for a period ranging from 30 minutes to 2 hours, for example 1 hour. Depending on the state of the product obtained (solid, precipitate), purification methods well known to those skilled in the art, such as filtration, washing, grinding, vacuum drying, flash chromatography, precipitation and refluxing, may be performed.

[0113] In the embodiment designated GP3-B, where the product did not precipitate, the reaction mixture may be concentrated, particularly in vacuum, and purified, particularly by flash chromatography. A second purification step, particularly selected from reprecipitation, trituration and recrystallization, may be performed.

[0114] In another embodiment named GP3-C, where the product did not precipitate, the reaction mixture may be concentrated, particularly in vacuum, and the resulting crude may be purified by trituration in a protic polar solvent, such as ethanol. The trituration may be carried out at a temperature between 20 and 100° C., particularly at room temperature. A second purification step may be carried out, particularly selected from reprecipitation, trituration and recrystallization.

[0115] Compounds of formula (II) as defined above may be obtained by S-alkylation of compounds of formula (III), wherein R 2 and R 3 is as defined above, and Alk is (C1-C5) alkyl.

[0116] According to the general protocol GP2, the compound of formula (III) can be placed in a polar aprotic solvent, such as dimethylformamide (DMF). Then, an alkyl halide of formula Alk-Hal, where Hal is a halide, such as iodine or bromine, and Alk is a (C1-C5) alkyl, such as methyl or ethyl, can be added, for example in the presence of an inorganic base, such as K2CO3, in a molar ratio in the range of 0.7-1.5, particularly 1, relative to the compound of formula (III), for example in a molar ratio in the range of 0.75-1.50, particularly 1.05 or 1.15, relative to the compound of formula (III). The reaction mixture can be stirred while the alkyl halide is being added.

[0117] In certain embodiments, the resulting mixture may be stirred for, for example, 8 to 16 hours or 12 to 24 hours, particularly for 12 hours at room temperature or at a temperature of 40 to 50°C.

[0118] In another embodiment, the resulting mixture may be stirred at a temperature in the range of -10°C to 10°C, particularly at 0°C or at room temperature, for example for 2 to 8 hours, particularly for 6 hours. It is possible.

[0119] Compounds of formula (III) as defined above can be obtained from compounds of formula (IV) according to General Protocol 1 (GP1), in which R 2 and R 3 is as defined above.

[0120] According to GP1, the compound of formula (IV) may be placed in a protic solvent, for example ethanol, in the presence of 2-thiohydantoin, for example in a molar ratio in the range of 0.85 to 1.15, in particular 1, relative to the compound of formula (IV), in the presence of an organic base, for example piperidine, for example in a molar ratio in the range of 0.85 to 1.15, in particular 1, relative to the compound of formula (IV), 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, in particular 1, relative to the compound of formula (IV). 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., in particular 80° C., for a period of 10 to 100 minutes, in particular 15 to 90 minutes. The reaction mixture may be irradiated, for example by microwaves.

[0121] 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 (II) with a primary amine.

[0122] 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 (2) to (31) as defined above or one of its pharma- ceutically acceptable salts, comprising the steps of: (i) reacting a compound of formula (II) [ka] where Alk is (C1-C5) alkyl; R 2 and R 3 is as defined above, Formula R 1 NH2 (wherein, R 1 is as defined above) with an amine of

[0123] The present invention further relates to a synthetic intermediate of formula (II): [ka] where Alk is (C1-C5) alkyl, in particular Alk is selected from the group consisting of ethyl and methyl, and R 2 and R 3 is as defined above.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] [Table 2] JPEG2024540216000011.jpg252170JPEG2024540216000012.jpg142170

[0130] Table 3 below lists analytical and spectroscopic data for the compounds presented in Table 2 above.

[0131] 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.

[0132] 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.

[0133] [Table 3] JPEG2024540216000014.jpg255155JPEG2024540216000015.jpg255169JPEG2024540216000016.jpg255161JPEG2024540216000017.j pg255150JPEG2024540216000018.jpg255152JPEG2024540216000019.jpg255155JPEG2024540216000020.jpg255166JPEG20245402160 00021.jpg255162JPEG2024540216000022.jpg255159JPEG2024540216000023.jpg255161JPEG2024540216000024.jpg255161JPEG202 4540216000025.jpg255166JPEG2024540216000026.jpg255166JPEG2024540216000027.jpg255163JPEG2024540216000028.jpg255151

[0134] pathology

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] Still according to this particular embodiment, the compounds of formula (I) of the present invention may be useful in regulating body temperature, which may be linked to the expression and activity of CLKs.

[0150] 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).

[0151] The following examples are offered by way of illustration and are not intended to limit the scope of the invention in any way.

[0152] 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.

[0153] Example 1 General Protocol 1 - Synthesis of N-Substituted (5Z)-5-(1,3-Benzothiazol-6-ylmethylene)-2-thioxo-imidazolidin-4-ones [ka]

[0154] In the above scheme, R 2 represents a hydrogen atom or a (C1-C3) alkyl group, and in particular, R 2 represents a hydrogen atom or a methyl group, and R 3 represents a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, particularly R 3 represents a methyl group.

[0155] GP1: A stirred solution of N-substituted 2-thiohydantoin (1 eq), appropriate heteroarylcarbaldehyde (1 eq), piperidine (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 indicated temperature for the appropriate time. After completion (after the aldehyde was consumed on TLC), the reaction medium was cooled and added dropwise to water. The precipitated solid was stirred for 30 minutes, then filtered through a fritted glass funnel, thoroughly dried and could be used in the next step without further purification. If necessary, a final trituration can be performed to remove trace impurities without significant loss of yield.

[0156] Example 1.1: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-thioxo-imidazolidin-4-one (1.1) [ka]

[0157] Compound (1.1) was synthesized according to GP1: the reaction was carried out on a scale of 33.43 mmol of 3-methyl-2-thiohydantoin with 1,3-benzothiazole-6-carbaldehyde, AcOH and piperidine. Reaction temperature: 110° C., time: 90 min. The final product required trituration. Yellow solid, 88% (8.12 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.45(br s,1H,NH,D2O exchange),9.48(s,1H),8.62(d,J=1.8Hz,1H),8.10(d,J=8.5Hz,1H),7.87(dd,J=8.5,1.8Hz,1H),6.78(s,1H),3.22(s,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 179.2,164.1,158.0,153.2,134.3,129.7,128.9,126.6,123.8,123.1,111.9,27.3. MS(ESI + ):[M+H] + 276.0.

[0158] Example 1.2: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-ethyl-2-thioxo-imidazolidin-4-one (1.2) [ka]

[0159] Compound (1.2) was synthesized according to GP1: the reaction was carried out on a 4.29 mmol scale of 3-ethyl-2-thiohydantoin with 1,3-benzothiazole-6-carbaldehyde, AcOH and piperidine. Reaction temperature: 110° C., time: 90 min. The final product required trituration in EtOH at 0° C. Brown / orange solid, 74% (914 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H12.45(bs,1H,NH,D2O exchange),9.48(s,1H),8.61(s,1H),8.10(d,J=8.4Hz,1H),7.86( dd,J=8.5,1.8Hz,1H),6.77(s,1H),3.84(q,J=7.1Hz,2H),1.18(t,J=7.1Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.5,163.7,158.0,153.2,134.3,129.7,128.9,126.5,123.8,123.1,112.0,35.6,12.8. MS(ESI + ):[M+H] + 290.2.

[0160] Example 1.3: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclopropyl-2-thioxo-imidazolidin-4-one (1.3) [ka]

[0161] Compound (1.3) was synthesized according to GP1: the reaction was carried out on a scale of 4.29 mmol of 3-cyclopropyl-2-thiohydantoin with 1,3-benzothiazole-6-carbaldehyde, AcOH and piperidine. Reaction temperature: 110° C., time: 90 min. The final product required trituration. Orange solid, 81% (1.041 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.37(bs,1H,NH,D2O exchange),9.47(s,1H),8.60(d,J=1.9Hz,1H),8.09(d,J=8.6Hz,1H),7.84(dd,J=8.6, 1.8Hz,1H),6.68(s,1H),2.80 (tt,J=6.6, 4.4Hz,1H),0.99(ddt,J=7.5,4.4,2.4Hz,4H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C180.3,164.4,157.9,153.1,134.3,129.8,128.8,126.4,123.7,123.0,111.3,23.9,6.1. MS(ESI + ):[M+H] + 302.2.

[0162] Example 1.4: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclobutyl-2-thioxo-imidazolidin-4-one (1.4) [ka]

[0163] Compound (1.4) was synthesized according to GP1: the reaction was carried out on a scale of 2.11 mmol of 3-cyclobutyl-2-thiohydantoin with 1,3-benzothiazole-6-carbaldehyde, AcOH and piperidine. Reaction temperature: 110° C., time: 90 min. The final product required trituration. Yellow solid, 62% (411 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.47(bs,1H,NH,D2O exchange),9.48(s,1H),8.61(d,J=1.8Hz,1H),8.10(d,J=8.5Hz,1H),7.85(dd,J=8.5,1 .8Hz,1H),6.72(s,1H),5.12(p,J=9.0Hz,1H),3.04-2.88(m,2H),2.23-2.12(m,2H),1.89-1.70(m,2H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.7,164.3,157.8,153.1,134.2,129.6,128.7,126.3,123.7,122.9,111.6,47.4,26.2,14.6. MS(ESI + ):[M+H] + 316.2.

[0164] Example 1.5: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclopentyl-2-thioxo-imidazolidin-4-one (1.5) [ka]

[0165] Compound (1.5) was synthesized according to GP1: the reaction was carried out on a scale of 4.29 mmol of 3-cyclopentyl-2-thiohydantoin with 1,3-benzothiazole-6-carbaldehyde, AcOH and piperidine. Reaction temperature: 110° C., time: 90 min. The final product required trituration. Orange solid, 78% (1.107 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.48(bs,1H,NH,D2O exchange),9.48(s,1H),8.62(s,1H),8.10(d,J=8.5Hz,1H),7.86(d,J=8.5Hz,1H ),6.72(s,1H),5.03(p,J=8.5Hz,1H),2.19-2.01(m,2H),1.98-1.76(m,4H),1.67-1.51(m,2H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 179.1,163.6,158.0,153.2,134.3,129.7,128.8,126.4,123.8,123.1,111.7,54.0,28.2,24.8. MS(ESI + ):[M+H] + 330.1.

[0166] Example 1.6: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclohexyl-2-thioxo-imidazolidin-4-one (1.6) [ka]

[0167] Compound (1.6) was synthesized according to GP1: the reaction was carried out on a scale of 4.29 mmol of 3-cyclohexyl-2-thiohydantoin with 1,3-benzothiazole-6-carbaldehyde, AcOH and piperidine. Reaction temperature: 110° C., time: 90 min. The final product required trituration. Orange solid, 76% (1.116 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 12.47(bs,1H,NH,D2O exchange),9.47(s,1H),8.60(s,1H),8.09(d,J=8.5Hz,1H),7.85(dd,J=8.5, 1.9Hz,1H),6.70(s,1H),4.60-4.46(m,1H),2.28-2.12(m,2H),1.89-1.73(m,2H),1.74-1.57(m,3H),1.39-1.10(m,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 178.8,163.8,158.0,153.2,134.3,129.7,128.8,126.3,123.8,123.1,111.7,54.0,28.2,25.4,24.8. MS(ESI + ):[M+H] + 344.3.

[0168] Example 2 General Protocol 2 - S-Alkylation of N-Substituted (5Z)-5-(1,3-Benzothiazol-6-ylmethylene)-2-thioxo-imidazolidin-4-ones [ka]

[0169] In the above scheme, Hal represents a halogen atom, in particular a halogen atom selected from iodine and bromine atoms; Alk is (C1-C5) alkyl; R 2 teeth, represents a hydrogen atom or a (C1-C3) alkyl group, particularly R 2 represents a hydrogen atom or a methyl group, and R 3represents a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, particularly R 3 represents a methyl group.

[0170] GP2: A suitable alkyl iodide (1.15 eq) was added dropwise to a stirred solution of N-substituted (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-thioxo-imidazolidin-4-one (1 eq) and K2CO3 (1 eq) in DMF (C=0.3 M) at a suitable temperature. The resulting mixture was stirred at the indicated temperature for a suitable time. After completion (TLC), the mixture was poured onto water. The precipitated solid was stirred for 30 min, then filtered through a fritted glass funnel, thoroughly dried, and could be used in the next step without further purification. Trace impurities could be removed by FC or trituration.

[0171] Example 2.1: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-methylsulfanyl-imidazol-4-one (2.1) [ka]

[0172] Compound 2.1 was synthesized according to GP2: the reaction was carried out with intermediate 1.1 (10.89 mmol) and MeI at room temperature for 12 h. Yellow solid, 97% (3.045 g). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 9.47(s,1H),8.94(d,J=1.6Hz,1H),8.47(dd,J=8.7,1.7Hz,1H),8.12(d,J=8.6Hz,1H),7.00(s,1H),3.10(s,3H),2.77(s,3H). MS(ESI + ):[M+H] + 290.1.

[0173] Example 2.2: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-ethyl-2-methylsulfanyl-imidazol-4-one (2.2) [ka]

[0174] Compound 2.2 was synthesized according to GP2: the reaction was carried out with intermediate 1.2 (1.21 mmol) and MeI at 45° C. for 24 h. The final product required trituration in MTBE. Yellow solid, 75% (275 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 9.48(s,1H),8.95(s,1H),8.49(d,J=8.6Hz,1H),8.13(d,J=8.6Hz,1H),7.01(s,1H),3.60(q,J=7.2Hz,2H),2.79(s,3H),1.19(t,J=7.2Hz,3H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 168.6,166.0,158.1,153.4,138.5,134.2,131.8,129.5,125.8,123.1,121.3,35.3,13.9,12.7. MS(ESI + ):[M+H] + 304.2.

[0175] Example 2.3: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclopropyl-2-methylsulfanyl-imidazol-4-one (2.3) [ka]

[0176] Compound 2.3 was synthesized according to GP2: the reaction was carried out with intermediate 1.3 (1.21 mmol) and MeI at 45° C. for 24 h. The final product required trituration in MTBE. Yellow solid, 90% (342 mg). 1H NMR (400MHz, DMSO-d6, 300K) δ H 9.46(s,1H),8.92(s,1H),8.46(d,J=8.6Hz,1H),8.11(d,J=8.7Hz,1H),6.93(s,1H),2.77-2.66(m,4H),1.01-0.85(m,4H). MS(ESI + ):[M+H] + 316.2.

[0177] Example 2.4: Synthesis of (5Z)-5-(1,3-Benzothiazol-6-ylmethylene)-3-cyclobutyl-2-methylsulfanyl-imidazol-4-one (2.4) [ka]

[0178] Compound 2.4 was synthesized according to GP2: the reaction was carried out with intermediate 1.4 (1.21 mmol) and MeI at 45° C. for 24 h. The final product required trituration in MTBE. Yellow solid, 76% (303 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 9.47(s,1H),8.94(d,J=1.6Hz,1H),8.47(dd,J=8.6, 1.7Hz,1H), 8.12(d,J=8.6Hz,1H),6.97(s,1H),4.43(p,J=8.7Hz,1H),2.90-2.70(m,5H),2.31-2.19(m,2H),1.88-1.69(m,2H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 169.2,166.20,158.0,153.4,138.6,134.1,131.8,129.4,125.7,123.0,121.1,47.1,27.6,14.6,13.3. MS(ESI + ):[M+H] + 330.2.

[0179] Example 2.5: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclopentyl-2-methylsulfanyl-imidazol-4-one (2.5) [ka]

[0180] Compound 2.5 was synthesized according to GP2: the reaction was carried out with intermediate 1.5 (1.82 mmol) and MeI at 45° C. for 24 h. Yellow solid, 95% (594 mg). 1 H NMR (400MHz, DMSO-d6, 300K) δ H 9.47(s,1H),8.93(s,1H),8.48(d,J=8.7Hz,1H),8.13(d,J=8.6Hz,1H),6.96(s,1H),4.3 2(p,J=8.4Hz,1H),2.78(s,3H),2.10-1.97(m,2H),1.96-1.76(m,4H),1.68-1.52(m,2H). 13 C NMR (101MHz, DMSO-d6, 300K) δ C 168.8,166.4,158.1,153.4,138.7,134.2,131.8,129.4,125.7,123.1,121.1,53.9,29.1,24.5,13.4. MS(ESI + ):[M+H] + 344.2.

[0181] Example 2.6 Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclohexyl-2-methylsulfanyl-imidazol-4-one (2.6) [ka]

[0182] Compound 2.6 was synthesized according to GP2: the reaction was carried out with intermediate 1.6 (1.21 mmol) and MeI at room temperature for 24 h. Yellow solid, 79% (344 mg). 1H NMR (400MHz, DMSO-d6, 300K) δ H 9.47(s,1H),8.92(s,1H),8.47(d,J=8.4Hz,1H),8.12(d,J=8.6Hz,1H),6.96(s,1H),3.83-3.69( m,1H),2.76(s,3H),2.17-2.00(m,2H),1.90-1.58(m,5H),1.42-1.23(m,2H),1.22-1.07(m,1H). MS(ESI + ):[M+H] + 358.3.

[0183] Example 3 General Protocol 3 - Addition of Amines to N-Substituted (5Z)-5-(1,3-Benzothiazol-6-ylmethylene)-2-Alkyl-Sulfanyl-Imidazol-4-ones [ka]

[0184] In the above scheme, Alk is (C1-C5) alkyl; R 2 represents a hydrogen atom or a (C1-C3) alkyl group, and in particular, R 2 represents a hydrogen atom or a methyl group, and R 3 represents a (C1-C4) alkyl group or a (C3-C6) cycloalkyl group, particularly R 3 represents a methyl group.

[0185] GP3: A suitable amine (x eq) in a suitable solvent (C=0.3M), N-substituted (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-alkylsulfanyl-imidazol-4-one (a)( A stirred solution of 1 eq) was heated in a sealed tube (heating block). Upon completion (after the isothiourea was consumed on TLC), the mixture was allowed to warm to room temperature.

[0186] GP3-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.

[0187] GP3-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.

[0188] GP3-C: No product precipitated: The reaction mixture was concentrated in vacuo. The resulting crude was triturated in EtOH (at room temperature or at reflux) and filtered through a fritted glass funnel.

[0189] (a) Depending on the amine, activation with AcOH or TEA.HCl may be necessary (see below for details).

[0190] Selected examples:

[0191] Example 3.1: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cyclohexylamino)-3-methyl-imidazol-4-one (2)

[0192] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) in THF with 3 eq cyclohexylamine at 120 °C (sealed tube, heating block) for 72 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 95 / 5). Isolated yield: 63%.

[0193] Example 3.2: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cycloheptylamino)-3-methyl-imidazol-4-one (3)

[0194] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq cycloheptylamine in THF at 120 °C (sealed tube, heating block) for 72 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 95 / 5). Isolated yield: 70%.

[0195] Example 3.3: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one (5)

[0196] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (R)-leucinol 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 reprecipitation from DCM / pentane at 0 °C. Isolated yield: 36%.

[0197] Example 3.4: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one (6)

[0198] The reaction was carried out according to GP3-B on a scale of 691 μmol of intermediate (2.1) with 4 eq (2R)-1-methoxy-4-methyl-pentan-2-amine and 4 eq AcOH in THF at 135 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 49%.

[0199] Example 3.5: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(ethoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one (7)

[0200] The reaction was carried out according to GP3-B on a scale of 291 μmol of intermediate (2.1) with 4 eq (2R)-1-ethoxy-4-methyl-pentan-2-amine and 6 eq AcOH in THF at 135 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 52%.

[0201] Example 3.6: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one (8)

[0202] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (1R,2R)-2-methoxycyclopentanamine 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 96 / 4). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 60%.

[0203] Example 3.7: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one (9)

[0204] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (1S,2S)-2-methoxycyclopentanamine 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 96 / 4). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 58%.

[0205] Example 3.8: Synthesis of (5Z)-2-(3-noradamantylamino)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one (10)

[0206] The reaction was carried out according to GP3-B on a scale of 587 μmol of intermediate (2.1) with 4 eq 3-noradamantamine and 6 eq AcOH in dioxane / EtOH (3 / 1) at 160 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). The final product required reprecipitation from DCM / EtOH / pentane at 0 °C. Isolated yield: 59%.

[0207] Example 3.9: Synthesis of (5Z)-2-(1-adamantylamino)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one (11)

[0208] The reaction was carried out according to GP3-B on a scale of 691 μmol of intermediate (2.1) with 4 eq 1-adamantylamine and 8 eq AcOH in dioxane / EtOH (3 / 1) at 175 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 31%.

[0209] Example 3.10: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-imidazol-4-one (12)

[0210] The reaction was carried out according to GP3-B on a scale of 691 μmol of intermediate (2.1) with 4 eq 3-aminoadamantan-1-ol and 8 eq AcOH in dioxane / EtOH (3 / 1) at 165 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). The final product required trituration from refluxing Et2O. Isolated yield: 42%.

[0211] Example 3.11: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one (13)

[0212] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq 3-methoxy-1-adamantylamine 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 94 / 6). Isolated yield: 35%.

[0213] Example 3.12: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one (14)

[0214] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq [2-(trifluoromethyl)phenyl]methanamine and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). The final product required trituration. Isolated yield: 29%.

[0215] Example 3.13: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-imidazol-4-one (15)

[0216] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). The final product required trituration in MTBE. Isolated yield: 16%.

[0217] Example 3.14: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one (16)

[0218] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (2R)-2-amino-2-phenyl-ethanol and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 30 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). Isolated yield: 53%.

[0219] Example 3.15: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one (17)

[0220] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (2S)-2-amino-2-phenyl-ethanol and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 30 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). Isolated yield: 43%.

[0221] Example 3.16: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one (18)

[0222] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (1R)-2-methoxy-1-phenyl-ethanamine and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 30 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). The final product required trituration in MTBE. Isolated yield: 50%.

[0223] Example 3.17: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-imidazol-4-one (19)

[0224] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (1R)-2-amino-1-phenyl-ethanol and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 30 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6). Isolated yield: 69%.

[0225] Example 3.18: Synthesis of (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one dihydrochloride (20)

[0226] The reaction was carried out according to GP3-B on a scale of 294 μmol of intermediate (2.1) with 3 eq tert-butyl N-[(2R)-2-amino-2-phenyl-ethyl]carbamate and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 6 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 94 / 6) followed by PTLC. The isolated carbamate was subjected to a final deprotection step with HCl (4M) in dioxane at 40 °C. Isolated yield: 39% (2 steps).

[0227] Example 3.19: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one (21)

[0228] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (4-methylthiazol-2-yl)methanamine and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 6 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). The final product required trituration. Isolated yield: 40%.

[0229] Example 3.20: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one (22)

[0230] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq tetrahydropyran-4-ylmethanamine and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 6 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). The final product required trituration. Isolated yield: 70%.

[0231] Example 3.21: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one (23)

[0232] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 5 eq of 4-(4-methylpiperazin-1-yl)aniline in dioxane at 150 °C (sealed tube, heating block) for 72 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). The final product required trituration. Isolated yield: 33%.

[0233] Example 3.22: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-(2-pyridylamino)imidazol-4-one (24)

[0234] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 5 eq 2-aminopyridine and 15 eq AcOH in dioxane at 150 °C (sealed tube, heating block) for 72 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). The final product required trituration. Isolated yield: 75%.

[0235] Example 3.23: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[[(3S)-tetrahydropyran-3-yl]amino]imidazol-4-one (25)

[0236] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (3S)-tetrahydropyran-3-amine and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). Isolated yield: 43%.

[0237] Example 3.24: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-imidazol-4-one (26)

[0238] The reaction was carried out according to GP3-B on a scale of 259 μmol of intermediate (2.1) with 3 eq (3R,4R)-3-aminotetrahydropyran-4-ol and 9 eq AcOH in dioxane at 120 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99 / 1 to 96 / 4). Isolated yield: 36%.

[0239] Example 3.25: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclobutyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one (29)

[0240] The reaction was carried out according to GP3-B on a scale of 252 μmol of intermediate (2.4) with 6 eq (2R)-1-methoxy-4-methyl-pentan-2-amine and 8 eq TEA.HCl in dioxane at 140 °C (sealed tube, heating block) for 48 h. Purification by FC (elution: DCM / MeOH: 99.5 / 0.5 to 98 / 2). The final product required reprecipitation from MTBE / pentane at 0 °C. Isolated yield: 28%.

[0241] Example 3.26: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclohexyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one (31)

[0242] The reaction was carried out according to GP3-B on a scale of 252 μmol of intermediate (2.6) with 6 eq (2R)-1-methoxy-4-methyl-pentan-2-amine and 8 eq TEA.HCl in dioxane at 140 °C (sealed tube, heating block) for 20 h. Purification by FC (elution: DCM / MeOH: 99.5 / 0.5 to 98 / 2). The final product required reprecipitation from MTBE / pentane at 0 °C. Isolated yield: 37%.

[0243] Example 4: biological activity

[0244] Materials and Methods

[0245] Protein kinase assays

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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- 33The 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.

[0252] 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).

[0253] Their activity has been classified according to two criteria: kinase inhibition potency and kinase selectivity.

[0254] Kinase inhibition potency is classified as follows: IC 50 was performed according to the range of values.

[0255] 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. 50These 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.

[0256] Kinase selectivity classification: IC of DYRK1A 50 Value of CLK1 IC 50 Value and IC of DYRK1B 50 The classification was based on a comparison with the IC values ​​of DYRK1A. 50 Value of CLK1 or DYRK1B IC 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.

[0257] [Table 4] JPEG2024540216000045.jpg64170

[0258] [Table 4A]

[0259] The most potent CLK1 inhibitors were IC 50 is 25 nM or less, and the compounds are (3), (4), (5), (6), (8), (9), (13), (12), (15), and (16).

[0260] The most potent CLK2 inhibitors were IC 50 is 10 nM or less, and the compounds are (4), (10), (11), (12), (13) and (15).

[0261] The most potent CLK3 inhibitors were IC 50 is 500 nM or less, and the compounds are (6), (8), (9), (12) and (25).

[0262] The most potent CLK4 inhibitors were IC 50 is 10 nM or less, and the compounds are (5), (8), (9), (10), (12), (13), (15), (16), (18), (19), and (23).

[0263] [Table 4B]

[0264] The most potent DYRK1A inhibitors are IC 50 is 25 nM, and the compounds are (4), (5), (6), (7), (10), (11), (12), (13), (15) and (23).

[0265] The most potent DYRK1B inhibitors are IC 50 is 10 nM, and the compounds are (6), (10), (11), (12), (13) and (15).

[0266] The most potent DYRK2 inhibitors are IC 50 is 100 nM, and the compounds are (3), (4), (6), (8), (10), (11), (12), (13), and (23).

[0267] The most potent DYRK3 inhibitors are IC 50 is 100 nM, and the compounds are (10), (11), (12), (13), and (23).

[0268] The most potent DYRK4 inhibitors are IC 50is 100 nM, and compounds (8), (10), (11) and (12).

[0269] [Table 4C]

[0270] [Table 4D]

[0271] [Table 4E]

[0272] [Table 4F]

[0273] Example 5: Comparison of biological activities of compounds (C1) and (C2) disclosed in International Publication WO2021 / 114314

[0274] (C1) corresponds to the compound of Example 45 in International Publication No. WO2021 / 114314, and corresponds to the compound of Example 88 in International Publication No. WO2021 / 114314.

[0275] The synthesis of the above compounds (C1) and (C2) which are outside the scope of the present invention is reproduced and described hereinafter.

[0276] Example 5.1: Spectroscopic and analytical characterization of compounds (C1) and (C2)

[0277] [Table 5]

[0278] Example 5.2: Synthesis of (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(isopropylamino)-3-methyl-imidazol-4-one (C1)

[0279] The reaction was carried out according to GP3-B on a scale of 460 μmol of intermediate (2.1) in anisole with 5 eq isopropylamine and 2 eq TEA.HCl at 140 °C (sealed tube, heating block) for 24 h. Purification by FC (elution: DCM / MeOH: 99.5 / 0.5 to 98.5 / 1.5). The final product required reprecipitation from DCM / pentane at 0 °C. Isolated yield: 42%.

[0280] Example 5.3: Synthesis of (5Z)-2-(1,3-benzothiazol-6-ylamino)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one (C2)

[0281] The reaction was carried out according to GP3-A on a scale of 460 μmol of intermediate (2.1) 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 final product required two successive triturations in refluxing MeOH. Isolated yield: 87%.

[0282] Example 5.4: Comparison of biological activity of compounds of the present invention to compounds (C1) and (C2)

[0283] The biological activity of the compounds of the present invention was compared with that of the prior art compounds (C1) and (C2) above.

[0284] [Table 6]

[0285] R 1is in the present invention a (C4-C6) alkyl group, which is necessarily substituted by a group selected from a hydroxy group and a (C1-C3) alkoxy group.

[0286] [Table 7]

[0287] In the present invention, R directly bonded to -NH 1 is necessarily substituted by a (C4-C7) heterocycloalkyl group, which may itself be substituted by a (C1-C4) alkyl group (compound (23) being a representative example). 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 with a hydroxy group (compound (15) being a representative compound). Finally, R 1 is (vi) an R'-L- group, bicyclic groups are not encompassed within the claims.

[0288] 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.

[0289] result

[0290] 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).

[0291] The compounds were preferably inhibitory against CLK1 (Table 4A), CLK4, DYRK1A (Table 4B), and DYRK1B.

[0292] 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.

[0293] conclusion

[0294] 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.

[0295] 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.

[0296] Leucettamines 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.

[0297] 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 (2) to (31) as defined above or any of their pharma- ceutically acceptable salts.

[0298] 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 (2) to (31) as defined above or any of their pharma- ceutically acceptable salts, and also at least one pharma- ceutically acceptable excipient.

[0299] The pharmaceutical compositions of the present invention may contain one or more compounds of the present invention in any of the forms described herein.

[0300] 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). malaria, infections caused by single-celled parasites, such as leishmaniasis, Chagas disease and sleeping sickness (Trypanosoma sp.), and bovine diseases due to single-celled pathogens, as well as for thermoregulation, comprising a compound of formula (I) as defined above or one of its pharmaceutical acceptable salts, or a compound (2) to (31) as defined above or one of its pharmaceutical acceptable salts, for use in the treatment and / or prevention of diseases selected from the group consisting of:

[0301] 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 one of the compounds of formula (I) as defined above or one of their pharmaceutical acceptable salts, or one of the compounds (2) to (31) as defined above or one of their pharmaceutical acceptable salts.

[0302] 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 compounds (2) to (31) 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.

[0303] A still further object of the invention consists of a compound of formula (I) as defined above or one of their pharma- ceutically acceptable salts, or of compounds (2) to (31) 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.

[0304] 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 compounds (2) to (31) as defined above or one of their pharmaceutical acceptable salts, according to the invention.

[0305] 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 (2) to (31) as defined above or one of its pharmaceutical acceptable salts, according to the invention.

[0306] 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 (2) to (31) 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.

[0307] 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.

[0308] 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 (2) to (31) 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.

[0309] According to a particular embodiment, the treatment is continuous or discontinuous.

[0310] "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.

[0311] 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.

[0312] 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). a therapeutic method for the treatment and / or prevention of diseases selected from the group consisting of infectious diseases caused by coronaviruses, cytomegaloviruses and human papillomaviruses; neuroinflammation; anemia; infectious diseases 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, comprising at least the step of administering an effective amount of a compound of formula (I) or one of its pharmaceutical acceptable salts, or of the compounds (2) to (31) as defined above or one of their pharmaceutical acceptable salts.

[0313] 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.

[0314] 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.

[0315] The compounds can be administered by any mode of administration, including intramuscular, intravenous, intranasal or oral routes, transdermal patch, etc.

[0316] 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).

[0317] The aforementioned additives are selected according to the dosage form and the desired mode of administration.

[0318] 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.

[0319] 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.

[0320] In a particular embodiment, the compounds of formula (I) according to the present invention are administered orally.

[0321] 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: R 2 is a hydrogen atom and (C 1 ~C 3 ) alkyl groups, R 3 is (C 1 ~C 4 ) alkyl group or (C 3 ~C 6 ) a cycloalkyl group, and where R 1 represents the following (i), (ii), (iii), (iv), (v), (vi) or (vii): (i) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups substituted by a group selected from (C 4 ~C 6 ) alkyl groups, (ii) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 3 ~C 8 ) a cycloalkyl group, (iii) (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; (vi) R'-L- group, where L is a single bond or (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 ) heterocycloalkyl groups, where (C 3 ~C 8 ) cycloalkyl has at least one carbon atom replaced by an oxygen atom or a sulfur atom, 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, R” is fluoro(C 1 ~C 4 ) a phenyl group optionally substituted by an alkyl group, and wherein at least one of R″ and L is substituted; 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), (vii) or (viii): (i) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups substituted by a group selected from (C 5 ~C 6 ) alkyl group, preferably C 6 -alkyl group, (ii) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 5 ~C 8 ) a cycloalkyl group, (iii) (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; (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 ) heterocycloalkyl groups, where (C 6 ~C 7 ) cycloalkyl has at least one carbon atom replaced by an oxygen atom or a sulfur atom, or (vi.2) (C 1 ~C 4 ) optionally substituted by alkyl groups (C 3 ~C 8 ) heteroaryl groups, Or, (viii) 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, R” is fluoro(C 1 ~C 4 ) a phenyl group optionally substituted by an alkyl group, and wherein at least one of R″ and L is substituted; 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 5 ~C 6 ) alkyl group, preferably C 6 -alkyl group, (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; (vi) R'-L- group, where: L is a single bond or (C 1 ~C 3 ) an alkanediyl group, and R' is selected from the group consisting of (vi.1) or (vi.2) below: (vi.1) optionally substituted with a hydroxy group (C 6 ~C 7 ) a heterocycloalkyl group, at least one of whose carbon atoms is replaced by an oxygen atom or a sulfur atom, 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 may be substituted with a group selected from the group consisting of a methoxy group and a hydroxy group (C 1 ~C 3 ) an alkanediyl group, R" is a phenyl group optionally substituted by a trifluoromethyl group, and wherein at least one of R" and L is substituted; 3. A compound of formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts.

4. L is a single bond, -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 formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts, wherein the compound is selected from the group consisting of:

5. (vi.1) R' is (C 5 ~C 8 When L is a heterocycloalkyl group, the (C 5 -C 8 )cycloalkyl has at least one carbon atom replaced by an oxygen atom or a sulfur atom, and L is a single bond or -CH 2 - group, (vi.2) R' is (C 3 ~C 8 ) When L is a heteroaryl group, L is a single bond or -CH 2 - group, (vi.3) When R″ is phenyl, L is a single bond, —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, 3. A compound of formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts.

6. R 1 represents the following group: Hydroxy groups and (C 1 ~C 3 ) alkoxy substituted by a group selected from (C 4 ~C 6 ) an alkyl group, or Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 3 ~C 8 ) a cycloalkyl group, or (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, 3. A compound of formula (I) according to claim 1 or 2, or any one of its pharmaceutically acceptable salts.

7. R 1 represents the following group: (C 5 ~C 6 ) a fused phenyl group selected from a phenyl group fused with a cycloalkyl, wherein said (C 5 ~C 6 ) cycloalkyl is substituted by a hydroxy group; (C 4 ~C 7 ) a phenyl group substituted by a heterocycloalkyl group, wherein (C 4 ~C 7 ) Heterocycloalkyl groups themselves are not limited to (C 1 ~C 4 ) optionally substituted by an alkyl group; Or, R″-L-group, where L is a hydroxy group, (C 1 ~C 3 ) alkoxy group and -NR b R c may be substituted by a group selected from the group (C 1 ~C 3 ) an alkanediyl group, R” is fluoro(C 1 ~C 4 ) a phenyl group optionally substituted by an alkyl group, and wherein at least one of R″ and L is substituted; and where R b and R c are independent, (C 1 ~C 6 ) selected from alkyl and hydrogen atoms; 3. A compound of formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts.

8. R 1 represents the R'-L- group, where: R' is (C 1 ~C 4 ) optionally substituted by alkyl groups (C 3 ~C 8 ) heteroaryl groups, and L is (C 1 ~C 3 ) alkanediyl or a single bond, 3. A compound of formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts.

9. R 1 represents the R'-L- group, where: R' is (C 3 ~C 8 ) heterocycloalkyl groups, where (C 3 ~C 8 ) cycloalkyl has at least one carbon atom replaced by an oxygen atom or a sulfur atom, and L is (C 1 ~C 3 ) alkanediyl or a single bond; 3. A compound of formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts.

10. R 1 represents (i), (ii), (iii), (iv), (v) or (vi) below: (i) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups substituted by a group selected from (C 4 ~C 6 ) alkyl groups, (ii) Hydroxy groups and (C 1 ~C 3 ) alkoxy groups (C 3 ~C 8 ) a cycloalkyl group, (iii) (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) R'-L- group, where: L is a single bond or (C 1 ~C 3 ) an alkanediyl group, and R' represents the following (vi.1) or (vi.2): (iv.1) a tetrahydropyranyl 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 ) 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; Or, (vi) 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 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 their pharmaceutically acceptable salts.

11. R 3 But (C 1 ~C 4 3. The compound of formula (I) according to claim 1 or 2, or any one of their pharmaceutically acceptable salts, wherein R is an alkyl group.

12. (2) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cyclohexylamino)-3-methyl-imidazol-4-one, (3) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cycloheptylamino)-3-methyl-imidazol-4-one, (4) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-(cyclooctylamino)-3-methyl-imidazol-4-one, (5) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(hydroxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (6) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (7) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-1-(ethoxymethyl)-3-methyl-butyl]amino]-3-methyl-imidazol-4-one, (8) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R,2R)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (9) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S,2S)-2-methoxycyclopentyl]amino]-3-methyl-imidazol-4-one, (10) (5Z)-2-(3-noradamantylamino)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one, (11) (5Z)-2-(1-adamantylamino)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one, (12) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[(3-hydroxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (13) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[(3-methoxy-1-adamantyl)amino]-3-methyl-imidazol-4-one, (14) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[[2-(trifluoromethyl)phenyl]methylamino]imidazol-4-one, (15) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S,2S)-2-hydroxyindan-1-yl]amino]-3-methyl-imidazol-4-one, (16) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (17) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1S)-2-hydroxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (18) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(1R)-2-methoxy-1-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (19) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]-3-methyl-imidazol-4-one, (20) (5Z)-2-[[(1R)-2-amino-1-phenyl-ethyl]amino]-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-imidazol-4-one dihydrochloride, (21) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[(4-methylthiazol-2-yl)methylamino]imidazol-4-one, (22) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-(tetrahydropyran-4-ylmethylamino)imidazol-4-one, (23) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]imidazol-4-one, (24) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-(2-pyridylamino)imidazol-4-one, (25) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-methyl-2-[[(3S)-tetrahydropyran-3-yl ]amino]imidazol-4-one, (26) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-2-[[(3R,4R)-4-hydroxytetrahydropyran-3-yl]amino]-3-methyl-imidazol-4-one, (27) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-ethyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (28) (5Z)-5-(1,3 benzothiazol-6-ylmethylene)-3-cyclopropyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (29) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclobutyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (30) (5Z)-5-(1,3-benzothiazol-6-ylmethylene)-3-cyclopentyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one, (31) (5Z)-5-(1,3-Benzothiazol-6-ylmethylene)-3-cyclohexyl-2-[[(1R)-1-(methoxymethyl)-3-methyl-butyl]amino]imidazol-4-one 2. The compound of formula (I) according to claim 1, selected from: or any one of their pharmaceutically acceptable salts.

13. A pharmaceutical composition comprising at least one compound according to claim 1, or any one of their pharmaceutically acceptable salts, or any one of compounds (2) to (31) according to claim 12, or any one of their pharmaceutically acceptable salts.

14. A synthetic method for producing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or any one of compounds (2) to (31) according to claim 12 or a pharmaceutically acceptable salt thereof, comprising: A compound of formula (II) 【Chemistry 2】 where R 2 and R 3 is 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

15. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, or at least one of the compounds (2) to (31) as defined in claim 12 or one of their pharmaceutically acceptable salts, for use as a medicament.

16. 10. An agent for use in 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, the agent comprising a compound of formula (I) according to claim 1, or one of its pharmaceutically acceptable salts, or at least one of compounds (2) to (31) according to claim 12, or one of their pharmaceutically acceptable salts.

17. 1. An agent 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, the agent comprising a compound of formula (I) according to claim 1 or one of its pharmaceutically acceptable salts, or at least one of compounds (2) to (31) according to claim 12, or one of their pharmaceutically acceptable salts.

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