TW200811163A - N-(2-thiazolyl)-amide derivatives as GSK-3 inhibitors - Google Patents

Abstract

The present invention relates to the use of N-(2-thiazolyl)-amide derivatives for the treatment and/or prophylaxis of a disease in which glycogen synthase kinase 3 (GSK-3) is involved, especially neurodegenerative diseases, such as Alzheimer's disease, or non-insulin dependent diabetes mellitus.

Description

200811163 IX. INSTRUCTIONS OF THE INVENTION [Technical Fields of the Invention] The present invention relates to N-(2-thiazolyl)-nonanthamine derivatives to diseases involving glycogen synthase kinase 3 (GSK-3) (especially neurodegenerative diseases) Therapeutic and/or prophylactic uses, such as Alzheimer's disease or non-insulin dependent diabetes. In addition, the present invention also provides novel GSK-3 inhibitors, a method of preparing the compounds, and pharmaceutical compositions comprising the same. [Prior Art] The search for new therapeutic agents has been greatly facilitated in recent years by a better understanding of the structure of enzymes and other biomolecules associated with the target disease. An important class of enzymes that have become the subject of extensive research is protein kinases. Many diseases are associated with abnormal cellular responses triggered by protein kinase-media events. These diseases include autoimmune diseases, inflammatory diseases, neurological diseases, neurodegenerative diseases, cancer, cardiovascular diseases, allergies and wheezing, Alzheimer's disease, or hormone-related diseases. . Therefore, finding a protein kinase inhibitor that can be used as an effective therapeutic agent has become a pragmatic effort in medicinal chemistry. Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that contains isoforms encoded by different genes (Coghlan et al., Chemistry & Biology 7). 793 -80 3 (2000); Kim and Kimmel, Curr. Opinion Genetics 200811163

Dev., 10, 5 0 8-5 1 4 (2000)). The sulphonic acid/serine kinase and glycogen synthase kinase-3 (GSK-3) play a key role in a variety of receptor-linked signaling pathways (Doble, BW, Woodgett, JR J. Cell Sci. 2) 0 0 3,1 1 6 : 1 1 7 5 - 1 1 8 6 ). Regulatory disorders within these pathways are considered to be key events in the development of several prevalent human disorders, such as type 2 diabetes (Kaidanovich 0, E1 dar-Finke 1 man H? Expert Opin. Ther. Targets, 2002, 6:555-561), Alzheimer's disease (Grimes CA, Jope RS, Prog. Neurobiol. 200 1,65:3 9 1 -426 ), CNS disorders such as manic depression and neurodegenerative diseases, And chronic inflammation (Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin 0, Woodgett J, Nature 2000, 406:86-90). Such diseases may result from or cause abnormal manipulation of certain cellular signaling pathways that function in GSK-3. GSK-3 has been found to phosphorylate and modulate the activity of many regulatory proteins. These proteins include proteinases, which are rate-limiting enzymes required for glycogen synthesis; microtubule-associated protein Tau; gene transcription factors, no-linkage protein (/3-catenin); translation initiation factor e 1 F2 B ; And ATP citrate lyase, axin, heat shock factor-1'c-Jnn'c-Myc, c-Myb, CREB, and CΕΡΒα. These diverse protein targets suggest that GSK-3 is involved in many aspects of cell metabolism, proliferation, molecular and development. Currently, inhibition of GSK3 may represent a strategy available to develop pharmaceutical entities for the treatment of such unmet diseases (Martinez A, Castro A, Dorronsoro I, Alonso M, Med. Res. Rev., 2002, 22: 373). - -6 - 200811163 3 84 ), respectively, including insulin simulation, tau dephosphorylation and amyloid treatment, or transcriptional modulation. The neurotoxic effects of soluble and deposited amyloid/5 peptidase (A yS ) are characteristic pathologies in the brain of patients with Alzheimer's disease (AD). Both in vitro and in vivo studies speculate that A-peptide induces loss of utility of the Wnt signaling pathway, and this mechanism appears to be destabilized by endogenous/3-catenin levels. (Activation of Wnt signaling rescues neurodegeneration and behavioural impairments induced by beta-amyloid fibrils, de Ferrari et al, Mol. Psychiatry. 2003; 8(2): 195-208) o Lithium or Wnt ligands in AD cells and Activation of the signaling pathway in animal experimental models can reduce the neurotoxic effects of A/3 by restoring the positive yS-catenin content and the performance of certain Wnt-target surviving genes, such as bcl-2. Disorders in the Wnt pathway component trigger certain events that may lead to the initiation and progression of AD (Signal transduction during amyloid-beta-peptide neurotoxicity: role in Alzheimer disease,

Fuentealba et al., Brain Res. Rev. 2004; 47(1-3): 275-89) ° The presence of neurofibrillary tangles in cerebral cortical neurons is another abnormality that occurs in the brains of AD patients. And hyperphosphorylated tau protein appears to be a major component of such neuronal deposits (Neurofibrillary tangles of Alzheimer disease share antigenic determinants with axonal microtubule-associated protein tau, Wood JG et al., Proc. Natl. Acad. Sci. USA 1 9 8 6; 83 ( 1 1 ): 4040-3 ). Tau 200811163 is a combination of six protein isoforms associated with microtubules that modulate the function of these cellular structures in the axonal chamber of a neuron. Tau can be phosphorylated by different microtubule-associated kinases, but GSK3 yS and cdk5 are the ones that contribute to the formation of microfibrillary tangles (Phosphorylation of human tau protein by microtubule-associated kinases: GSK3 β and cdk 5 are Key participants, Flaherty et al., J. N eur o sci. Res. 2000; 62:463 -472 ). Indeed, the activity of GSK-3 appears to trigger a combination of filaments that form neurofibrillary tangles (Glycogen synthase k inas e 3 alteration in Alzheim er disease is related to neurofibrillary tangle fomation, Baum et al ·, Mol. C hem .N europathol. 1 996; 29 (2-3): 253 -6 1 ). Therefore, the phosphoric acid of the protein tail is another key role for GSK-3, which has an effect on AD pathology. GSK-3 may be an important target for the treatment of this disease, not only for its modulation in the Wnt pathway, but also for its sacral nerves. The influence of the formation of fiber entanglement.

Another pathology involved in Wnt signaling is Parkinson's Disease. One of the physiological characteristics of this disease is the reduction of neurons that produce dopamine, but the cause of this event is not fully known. Wnt proteins play an important role in the differentiation process of these neural cells. Normalization of/5-catenin levels via GSK-3 inhibitors leads to an increase in dopaminergic neuron differentiation (GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain 200811163 precursors increased differentiation into dopamine neurons, Castelo-Branco et al J Cell Sci. 2004; 117 (Pt24): 5 73 1 - 7 ) ° GSK-3 also modulates insulin by phosphorylation of glycogen synthase, an enzyme that catalyzes the condensation of glucose monomers to form glycogen. Cellular action plays an important role. Phosphorylation of glycogen synthase via GSK-3 and other kinases leads to its inactivation and this event attenuates the role of insulin in cells. In fact, there are several selective GSK-3s. Inhibitors have been shown to mimic insulin action in in vitro and in vivo models (Insulin mimetic action of synthetic phosphory crystallization peptide inhibitors of glycogen synthase kinase-3 ? Plotkin et al., Pharmacol Exp Ther. 2 003; 3 05(3 ” 974-80) According to the results of these experiments, the inhibition of GSK·3 has a therapeutic effect in the treatment of insulin-resistant and type 2 diabetes. Based on the above, GSK_3 inhibitors are potential treatments for Alzheimer's disease, Parkinson's disease, diabetes and certain other diseases.

Tail is one of the major proteins in cells that promote microtubule stability. Microtubules are the main component of the cytoskeleton, an important small organ of cells, especially for neurons. The primary role of the cytoskeleton in neurons is to provide structural support to form axonal and somatodendritic compartments, all of which are part of the neural network necessary for the proper functioning of the CNS. The cytoskeleton is a key component of neuronal survival and many neuronal and neurodegenerative diseases are characterized by their abnormalities. Therefore, tau and other eggs involved in the cytoskeletal structure can be a promising therapeutic for many neuronal and neurodegenerative diseases. The tail heterotypic system comes from alternative mRNA splicing of a single gene. It results in six different peptide chains with molecular weights between 50 and 70 kDa. Tau proteins are highly expressed in the central and peripheral nervous systems, and they are particularly abundant in neuronal axons, where they contribute to the organization and integrity of cell junctions in the CNS. Some studies (Brandt & Lee, J Biol. Chem. 1 993, 26 8, 341 4-34 1 9 and Trinczek et al., Mol. Biol. Cell. 1 995, 6? 1 887- 1 902 ) Tau has been shown to promote microtubule nucleation, growth and combination. These functions of tau are regulated by a phosphorylation/dephosphorylation procedure occurring at multiple sites in its peptide chain. Many kinases are capable of phosphorylating these sites in vitro, but fewer kinases can do this in vivo. Under normal physiological conditions, there is a balance between phosphorylated tau that binds to microtubules and other proteins and dephosphorylated tau. However, certain pathological events may break this balance, eliminating the interaction between tau and microtubules and disassembling the two cytoskeletal components. Phosphorylation in other parts of tau induces tau-tau interaction and subsequent increase in tail oligomer formation, which ultimately aggregates into neurofibrillary tangles (NFTs). All of these changes induce damage to the microtubule delivery system along the axonal to neurite, causing damage to neuronal function and eventual cell death. Therefore, the loss of regulation of tau is considered to be a Toto's neurological disorder, commonly known as the characterization of tauopathy (taupathies), which is characterized by the abnormal accumulation of tau filaments in the brain. Some famous tauopathies are, together with -10- 200811163 others, Alzheimer's disease, Gerstmann-StrSussler-Scheinker disease, Pick's disease, amyotrophic lateral sclerosis (ALS), Creutzfeld - Jakob disease, Down's syndrome or prion cerebellar granule protein vascular disease. Many of today's researchers are focused on the loss of regulation and accumulation of amyloid plaques in tan (another major pathological hallmark of Alzheimer's disease. Some authors (Price et al, Annu. Rev. Genet, 1998) , 32,461-493 and Selkoe, Trends Cell Biol. 1 99 8, 8? 447-453 ) It is speculated that the amyloid pathology occurs at the upstream end of the tau disease, but the relevant mechanisms are not clearly explained. It is believed that the deposition of microfibrillar amyloid/5 induces phosphorylation of tail, which in turn induces neuronal degeneration. Based on prior art and considering GSK-3 enzymes and tau proteins in a range of important human diseases and disorders, especially It is a direct involvement in neuronal and neurodegenerative disorders, and there is a need to find an effective agent for the enzyme and a potent inhibitor of tau protein phosphorylation for the treatment of such diseases and disorders. The invention provides a family of compounds, i.e., N.s(2-thiazolyl)-indolamine derivatives, as defined by (formula) as detailed below, which exhibits an inhibitory effect on GSK-3. These are thus useful in the treatment of GSK-3. kick in Diseases and symptoms, especially neuronal and neurodegenerative diseases and symptoms. In addition, many compounds have an inhibitory effect on tau protein phosphorylation in many neurodegenerative diseases, so the compound of formula (I) even It may have the dual effect of treating or preventing neuronal and neurodegenerative diseases. Thus, in a first aspect of the invention, a compound of formula (I) is provided:

among them

Ri and R2 are each independently selected from the group consisting of hydrazine, N02, halogen, -NH2, -CF3, Κ6 linear alkyl or -CN; m is 0, 1, 2, 3, 4, 5 or 6; The group consisting of: - (A) or (B) thiol, respectively bonded to the 2nd or 3rd position;

- (C) carbazolyl, bonded at the 3rd position; -12- 200811163

Re Rs - mouth ratio B group, the bond is in any of the 2nd to 6th positions f -phenyl wherein R 3 is selected from fluorene or CrG linear alkyl; R 4 , R 5 , R 6 and R 7 are each independently selected from Η, C, Ci-C6. Alkoxy or halogen, R8 is selected from η or C^-Ce alkyl; or any pharmaceutically acceptable salt, solvate or prodrug thereof, for treatment or prevention The drug route of the disease or symptom of GSK-3. Compounds of formula (I) can be used in assays where GSK-3 bioassays need to be modulated. Therefore, in another aspect, the present invention relates to a compound of formula (I) or any salt or solvate thereof as defined in the specification as a reagent for the regulation of GSK-3 (preferably as a reagent for inhibiting activity) The purpose of the use. Another aspect of the invention relates to a method of treating GSK-3 comprising administering to a patient in need of such treatment an amount of a compound of the formula (Ϊ) or a pharmaceutical composition thereof. In another aspect of the invention, a novel compound of formula (I): and 1 - C 6 is used for the preparation of the above-mentioned biological test GSK-3 disease. One of the less -13- 200811163

among them

Ri and R2 are each independently selected from Η, N〇2, halogen, -NH2, -CF3, or -CN; only at least one of 1^ and R2 is not Η; m is 0, 1, 2, 3 , 4, 5 or 6; X is selected from the group consisting of: - Formula (A) or (B) thiol, respectively bonded to the 2 or 3 position;

- (C) carbazolyl, bonded in the third position; -14- 200811163

R6 r5 and • a pyridyl group, bonded at any of positions 2 to 6; wherein R 3 is selected from hydrazine or CMC 6 linear alkyl; R 4 , R 5 , R 6 and R 7 are each independently selected from hydrazine, CrCs Alkyl, C--C6-oxime or halogen; R8 is selected from 11 or alkyl; or any pharmaceutically acceptable salt, solvate and prodrug thereof. According to another aspect, the invention relates to a novel compound of formula (I) as a medicament. Another aspect of the invention relates to a pharmaceutical composition comprising at least one novel compound of formula (I), or any pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant Or vehicle. Finally, another aspect of the invention relates to a process for the preparation of the novel compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION In the definition of the compound of the formula (I) above, the following terms have the meanings indicated by -15-200811163. "c^Ce alkyl" means a linear or branched hydrocarbon chain consisting of carbon and hydrogen atoms, free of unsaturated bonds, having from 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. A group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or the like. "Ci-Ce linear alkyl" means a linear hydrocarbon chain consisting of carbon and hydrogen atoms, containing no unsaturated bonds, having from 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond, For example, methyl, ethyl, n-propyl, n-butyl, n-pentyl and the like. The alkoxy group "a formula - 〇Ra group, where Ra is an alkyl group as defined above"; for example, a methoxy group, an ethoxy group, a propoxy group or the like. "Halogen" means a chlorine, bromine, fluorine or iodine substituent. In a first aspect, the invention provides a compound of formula (I):

(I) where

Ri and R2 are each independently selected from the group consisting of hydrazine, -N〇2, halogen, -NH2, -CF3, CrQ linear alkyl or -CN; m is 0, 1, 2, 3, 4, 5 or 6; a group selected from the group consisting of: - (A) or (B) D, which is bonded to the position of the second or 3-16-200811163;

• Formula (c) carbazolyl, bonded at position 3;

Re Rs -pyridyl, bonded at any of positions 2 to 6; and -phenyl wherein R 3 is selected from fluorene or Ci-Cs linear alkyl; R 4 , R 5 , R 6 and R 7 are each independently selected from hydrazine , CrCe alkyl, C^-Cs alkoxy or halogen, R8 is selected from hydrazine or C^-Cs alkyl; or any pharmaceutically acceptable salt, solvate and prodrug thereof, for preparation Or prevent the use of GSK-3 vectors for the disease or symptoms of the drug -17- 200811163. In a preferred embodiment, the compound of the formula (I) used in the present invention is a compound wherein X is a hydrazine of the formula (A) or (B) defined above at the 2nd or 3rd position, respectively. Also preferred are compounds wherein X is a carbazole compound of formula (C) as defined above at the third position. Still other preferred compounds are those wherein the X system is bonded to the pyridyl group of any of the 2nd to 6th positions. In another specific embodiment, the compound of the formula (I) used in the present invention is a compound wherein m is 0, 1, 2, 3, 4, 5 or 6 when X is pyridine. More preferably, the compound wherein m is 1, 2 or 3. In another preferred embodiment, the compound of formula (I) is a compound wherein the halogen is fluorine, chlorine or iodine. Other preferred compounds are those in which at least one of R! and R2 is different from the latter. Further, other preferred compounds are those in which at least one of R! and R2 is a leader. In another preferred embodiment, one of R1 and r2 is Ν〇2, halogen or alkyl, more preferably Ν02. Even more preferably, one of Ri and R2 is N〇2 and the other is a compound of ruthenium. Particularly preferred is a compound of 11! which is oxime 02 and R2 is ruthenium. In another preferred embodiment, R3 is selected from the group consisting of hydrazine or methyl. Further, in another preferred embodiment, R4 to R7 are selected from ruthenium or CmQ alkoxy groups, and preferably all of R4 to R7 are ruthenium. Compounds wherein R8 is selected from hydrazine or methyl are also preferred. -18- 200811163 According to another preferred embodiment, the compound of the formula (I) used in the present invention is selected from the following compounds: o2n

-19- 200811163

Or any pharmaceutically acceptable salt, solvate and prodrug thereof. Within the framework of the present invention, a disease or condition mediated by GSK-3 means any disease or condition in which GSK-3 is involved, preferably any disease or condition requiring GSK-3 inhibition. Such diseases or conditions include, but are not limited to, any disease or condition selected from the group consisting of diabetes, symptoms associated with diabetes, chronic neurodegenerative symptoms (including dementia such as Alzheimer's), Parkinson's disease, Progressive hypernuclear sputum, subacute sclerosing encephalitis Parkinson's disease, posterior encephalitis Parkinson's disease, boxer pugilistic encephalitis, Guam Parkinson's disease dementia complex, Biek's Pick's disease ' Gerstmann-Straussler-

Scheinker's disease, Creutzfeld-Jakob's disease, prion protein amyloid-protein vascular disease, cerebral cortical basal ganglia degeneration, frontal and patellofemoral dementia, Huntington's disease, AIDS-20- 200811163 Related dementia, amyotrophic lateral sclerosis, relapsing sclerosis, and neurological traumatic diseases such as acute stroke, epilepsy, mood disorders (such as depression), schizophrenia and bipolar disorder, manic depression disorder, After the recovery of function, the promotion of stroke, cerebral hemorrhage (for example, due to cerebral amyloid angiopathy alone), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovarian syndrome, Symptom X, ischemia, brain injury, especially traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammation Diseases, cancers, and hyperproliferative diseases such as hyperplasias and immunodeficiency. In a preferred embodiment, the disease or condition is selected from the group consisting of progressive hypernuclear warts, Beek's disease, cerebral cortical basal ganglia degeneration, frontal and patellofemoral dementia, Huntington's disease, muscle Atrophic lateral sclerosis, relapsing sclerosis, and neurotrauma diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, manic depressive disorder, promotion of stroke after functional recovery, cerebral hemorrhage ( For example, because of cerebral amyloid angiopathy alone, obesity, syndrome X, ischemia, brain injury, especially traumatic brain injury, cancer, leukopenia, Down syndrome, Raytheon Small body disease, inflammation, chronic inflammatory disease, cancer or hyperproliferative diseases such as proliferative diseases. More preferably, the disease or condition is selected from the group consisting of Alzheimer's disease, diabetes, Parkinson's disease, epilepsy or mood disorder. Unless otherwise stated otherwise, the compounds of formula (I) useful in the present invention are also intended to include only one or more isotopically enriched atoms in the presence of different compounds. For example, a compound having the structure of the present invention, but substituting hydrogen with hydrazine or hydrazine, or replacing carbon with 13c- or 14C-enriched carbon, or replacing nitrogen with 15N-enriched nitrogen is within the scope of the invention. The term "pharmaceutically acceptable salts, solvates and prodrugs" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, after administration to a patient, A compound as described herein can be provided (directly or indirectly). However, it is to be understood that non-pharmaceutically acceptable salts are also within the scope of the invention as they are useful in the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art. For example, a pharmaceutically acceptable salt of a compound of formula (I) is synthesized from a parent compound containing a basic or acidic group by conventional chemical methods. Generally, such salts are, for example, prepared by reacting such compounds in the form of the free acid or base with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or mixtures of the two. Generally, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred. Examples of the acid addition salt include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; and organic acid addition salts such as acetate, cis Butenedioates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, and p-toluenesulfonates. Examples of the base addition salts include inorganic salts such as sodium salts, potassium salts, calcium salts, ammonium salts, magnesium salts, aluminum salts and lithium salts; and organic base salts such as ethylenediamine salts, ethanolamine salts, N, N a dialkylethanolamine salt, a triethanolamine salt, a glucosamine salt, and a basic amino acid salt. -22- 200811163 Particularly advantageous derivatives are those which increase the bioavailability of the compounds of the invention when administered to a patient (for example, by allowing the orally administered compound to be more smoothly absorbed into the blood) or Delivery of the parent compound to a biological compartment, such as the brain or lymphatic system, can be enhanced relative to the parent species. The compound of the formula (I) used in the present invention may be in a crystalline form, may be a free compound or a solvate (e.g., a hydrate) and both forms are encompassed within the scope of the present invention. Solvent combining methods are generally known in the art. Suitable solvates are all pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate. The compounds of formula (I) or their salts or solvates for use in the present invention are preferably in a pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, with the other, excluding normal pharmaceutical additives such as diluents and carriers, having a pharmaceutically acceptable level of purity, and excluding substances believed to be toxic at normal dosage levels. The purity level of the drug is preferably higher than 50%, more preferably higher than 70%, and the best is higher than 90%. In a preferred embodiment, there is more than 95% of the compound of formula (I), or a salt, solvate or prodrug thereof. The above compound of the formula (I) used in the present invention may include a mirror image isomer which is present due to the presence of a chiral center or an isomer (e.g., 'Z, E) which is present due to the presence of a complex bond. Single isomers, mirror image isomers or non-image isomers and mixtures thereof are within the scope of the invention. Formula (Ο compounds can be used in biological assays that require modulation of GSK-3 activity. Thus, in another aspect, the invention relates to a compound of formula -23- 200811163 (I), or any salt or solvate thereof, as defined above The use as a reagent for the regulation of GSK-3, preferably as a reagent for inhibiting the activity of GSK-3, in a bioassay. Another aspect of the invention relates to the treatment or prevention of a disease, disorder or GSK-3-related disease A method of symptom comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or preferably any salt or solvate, or a pharmaceutical composition thereof. Aspects relating to a novel compound of formula (I):

(I) wherein R1 and R2 are each independently selected from the group consisting of hydrazine, -N02, halogen, -NH2, -CF3 or -CN; but the limitation is that at least one of R! and r2 is different from hydrazine. m is 〇, 1, 2, 3, 4, 5 or 6; X is selected from the group consisting of: - Formula (A) or (B) thiol, respectively bonded at the 2nd position; 24-200811163

Only 6 «5 - (c) carbazolyl, bonded to the 3rd position;

a pyridyl group bonded to any of the 2nd to 6th positions; wherein R3 is selected from the group consisting of hydrazine or Ci-Q linear alkyl; and the R4, R5, R6 and R7 are each independently selected from the group consisting of ruthenium, Rrh fluorenyl, Ci-C6 alkoxy or halogen, R8 is selected from hydrazine or CVC6 alkyl; or any pharmaceutically acceptable salt, solvate and prodrug thereof. In a preferred embodiment of the invention, the compound of formula (I) wherein X is a compound of formula (A) or (B) as defined above at position 2 or 3, respectively. Further, another preferred compound is a compound wherein X is a carbazole of the formula (C) defined above at the 3rd position. Further preferred compounds are those wherein the X system is bonded to the pyridyl group of any of the 2nd to 6th positions. In another preferred embodiment, the compound of formula (I) is a compound wherein m is 1, 2, 3, 4, 5 or 6 and more preferably m is 1, 2 or 3 when X is pyridine. In another particular embodiment, the compound of formula (I) is a compound wherein when X is pyridine, the halogen is fluorine, chlorine or a tablet. Other preferred compounds are those in which 1 and R2 are deuterium. Preferably, one of Ri and R2 is -Ν〇2. Thus, a more preferred compound is one in which one of I and R2 is -Ν02 and the other is a compound of hydrazine. Even more preferred compounds are those wherein Ri is Ν02 and R2 is ruthenium. In another preferred embodiment, R3 is selected from the group consisting of hydrazine or methyl. Further, preferred compounds are those wherein R4 to R7 are each independently selected from methoxy or H. Preferably, all of R4 to R7 are H. Compounds wherein R8 is selected from hydrazine or methyl are also preferred. According to a preferred embodiment, the compound of formula (I) is selected from the group consisting of:

-26- 200811163

Η or any of its pharmaceutically acceptable salts, solvates and prodrugs. Unless otherwise stated otherwise, the novel formula (n compounds are also intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, 'having the structure of the invention, but replacing the hydrogen with deuterium or tritium, It is within the scope of the invention to either replace the carbon with 13c- or 14C-enriched carbon or replace the nitrogen with 151 enriched nitrogen. The term "pharmaceutically acceptable salts, solvates and prodrugs, Reference to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, after administration to a patient, is capable of providing (directly or between -27 and 200811163 grounded) as described herein Compounds, however, it is to be understood that acceptable salts are also within the scope of the invention as a result of the preparation of the pharmaceutically acceptable salts thereof, salts, prodrugs and methods known in the art of derivatization. For example, the pharmaceutically acceptable compound of the novel compound of formula (I) is conventionally synthesized from a parent compound containing a basic or acidic group. Typically, such salts are, for example, such as via free acid. Prepared by reacting a stoichiometric amount of the appropriate base or acid in a solvent in water or a mixture of the two. Typically, examples of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol addition salts include Mineral acid addition salts such as hydrochloride, hydroiodide, sulfate, nitrate, phosphate; and salts such as acetate, maleate, fumarate, oxalic acid Salts, succinates, tartrates, malate salts, methane sulfonates, and p-toluene sulfonates. Base addition salts include inorganic salts such as sodium, potassium, calcium, ammonium, magnesium And a lithium salt; and an organic base salt such as an ethylenediamine salt, an ethanolamine salt, an alkylethanolamine salt, a triethanolamine salt, a glucosamine salt, and a base salt. Particularly advantageous derivatives are added to the novel compounds herein to add the present invention The bioavailability of the compound (eg, can be more smoothly absorbed into the blood via the compound) or its phase species can enhance the parent compound to the biological compartment (eg, brain or lymphatic delivery. Non-pharmaceutical, etc.) Well received Salt chemical method or base form or in the case of organically preferred or acetonitrile, salt, hydrobromine organic acid plus salt, lemon, almond acid, salt, aluminum salt, bismuth, bismuth diammonic acid Oral administration to the parent system) 28-200811163 The novel compound of formula (I) may be in crystalline form, may be a free compound or a solvate (such as a 'hydrate) and both forms are encompassed within the scope of the invention The solvating methods are generally known in the art. Suitable solvates are all pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate. The compounds or their salts or solvates are preferably in a pharmaceutically acceptable or substantially pure form. The pharmaceutically acceptable form means, with the other, excludes normal pharmaceutical additives such as diluents and carriers. In addition to the agent, it has a pharmaceutically acceptable level of purity and does not include substances believed to be toxic at normal dosage levels. The purity level of the drug is higher than 50%, more preferably higher than 70%, and the best is higher than 90%. In a preferred embodiment, there is more than 95% of a compound of formula (I), or a salt, solvate or prodrug thereof. The novel compound represented by the above formula (I) may include a mirror image isomer present due to the presence of a chiral center or an isomer (e.g., Z, E) due to the presence of a complex bond. Single isomers, mirror image isomers or non-image isomers and mixtures thereof are within the scope of the invention. The invention further provides a pharmaceutical composition comprising at least one novel compound of formula (I), or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, in addition to a pharmaceutically acceptable carrier, The agent or vehicle is used for administration to a patient. Examples of the pharmaceutical composition include any solid (tablet, nine-dose, capsule, granule, etc.) or liquid (solution, suspension or emulsion) composition for oral, topical or parenteral administration. -29- 200811163 In a preferred embodiment, the pharmaceutical composition is in oral form. Suitable dosage forms for oral administration may be tablets and capsules and may contain conventional excipients known in the art such as binders such as syrup, gelatin, gelatin, sorbitol, tragacanth, or polyvinylpyrrol. An alkanone; an elixir such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; a tableting lubricant such as, for example, magnesium stearate; a disintegrating agent such as starch, polyvinylpyrrolidone, Sodium starch glycolate, or microcrystalline cellulose; or a pharmaceutically acceptable wetting agent such as sodium lauryl sulfate. The solid oral compositions can be prepared by conventional methods of blending, tumbling or tableting. The active agent can be distributed throughout the bulk of the compositions using a plurality of chelating agents using repeated blending operations. These operations are the subject of skill in the art. Tablets may be prepared, for example, by wet or dry granulation and optionally coated according to methods well known in the ordinary pharmaceutical practice, especially with an enteric coating. The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or freeze-dried products, in a suitable unit dosage form. A suitable excipient such as a bulking agent (b u 1 k i n g a g e n t ), a buffer or a surfactant may be used. The proposed compositions can be prepared using standard methods such as those described or referenced in the Spanish and U.S. Pharmacopoeias and similar reference books. The administration of the novel compound (I) or composition of the present invention can be carried out by any appropriate method such as intravenous infusion, oral preparation, and intraperitoneal and intravenous administration. Oral administration is preferred because of the chronic nature of many diseases that are convenient for the patient and to be treated. -30- 200811163 In general, the effective dosage of a novel compound of the invention will depend on the relative potency of the selected compound, the severity of the disorder being treated, and the weight of the patient. No, the active compound is typically administered once or several times a day, for example 1, 2, 3 or 4 times a day, with typical daily doses ranging from oj to 1000 mg/kg/day. In another aspect, the invention relates to the use of a novel compound of formula (I) as a medicament. The novel compounds of formula (I) may be derived from a pathway strategy comprising formula (II), (III) and (IV) pyridyl, oxazolyl or decanoic acid:

Wherein R3 is selected from the group consisting of hydrazine or CPC6 linear alkyl; R4, R5, R6 and R7 are each independently selected from the group consisting of hydrazine, alkyl, Ci-C6 or a halogen; R8 is selected from hydrazine or CrQ alkyl and m An integer from 0 to 6; conveniently coupled to a thiazole of the formula (V): -31 - 200811163

Wherein Ri and R2 are each independently selected from the group consisting of Η, -N〇2, halogen, ΝΗ2 • CN, but the limitation is that at least one of Ri and R2 is not defective. Compounds of formula (Π), (III), (IV) and (V) are all commercially available. General procedure for a group of compounds wherein χ = pyridine In a particular embodiment of the invention, X is a ruthenium ratio compound of formula (I) according to the following general procedure. A solution of the corresponding formula (I) pyridine acid in anhydrous tetrahydrofuran (hereinafter referred to as THF), 1.5 equivalent of hydrazine, Ν'·carbonyldiimidazole (hereinafter referred to as DCI) in anhydrous form as an activator. The resulting mixture was stirred at room temperature for about 4 hours. Then, 1 equivalent of the corresponding formula (Vazole/THF) was added to the reaction mixture, and this was stirred at room temperature for about 8 to 10 hours. On the reverse, the solvent was distilled off and The obtained crude product is dissolved in CH2C12 and washed. The purification is carried out according to the general purification method known to the expert. Or the same as the addition of pyridine to the THF to 5) thiophene completion -32- 200811163

General procedure for a group of compounds wherein x = carbazole In another particular embodiment of the invention, the compound of formula (I) wherein X is oxazole is obtained according to the general procedure described below. To the corresponding oxazole-acid/anhydrous THF solution of formula (III), 1.5 equivalents of CDI/anhydrous THF was added as an activator. The resulting mixture was stirred at room temperature for about 4 to 5 hours. Then, 1 equivalent of the corresponding thiazole of formula (V) / TH F was added to the reaction mixture and it was stirred at room temperature for about 8 to 10 hours. When the reaction was completed, the solvent was distilled off and the obtained crude product was dissolved in CH2C12 and washed with water. Purification is carried out according to general purification methods known to the expert. -33- 200811163

General procedure for a group of compounds wherein χ = 吲哚 In another particular embodiment of the invention, the compound of formula X in formula (I) is obtained according to the general procedure described below. To the solution of the formula (IV) 无水 anhydrous THF was added 1.5 equivalents of CDI/anhydrous THF as a solvent. The resulting mixture was stirred at room temperature for about 4 to 5 hours. Then 1 equivalent of the corresponding thiazole of formula (V) / THF was added to the mixture and this was stirred for about 8 to 1 hour. When the reaction is complete, the resulting crude product is dissolved in CH 2 C 12 and extracted with water. Purification of the roots is known to be carried out by a general purification method. For 吲哚 酸-acid / for activation in the reaction room temperature and will be according to experts -34- 200811163

The following examples are given to further illustrate the invention, but they should not be construed as limiting the scope of the invention. [Examples] Preparation Examples Hereinafter, a detailed description of the preparation of certain compounds of the formula (I) according to the present invention is given. Example 1 Preparation of N-(5-nitro-thiazol-2-yl)·2·pyridin-3-yl-acetamide (Compound 13) -35- 200811163 o2n

0

Add 1.5 equivalents of CDI (18 mmol, 2.916 g) / anhydrous THF and 1 equivalent of NEt3 ( 1.66 mL) to a solution of 3-pyridine acetic acid hydrochloride (2.076 g, 12 mmol) in dry THF. . The resulting mixture was stirred at room temperature for 4 hours. Then, 2-amino-5-nitro-thiazole (12 mmol, 1.740 g) / THF was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. When the reaction was completed, the solvent was evaporated and the obtained brown crude product was dissolved in CH2C12 and water. This mixture produced a yellow precipitate which was filtered and washed with water to give the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 38 ( dd, 1H ) ; 7·74 ( d,1H ) ; 8.50 ( d,1H ) ; 8·52 ( s, 1 H ) ; 8.63 ( s,1 H ) 13C-NMR ( DMSO ) : 3 8.5 2 123.4; 129.7; 137.1; 141.7; 142.6; 148.1; 150.3; 161.8; 170.7 Example 2 1H-indoleazole-3-carboxylic acid (5-nitro-thiazol-2-yl)-decylamine (Compound 11) Preparation -36- 200811163

The internal solution of 3-acid oxime acid (3 mmol, 486 mg) in anhydrous THF and 1 ml of anhydrous dimethylformamide (DMF) to increase the solubility of the carbazole was introduced into 1.5 equivalents. CDI (4.5 mM '729 mg) / anhydrous THF. The resulting mixture was stirred at room temperature for 4.5 hours. Then, 2-amino-5-nitro-thiazole (3 mmol, 43 5 mg) / THF was added to the reaction mixture and this was stirred at room temperature for 10 hr. When the reaction was completed, the solvent was evaporated and the obtained crude product was dissolved in CH.sub.2 C.sub.2 and extracted with water (3×10 mL). The organic layer was dehydrated with NaS04. The solvent was then removed in vacuo and the residue was purified eluting eluting eluting eluting eluting eluting 1H ) ; 7.51 ( t 1 Η ) ; 7.72 ( d , 1H ) ; 8.21 ( d , 1 H ); 8.67 ( s , 1H ) 13c-nmr ( DMSO ) : 107.9 ; 111.2 ; 120.8 ; 122.0 12 3.4 ; 127.1 ; 135.5; 14 1.2 ; 141.8 ; 142.7 ; 161.7 161.8 Example 3 Preparation of 2-(indol-3-yl)-N-(5-nitro-thiazol-2-yl)-acetamide (Compound 4) - 37- 200811163

To the anhydrous solution was added 1.5 equivalents of CDI (18 mmol, 2.916 of water, THF), and the mixture was stirred at room temperature for 5 hours. To the mixture, 2-amino-5-nitro-thiazole (12 mmol)/THF was added and this was stirred at room temperature for 10 hours. When the reaction was carried out, the solvent was evaporated and the obtained brown crude product was dissolved. The organic layer was dehydrated with NaS04. The solvent was removed in vacuo and the residue obtained was taken from CH2Cl2/MeOH to give the desired compound as a yellow solid (2.260 g, 62%, 3 03 Μ) ^-NMR (DMSO): 3.96 (s, 2H); 6.97-7 5H); 8.6 (s, 1H); 1 0.9 (NH); 1 3.26 (NH) 13C-NMR (DMSO): 32.1; 106.4; 118.6; 121.1; 124.4; 126.9; 136.0; 141.7; 161.9; 171.5 Example 4 N-(5-chloro-thiazol-2-yl)-2-(indol-3-yl)-acetamide (6) Preparation of THF in gram) / no I, in the reverse, 1.740 5 full time, ] and water with water, after the "object washing +), 5 (m, 118.4; 142.6; compound -38- 200811163

To a solution of 3-indole-acetic acid (5 25.5 mg, 3 mmol) in dry THF was added 1.5 eq. CDI (4.5 mM, 729 s) / anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours. Then, a solution of 2-amino-5-chloro-thiazole (3 mmol, 513.5 mg) and 1 equivalent of NEt3 (1.66 ml) in THF was added to the reaction mixture and this was stirred at room temperature 1 〇 hour. When the reaction was completed, the solvent was evaporated and the obtained red oil was dissolved in CH.sub.2 C.sub.2 and extracted with water (3.times.30 liters). The organic layer was dehydrated with NaS04. The solvent was then removed in vacuo and the residue was purified EtOAc EtOAc EtOAc EtOAc EtOAc. ;) H-NMR (DMSO): 3.92 (s, 2H); 6.97 (m, 1H); 7.08 (m, lH); 7.25 (d, lH); 7.36 (m, 1H); 7.50 (s, lH) ; 7.56 (d, lH); 8.6 (s, lH); 10.9 (NH); 1 2.56 (NH) 13C-NMR (DMSO): 3 1.85; 1 07.05; 111.38; 117.88; 118.45; 118.51; 121.06; ; 1 26.96 ; 135.51 ; 1 3 5.99 ; 1 5 6.00 ; 170.20 -39- 200811163 Example 5 2-( 5-Methoxy-indol-3-yl)-N-( 5-nitro-thiazole-2 Preparation of _yl)-acetamide (Compound 7)

Add 1.5 equivalents of CDI (3 mmol, 486 mg) / anhydrous THF to a solution of (5-methoxy-indolyl)-acetic acid (410 mg, 2 mmol) in dry THF. . The resulting mixture was stirred at room temperature for 5 hours. Then, 2-amino-5-nitro-thiazole (2 mmol, 290 mg) / THF was added to the mixture and the mixture was stirred at room temperature for 10 hours. When the reaction was completed, the solvent was evaporated and the obtained brown crude product was dissolved in CH.sub.2 C.sub.2 and extracted with water (3×30 mL). The organic layer was dehydrated with NaSCU. The solvent was then removed in vacuo and the residue was purified eluting eluting eluting eluting eluting eluting eluting 3.95 ( s, 2H) ; 6.75 ( dd, lH) ; 7.9 (s, lH) ; 7.25 (m, 2H ) ; 8.71 (s, lH) ; 10.90 ( 1H, NH) 】 3C-NMR ( DMSO ) ·· 32.17 ; 55.33 ; 100.40 ; 106.18 ; 111.15 ; 112.09 ; 125.01 ; 127.31 ; 131.13 ; -40 - 200811163 14 1.62 ; 142.71 ; 153.15 ; 162.01 ; 171.60 Example 6 2-(1-methyl·吲哚-3- Preparation of -N-(5-nitro-thiazol-2-yl)-acetamide (Compound 8)

To a solution of (1-methyl-indol-3-yl)-acetic acid (567.6 mg, 3 mmol) in dry THF was added 1.5 eq. CDI (4.5 m. The resulting mixture was stirred at room temperature for 5 hours. Then, 2-amino-5-nitro-thiazole (3 mmol, 43 5 mg) / THF was added to the reaction mixture and this was stirred at room temperature for 1 hr. When the reaction was completed, the solvent was evaporated and the obtained brown crude product was dissolved in CH2C12 and washed with water (3 x 30 ml). The organic layer was dehydrated with NaS04. The solvent was then removed in vacuo and the residue was purified using EtOAc EtOAc EtOAc EtOAc (EtOAc) iH-NMR (DMSO): 3.76 (s,3H); 3.96 (s, 2H); 7.04 (t,lH); 7.13 (t,lH); 7.28 (s,lH); 7.41 (d,lH); (d, lH); 8.62 (s, lH) 13C-NMR (DMSO): 31.80; 32.25; 1 05.64; -41 - 200811163 109.61; 118.59; 118.67; 121.20; 127.21; 128.56; 136.39; 141.69; 142.59; 171.31 Example 7 Preparation of 2-(2-methyl-indol-3-yl)·Ν·(5-nitro-thiazol-2-yl)·acetamide (Compound 9)

Add 15 equivalents of CDI (4.5 mM, 729 mg) / anhydrous to a solution of (2-methyl-indole-3-yl)-acetic acid (567.6 mg, 3 mmol) in dry THF THF. The resulting mixture was stirred at room temperature for 5 hours. Then, 2-amino-5-nitro-thiazole (3 mmol, 43 5 mg) / THF was added to the reaction mixture and the mixture was stirred at room temperature for 10 hours. When the reaction was completed, the solvent was evaporated and the obtained brown crude product was dissolved in CH.sub.2 C.sub.2 and extracted with water (3×30 mL). The organic layer was dehydrated with NaS04. Then, the solvent was removed in vacuo and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc -NMR (DMSO): 2.30 (s, 3H); 3·96 (s, 2H); 6·71 (t, 1H); 6.86 (t, 1H); 7.21 (d, 1H); 7.41 (d, lH) ; 8.60 (s, lH); 10.90 (1H, -42-200811163 NH); 13·21 (1H, NH) 13C-NMR (DMSO): 11.35; 3 0.83; 1 02.66; 110.35; 117.49; 118.36; 1 28.09 ; 1 3 3.68 ; 1 3 4.96 ; 141.67 ; 1 42.5 8 ; 161.79 ; 171.58 Example 8 5-methoxyindole-2-carboxylic acid (5-nitro-thiazol-2-yl)- Preparation of decylamine (Compound 1 〇)

To a solution of 5-methoxy-indole-2-carboxylic acid (382 mg, 2 mmol) in dry THF was added 1.5 eq. CDI (3 mmol, 486 mg) / anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours. Then, 2-amino-5-nitro-thiazole (2 mmol, 290 mg) / THF was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. When the reaction was complete, the solvent was evaporated and the obtained brown crude product was dissolved in CH.sub.2 C.sub.2 and extracted with water (3×30 mL). The organic layer was dehydrated with NaS04. Then, the solvent was removed in vacuo and the residue obtained was purified by EtOAc EtOAc EtOAc EtOAc EtOAc 5%, 317Μ·) 1H-NMR (DMSO): 3.79 (s, 3Η); 6.95 ( dd, -43- 200811163 1H); 7.15 (s, 1H); 7.37 (d, lH); 7.67 ( s ^ 1H ; 8.81(s,lH) ;&quot;·90(1Η,ΝΗ) ;13·41(1Η, NH ) I3C-NMR ( DMSO ) : 55.19 ; 1 02.08 ; 107.11 ; 113.45 ; 117.11 ; 1 27.07 ; 128.14 ; 1 3 3.27 ; 141.75 ; 1 42.74 ; 1 54.07 ; 1 5 9.9 8 ; 162.41 Biological examples For the compounds obtained in Examples 1-8, together with the other 12 compounds of formula (I), at different concentrations, Two different assays were used to determine their biological activity. Gsk-3 β m m : This test is based on the detailed description of the program in Upstate Cat. 1 4-3 06 with minor modifications. Recombinant human glycogen synthase kinase 3/3 in MOPS 11 mM ρΗ7·4, EDTA 0.2 mM, EGTA 1,25 mM, MgCl 2 2 6,25 mM and sodium orthovanadate 0.25 mM at 62.5 //M phosphate - glycogen synthase peptide-2 (GS-2) (TOCRIS, Cat. 1 3 52 ) » 0.5 // Ci γ - 3 〇P-ATP and unlabeled ATP (Sigma, A-9187) are present in the end Concentration 1 2.5 // Μ Check. After 30 minutes at a temperature of 30 ° C, the liquid was spotted on P8 1 cellulose cellulose paper. The filter paper was washed four times, each time with phosphoric acid for at least 1 minute and counted in a flash-batch and (PerkinElmer, Micr〇beta 1 450) with a flash-blend solution. The live-44-200811163 strain of GSK-3 was tested in the presence of compounds synthesized according to Examples 1 to 8 and in the presence of an additional 12 compounds of formula (I) at concentrations of 25 and 50 ν Μ . The results obtained are shown in Table 1 below and the inhibition of 0 tau phosphorylation is expressed as a percentage of GSK-3 activity: Human neuroblastoma SHSY5Y cells were seeded in the minimum essential nutrient requirement medium/nutrient mixture F-12. One day later, the cells were treated with the sample at 37 ° C for 18 hours. After treatment, the culture was washed with phosphate buffered saline and extracted at 4 ° C (10 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1 mM EDTA, 2 mM Na3V〇4, 1% Triton X- 100, 10% glycerol, 0.1% SDS, 0.5% sodium deoxycholate, 1 mM PMSF and protease inhibitor cocktail (Roche, Cat 1 697 498)) were lysed for 30 minutes. Quantification of phosphorylated human Tail was performed by taking a cell lysate fraction and using a phosphorylation-specific antibody against PS [PS 3 96] in a sandwich ELISA (Biosource, Cat KHB7031). Tau phosphorylation was determined by measuring the absorbance at 450 nm (nm) in a microplate reader (Cultek, Anthos 2010). The effect of the compound synthesized according to Examples 1-8 and the other 12 compounds of the formula (I) was determined at different final concentrations, i.e., 50, 100 and 20 0 #Μ. Not all compounds of formula (I) are tested at all of these concentrations. The results shown by "NEG" and "POS" in Table 1 (shown below) mean "negative" and "positive", respectively; "NEG" means the compound (I) mentioned in the range 5 - 45 - 200811163 No inhibition of tau phosphorylation was detected at concentrations; "POS" means that inhibition of tau phosphorylation was detected at the indicated concentrations. Table 1 Compound numbering formula GSK-3 Activity % Intracellular Tau phosphorylation inhibition 25 μΜ 50 μΜ 50 μΜ 100 μΜ 200 μΜ Compound 1 37,35 18.89 NEG NEG NEG Compound 2 s I . (Υλ 59.64 38.96 1 / 1 Compound 3 73.79 53.35 / / 1 Compound 4 (Example 3) 6.29 8.51 NEG POS POS Compound 5 19.05 12.45 POS POS POS Compound 6 (Example 4) 29.38 14.61 1 1 / Compound 7 mmms) 43.94 32.2 NEG POS 1 -46 - 200811163 Compound Number Formula GSK-3 Activity % 25 50 Intracellular Tau phosphorylation inhibition 50 100 200 μΜ μΜ μΜ μΜ μΜ

-47- 200811163

-48- 200811163 Compound No. GSK-3 Activity % Intracellular Tau phosphorylation inhibition 25 μΜ 50 μΜ 50 μΜ 100 μΜ 200 μΜ Compound 20 N Η 13.73 8.05 POS POS / In addition to tau phosphorylation assay, also by measuring LDH release (Roche, Cat 1 644 793) to quantify cell death caused by the potential toxicity of the above compounds 1, 4, 5, 7, 8, 9, 10, 1 1 , 2 2, 1 3 and 14 Determination. For the quantitative determination of cell viability, the cell lysate fraction is immersed in an equal volume of the reaction mixture at room temperature for 20 to 30 minutes. Absorbance measurements were performed in a microplate reader (Cultek, Anthos 2010) equipped with a 490-492 nm filter. For compounds 4, 5, 13 and 14, cell viability was measured after 24 hours of treatment (see Table 2), while compounds 1, 7, 8, 9, 10, 1 and 12 were treated at 18 hours. Post-measurement (see Table 3) was performed in SH-SY5Y cells. It is believed that if less than 80% of the cells survive after treatment with the compound, the compound is considered toxic. Table 2 Compound number cell viability % ΙΟμΜ 25uM 50μΜ 100μΜ Compound 4 91·7±1·9 90±3.7 / / Compound 5 87.8±3.8 86·1±8.4 / / Compound 13 / / 94.1±1.8 86.5+4.7 Compound 14 / / 87±6·0 85·4 Earth 2·7 -49- 200811163

Table 3 Compound number cell viability % 50μΜ ΙΟΟμΜ Compound 1 103.2 Soil 17 101.0 Soil 17 Compound 7 99·8±8·6 92.9±11.1 Compound 8 103±7.7 85.5 Soil 6.5 Compound 9 91.6±5.9 90.8±5.5 Compound 10 84.7± 2.7 90.6±7.2 Compound 11 95.3±3.3 93.9±5.6 Compound 12 95.7±4.2 93·7±7·1 From the results obtained, the compound of formula (I) can therefore be regarded as non-toxic-50-

Claims (1)

200811163 X. Patent application scope 1 · A compound of formula (I): Wherein R! and R2 are each independently selected from the group consisting of hydrazine, -N02, halogen, -NH2, -CF3, CrCe linear alkyl or -CN; m is 0, 1, 2, 3, 4, 5 or 6; A group selected from the group consisting of: - (A) or (B), respectively bonded to the 2nd or 3rd position - formula (C) carbazole, bonded in the 3rd position; -51 - 200811163 R3 R7 Re R5 r4 (C) - pyridine, bonded at any of positions 2 to 6; and -phenyl i wherein R 3 is selected from Η or Κ 6 linear alkyl; R 4 , R 5 , R 6 and R 7 are each Independently selected from hydrazine, C]-C6 alkyl, alkoxy or halogen, R8 is selected from hydrazine or (^-(:6 alkyl; or any pharmaceutically acceptable salts, solvates and prodrugs thereof) For the use of a medicament for the treatment or prevention of a disease or condition caused by GSK-3. 2. The use according to claim 1 of the scope of the patent application, wherein X is a patent application scope which is bonded to the second or third position, respectively. The formula (A) or (Β) defined in the first item. 3. The use according to item 1 of the scope of the patent application, wherein X is the formula defined in the first item of the patent application scope of the third position. (C) 吲 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 Wherein m is 1, 2, • 52 - 200811163 3, 4, 5 or 6, and preferably 1 or 2. 6. The use according to any one of claims 1 to 5, The halogen is fluorine, chlorine or agglomerate. 7. The use according to any one of claims 1 to 5, wherein at least one of Ri and R2 is different from H. 8. According to claim 1 The use of any of the five items, wherein one of R! and R2 is Η. 9. The use according to any one of claims 1 to 5, wherein one of 1^ and r2 is νο2, halogen Or C!-C6 linear alkyl, and preferably Ν Ο 2. 1 〇. The use according to any one of claims 1 to 5, wherein R is N〇2 and R2 is Η. 1. The use according to any one of claims 1 to 5, wherein R3 is selected from the group consisting of hydrazine or methyl. 12. The use according to any one of claims 1 to 5, wherein R4 to R7 Is independently selected from the group consisting of: or alkoxy, and preferably all of R4 to R7 are hydrazine. 13. The use according to any one of claims 1 to 5, wherein R8 is selected from the group consisting of hydrazine or methyl 14. The use according to claim 1, wherein the compound of formula (I) is selected from the group consisting of: -53- 200811163 O2n -54- 200811163 Or any pharmaceutically acceptable salt, solvate or prodrug thereof. The use according to any one of claims 1 to 5, wherein the medicament is for the treatment or prevention of a disease or condition requiring GSK-3 inhibition. The use according to any one of claims 1 to 5, wherein the disease or symptom is selected from the group consisting of diabetes, symptoms associated with diabetes, chronic neurodegenerative symptoms (including dementia such as Alzheimer's disease) (Alzheimer's disease)), Parkinson's disease, progressive hypernuclear fistula, subacute sclerosing encephalitis Parkinson's disease, posterior encephalitis Parkinson's disease, boxer Bergenson's disease (pugilistic encephalitis) ), Guam Parkinson-Dementia Syndrome Complex, Pick's disease, Gerstmann-Straus si er-Scheinker, Creutzfeld-Jakob, prion protein cerebral amyloid angiopathy, Cerebral cortical basal ganglia degeneration, frontal and patellofemoral dementia, Huntington's disease, AIDS-related dementia, amyotrophic lateral sclerosis, relapsing sclerosis, and neurological traumatic diseases Such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, manic depression disorder, machine-55- 200811163 can recover Post-stroke promotion, cerebral hemorrhage (eg due to cerebral amyloid angiopathy alone), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovarian syndrome, syndrome X, ischemia, brain injury, especially traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory disease, Cancer and hyperproliferative diseases such as hyperplasia and immunodeficiency. 17. The use according to claim 16, wherein the disease or condition is selected from the group consisting of Alzheimer&apos;s disease, diabetes, Parkinson&apos;s disease, epilepsy or mood disorder. 1 8 . The use according to claim 17 of the patent application, wherein the disease or symptom is selected from the group consisting of Alzheimer's disease, Parkinson's disease, epilepsy or mood disorder. 1 9 · A compound of formula (I) or any salt or solvate thereof according to any one of claims 1 to 14 of the patent application as a reagent for regulating GSK-3 in a bioassay (preferably Use as a reagent for inhibiting the activity of g SK · 3). 20. - Compound of formula (I): -56- 200811163 wherein R and R2 are each independently selected from the group consisting of hydrazine, -N02, halogen, -NH2, -CF3 or -CN; however, the limitation is that at least one of R! and R2 is different; m is 0, 1, 2, 3, 4, 5 or 6; X is selected from the group consisting of: - Formula (A) or (B) 吲哚, respectively bonded to the 2nd or 3rd position; Rs or - a formula (C) carbazole bonded to the third position; And -pyridine, bonded at any of positions 2 to 6; -57- 200811163 wherein R3 is selected from hydrazine or Ci-Ce linear alkyl; R4, R5, R6 and R7 are each independently selected from hydrazine , CrCs alkyl, C^-Cb alkoxy or halogen; R8 is selected from hydrazine or CrC6 alkyl; or any pharmaceutically acceptable salts, solvates and prodrugs thereof. 2 1. A compound according to claim 20, wherein X is a hydrazone of formula (A) or (B) as defined in claim 20 of the claim 2 or 3, respectively. 22. A compound according to claim 20, wherein X is a carbazole of formula (C) as defined in claim 20 of the third position. A compound according to claim 20, wherein X is a pyridine bonded to any of the 2nd to 6th positions. 24. A compound according to claim 23, wherein m is 1, 2, 3, 4, 5 or 6, and preferably m is 1 or 2. The compound according to any one of claims 20 to 24, wherein the halogen is fluorine, chlorine or iodine. A compound according to any one of claims 20 to 24, wherein one of Ri and R2 is H. 2 7. A compound according to any one of claims 20 to 24, wherein one of R! and R2 is N〇2. A compound according to any one of claims 20 to 24, wherein R] is N〇2 and R2 is Η. The compound according to any one of claims 20 to 24, wherein R4 to R7 are selected from methoxy or hydrazine, and preferably all of R4 to R7 are hydrazine. The compound according to any one of claims 20 to 24, wherein R3 is selected from the group consisting of hydrazine or methyl. The compound according to any one of claims 20 to 24, wherein R8 is selected from the group consisting of hydrazine or methyl. 32. A compound according to claim 20, which is selected from the group consisting of: -59- 200811163 Μ Or any pharmaceutically acceptable salt, solvate or compound thereof. The compound according to any one of claims 20 to 24, which is a medicament. a pharmaceutical composition for treating or preventing a disease or condition mediated by glycogen synthase kinase 3 (〇s κ _ 3), comprising at least one of the scope of claims 20-20 to 32 A compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined in any one, and a pharmaceutically acceptable carrier, adjuvant or vehicle. 35. A method of preparing a compound of the formula (1) as defined in any one of claims 20 to 32, which comprises pyridyl-acids of the formulae (Π), (III) and (IV), Carbazolyl acid or sulfhydryl-acid: Wherein -60- 200811163 R3 is selected from hydrazine or CrQ linear alkyl; R4, R5, R6 and R7 are each independently selected from hydrazine, CrCe alkyl, alkoxy or halogen, and R8 is selected from hydrazine or CrQ alkyl. And m is 0, 1, 2, 3, 4, 5 or 6; respectively coupled with the thiazole of formula (V): Wherein R, and R2 are each independently selected from the group consisting of hydrazine, -N02, halogen, -NH2, -CF3 or -CN; but the limitation is that at least one of Ri and R2 is different from hydrazine. -61 - 200811163 VII. Designated representative map: (1) The representative representative of the case is: (2) The symbol of the representative figure of this representative figure is simple: No. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula: